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  • 1. Chapter 38Maternal and Fetal Infections Patrick Duff, MD, Richard L. Sweet, MD, and Rodney K. Edwards, MD, MSInfectious disease is the single most common problem encountered Predisposing factors associated with vaginal colonization withby the obstetrician. Some conditions, such as urinary tract infections, C. albicans include diabetes mellitus, pregnancy, obesity, recent useendometritis, and mastitis, pose a risk primarily to the mother. of antibiotics, steroids, and immunosuppression. Pregnancy isOther disorders, such as group B streptococcal (GBS) infection, herpes associated with not only increased colonization but also increasedsimplex infection, rubella, cytomegalovirus infection, and toxoplas- susceptibility to infection and lower cure rates. Previously, oralmosis are of principal concern because of the risk of fetal or neonatal contraceptives were thought to increase colonization of yeast in thecomplications. Still others, such as human immunodeficiency virus vagina. However, with the advent of low-dose oral contraceptives,(HIV) infection and syphilis, may cause serious morbidity for both no increase in Candida isolation among oral contraceptive users hasmother and baby. been noted.4 This chapter reviews the twenty-nine most common infections that Other risk factors for C. albicans have been described. In aoccur during pregnancy. Each section considers the epidemiology, population of women attending a sexually transmitted disease (STD)pathogenesis, diagnosis, and treatment of an individual infectious clinic, Eckert and associates5 reported that the principal risk factorsdisease with which the obstetrician should be familiar. were condom use, luteal phase of the menstrual cycle, sexual frequency greater than four times per month, recent antibiotic use, young age, past gonococcal infection, and absence of current bacterial vaginosis. Recently, Beigi and coworkers6 noted additional risk factors, includingCandidiasis (Monilial marijuana use, use of depo-medroxyprogesterone acetate, sexual activ-Vaginitis) ity within the past 5 days, concurrent Lactobacillus colonization, and concurrent GBS colonization.Vulvovaginal candidiasis (VVC) is primarily caused by Candida albi- Symptomatic VVC affects 15% of pregnant women. The hormonalcans. Other species, such as Candida glabrata, Candida parapsilosis, environment of pregnancy, in which high levels of estrogen produceCandida tropicalis, and Candida lusitaniae, are responsible for fewer an increased concentration of vaginal glycogen, accounts for thethan 10% of cases. C. albicans is a saprophytic yeast that exists as part increased frequency of symptomatic infection in gravid patients. Inof the endogenous flora of the vagina. The organism is present in the addition, suppression of cell-mediated immunity in pregnancy mayvagina of approximately 25% to 30% of sexually active women.1 It may decrease the ability to limit fungal proliferation.become an opportunistic pathogen, especially if host defense mecha-nisms are compromised. However, the biologic mechanisms that allowthis commensal microorganism to become a pathogen are not com- Pathogenesispletely understood.2 Systemic candidiasis is a rare event in gravid As mentioned previously, the pathogenesis by which C. albicans evolvespatients, occurring only in the presence of disease entities causing from a commensal microorganism colonizing the vagina to the patho-significant debilitation (e.g., sepsis, malignancy). VVC is a much more genic microbe involved in vulvovaginal vaginitis, invasive Candidacommon infection and is the second most common cause of vaginitis infections, and disseminated candida sepsis is poorly understood.after bacterial vaginosis. Kalo-Klein and Witkin7 suggested that hormonal status may modulate the immune system, and, as a result, influence the pathogenicity of Candida species. They noted that the host responses to C. albicans wereEpidemiology decreased in the luteal phase. Recently, Giraldo and colleagues8 reportedSeventy-five percent of women will have at least one episode of VVC that a variant (gene polymorphism) in the gene coding for theduring their life, and 40% to 45% will have two or more episodes.1 mannose-binding lectin (MBL), a critical component of the mucosalC. albicans is the predominant yeast isolated (>90% of cases) from innate immune system, was more frequently found in women withpatients with VVC, with other species (i.e., C. glabrata, C. parapsilosis, recurrent VVC than in those with acute VVC or controls.and C. tropicalis) being less commonly recovered. In the past, it was The pathogenesis of invasive candidiasis is similar to that associatedbelieved that non-albicans species were becoming increasingly with bacterial microorganisms. Initially, there must be colonizationcommon, especially in cases of recurrent VVC. However, in a recent resulting from adhesion of C. albicans to the skin or vaginal mucosa;study, Sobel and colleagues3 reported that C. albicans was recovered this is followed by penetration of epithelial barriers, resulting in locallyfrom 401 (94%) of 425 women with recurrent VVC. invasive or widely disseminated disease.9
  • 2. 740 CHAPTER 38 Maternal and Fetal Infections Congenital candidiasis characteristically manifests at birth or VVC should have vaginal cultures for yeast. In patients with recurrentwithin the first 24 hours after birth. It usually results from an intra- VVC, the laboratory should be requested to identify the species ofuterine infection or heavy maternal vaginal colonization at the time of Candida recovered.labor and delivery. The potential mechanisms for intrauterine Candida The clinical manifestations of congenital candidiasis range frominfection are quite similar to those of bacterial intra-amniotic infec- superficial skin infection and oral infection to severe systemic diseasetion, including hematogenous spread from mother to fetus, invasion with hemorrhage and necrosis of the heart, lungs, kidneys, and otherof intact membranes, and ascending infection following rupture of the organs. The most common route of infection is by direct contactmembranes.9,10 In contrast to bacterial neonatal sepsis, the presence of during delivery through an infected vagina. Oropharyngeal candidiasisan intrauterine foreign body, most commonly a cerclage suture, is a of the neonate (thrush) is the most frequent manifestation of congeni-recognized risk factor for congenital candidiasis. VVC has not been tal infection.associated with preterm birth, preterm labor, low birth weight, or pre-mature rupture of the membranes (PROM).10,11 Recurrent VVC is defined as four or more episodes of symptomatic TreatmentVVC in 1 year. Recurrent VVC occurs in a small percentage of women The regimens recommended by the Centers for Disease Control and(<5%). The pathogenesis of recurrent VVC is poorly understood, and Prevention (CDC) for the treatment of VVC are listed in Table 38-1.12the majority of those affected do not have any apparent predisposing Short-course topical formulations (i.e., single-dose and 1- to 3-dayor underlying conditions. C. glabrata and other non-albicans Candida regimens) effectively treat uncomplicated VVC, providing relief ofspecies are recovered from in 10% to 20% of women with recurrent symptoms and negative cultures in 80% to 90% of patients who com-VVC.12,13 plete therapy. Intravaginal preparations of butoconazole, clotrimazole, miconazole, and tioconazole are available over the counter (OTC). According to the CDC, women who previously were diagnosed withDiagnosis VVC are not necessarily more likely to accurately diagnose themselves.The clinical manifestations in pregnancy are similar to those in the Therefore, women whose symptoms persist after use of an OTC prepa-nonpregnant state; they include pruritus and burning, dysuria, ration or who have a recurrence of symptoms within 2 months shoulddyspareunia, fissures, excoriations with secondary infection, and be assessed with office-based testing.12pruritus ani. The vaginal discharge is usually thick, white, and VVC is not usually acquired through sexual intercourse, so treat-curdlike. ment of sex partners is not recommended. Treatment of partners The diagnosis of VVC can be made in a woman who had signs and should be considered for women who have recurrent VVC and for malesymptoms of vaginitis when either (1) a 10% potassium hydroxide sex partners with balanitis.12(KOH) wet preparation or Gram staining of a vaginal discharge sample The CDC recommends that topical azole therapies be the first linereveals yeasts or pseudohyphae, or (2) a culture discloses yeast.12 The of treatment in pregnancy for VVC. These topical medications shouldvaginal pH in women with VVC is normal (<4.5). Women with a posi- be applied for 7 days. For complicated cases of VVC, a longer durationtive KOH wet mount should be treated for VVC. Women who have of initial therapy (e.g., 7 to 14 days of topical therapy or a 100-mg,negative KOH smear despite clinical signs and symptoms suggestive of 150-mg, or 200-mg oral dose of fluconazole every third day for a total TABLE 38-1 RECOMMENDED REGIMENS FOR TREATMENT OF VULVOVAGINAL CANDIDIASIS IN PREGNANT AND NONPREGNANT WOMEN Antifungal Agent Formulation Regimen Intravaginal Agents Butoconazole 2% cream* 5 g intravaginally for 3 days 2% cream (Butoconazole 1—sustained release) 5 g single intravaginal application Clotrimazole 1% cream* 5 g intravaginally for 7-14 days 100 mg vaginal tablet One tablet qd for 7 days 100 mg vaginal tablet Two tablets at one time daily for 3 days Miconazole 2% cream* 5 g intravaginally for 7 days 100 mg vaginal suppository* One suppository qd for 7 days 200 mg vaginal suppository* One suppository qd for 3 days 1200 mg vaginal suppository* One suppository qd for 1 day Nystatin 100,000-unit vaginal tablet One tablet qd for 14 days Tioconazole 6.5% ointment* 5 g intravaginally in a single application Terconazole 0.4% cream 5 g intravaginally for 7 days 0.8% cream 5 g intravaginally for 3 days 80 mg vaginal suppository One suppository qd for 3 days Oral Agent Fluconazole 150 mg oral tablet One tablet in single dose *Over-the-counter preparation. From Centers for Disease Control and Prevention: Sexually Transmitted Diseases Treatment Guidelines, 2006. MMWR Recommendations and Reports 55(RR-11):1-94, 2006.
  • 3. CHAPTER 38 Maternal and Fetal Infections 741of 3 doses) should be considered. Fluconazole is a U.S. Food and Drug zole had a significantly higher frequency of preterm delivery.20 Accord-Administration (FDA) class C drug. It should be reserved for highly ingly, although symptomatic pregnant women with trichomoniasisselect patients, such as those who are allergic to topical antifungal should be treated to relieve symptoms, routine screening and treat-medications or who have recurrent persistent infection.12 ment are not recommended.Trichomoniasis Bacterial VaginosisClinical Presentation Epidemiology and PathogenesisTrichomonas vaginalis is a common cause of vaginitis, with infection This infection was formerly called nonspecific vaginitis, Gardnerellaoften characterized by intense pruritus, strong odor, and dysuria. vaginalis vaginitis, or Haemophilus vaginalis vaginitis; bacterial vagino-Physical examination typically shows a malodorous, yellow-green, sis (BV) is the preferable term. The condition is marked by a majorfrothy discharge. However, variations of the gross appearance occur in shift in vaginal flora from the normal predominance of lactobacilli toapproximately 50% of cases, with many women showing minimal or a predominance of anaerobes, which are increased 100-fold comparedno symptoms. The diagnosis may be confirmed by microscopic exami- with normal secretions. G. vaginalis is present in 95% of cases but alsonation of a smear of the discharge diluted with saline. The examination is present in 30% to 40% of normal women. Mycoplasma hominis inreveals many leukocytes and bacteria; trichomonads are recognized by vaginal secretions is increased significantly in cases of BV.their size (slightly larger than leukocytes) and active flagella. The sen- BV is the most common type of infectious vaginitis. Between 10%sitivity of wet mount is only 60% to 70%.14 Cultures for Trichomonas and 30% of pregnant women fulfill the criteria, but half of them areare more sensitive than wet mount, and commercial systems are avail- asymptomatic.able to facilitate culture of this parasite. There currently are two point-of-care diagnostic tests available, the OSOM Trichomonas Rapid Test(Genzyme Diagnostics, Cambridge, MS) and the Affirm VP III (Becton DiagnosisDickenson, San Jose, CA). These tests have better sensitivity than Clinically, the primary symptoms are discharge and odor. Itchingwet mount, but false-positive results may be a problem, especially in usually is not prominent. Diagnosis of BV is based on the presence oflow-prevalence populations. three of the following four clinical features: (1) an amine-like or fishy The prevalence of T. vaginalis vaginitis in pregnancy ranges from odor that may be accentuated after addition of KOH or after coitusless than 10% to 50%, depending on the patient population. Conse- (owing to the alkaline pH of semen); (2) a thin, homogeneous, gray orquently, it has been difficult to establish whether the incidence of this white discharge; (3) an elevated pH (≥4.5); and (4) on wet mount, truevaginal infection truly is increased in pregnant women. “clue” cells (squamous epithelial cells so heavily stippled with bacteria that their borders are obscured). Typically in cases of BV, clue cells account for more than 20% of epithelial cells, and there are few leu-Adverse Effects in Pregnancy kocytes. An experienced observer will note an increase in numbers andAn increased rate of PROM at term has been linked to positive genital kinds of bacteria and a reduction in numbers of lactobacilli. A Gramtract cultures for T. vaginalis (27.5% with infection versus 12.8% stain of vaginal secretions also demonstrates the shift in bacteria andwithout; P < .03).15 In the large National Institutes of Health infection clue cells.and prematurity study, T. vaginalis infection at midpregnancy wasassociated significantly with low birth weight (odds ratio [OR], 1.3;95% confidence interval [CI], 1.1 to 1.5), preterm delivery (OR, 1.3; Adverse Effects in PregnancyCI, 1.1 to 1.4), and PROM (OR, 1.4, CI, 1.1 to 1.6), even after adjust- Evidence consistently has associated BV with increased likelihoods ofment for confounding factors and other microbes.16 In addition, preterm delivery,21-24 clinical chorioamnionitis,25 histologic chorioam-trichomoniasis has been associated with increased rates of HIV nionitis,26 and endometritis.27 The risk for preterm delivery amongtransmission.17,18 women with BV has varied (OR, 1.4 to 8) but has been significant in all populations studied.TreatmentThe recommended treatment for trichomoniasis is oral metronidazole, Treatment2 g in a single dose. An alternative regimen is metronidazole, 500 mg In nonpregnant women, the most consistent cure rates (90%) haveorally twice a day for 7 days.12 No consistent association has been been achieved with metronidazole (e.g., 500 mg twice a day for 7 days).demonstrated between use of metronidazole in pregnancy and terato- Lower cure rates (60% to 80%) are observed with a single 2.0-g dosegenesis or mutagenesis in infants.19 Tinidazole, another nitroimidazole of metronidazole. Oral clindamycin (300 mg twice a day for 7 days) isdrug, recently was approved by the FDA for treatment of trichomonia- effective in treating nonpregnant patients and appears to be safe insis (2 g orally in a single dose). However, metronidazole should be pregnancy. Vaginal clindamycin cream (2%) and metronidazole gelfavored for the treatment of pregnant women because of its superior (0.75%) also are effective in nonpregnant women. However, the pre-safety profile. Topical agents often are unsuccessful in relieving symp- ferred regimens in pregnancy are shown in Table 38-2. There istoms or in eradicating this protozoon. no longer an exclusion for use of metronidazole in any trimester Among women with asymptomatic trichomoniasis in pregnancy, of pregnancy. A recent meta-analysis showed no evidence oftreatment in the second trimester (two 2.0 g doses 48 hours apart at teratogenesis.12,28-3016 to 23 weeks, repeated at 24 to 29 weeks) did not result in better In view of the consistent association of BV with adverse pregnancypregnancy outcomes than did placebo. Indeed, those given metronida- outcomes, clinical treatment trials have been undertaken. Three trials,
  • 4. 742 CHAPTER 38 Maternal and Fetal Infectionsall conducted in patients who were considered to be at high risk (on agree with their recommendation of treatment with oral metronida-the basis of either a previous preterm birth or other high-risk demo- zole for at least 7 days in women at high risk (e.g., those with previousgraphic features), revealed improvement in outcome with prenatal preterm birth). Screening and treatment of these high-risk womentreatment of BV (Table 38-3). In a group of women who experienced should occur at the first prenatal visit. Recommendations for manage-a spontaneous preterm birth due to preterm labor or PROM during ment of BV in pregnancy are presented in Table 38-4.a previous pregnancy, treatment of BV with oral metronidazole ledto a significant reduction in preterm birth, low birth weight, andPROM (P < .05 for each).31 In a prospective, two-phase trial involving Gonorrhea1260 women, treatment of BV significantly decreased preterm birth(P < .05).32 Finally, among women at risk because of a previous Gonorrhea, which is caused by the gram-negative diplococcus, Neisse-preterm birth or low maternal weight, treatment with a combination ria gonorrhoeae, is probably the oldest known STD. Almost 340,000of metronidazole and erythromycin significantly improved pregnancy new infections with N. gonorrhoeae were reported in the United Statesoutcome compared to placebo in patients who had BV (P < .006); in in 2005,38 making gonorrhea the second most commonly reportedthose patients without BV, pregnancy outcome was not improved.33 communicable disease in the nation. In a treatment trial of women at low risk of preterm delivery, oralmetronidazole (twice daily for 2 days at 24 weeks, with repeat treat-ment, if needed, at 29 weeks) led to no reduction in preterm birth Epidemiologyoverall but produced a significant reduction in the subgroup of women The CDC received 339,593 reports of gonorrhea in 2005. However,with a previous preterm birth.34 In the Maternal-Fetal Medicine Units even this volume of reports underestimates the incidence, and publicNetwork treatment trial of women with asymptomatic BV, the treat- health experts estimate that 600,000 new cases of N. gonorrhoeae infec-ment regimen also was short (two 2.0-g doses at 16 to 24 weeks and tion occur each year in the United States. From 1975 through 1997,again at 24 to 30 weeks, with the repeat treatment at least 14 days after there was a dramatic decrease of 74% in reported cases of gonorrhea.the initial doses). Use of metronidazole in this regimen led to no In 1998, an 8.9% increase occurred, followed by plateauing of thesignificant improvement overall or in any subgroup (e.g., women number of reported cases.38,39with a previous preterm birth).35 These studies are summarized in In 2003, for the first time, the reported gonorrhea rate was higherFigure 38-1. In view of these disparate results, the American College among women (118.8 per 100,000 population than among men (113of Obstetricians and Gynecologists (ACOG)36 concluded in 2001, per 100,000).40 Disappointingly, in 2005, both the number of reported“Currently, there are insufficient data to suggest [that] screening and cases and the prevalence rate of gonorrhea increased for the first timetreating women at either low or high risk will reduce the overall rateof preterm birth.” However, Goldenberg and colleagues37 reached a different conclu- Study Effectsion, taking into consideration the metronidazole regimen used. We Lowering of Increasing of preterm birth preterm birth Morales, 1994 TABLE 38-2 CDC-RECOMMENDED REGIMENS McGregor, 1995 FOR TREATING BACTERIAL Hauth, 1995 VAGINOSIS McDonald, 1997 (overall) (previous PTB) Metronidazole 500 mg PO bid for 7 days Carey, 2000 (overall) OR (previous PTB) Metronidazole 250 mg PO tid for 7 days OR FIGURE 38-1 Bacterial vaginosis treatment trials. Summary of Clindamycin 300 mg PO bid for 7 days treatment trials of bacterial vaginosis in pregnancy to prevent preterm birth. TABLE 38-3 STUDIES OF BACTERIAL VAGINOSIS IN PREGNANCY IN PATIENTS AT HIGH RISK FOR PRETERM DELIVERY Preterm Birth Antibiotic No Treatment Study Design Study Population Treatment (%) or Placebo (%) Significance (P) Morales et al, 1994 Randomized, 80 women with previous 18 39 <.05 placebo-controlled spontaneous preterm birth in Florida Hauth et al, 1995 Randomized, 258 women with previous 31 49 .006 placebo-controlled preterm birth or low maternal weight in Alabama McGregor et al, 1995 Nonrandomized, 1260 women in Colorado with 9.8 18.8 .02 two-phase trial a 15% preterm birth rate Modified from Gibbs RS, Eschenbach DA: Use of antibiotics to prevent preterm birth. Am J Obstet Gynecol 177:375, 1997.
  • 5. CHAPTER 38 Maternal and Fetal Infections 743in almost a decade. In a recent cross-sectional cohort study, The A number of risk factors for gonorrhea among sexually activeNational Longitudinal Study of Adolescent Health reported that the women have been elucidated. Young age is the greatest risk factor, withoverall prevalence of gonorrhea in the United States was 0.43% (CI, sexually active women younger than 25 years of age being at highest0.29% to 0.63%).41 The prevalence of gonorrhea in pregnancy ranges risk for gonorrhea infection. Other risk factors for gonorrhea includefrom 0% to 10%, with marked variations according to risk status and previous gonococcal infection, presence of other STDs, multiple sexgeographic locale.42 partners, new sex partners, inconsistent condom use, drug use, and commercial sex work. Nonwhite race, low socioeconomic status, inner- city dwelling, and unmarried status are additional risk factors for infec- TABLE 38-4 RECOMMENDATIONS FOR tion with N. gonorrhoeae (Figs. 38-2 and 38-3).12 MANAGEMENT OF BACTERIAL VAGINOSIS IN PREGNANCY Pathogenesis Symptomatic pregnant women with BV can be treated safely in Transmission of N. gonorrhoeae occurs almost solely by sexual contact, any trimester with oral metronidazole or clindamycin. and the risk of transmission from an infected male to a female partner Routine screening and treatment of BV in asymptomatic women is 50% to 90% with a single exposure.43 The incubation period is 3 to at low risk for preterm birth cannot be endorsed (USPTF: D 5 days. recommendation). Infection with N. gonorrhoeae in pregnancy is a major concern. Screening for BV may be considered in asymptomatic women at Although gonococcal ophthalmia neonatorum has been recognized high risk for preterm birth, such as those with previous preterm since the late 19th century as a significant consequence of maternal birth. Women who test positive should be treated. The value of rescreening and retreating is unclear. infection with N. gonorrhoeae, it is only in the last 40 years that an association has been recognized between maternal infection with N. BV, bacterial vaginosis; USPTF, U.S. Preventive Services Task Force. gonorrhoeae and disseminated gonococcal infection (DGI), amniotic 500 Men 400 Women Incidence 300 200FIGURE 38-2 Incidence of gonorrhea per 100,000 population, 100by sex—United States, 1990-2005. The overall incidence ofgonorrhea in the United States has declined since 1975 but 0increased in 2005 for the first time since 1999. In 2005, incidence 1990 1995 2000 2005was slightly higher among women than among men. 2,200 2,000 1,800 1,600 1,400 Incidence 1,200 1,000 800 600 400 200 0 1990 1995 2000 2005 YearFIGURE 38-3 Gonorrhea incidence per 100,000 population, by Black, non-Hispanicrace/ethnicity—United States, 1990-2005. Gonorrhea incidence American Indian/Alaska Nativeamong blacks decreased considerably during the 1990s, but blacks Hispaniccontinue to have the highest rate among all races/ethnicities. White, non-HispanicIn 2005, gonorrhea incidence among non-Hispanic blacks was Asian/Pacific Islanderapproximately 18 times greater than among non-Hispanic whites.
  • 6. 744 CHAPTER 38 Maternal and Fetal Infectionsinfection syndrome, and perinatal complications including PROM, but incubation periods of up to 21 days have been reported. A frankchorioamnionitis, preterm delivery, intrauterine growth restriction, purulent conjunctivitis occurs and usually affects both eyes. Untreatedneonatal sepsis, and postpartum endometritis.4 gonococcal ophthalmia can rapidly progress to corneal ulceration, Adherence of N. gonorrhoeae to the mucosal epithelium of the resulting in corneal scarring and blindness.genital tract is the initial step in the pathogenesis of gonococcal infec-tion. Attachment of N. gonorrhoeae is mediated by pili and other Gonococcal Infection in Pregnancysurface proteins (e.g., porin protein, opacity-associated proteins, and in the Neonatereduction-modifiable protein). Lipopolysaccharides, immunoglobulin The effects of gonorrheal infection on both mother and fetus were notA, and iron-repressible proteins are additional gonococcal virulence fully appreciated until 4 decades ago.4,46,47 Studies at that time identifiedfactors. Once N. gonorrhoeae attaches to mucosal cells, it enters the cell an association between untreated maternal endocervical gonorrheavia endocytosis. Subsequently, the organism releases endotoxin, result- and perinatal complications, including PROM, preterm delivery, cho-ing in widespread cell damage.44 rioamnionitis, neonatal sepsis, and maternal postpartum sepsis. The amniotic infection syndrome is an additional manifestation of gonococcal infection in pregnancy. This condition is characterized byClinical Manifestations placental, fetal membrane, and umbilical cord inflammation that occurs after PROM and is associated with infected oral and gastricAnogenital Gonorrhea aspirate, leukocytosis, neonatal infection, and maternal fever. PretermThe clinical manifestations of gonococcal infection are dependent on delivery is common, and perinatal morbidity may be significant.46the site of inoculation and whether the infection remains localized orspreads systematically. The overwhelming majority of women with N.gonorrhoeae infection are asymptomatic. This observation is particu- Diagnosislarly true in pregnancy. The endocervix is the primary site of infection. The diagnosis of infection with N. gonorrhoeae requires sampling ofWhen symptoms develop, they usually include vaginal discharge and potentially infected sites. Available methods include culture, nucleicdysuria. On examination, a mucopurulent discharge is usually appar- acid hybridization tests, and nucleic acid amplification tests (NAATs).48ent in the endocervical canal. Inflammation of the Skene or Bartholin Unlike for Chlamydia trachomatis infection, the CDC has not providedglands may occur. In patients who engage in rectal intercourse, a muco- guidance with respect to general or targeted screening for gonorrheapurulent proctitis may also be apparent. infection.49 Even in the absence of formal guidelines, gonorrhea screen- ing has been implemented in conjunction with routine chlamydialDisseminated Gonococcal Infection screening. Implementation of these joint screening protocols has beenDGI is an important presentation of gonorrhea in pregnancy. Pregnant shown to be cost-effective.women, especially during the second and third trimester, appear to be Screening for gonorrhea during pregnancy is clearly cost-effectiveat increased risk for disseminated infection, which has two stages. The if the prevalence exceeds 1%. Therefore, the CDC recommends that allearly, bacteremic stage is characterized by chills, fever, and typical skin pregnant women at risk for gonorrhea, as well as those living in an arealesions. The lesions appear initially as small vesicles, which become where the prevalence of N. gonorrhoeae is high, be tested for N. gonor-pustules and develop a hemorrhagic base. The center becomes necrotic. rhoeae at their first prenatal visit.12 Targeted patients includeSuch lesions can occur anywhere on the body but are most frequentlypresent on the volar aspects of the arms, hands, and fingers. They fade 1. Partners of men with gonorrhea or urethritiswithout residual scarring. Blood cultures are positive for N. gonor- 2. Patients known to have other STDs, including HIV infectionrhoeae in 50% of patients in whom culture is done during the bacte- 3. Patients with multiple sex partnersremic stage. DGI is occasionally complicated by perihepatitis and 4. Young, unmarried inner-city womenrarely by endocarditis or meningitis. Joint symptoms are frequently 5. Intravenous drug userspresent during this stage, as well as in the second, septic arthritis phase. 6. Women with symptoms or signs of lower genital tractThis stage is characterized by a purulent synovial effusion. The knees, infection.ankles, and wrists are most commonly involved. Blood cultures duringthis stage are usually sterile. Gonococci may be isolated from the septic The CDC and the ACOG recommend that at-risk women bejoints during the second stage. The infection may become chronic or rescreened for N. gonorrhoeae during the third trimester.12,50 A recentprogress to septic arthritis and joint destruction.12 study demonstrated the value of a repeat screen in the third trimester for N. gonorrhoeae among at-risk women who had an initial negativePharyngeal Gonorrhea early pregnancy screen.42 In this study, 38 (5.1%) of 751 at-risk womenThe majority of patients with pharyngeal infections with N. gonor- had gonorrhea (based on a positive DNA direct assay) at their firstrhoeae are asymptomatic. If they are symptomatic, the most common prenatal visit. An additional 19 women (2.5%) were newly positive atfinding is a mild sore throat and erythema; lesions and exudates may their third-trimester screen. In other words, approximately one thirdalso be present. Pharyngeal gonorrhea is more common during preg- of at-risk women tested positive for N. gonorrhoeae only on the repeatnancy than in nonpregnant women.45 third-trimester screen. Several reliable nonculture assays for detection of N. gonorrhoeaeNeonatal Gonococcal Ophthalmia have become available and are increasingly being used.48 They includeGonococcal ophthalmia neonatorum has been recognized since 1881. nonamplified DNA probe tests (discussed later) and NAATs such asIntroduction of routine prophylaxis with silver nitrate resulted in a polymerase chain reaction (PCR), ligase chain reaction (LCR),rapid reduction in this complication. Most newborns who have gonor- transcription-mediated amplification (TMA), and strand displace-rhea acquire it during passage through an infected cervical canal. ment assay (SDA). These newer technologies compare favorably toGonococcal ophthalmia is usually observed within 4 days after birth, culture with selective media. For nonamplified DNA probes, the sen-
  • 7. CHAPTER 38 Maternal and Fetal Infections 745sitivity ranges from 89% to 97%, and the specificity is 99%. For NAATs, TABLE 38-5 RECOMMENDATIONS FOR THEthe sensitivity and specificity are both excellent (>99%). Whereas the TREATMENT OF UNCOMPLICATEDintroduction of dual, single-swab NAATs for detection of C. trachoma- GONORRHEA OF THE CERVIX,tis and N. gonorrhoeae has simplified testing and facilitated expansion URETHRA, AND RECTUMof STD screening to nontraditional settings, there is a downsideto single-swab NAATs.51 First, the prevalence of N. gonorrhoeae is Recommended Regimens (in addition to treatment forsubstantially lower than that of C. trachomatis, especially in most chlamydial infection if not ruled out)community-based settings.52 As a result, when providers intend to Ceftriaxone* 125 mg IM in a single dosescreen primarily for C. trachomatis, they are also screening for N. gon- Cefixime* 400 mg PO in a single doseorrhoeae. The potential for false-positive N. gonorrhoeae test resultsincreases because the positive predictive value of a test decreases as the Alternative Regimens Spectinomycin* 2 g IM in a single doseprevalence of disease decreases. Second, as NAATs replace culture Single-dose cephalosporin* regimensassays, fewer isolates are available for antibiotic susceptibility testing.As a result, monitoring of trends in antimicrobial susceptibility of N. *Recommended for use in pregnancy.gonorrhoeae, a major public health issue, may be compromised. From Centers for Disease Control and Prevention: Update to CDC’s Sexually Transmitted Diseases Treatment Guidelines, 2006: Fluoroquinolones No Longer Recommended for Treatment of Gonococcal Infections. MMWR Morb Mortal Wkly Rep 56(14):332-336,Treatment 2007.The treatment of gonococcal infection in pregnant women is similarto that in nonpregnant women, with the exception that tetracyclineshould not be used for concomitant chlamydial infection. Both asymp- TABLE 38-6 RECOMMENDATIONS FOR THEtomatic and symptomatic infections should be treated. TREATMENT OF COMPLICATED The treatment of gonococcal infection in the United States has been GONORRHEA (DISSEMINATEDinfluenced by two factors. First, there has been increasing prevalence GONOCOCCAL INFECTION,and spread of infections caused by antibiotic-resistant N. gonorrhoeae, MENINGITIS, ENDOCARDITIS)such as penicillinase-producing N. gonorrhoeae, tetracycline-resistant Recommended RegimenN. gonorrhoeae, and chromosomally mediated N. gonorrhoeae, Ceftriaxone* 1 g IM or IV q24hwhich is resistant to multiple antibiotics. Moreover, in recent years,quinolone-resistant N. gonorrhoeae (QRNG) has emerged as a major Alternative Regimenspublic health problem.12,53 QRNG continues to spread and increase in Cefotaxime* 1 g IV q8hprevalence, making treatment of gonorrhea with quinolones such as Ceftizoxime* 1 g IV q8hciprofloxacin inadvisable in many geographic areas and populations. Spectinomycin* 2 g IM q12hAccording to the CDC,12 resistance to ciprofloxacin usually indicates *Recommended for use in pregnancy.resistance to other quinolones. QRNG is common in parts of Europe, From Centers for Disease Control and Prevention: Update to CDC’sthe Middle East, Asia, and the Pacific and is becoming increasingly Sexually Transmitted Diseases Treatment Guidelines, 2006:common in the United States. For example, in California the rate of Fluoroquinolones No Longer Recommended for Treatment ofQRNG increased from less than 1% in 1999 to more than 20% in the Gonococcal Infections. MMWR Morb Mortal Wkly Rep 56(14):332-336,second half of 2003.54 Similarly high rates of QRNG have been reported 2007.in Hawaii.55 As a result, in 2005, the CDC advised that quinolonesshould not be used in California or Hawaii.56 In 2004, 6.8% of isolates achieve as high or as sustained serum levels as the 125-mg ceftriaxonecollected by CDC’s Gonococcal Isolate Surveillance Project (GISP)57 dose. Cefixime, in a 400 mg oral dose, cures 97.4% of uncomplicatedwere resistant to ciprofloxacin. QRNG was more common among men urethral, cervical, and anogenital gonorrhea.59 Ciprofloxacin is safe, iswho have sex with men (MSM) than among heterosexual men (23.9% inexpensive, and can be administered orally, but it is no longer univer-versus 2.9%).39,58 Subsequently, the prevalence of QRNG increased in sally effective against N. gonorrhoeae in the United States. The sameother areas of the United States, leading to changes in recommended holds true for ofloxacin and levofloxacin. In addition, quinolonestreatment regimens by other states and local areas. In a 2007 update should not be used during pregnancy.to its Sexually Transmitted Diseases Treatment Guidelines, the CDC Several alternative antimicrobial agents are suggested by the CDCannounced that quinolones are no longer recommended for the treat- for treatment of uncomplicated gonococcal infections of the cervix,ment of gonorrheal infections.407 urethra, and anorectum. Spectinomycin is effective (cure rate >98%), The second factor that influences treatment recommendations is but it is expensive and is available only as an injection. In addition, itthe high frequency (20% to 50%) of coexisting chlamydial infection in is not readily available any longer. During pregnancy, it is useful forwomen infected with N. gonorrhoeae. This finding has led to the rec- patients who are allergic to cephalosporins. Alternative single-doseommendation that women treated for gonococcal infection should cephalosporins include ceftizoxime 500 mg IM, cefoxitin 2 g IMalso be treated routinely for chlamydia.12 Current CDC recommenda- with probenecid 1 g orally, and cefotaxime 500 mg IM. Alternativetions for the treatment of N. gonorrhoeae in pregnancy are listed in single-dose oral quinolones (not recommended for pregnancy)Tables 38-5 and 38-6. include gatifloxacin 400 mg, norfloxacin 800 mg, and lomefloxacin Ceftriaxone in a single intramuscular injection of 125 mg provides 400 mg. The CDC suggests that cefpodoxime and cefuroxime axetil assustained, high bactericidal levels in blood and is safe and effective for additional oral alternatives for treatment of uncomplicated urogenitaltreatment of uncomplicated gonorrhea, curing 98.9% of urethral, cer- gonorrhea.12vical, and anorectal infections.12,59 The antimicrobial spectrum of cefix- As noted by the CDC, effective management of STDs such asime is similar to that of ceftriaxone, but the 400-mg dose does not gonorrhea requires treatment of the woman’s current sex partner or
  • 8. 746 CHAPTER 38 Maternal and Fetal Infectionspartners to prevent reinfection. Patients should be instructed to refer ery, premature rupture of the membranes, low birth weight, andtheir sex partners for evaluation and treatment. Alternatively, patient- neonatal death.4,62 Untreated C. trachomatis infection also may resultdelivered treatment for sex partners is also effective.12,60 in neonatal conjunctivitis or pneumonia or both.4,63 Pregnant women should not be treated with quinolones or tetra- C. trachomatis may be differentiated on a serologic basis into 15cyclines. Pregnant women infected with N. gonorrhoeae should be recognized serotypes. Three of these serotypes (L1, L2, L3) cause lym-treated with one of the recommended or alternative cephalosporins. phogranuloma venereum. The other serotypes cause endemic blindingThose who cannot tolerate cephalosporins should be treated with spec- trachoma (A, B, Ba, and C) or inclusion conjunctivitis, newborn pneu-tinomycin 2 g IM as a single dose, if it is available. Either amoxicillin monia, urethritis, cervicitis, endometritis, pelvic inflammatory disease,or azithromycin is recommended as treatment for presumed concomi- and the acute urethral syndrome (strains D through K).4tant chlamydial infection during pregnancy.12 Patients with DGI should be hospitalized for initial therapy (seeTable 38-6). In addition, patients with DGI should be evaluated clini- Epidemiologycally for evidence of endocarditis or meningitis. All of the recom- As noted by Peipert,64 the prevalence of C. trachomatis infectionmended and alternative regimens for DGI should be continued for 24 depends on the characteristics of the population studied. Prevalenceto 48 hours after improvement begins. At that time, therapy may be rates in the United States vary significantly, ranging from 4% to 12%switched to cefixime, 400 mg orally twice daily. With gonococcal men- among family planning clinic attendees, from 2% to 7% among collegeingitis and endocarditis, the recommended regimen is ceftriaxone 1 to students, and from 6% to 20% among STD clinic attendees.4 Recently,2 g IV every 12 hours. Meningitis requires 10 to 14 days of therapy, in the National Longitudinal Study of Adolescent Health,65 the overalland treatment for endocarditis should be continued for a minimum prevalence of chlamydial infection was found to be 4.19%, with womenof 4 weeks.12 (4.74%; CI, 3.93% to 5.71%) more likely to be infected than men With use of recommended treatment, follow-up testing to docu- (3.67%; CI, 2.93% to 4.58%). In 2005, more than 975,000 cases ofment eradication of gonorrhea is no longer recommended. Instead, chlamydial genital infection were reported to the CDC, almost 50,000rescreening in 2 to 3 months to identify reinfection is suggested. If more than in 2004. The CDC estimates that the true frequency ofother antimicrobial agents are used for the treatment of N. gonor- chlamydial infection each year is 3 million cases, the majority of whichrhoeae, follow-up assessment is suggested. Follow-up cultures should are not reported to public health officials.61be obtained from the infected site 3 to 7 days after completion of treat- The prevalence of C. trachomatis infection among pregnant womenment. Specimens should be obtained from the anal canal as well as the is about 2% to 3% but may be higher in certain high-risk populations.4endocervix; failure to obtain a specimen from the anal canal results Among pregnant women, risk factors for chlamydial infection includein missing 50% of resistant N. gonorrhoeae strains. With NAATs, the following:repeat testing should be performed 3 weeks after treatment. Patientswho have symptoms that persist after treatment should be evaluated 1. Unmarried statusby culture, and isolated organisms should be tested for antimicrobial 2. Age younger than 25 yearssusceptibility.12 3. Multiple sex partners 4. New sex partner in past 3 months 5. Black racePrevention 6. Presence of another STDPrimary prevention of gonorrhea requires adopting safe sex practices, 7. Partners with nongonococcal urethritisincluding condom use; limiting the number of sexual partners; and 8. Presence of mucopurulent endocervicitisensuring that sexual partners are evaluated and treated. The increasing 9. Sterile pyuria (acute urethral syndrome)frequency of asymptomatic gonorrhea infection in women makes 10. Resident of socially disadvantaged communityscreening for N. gonorrhoeae during the antepartum period an impor- 11. Late or no prenatal caretant aspect of preventing the perinatal morbidity associated with thisorganism. At-risk patients should be rescreened in the third trimester. Detection rates as high as 25% to 30% have been reported inInstillation of a prophylactic agent into the eyes of all newborn infants screening and prospective studies of such populations. In the Pretermis recommended to prevent gonococcal ophthalmia neonatorum. The Prediction Study of the National Institute of Child Health and Humanrecommended agents are erythromycin (0.5%) ophthalmic ointment, Development Maternal-Fetal Medicine Units Network, the overalltetracycline (1%) ophthalmic ointment, and silver nitrate (1%) prevalence of C. trachomatis among pregnant women was 11%.6 In anaqueous solution. interesting follow-up study, Sheffield and colleagues66 demonstrated that chlamydial infection resolved spontaneously in almost half of infected pregnant women, especially in older women and with increas-Chlamydial Infection ing time since diagnosis. Infants born to women with a chlamydial infection of the cervixC. trachomatis infection is the most common bacterial STD in the are at a 60% to 70% risk of acquiring the infection during passageUnited States, with an estimated 3 million new infections annually. The through the birth canal. Approximately 25% to 50% of exposed infantsestimated cost of untreated chlamydial infection and their sequelae is acquire conjunctivitis in the first 2 weeks of life, and 10% to 20%more than $2 billion annually.12,61 develop pneumonia within 3 or 4 months.4 In women, untreated chlamydial infection results in substantialadverse reproductive effects, including pelvic inflammatory diseaseand its sequelae of tubal factor infertility, ectopic pregnancy, and Pathogenesischronic pelvic pain. Chlamydial infection during pregnancy is associ- Chlamydiae are obligate intracellular bacteria separated into their ownated with several adverse maternal outcomes, including preterm deliv- order, Chlamydiales, on the basis of a unique growth cycle that distin-
  • 9. CHAPTER 38 Maternal and Fetal Infections 747guishes them from all other microorganisms. This cycle involves that pregnant women with chlamydial cervical infection at their initialinfection of the susceptible host cell by a chlamydia-specific phagocytic prenatal visit were at increased risk for endometritis after vaginalprocess, so that these organisms are preferentially ingested. After delivery. However, multiple other studies have failed to confirmattachment and ingestion, the chlamydiae remain in a phagosome such an association.71,72,76-78throughout the growth cycle, but surface antigens of chlamydiaeappear to inhibit phagolysosomal fusion. These two virulence factors—enhanced ingestion and inhibition of phagolysosomal fusion—attest Diagnosisto an exquisitely adapted parasitism. Until recently, the optimum diagnostic test for chlamydial infection Once in the cell, the chlamydial elementary body, which is the infec- was tissue culture. However, culture requires cold storage, a susceptibletious particle, changes to a metabolically active replicating form called tissue culture cell line, a 1-week waiting time for results, and substantialthe reticulate body, which synthesizes its own macromolecules and technical expertise. In addition, culture is expensive and, with thedivides by binary fission. Chlamydiae are energy parasites; because advent of NAATs, has been shown to be relatively insensitive (65% tothey do not synthesize their own adenosine triphosphate, energy-rich 85%).compounds must be supplied to them by the host cell. By the end Before the introduction of NAATs, antigen-detection methods wereof the growth cycle (approximately 48 hours), most reticulate widely used. To a large extent, these antigen detection tests have nowbodies have reorganized into elementary bodies, which are released been replaced by DNA/RNA-based methods, both nonamplified andthrough mechanical disruption of the host cell to initiate new infection amplified types. Nonamplified tests such as the Gen-Probe PACE-2cycles. assay (Gen-Probe, San Diego, CA) use DNA/RNA hybridization tech- Chlamydia are unique bacteria that do not stain with Gram stain. nology. In a large multicenter study, Black and coauthors79 reportedIn many respects, they are similar to other bacteria: They contain DNA that the sensitivity of PACE-2 ranged from 60.8% to 71.6%, and theand RNA, are susceptible to certain antibiotics, have a rigid cell wall specificity ranged from 99.5% to 99.6%. An important advantage ofsimilar in structure and content to those of gram-negative bacteria, DNA probe–based testing is that it can be used in conjunction with aand multiply by binary fission. However, they differ from other bacte- probe for the detection of N. gonorrhoeae in a single swab. Additionalria and resemble viruses in being obligate intracellular parasites. They advantages include ease of transport, ability to batch specimens, andmay be regarded as bacteria that have adapted to an intracellular envi- decreased cost. As a result, by the late 1990s, the DNA probe becameronment. They need viable cells for multiplication and survival.4 the most widely used diagnostic test for C. trachomatis infection in the United States. More recently, DNA/RNA amplification technology has beenAdverse Pregnancy Outcome introduced into clinical practice. NAATs have excellent sensitivity andControversy exists as to whether maternal cervical C. trachomatis specificity for chlamydial testing. Currently, clinically available NAATsinfection is associated with adverse pregnancy outcome. Although include tests based on PCR (Roche Molecular Systems, Branchburg,some studies have demonstrated an association of maternal chlamy- NJ), TMA (AMP.CT Gen-Probe), and SDA (Bectun Dickenson, Sparks,dial infection with preterm birth, low birth weight, PROM, and peri- MD). LCR-based tests (Abbott Laboratories, Chicago) are no longernatal death,67-69 others have failed to confirm such an association.4,70 available. NAATs have performed better than culture, antigen detec-Harrison71 and Sweet72 and their colleagues demonstrated that a sub- tion, or DNA probe techniques for detection of C. trachomatis.12,80,81 Agroup of infected women in whom immunoglobulin M (IgM) anti- major advantage of NAATs is their ability to identify patients with abody was present were at significantly increased risk for PROM, low inoculum of C. trachomatis. Moreover, NAATs have demonstratedpreterm birth, and delivery of a low-birth-weight infant. These authors excellent sensitivity and specificity for detecting chlamydia in urinepostulated that IgM seropositivity reflected recent acquisition and specimens, allowing noninvasive screening for C. trachomatis. However,acute chlamydial infection, which may play a more important role than use of a vaginal swab has been shown to have equivalent or betterchronic infection.62 sensitivity and specificity and is better accepted by patients, especially In additional attempts to address the role of C. trachomatis in when patient-obtained specimens are used.82-84adverse pregnancy outcome, researchers have undertaken treatment According to the CDC, all pregnant women should be routinelystudies of chlamydial infection in pregnant women. In a historical tested for C. trachomatis at their first prenatal visit.12 Women youngercontrol study, Ryan and colleagues73 reported that untreated chla- than 25 years of age and those at increased risk for chlamydial infectionmydia-infected pregnant women in a high-prevalence population also should be retested during the third trimester to prevent maternal(21% positive) had a significantly increased incidence of PROM and postnatal complications and chlamydial infection in the infant. Inof low-birth-weight infants and decreased perinatal survival compared addition, the CDC suggests that first-trimester screening might preventwith treated women or women not infected with chlamydia. Similarly, the adverse effects of chlamydial infection during pregnancy (e.g.,Cohen and coworkers74 reported that treatment of chlamydial infec- preterm birth, PROM, low birth weight).tion resulted in decreased rates of preterm delivery, PROM, pretermlabor, and fetal growth restriction. There were experimental designflaws or limitations in both studies. However, because it is unethical to Treatmentconduct a prospective, randomized, placebo-controlled trial in which Screening of sexually active women for chlamydial infection is asome patients are not treated, these studies are the best available to national priority in the United States.85,86 Identification and treatmentdate. of women infected with C. trachomatis prevent horizontal transmis- The role of cervical chlamydial infection in producing postpartum sion to sex partners and vertical transmission of C. trachomatis toendometritis is also controversial. Early studies in the ophthalmology infants during birth.12 In addition, treatment of chlamydial infectionliterature demonstrated an association between inclusion conjunctivi- early in pregnancy seems to reduce the rate of adverse pregnancy out-tis in newborns and an increased risk for postpartum infection in their comes (e.g., preterm birth, intrauterine growth restriction, low birthmothers. In a prospective study, Wager and associates75 demonstrated weight, PROM).4,64
  • 10. 748 CHAPTER 38 Maternal and Fetal Infections TABLE 38-7 TREATMENT RECOMMENDATIONS discussed previously, routine screening of all pregnant women at the FOR CHLAMYDIAL INFECTION IN first prenatal visit and screening of all nonpregnant women 25 years of age and younger is recommended. In addition, women older than PREGNANT WOMEN 25 years of age who are at increased risk for chlamydial infection (e.g., Recommended Regimens multiple sex partners, new sex partner recently, previous chlamydial Azithromycin 1 g PO in a single dose infection, other STDs) should be screened. This approach has been Amoxicillin 500 mg PO tid for 7 days shown to both reduce the prevalence of chlamydial infection and decrease the risk of complications such as pelvic inflammatory disease Alternative Regimens and perinatal transmission.86 Erythromycin base 500 mg PO qid for 7 days Erythromycin base 250 mg PO qid for 14 days Erythromycin ethylsuccinate 800 mg PO qid for 7 days Erythromycin ethylsuccinate 400 mg PO qid for 14 days Human Papillomavirus From Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2006. MMWR Infection Recommendations and Reports 55(RR-11):1-94, 2006. Human papilloma virus (HPV) is a double-stranded DNA virus that The CDC recommendations for treatment of chlamydial infection is a member of the papovavirus family. More than 100 HPV types havein pregnant women are listed in Table 38-7. Doxycycline, ofloxacin, been identified; of these, 35 primarily infect the genital tract. HPV isand levofloxacin are recommended for nonpregnant women but are the most common sexually transmitted infection in the United States,contraindicated in pregnancy. In 2006, azithromycin, as a single 1-g with approximately 6.2 million new HPV infections occurring eachdose, was added to the list of recommended regimens for treatment of year.92chlamydial infection during pregnancy. Single-dose therapy with HPV infection may result in either clinically apparent, grosslyazithromycin definitely improves patient compliance.12 visible disease (e.g., genital warts) or subclinical disease. The majority Amoxicillin, 500 mg orally three times daily for 7 days, was initially of HPV infections are asymptomatic, unrecognized, or subclinical. Thedemonstrated to be effective for treatment of chlamydial infection common genital HPV types can be divided into two major categoriesduring pregnancy by Crombleholme and colleagues.87 Multiple studies based on their oncogenic potential. HPV types in the low oncogenichave since confirmed the efficacy and safety of amoxicillin, including risk group include types 6, 11, 42, 43, and 44. These types are associateda Cochrane Collaboration review of 11 randomized trials for the treat- with genital warts, condylomata, and some cases of low-grade squa-ment of chlamydia during pregnancy.88 mous intraepithelial lesions. The high oncogenic risk group includes Although erythromycin regimens were once the mainstay for treat- types 16, 18, 20, 31, 45, 54, 55, 56, 64, and 68. These high-risk typesment of chlamydial infection during pregnancy, the frequent gastro- are frequently detected in women with high-grade squamous intraepi-intestinal side effects associated with erythromycin, which lead to thelial neoplasia and invasive cancers. The majority of the clinicallynoncompliance, have relegated them to alternative status.12 In a recent apparent lesions are the classic genital warts (condyloma acumina-observational cohort, Rahangdale and coworkers89 reported that the tum). An estimated 1% of sexually active adults are diagnosed annuallytreatment efficacy for erythromycin was 64%, compared to 97% for with genital warts.azithromycin and 95% for amoxicillin. Erythromycin estolate is con-traindicated in pregnancy due to drug-related hepatotoxicity. Thelower dose, 14-day regimens for erythromycin can be used if gastro- Epidemiologyintestinal tolerance is an issue, especially for women who are allergic Sexual transmission is the primary route for transmission of HPV, andto amoxicillin and azithromycin. both urogenital and anorectal infections are seen.4 The highest-risk Unlike in nonpregnant women and men, repeat testing (preferably groups for HPV infection are sexually active adolescents and youngby NAATs) 3 weeks after completion of therapy is recommended for adults, with 75% of new HPV infections occurring among thoseall pregnant women to ensure cure, in light of the sequelae that can 15 to 24 years old. HPV is highly contagious, and transmission ratesoccur in the mother and newborn infant if chlamydial infection per- are high, with approximately 65% of sexual contacts becoming infected.sists. Sex partners should be referred for evaluation, testing, and treat- Although it is rare, perinatal transmission, especially of HPV types 6ment. The CDC suggests that, if concerns exist that sex partners will and 11, can occur.4not seek evaluation and treatment, consideration should be given for Risk factors for HPV infection include early onset of sexual activity,delivery of antibiotic therapy (either a prescription or medication) by multiple sexual partners, increased frequency of intercourse, exposurefemale patients to their sex partners. This approach decreases the rate to sex partner with genital warts, failure to use condoms, and cigaretteof persistent or recurrent chlamydia compared with standard partner smoking.4 In addition, Winer and colleagues93 observed that smoking,referral.12,90,91 oral contraceptive use, and report of a new male partner—in particu- lar, one the patient knew for less than 8 months before sex occurred or one who reports having other partners—were predictive of newPrevention HPV infection. Furthermore, pregnancy is associated with an increasedPrimary prevention of chlamydial infection requires decreasing the risk presence of HPV infection and genital warts, and immunosuppressiveof exposure to men infected with C. trachomatis. Although abstinence states (e.g., HIV infection with low CD4+ T-cell count) result inwould accomplish this, it is often not a practical approach. Mutual increased viral titers of HPV and more rapid progression of HPVmonogamous relationships and safe sexual behaviors (e.g., condom use) disease–associated cervical intraepithelial neoplasia (CIN).4are effective. A chlamydia vaccine may be developed in the future. Respiratory papillomatosis (laryngeal papilloma) is a rare disease Secondary prevention requires population-based screening for in the neonate that is caused by HPV-6 and HPV-11. Laryngeal papil-chlamydia and treatment of infected women and their sex partners. As lomas can be particularly troublesome, because they may produce
  • 11. CHAPTER 38 Maternal and Fetal Infections 749respiratory distress secondary to obstruction and because recurrenceafter treatment is common. Transplacental and intrapartum transmis- HSIL Cancersion of HPV can occur, as well as infection via contact during theneonatal period.4 Persistent high Because genital papillomavirus infection is so common and respi- risk HPV Atypiasratory papillomatosis is rare, the risk of intrapartum transmission is LSIL Containmentlow, perhaps on the order of 1 case of juvenile respiratory papilloma-tosis per 1000 children born to infected mothers. Watts and associates94 RRreported that, among 151 pregnant women evaluated for HPV by clini-cal, colposcopic, and PCR tests at less than 20, 34, and 36 weeks of Sustained Inoculation Latencygestation, 112 (74%) had evidence of HPV. HPV was identified in only remission3 (4%) of 80 infants born to women with HPV detected at 34 to 36weeks’ gestation, but it also was found in 5 (8%) of 63 infants born to RRwomen in whom HPV DNA was not detected. Tenti and coworkers95 EGW Containmentalso demonstrated that pregnant women with latent HPV infectionhave a low potential for transmitting the virus to the oropharyngealmucosa of their newborns. Although these authors reported that HPV FIGURE 38-4 Natural history of human papillomavirus infection. EGW, external genital warts; HPV, human papillomavirus infection;DNA was detected in 11 neonates born vaginally to HPV-positive HSIL, high-grade squamous intraepithelial lesion; LSIL, low-gradewomen (vertical transmission rate, 30%; CI, 15.9% to 47%), all infants intraepithelial lesion; RR, recurrences.tested negative by 5 weeks after birth and remained so throughoutthe 18-month follow-up period. These findings suggest that theinfants who were HPV-positive at birth were contaminated and not infection. HPV enters cells in the basal layer of the epithelium andinfected. matures as it passes through the parabasal, spinous, and granular layers Other recent studies have supported the finding that the risk of of the epithelium.93,99perinatal transmission of HPV is low.96,97 Of these, the most informa- Following acute HPV infection, several clinical scenarios can occurtive was the study by Smith and colleagues.96 They detected HPV type- (Fig. 38-4). Latent viral infection occurs when the HPV genome isspecific concordance in only 1 mother/infant pair among the 6 (3.7%) stabilized as a nonintegrated episome and remains in host cells withoutinfants born to 164 mothers with cervical HPV infection. In addition, causing clinical or morphologic changes in the squamous epitheliuma third of the HPV-positive newborns were born to mothers who tested of the genital tract. Latency can lead to sustained remission, which isnegative for HPV DNA during pregnancy. the case in the vast majority of HPV infections. Alternatively, active infection may occur, depending on the type of HPV present. Low-risk HPV types, especially 6 and 11, cause proliferation of squamousPathogenesis epithelial cells with resultant formation of genital warts. High-riskGenital HPV infections are transmitted primarily by sexual activity. oncogenic HPV types may become integrated into the host genome,Clinical lesions and subclinical infections occur in the urogenital and resulting in CIN. CIN may progress to precancerous lesions (CIN 2anorectal areas. As noted previously, the infectivity rate is high, with and 3) and, ultimately, to invasive cervical cancer. Alternatively,transmission occurring to sexual partners in approximately 65% of CIN may resolve spontaneously, especially CIN 1 and, to a lesser extent,cases. The average incubation period is 2 to 3 months. CIN 2. The HPV viral genome consists of three major regions; two protein-encoding regions (early and late gene regions) and a noncodingupstream regulatory region (URR). The URR controls transcription of Diagnosisboth the early and the late region, resulting in regulation of viral pro-teins and production of infectious particles. The early region contains Genital Wartsopen reading frames (ORFs), which are transcriptional units that The diagnosis of genital warts is usually made by visual inspection.encode for a series of proteins designated E1, E2, E4, E5, E6, and E7. Early Biopsy is required only in certain circumstances: (1) the diagnosis isregion gene expression controls replication, transcription, and cellular uncertain; (2) the lesions do not respond to standard therapy; (3) thetransformation of viral DNA. Most importantly, it also plays a role in disease worsens during therapy; (4) the patient is immunocompro-unregulated cellular proliferation. Whereas E6 and E7 encode proteins mised; or (5) the warts are pigmented, indurated, fixed, bleeding, orinvolved in viral replication, they are the oncogenic genes and also code ulcerated. Use of HPV nucleic acid tests is not recommended in theproteins critical for host cell immortalization and transformation. The routine diagnosis and management of visible genital warts.12late gene region contains two ORFs (L1 and L2), which encode struc-tural proteins responsible for production of the viral capsid. The L1 Asymptomatic Human Papillomavirus Infectionprotein is the key component of the recently introduced HPV vaccine Because HPV cannot be cultured, detection of asymptomatic infectionand is highly immunogenic.98 requires identification of viral nucleic acid (DNA or RNA) or capsid Acute HPV infection occurs when microtrauma secondary to protein.12,100 Only the Digene Hybrid Capture 2 (HC 2) High-Risksexual intercourse allows virus to enter the skin or mucosa of the HPV DNA Test (Qiagen Digene, Gaithersburg, MD) is approved by thegenital tract. The postpubertal adolescent cervix is characterized by a U.S. FDA for clinical use. This test uses liquid nucleic acid hybridiza-large transformation zone which is more susceptible to minor trauma tion to detect 13 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52,during sexual intercourse and whose immature columnar epithelial 56, 58, 59, and 68). Type-specific results are not reported; rather, thecells are particularly susceptible to HPV. This may explain why young, specimen is identified as positive or negative for high-risk HPV. Insexually active adolescents are at the greatest risk for acquiring HPV particular, the HC2 High-Risk HPV test is approved for triage of
  • 12. 750 CHAPTER 38 Maternal and Fetal Infectionswomen with Papanicolaou (Pap) test results showing atypical squa- TABLE 38-8 CLASSIFICATION OF URINARYmous cells of undetermined significance (ASC-US) and, in combina- TRACT INFECTIONStion with the Pap test, for cervical cancer screening in women olderthan 30 years of age. Asymptomatic bacteriuria (ASB) Acute uncomplicated cystitis Less sensitive methods for detection of suspected HPV infection Recurrent cystitisinclude cytologic evidence of HPV (koilocytosis), colposcopy, biopsy, Acute uncomplicated pyelonephritisand acetic acid application. Although they are not available for clinical Complicated urinary tract infectionuse, PCR assays targeting genetically conserved regions of the L1 gene Multiple frequent recurrencesand HPV serologic assays to detect antibodies to the L1 viral protein High probability of drug-resistant uropathogenhave been used in research and epidemiologic studies. Increased risk for sepsis syndromeTreatmentOptions for treatment of genital warts during pregnancy are limited. with an associated direct cost of $1.6 billion.103 In women, UTIs areThe safety of podophyllin resin, podofilox, or imiquimod in pregnancy divided into five major categories104,105 (Table 38-8).has not been established. Trichloracetic acid (TCA) or bichloracetic Women are 14 times more likely to develop UTIs than men. Pre-acid (BCA), 80% to 90% solution, may be used on a weekly basis. sumably, this female predominance is the result of several factors,Alternatively, the lesions may be excised by scissors, scalpel, curettage, including (1) a shorter urethra in women; (2) continuous contamina-or electrosurgery. Cryosurgery can be used to treat vaginal lesions.12 tion of the external one third of the urethra by pathogenic bacteriaTreatment should be limited to patients who have multiple, confluent from the vagina and rectum; (3) failure of females to empty their blad-lesions. ders as completely as males; and (4) movement of bacteria into the As noted by the CDC, it is unclear whether cesarean delivery pre- female bladder during sexual intercourse.4vents juvenile-onset recurrent respiratory papillomatosis.12,101 There- UTI is the most common medical complication of pregnancy. UTIsfore, cesarean delivery should not be performed solely to prevent occur in up to 20% of pregnancies and account for 10% of antepartumtransmission of HPV infection to the newborn. Cesarean delivery hospitalizations.4,106 Among pregnant women, almost all UTIs fall intoshould be considered if obstruction of the pelvic outlet is likely or if three categories: (1) ASB; (2) acute cystitis; and (3) acute pyelonephri-vaginal delivery would result in excessive bleeding because of multiple tis. Of critical importance is the recognition that the normal physio-confluent lesions. logic changes associated with pregnancy (e.g., progesterone effect on ureteral smooth muscle peristalsis, obstruction of the ureters by the enlarging uterus) predispose pregnant women with ASB to the devel-Prevention opment of acute pyelonephritis. Moreover, UTIs in pregnancy placeTransmission of HPV occurs through contact with infected genital the fetus and mother at risk for substantial morbidity and evenskin, mucous membranes, or body fluids from a sexual partner with mortality.4,104clinical or subclinical HPV infection. As with other STDs, preventingthe spread of HPV to a susceptible population is more cost-effectivethan secondary prevention. Prevention of HPV transmission incorpo- Asymptomatic Bacteriuriarates the following approaches: (1) abstinence (most effective, but maynot be practical); (2) long-term mutual monogamy with a single Epidemiologypartner; (3) limiting the number of sexual partners; (4) limiting sexual Obstetricians have long recognized the serious nature of symptomaticcontacts to men who have been abstinent for a longer period of time; UTIs in pregnancy. However, it was not until the early 1960s that Kass(5) having a circumcised partner; (6) using latex condoms; and (7) demonstrated that significant bacteriuria can occur in the absence ofreceiving the HPV vaccine. symptoms or signs of UTI.107 He established quantitative bacteriology The most exciting new development for prevention of HPV infec- as the indispensable laboratory aid for the diagnosis, follow-up, andtion is the introduction into clinical practice of prophylactic HPV confirmation of cure of UTI. From these studies evolved the com-vaccines. The first such vaccine to become available was the quadriva- monly accepted definition of ASB: the presence of 105 or more colonieslent HPV vaccine, Gardisil (Merck & Co., Whitehouse Station, NJ), of a bacterial organism per milliliter of urine on two consecutive clean,which protects against HPV types 6, 11, 16, and 18.100,102 midstream-voided specimens in the absence of signs or symptoms of Neither routine surveillance for HPV infection nor partner notifi- UTI. Persistent ASB was identified in 6% of pregnant patients. Acutecation is deemed useful for HPV prevention. The rationale for this pyelonephritis developed in 40% of the patients with ASB who receivedconclusion is that HPV is so prevalent that most partners are already placebo, but pyelonephritis rarely occurred when bacteriuria was elim-infected. In addition, no prevention or treatment strategies are recom- inated. Kass also noted that rates of neonatal death and prematuritymended for partners. Similarly, no treatment strategies or prevention were two to three times greater in bacteriuric women receiving placebostrategies are recommended for prevention of perinatal transmission than in nonbacteriuric women or bacteriuric women whose infectionof HPV. Therefore, cesarean delivery for prevention of HPV infection was eliminated by antibiotics. He concluded that detection of materialin newborns is not indicated. bacteriuria would identify patients at risk for pyelonephritis and premature delivery and maintained that pyelonephritis in pregnancy could be prevented by detection and treatment of bacteriuria in earlyUrinary Tract Infection pregnancy. Moreover, Kass estimated that 10% of premature births could be prevented by such a program.107Urinary tract infections (UTIs) are a major public health problem in Most cases of ASB in pregnancy are detected at the initial prenatalthe United States, affecting approximately 11 million women annually, visit, and relatively few pregnant women acquire bacteriuria after the
  • 13. CHAPTER 38 Maternal and Fetal Infections 751initial visit. Thus, the bacteriuria antedates the pregnancy. The preva- in the rate of low-birth-weight infants (from 15% to 10%) in womenlence of ASB in pregnant women ranges from 2% to 11%, with the whose bacteriuria was treated. Therefore, it appears that maternal ASBmajority of investigations reporting 4% to 7%. An increased preva- is a risk factor for preterm delivery and low birth weight and that thislence of bacteriuria in females has been associated with lower socio- risk can be reduced by screening and treatment of ASB in pregnanteconomic status, diminished availability of medical care, and increased women.119 With recognition that ASB increases the risk for developingparity. Recently, Thurman and coworkers determined that sickle cell acute pyelonephritis and preterm delivery and low birth weight, thetrait carriers are not more susceptible than other pregnant women to ACOG and the U.S. Preventive Services Task Force recommend screen-ASB.108 ing to detect ASB in pregnancy.120,121 Untreated ASB during pregnancy often leads to acute pyelonephri- Symptomatic UTI is more often found in pregnant women than intis. Women with ASB in early pregnancy are at a 20- to 30-fold increased nonpregnant women. This observation suggests that some factorsrisk of developing acute pyelonephritis during pregnancy, compared present during gestation allow bacteria to replicate in the urine andto pregnant women without bacteriuria.109 Studies performed in the ascend to the upper urinary tract. Several findings support this view.41960s, using sulfonamides or nitrofurantoin, demonstrated that anti- The normal female urinary tract undergoes dramatic physiologic andmicrobial treatment of ASB during pregnancy significantly reduced the anatomic changes during pregnancy. Briefly, a decrease in ureteralrisk of developing pyelonephritis, from about 20% to 35% to between muscle tone and activity results in a lower rate of passage of urine1% and 4%. Before the advent of universal screening for ASB in early throughout the urinary collecting system. The upper ureters and renalpregnancy, the reported rate of acute pyelonephritis in pregnancy was pelves become dilated, resulting in a physiologic hydronephrosis of3% to 4%; afterward, it was 1% to 2%.110,111 Similarly, studies in Europe pregnancy. These changes are caused by the effects of progesterone onassessing the implementation of screening and treatment programs for muscle tone and peristalsis and, more important, by mechanicalASB in pregnant women demonstrated a significant reduction in the obstruction of the enlarging uterus. Changes in the bladder also occurrate of acute pyelonephritis in pregnancy.112,113 For this reason, it is in pregnancy, including decreased tone, increased capacity, and incom-important that the presence of bacteriuria be identified. Other claims, plete emptying, all of which predispose to vesicoureteric reflux. Hypo-such as that ASB predisposes the patient to anemia, preeclampsia, and tonia of the vesicle musculature, vesicoureteric reflux, and dilation ofchronic renal disease, are controversial and unproven. the ureters and renal pelves result in static columns of urine in the Kass107 initially reported an association between ASB and prematu- ureters, facilitating the ascending migration of bacteria to the upperrity and observed that eradication of bacteriuria with antimicrobial urinary tract after bladder infection is established. The hypokinetictherapy significantly reduced the rate of preterm delivery. He proposed collecting system reduces urine flow, and urinary stasis occurs, predis-that early detection and treatment of bacteriuria would prevent 10% posing to infection.to 20% of preterm births. Subsequently, numerous studies demon- Alterations in the physical and chemical properties of urine duringstrated conflicting results regarding bacteriuria and prematurity. pregnancy exacerbate bacteriuria, further predisposing to ascendingKincaid-Smith and Bullen114 suggested the hypothesis that underlying infection. Because of the increased excretion of bicarbonate, urinaryrenal disease is the major cause of the excessive risk of prematurity or pH rises, encouraging bacterial growth. Glycosuria, which is commonlow birth weight among bacteriuric pregnant women. The many dif- in pregnancy, favors an increase in the rate of bacterial multiplication.ferent definitions for prematurity used in the literature contributed to The increased urinary excretion of estrogens may also be a factor inthis confusion. the pathogenesis of symptomatic UTI during pregnancy. In animal More recent studies, including meta-analyses, demonstrated an experiments, estrogen enhances the growth of strains of Escherichiaassociation between ASB and low birth weight and preterm delivery.115-118 coli that cause pyelonephritis and predispose to renal leukocyte migra-Bacteriuria is only one of many factors that may influence the onset tion, phagocytosis, and complement activity. The cumulative effect ofof premature labor. Because both the incidence of bacteriuria in preg- these physiologic factors is an increased risk that infection in thenancy and the incidence of prematurity vary inversely with socioeco- bladder may ascend to the kidneys.nomic status, any relationship between bacteriuria and gestational Pathogenic characteristics of microorganisms such as E. coli arelength and birth weight may be complex and difficult to establish. In major determinants of UTI. These include pili (adherence), K antigenan attempt to resolve this controversy, Romero and colleagues115 used (antiphagocytic activity), hemolysin (cytotoxicity), and antimicrobialthe technique of meta-analysis to assess the relationship between ASB resistance. Host susceptibility factors include anatomic or functionaland preterm delivery and/or low birth weight. Meta-analysis confirmed abnormalities of the urinary tract and uroepithelial and vaginal epi-a statistically significant increased risk for low-birth-weight infants thelial cells with increased attachment of uropathogenic E. coli. Womenamong bacteriuric women. Their study also demonstrated a significant who do not secrete the ABO blood group antigens are particularlyassociation between bacteriuria and preterm delivery and showed a likely to harbor pathogenic E. coli in the urogenital epithelium.statistically significant reduction in the incidence of low birth weightamong bacteriuric women treated in eight placebo-controlled treat- Pathogenesisment trials. In general, the urinary tract is sterile, with the exception of the distal Meis and colleagues117 demonstrated in a multivariate analysis that urethra, which is often colonized with bacteria from the skin andbacteriuria significantly increased the occurrence of preterm birth vaginal and anal flora. Ascension of bacteria from the urethra into the(relative risk, 2.03; CI, 1.50 to 2.75). Schieve and colleagues,116 in an bladder results in ASB. Bacteria associated with ASB derive from theanalysis of 150,000 births in the University of Illinois Perinatal Network normal flora of the gastrointestinal tract, vagina, and periurethral area.database, reported that women with antepartum UTI were at increased In addition, instrumentation of the urinary tract (e.g., bladder cathe-risk for delivering preterm and low-birth-weight infants. With multi- terization) may introduce bacteria into the bladder of patients withoutvariate analysis, the odds ratios were 1.4 (CI, 1.2 to 1.6) and 1.3 (CI, prior colonization. In women with ASB, bacteria persist in the urinary1.1 to 1.4) for low-birth-weight and preterm birth, respectively. More- tract but do not elicit sufficient enough host response to result in eitherover, Smaill118 reported a meta-analysis of treatment versus placebo symptoms or eradication of the bacteria from the urinary tract. Factorstrials for ASB in pregnancy that demonstrated a one-third reduction such as host susceptibility, bacterial virulence, incomplete bladder
  • 14. 752 CHAPTER 38 Maternal and Fetal Infectionsemptying, obstruction, or presence of a foreign body (e.g., catheter) in order to minimize the cost and the toxic effects of these drugs inpredispose to persistence of bacteria.109 mother and fetus. Because most antibacterial agents are excreted by As noted in many studies, E. coli is overwhelmingly the most fre- glomerular filtration, therapeutic concentrations are readily achievedquent microorganism recovered in patients with ASB, including preg- in the urine. In fact, the concentration of these drugs in urine greatlynant women.4 Other gram-negative enterobacteria (e.g., Klebsiella, exceeds that required for the treatment of most UTIs. Even drugs thatProteus) and gram-positive bacteria such as Staphylococcus saprophyti- do not reach therapeutic concentrations in serum, such as nitrofuran-cus, GBS, and the enterococcus cause the remaining cases of ASB in toin, reach significant concentrations in urine.132young, sexually active women. No single agent is clearly better than another. At present, it is gener- A series of studies compared genetic markers or phenotypic expres- ally accepted that short courses of treatment are preferable, becausesion of potential bacterial virulence factors among E. coli strains iso- (1) the duration of initial therapy does not affect the recurrence rate,lated from various types of UTIs.109,122,123 One of those publications123 (2) a short course minimizes the adverse drug effects in mother andfocused on E. coli isolates from pregnant women. Among patients with fetus, (3) emergence of resistant bacteria is discouraged, (4) patientASB, E. coli strains demonstrated a lower frequency of genetic markers compliance is enhanced, and (5) costs are kept to a minimum.or phenotypic expression of virulence factors than did those recovered Although a 3-day course of antibiotic therapy is recommended forfrom patients with acute cystitis or acute pyelonephritis. the treatment of uncomplicated UTI in nonpregnant women, until Several studies have shown that the incidence of ASB in nonpreg- recently a 7-day course was preferred for pregnant women.105 However,nant women is comparable to the incidence in pregnant women in the a Cochrane Collaboration systematic review concluded that theresame locale.107-109 It appears that most women in whom bacteriuria is was insufficient evidence to recommend a duration of antimicrobialfirst discovered during pregnancy have acquired ASB earlier in life. therapy for pregnant women among the single-dose, 3-day, 4-day, andAlthough pregnancy per se does not cause any major increase in inci- 7-day treatment regimens.133 Most experts prefer the 7-day approach.dence of bacteriuria, it does predispose to the development of acute Treatment of ASB is empiric, and in vitro susceptibility testing is notpyelonephritis in bacteriuric patients. recommended for the initial positive culture.4 A wide variety of antimicrobial agents have been used successfullyDiagnosis for management of ASB in pregnancy (Table 38-9). These includeAlthough the diagnosis of ASB was originally based on obtaining two β-lactam antibiotics such as ampicillin and cephalosporins which doconsecutive midstream urine cultures containing at least 100,000 not pose any significant risk to the fetus. Other commonly usedcolony-forming units per milliliter (CFU/mL) of a uropathogen, a antibiotics include short-acting sulfonamides, nitrofurantoin, andsingle positive urine specimen is used for clinical diagosis.4,124 Urine trimethoprim-sulfamethoxazole.cultures are relatively expensive and require 24 to 48 hours for results.Therefore, inexpensive, rapid, office-based screening tests have under-gone clinical testing. These include microscopic urinalysis, nitrite and TABLE 38-9 ANTIMICROBIAL TREATMENT OFleukocyte esterase dipstick, Gram stain, Uricult dip slide, Cult-Dip ASYMPTOMATIC BACTERIURIAPlus, and Uristat test. However, although it is more costly than rapidtests, urine culture remains the screening test of choice for detecting AND ACUTE CYSTITIS DURINGASB in pregnancy.4,124-126 PREGNANCY Recent investigations have reconfirmed the lack of sensitivity and Antimicrobial Agent Regimenspecificity of alternate methodologies for the diagnosis of ASB, par-ticularly in pregnant women.127,128 As noted by McNair and col- Single-Dose Treatments**leagues,127 the potential serious sequelae of undiagnosed and untreated Ampicillin* 2gASB mandate that urine culture be used to detect ASB in pregnant Amoxicillin* 3gwomen. Both the U.S. Preventive Services Task Force and the Infectious Nitrofurantoin monohydrate 200 mg macrocrystals (Macrobid)Disease Society of America (IDSA) concur with this recommenda- Trimethoprim-sulfamethoxazole DS 320/1600 mgtion.109,121 Although there is consensus that all pregnant women shouldbe screened for ASB by urine culture at least once in early pregnancy, 3-Day or 7-Day Treatmentsno recommendation has been made for or against repeated screening Ampicillin* 250 mg qidof culture-negative women in later pregnancy. Our approach is not to Amoxicillin* 500 mg tidrescreen culture-negative, asymptomatic women later in pregnancy Cephalexin* 250-500 mg qidunless there is a history of recurrent UTIs. Nitrofurantoin monohydrate 100 mg bid macrocrystalsTreatment Sulfisoxazole Initial 2 g dose, then 1 g qidDetection and treatment of ASB give the obstetrician an opportunity Trimethoprim-sulfamethoxazole DS 160/800 mg bidto prevent significant medical complications of pregnancy. Screening Suppressive Therapyat the original antenatal visit, appropriate treatment, and eradication Nitrofurantoin monohydrate 100 mg qhs (duration ofof bacteriuria significantly reduce the frequency of antenatal acute macrocrystals pregnancy)pyelonephritis. Clinical trials demonstrate that treatment of ASB Trimethoprim-sulfamethoxazole DS 160/800 qhs (duration ofreduces the risk of acute pyelonephritis in pregnancy by 80% to 90%, pregnancy)to about 1% to 4%.129-131 In addition, screening and treatment of ASBsignificantly reduce the risks for preterm delivery and delivery of a *Only in geographic areas with low levels of resistance to Escherichia coli.low-birth-weight infant.115-118 **Should not be used in pregnancy because of unacceptably high rate Treatment should be designed to maintain sterile urine throughout of failure.pregnancy, using the shortest possible course of antimicrobial agents DS, double strength.
  • 15. CHAPTER 38 Maternal and Fetal Infections 753 The quinolones are not approved for use during pregnancy because antimicrobial therapy, compared with only 17% of patients with acuteof concerns regarding their teratogenic effect on fetal cartilage. cystitis.However, use of fluoroquinolones for resistant microorganisms is Acute cystitis tends to occur during the second trimester.139 This alsoappropriate. In such instances, ciprofloxacin 250 mg twice daily or differs from the pattern seen with ASB (in which almost all cases arelevofloxacin 250 mg daily may be used. Use of ampicillin or amoxicillin diagnosed in the first trimester) or with acute pyelonephritis (diag-has been questioned for treatment of UTIs, because the predominant nosed in the first and third trimesters). In addition, acute cystitis doesetiologic organism is E. coli, and resistance rates of E. coli to ampicillin not increase the risk for preterm birth, low birth weight, or acute pyelo-in the United States are 30% or greater.105 Of additional concern is the nephritis.4,104,124 In fact, the only morbidity associated with acute cystitisdecreased susceptibility of E. coli to trimethoprim-sulfamethoxazole, in pregnancy is the discomfort that occurs with symptomatic UTI.which ranges from 5% to 15% depending on the geographicarea.105,134-136 Pathogenesis When short courses of therapy are prescribed for ASB during preg- As reported by Scholes and associates,140 the major risk factors for acutenancy, continuous surveillance for recurrent bacteriuria by repeat cystitis in young women are a history of prior acute cystitis and fre-urine cultures is essential. It is appropriate to treat recurrent ASB with quent or recent sexual activity. By 24 years of age, approximately 1 inantimicrobial agents on the basis of the microorganism’s sensitivities 3 women have experienced at least one episode of acute cystitis, andfor the remainder of the pregnancy and for at least 2 weeks after deliv- 30% to 40% have one or more recurrences.141 Nonsecretors of ABOery. Alternatively, a short course of therapy with urine culture screen- blood group antigens are at increased risk for recurrent cystitis.142ing at each prenatal visit may be instituted. Persistent ASB should As in ASB, the microorganisms associated with acute cystitis origi-necessitate continuous antimicrobial therapy for the duration of preg- nate from the flora of the gastrointestinal tract, vagina, and periure-nancy. A single daily dose of nitrofurantoin, 100 mg, preferably after thral area and ascend via the urethra to colonize and infect the bladder.the evening meal, is recommended. Alternatively, short-acting sulfon- The most common bacteria isolated from the urine of women withamide preparations such as trimethoprim-sulfamethoxazole may be acute cystitis is E. coli (80% to 85%), followed by S. saprophyticus, otherprescribed. gram-negative enterobacteria (e.g., Klebsiella pneumoniae, Proteus mirabilis), GBS, and the enterococcus.4PreventionBecause ASB antedates pregnancy and typically is not acquired during Diagnosispregnancy, there is no prevention strategy available. Recurrent ASB has In nonpregnant women, the diagnosis of acute uncomplicated cystitisbeen noted in up to 30% of pregnant women.137 Close monitoring with relies on symptoms of dysuria, urgency, and frequency plus evidencefrequent urine cultures after diagnosis and treatment of ASB in early of pyuria (microscopic or dipstick). In pregnancy, culture confirma-pregnancy can prevent recurrent or persistent ASB. Most importantly, tion is recommended.4 Once cystitis is suspected, either a catheterizeddiagnosis, treatment, and eradication of ASB in pregnant women sub- specimen or a clean-catch midstream specimen for urinalysis andstantially reduce the occurrence of acute pyelonephritis and reduce the culture should be obtained before treatment with antibiotics. However,incidence of preterm births. because of the symptomatology of acute cystitis and the danger of upward extension of the infection to the kidney, it is not advisable to await the results of culture. The constellation of symptoms and dem-Cystitis in Pregnancy onstration of white blood cells and bacteria on urinalysis should beAcute cystitis is a distinct syndrome characterized by urinary urgency, sufficient grounds for beginning therapy.frequency, dysuria, and suprapubic discomfort in the absence of sys- Urine dipstick testing has replaced microscopy because it is cheaper,temic symptoms such as high fever and costovertebral angle tender- faster, and more convenient. The presence of either nitrite or leukocyteness. Gross hematuria may be present; the urine culture is invariably esterase is considered a positive result, with a sensitivity of 75% and apositive for bacterial growth. The gold standard for diagnosing acute specificity of 82%.144 Whereas a positive result is highly predictive ofcystitis, in the past, has been a quantitative culture containing at least UTI, a negative dipstick test does not rule out an infection in acutely100,000 CFU/mL. Stamm and coworkers138 demonstrated that a urine symptomatic women.143 A clean midstream urine or catheter specimenculture positive for bacterial growth with more than 100 CFU/mL, in with greater than 102 bacteria per milliliter obtained from an acutelycombination with symptoms of dysuria and frequency, is sufficient to dysuric woman is diagnostic of acute cystitis.138confirm the diagnosis of cystitis, particularly if the urine sample wasobtained by catheterization. Treatment Pregnant women with acute cystitis should receive immediate therapyEpidemiology with an antibiotic agent. The organisms most commonly isolated inThe incidence of acute cystitis among pregnant women ranges from acute cystitis are E. coli, other gram-negative facultative organisms, S.0.3% to 1.3%.123 Harris and Gilstrap139 reported a recurrence rate saprophyticus, and GBS. The duration of therapy in cystitis should beof 1.3% for cystitis during pregnancy. Although increased diagnosis 3 to 7 days. Single-dose therapy is not recommended in pregnancy. Theand treatment of ASB reduced the incidence of pyelonephritis at antimicrobial agents used to treat cystitis in pregnancy are similar totheir institution, the incidence of acute cystitis remained constant. those for ASB and are summarized in Table 38-9. Relief of symptomsOn initial screening urine cultures, 64% of the patients who occurs in more than 90% of women within 72 hours after treatmentultimately developed cystitis had negative cultures; in contrast, only a initiation.144minority of those patients with ASB and acute pyelonephritis had In pregnant women with acute cystitis, a “test of cure” urine exami-negative cultures. The authors noted that the recurrence pattern in nation should be performed 1 to 2 weeks after completion of therapy.patients with acute cystitis was also different from that in patients with If it is positive, a different regimen than that used initially should beeither bacteriuria or acute pyelonephritis. Disease recurred in 75% of started. Continuous prophylaxis (at bedtime) is recommended forpatients with acute pyelonephritis who were not given suppressive women who have three or more symptomatic UTIs in a 12-month
  • 16. 754 CHAPTER 38 Maternal and Fetal Infectionsperiod. Either nitrofurantoin or trimethoprim-sulfamethoxazole is by the effects of progesterone on muscle tone and peristalsis in therecommended. Postcoital prophylaxis is an alternative option.4 ureters and the mechanical obstruction of the enlarging uterus, facili- tates ascent of bacteria into the upper urinary tract.4Prevention Alterations in the physical and chemical properties of urine duringBecause the risk for acute cystitis is not associated with the presence pregnancy also facilitate ascending infection. Bacterial growth isof ASB, screening for and treatment of ASB early in pregnancy does enhanced by the elevated urinary pH during pregnancy. Glycosuria isnot reduce the incidence of acute cystitis in pregnancy. Moreover, more frequent and also enhances bacterial growth. The increasedone of the major risk factors for acute cystitis, use of a diaphragm urinary excretion of estrogen also may play a role in the pathogenesisand spermicide for contraception, is not an issue during pregnancy. of acute antepartum pyelonephritis. Estrogen has been shown to accel-However, recurrent acute cystitis can be prevented with daily antibiotic erate the growth of strains of E. coli that cause pyelonephritis.4,146,147prophylaxis. Nitrofurantoin and trimethoprim-sulfamethoxazole are Pathogenic mechanisms also exist in the microorganisms associatedacceptable alternatives. with acute pyelonephritis. The requisite first step for establishing colonization or infection in the urinary tract is bacterial adherence to urogenital epithelium. E. coli attaches to uroepithelium via twoAcute Pyelonephritis adhesions: P fimbriae (pap encoded adhesions) and type 1 pili. TheAcute pyelonephritis is one of the most common medical complica- prevalence of E. coli strains expressing P fimbriae from patients withtions of pregnancy.4,144 Despite recommendations for routine screening acute pyelonephritis (75% to 100%) is significantly greater than amongof pregnant women and treatment of ASB, the incidence of acute fecal strains from persons without UTI. On the other hand, type 1 pilipyelonephritis in pregnancy ranges from 1% to 2.5%. In a recent large are almost universally expressed among uropathogenic and fecal com-prospective cohort at Parkland Hospital, the incidence of antepartum mensal E. coli strains.148acute pyelonephritis was 14 per 1000 deliveries.144 Recurrence during The most common bacteria associated with acute pyelonephritisthe same pregnancy is frequent, occurring in 10% to 18% of cases. In are E. coli, Klebsiella species, and Enterobacter species. Dunlow andaddition, acute pyelonephritis in pregnancy can cause significant Duff149 reported that, in a group of women with antepartum pyelone-maternal morbidity and, in rare instances, maternal and fetal phritis, E. coli (80%) was the dominant pathogen, with K. pneu-mortality.4,106,144 moniae (7.4%), Staphylococcus aureus (6.7%), and P. mirabilis (2%) isolated much less frequently. More recently, Hill and colleagues144Epidemiology observed that the predominant microorganisms recovered fromAs noted, the incidence of acute pyelonephritis in pregnancy ranges patients with acute antepartum pyelonephritis were E. coli (70%),from 1% to 2.5%. The incidence varies depending on several factors, Klebsiella-Enterobacter (3%), Proteus (2%), and gram-positive bacteria,including population characteristics, prevalence of ASB, whether including GBS (10%).routine screening with culture and treatment of ASB occurs, andwhether patients receive prenatal care, especially early first-trimester Diagnosisassessment. Acute pyelonephritis is characterized by fever, chills, flank pain, dysuria, The major risk factors for acute pyelonephritis are previous epi- urgency, and frequency. Nausea and vomiting may also be present. Onsodes of acute pyelonephritis and the presence of ASB.4 In the absence physical examination, fever and costovertebral angle tenderness areof routine screening and treatment of ASB, up to 40% of pregnant often present. Laboratory abnormalities include pyuria and bacteri-women with ASB will develop acute pyelonephritis. Therefore, screen- uria. White blood cell casts are highly predictive of acute pyelonephri-ing and treatment of ASB dramatically reduce the incidence of pyelo- tis. The diagnosis is ultimately confirmed by a positive urine culture.4nephritis. With universal screening, the reported incidence is 1% to As noted by Sheffield and Cunningham,104 the clinical findings of2%,110,111,145 Among pregnant women not receiving suppressive antimi- acute pyelonephritis in pregnancy are similar to those described incrobial therapy to prevent acute pyelonephritis for the duration of nonpregnant women. Onset of symptoms is usually abrupt. Fever ispregnancy, recurrence has been noted in up to 60%; with suppressive universal, and the diagnosis is suspect if it is absent. In 50% of casestherapy, the recurrence rate is less than 10%.4,145 Other predisposing occurring during pregnancy, pyelonephritis is unilateral and on thefactors for acute pyelonephritis during pregnancy include obstructive right side. Unilateral left side and bilateral infections are each presentand neurologic diseases affecting the urinary tract and the presence of in 25% of cases. Most likely, right urethral obstruction secondary toureteral or renal calculi. uterine dextrorotation explains the right-sided predominance seen in Recently, Hill and coworkers144 examined the incidence of risk pregnancy.factors among women with acute antepartum pyelonephritis. Overall, Although 10% to 20% of pregnant women with acute pyelonephri-13% had at least one maternal risk factor for antepartum pyelonephri- tis are bacteremic, the usefulness of obtaining routine blood culturestis. As demonstrated in the older literature, the most common risk in suspected cases of acute uncomplicated pyelonephritis has beenfactor was a previous history of pyelonephritis and ASB. Other factors questioned.150,151 The rationale for this new approach includes the factsinclude young maternal age and nulliparity. that blood cultures are expensive, the bacterium isolated is invariably the organism recovered from the urine culture, and change of antibio-Pathogenesis tics usually is based on lack of clinical response rather than cultureAlthough ASB is no more frequent in pregnant than in nonpregnant results.women, acute pyelonephritis is a much more frequent sequela during Pyelonephritis is not only a serious risk for preterm labor andpregnancy. Several factors during pregnancy facilitate bacterial replica- delivery but also a serious threat to maternal well-being. Up to 20%tion in urine and ascent to the upper urinary tract. In the bladder, of pregnant women with acute pyelonephritis develop evidence ofthere is decreased tone, increased capacity, and incomplete emptying; multiorgan system involvement secondary to endotoxemia and theas a consequence, there is a predisposition for vesicoureteric reflux to sepsis syndrome.4,152,153 The primary pathogenic mechanism resultsoccur. Moreover, the physiologic hydronephrosis of pregnancy, caused from endothelial activation followed by capillary fluid leakage and
  • 17. CHAPTER 38 Maternal and Fetal Infections 755extravasation, with resultant decreased perfusion of vital organs. This 4. Duration of adequate urinary and renal tissue levelsvascular derangement worsens the hypovolemia that is often present 5. Effect of antimicrobial agent on the fecal and vaginal floraas a result of fever and vomiting, leading to hypotension. 6. Adverse side effects Multiple sepsis-related complications have been reported in preg- 7. Costnant women with acute pyelonephritis. Anemia, caused by hemolysis 8. Public health concerns regarding development of resistanceinitiated by endotoxemia, occurs in 23% to 66% of these patients.Rarely, evidence of disseminated intravascular coagulation (DIC) may Limited information has been published to assist in determiningbe present. With severe sepsis, DIC is common and is associated with optimal antimicrobial regimens and duration of therapy forpotentially serious complications (e.g., purpura fulminans).4,152,153 treatment of acute uncomplicated pyelonephritis in pregnant women. Before the recognition that aggressive fluid resuscitation is a critical Moreover, the management of acute pyelonephritis has become morecomponent of the management of acute pyelonephritis in pregnancy, complex with the trend for increasing resistance of uropathogens,approximately 20% of pregnant women with acute pyelonephritis had especially resistance to β-lactam antibiotics (e.g., ampicillin) andtransient renal dysfunction, as documented by decreased creatinine trimethoprim-sulfamethoxazole.136,156clearance.154 More recently, with aggressive fluid resuscitation, the rate For purposes of treatment, patients with acute uncomplicatedof renal dysfunction is 7%.144 Although renal dysfunction may be pyelonephritis may be stratified into two groups: those with severetransient, it is important to recognize its presence so that nephrotoxic disease, who require hospitalization and parenteral antibiotics, andantimicrobial agents (e.g., aminoglycosides) can be withheld, used those with mild to moderate disease, who can be treated on an outpa-with caution, or not used at all. In addition, antibiotics that are excreted tient basis with oral agents. As described in the IDSA guidelines, mildby the kidney should be administered in reduced dosages. disease is characterized by low-grade fever, normal or slightly elevated Cunningham and coworkers153 initially reported that acute pyelo- white blood cell count, and absence of nausea and vomiting.136 Patientsnephritis of pregnancy may be complicated by adult respiratory requiring hospitalization are those with high fevers, high white blooddistress syndrome (ARDS). Acute respiratory insufficiency, the most cell counts, vomiting, dehydration, evidence of sepsis, or no responsecommon serious complication of severe sepsis, develops in 2% to 8% during an initial period of observation.of pregnant women with acute pyelonephritis.4,155 Hill and associates144 The management of acute pyelonephritis in pregnant womenreported that 7% of pregnant women with acute pyelonephritis devel- follows many of the same principles used for nonpregnant women,oped respiratory insufficiency. The pathophysiology involves cytokine with several important differences. In general, fluoroquinolones shouldinflammatory injury to vascular endothelium, which leads to increased be avoided in pregnancy, unless no alternative antimicrobial agent isalveolar membrane permeability. ARDS should be suspected in patients available. Second, although earlier studies suggested that outpatientwho present with dyspnea, tachypnea, hypoxemia, or a chest radio- oral therapy is an acceptable alternative for mild to moderate pyelone-graph suggestive of pulmonary edema or ARDS. phritis,151,159,160 most experts currently recommend that pregnant Towers and colleagues155 identified several risk factors for ARDS in women with acute pyelonephritis be initially assessed during a 12- topatients with antepartum pyelonephritis: elevated maternal heart rate 24-hour hospital stay before a decision is made about outpatient man-(>110 beats/min); use of a tocolytic agent; use of ampicillin as the sole agement. Finally, because of the potential for renal dysfunction andantibiotic; temperature 103° F or higher within the first 24 hours; and respiratory insufficiency in pregnant women with acute pyelonephritis,fluid overload. More recently, in a study of 440 cases of acute antepar- careful monitoring of renal function, urinary output, and respiratorytum pyelonephritis, Hill and coworkers144 reported that women with status, including pulse oximetry, is necessary.respiratory insufficiency received more intravenous fluids during the Management of acute pyelonephritis in pregnancy is outlined infirst 48 hours and had higher maximum temperatures, higher heart Table 38-10. Because of the frequency of dehydration, respiratoryrates, lower hematocrits, and higher rates of septicemia. Moreover,tachypnea was present only in patients with respiratory insufficiency.Fortunately, most cases with pulmonary capillary injury respondto oxygen supplementation and diuresis. However, intubation and TABLE 38-10 MANAGEMENT OF ACUTEmechanical ventilation are required in severe cases. The cytokine PYELONEPHRITIS IN PREGNANTinflammatory response may also lead to uterine contractions.124 WOMEN In-hospital observation with assessment for 12-24 hrTreatment Urinalysis and urine cultureThe management of acute uncomplicated pyelonephritis in pregnant Complete blood count, serum creatinine, electrolyteswomen has changed dramatically since the 1990s. Traditionally, patients Frequent monitoring of vital signs (especially for onset ofwith acute uncomplicated pyelonephritis were hospitalized and treated tachypnea)with parenteral antimicrobial therapy, but more recent studies have Monitoring of urine output (consider Foley catheter)demonstrated that, for women with mild to moderate disease, oral Intravenous crystalloid fluid resuscitation to maintain urinetherapy on an outpatient basis is appropriate. In addition, the duration output at ≥30-50 mL/hrof therapy has been reduced from 6 weeks to 2 weeks.156-158 Chest radiograph and arterial blood gas analysis in patients with Hooton156 outlined factors that should be considered when dyspnea or tachypneaselecting agents for empiric treatment of uncomplicated acute Intravenous antimicrobial therapy Patients who respond to initial parenteral antimicrobial and fluidpyelonephritis: resuscitation may be discharged after 12-24 hr of observation with oral antimicrobial agent to complete 14 days of therapy 1. Antimicrobial spectrum of the agent Patients with high fever, signs of respiratory insufficiency, poor 2. Pharmacokinetics allowing for infrequent dosing intervals urine output, evidence of sepsis, or inability to tolerate oral 3. Prevalence of resistance among uropathogens in the geographic medication require hospitalization area
  • 18. 756 CHAPTER 38 Maternal and Fetal Infectionsinsufficiency, and renal dysfunction associated with acute pyelonephri- respond, investigation for urinary obstruction or complicationstis in pregnancy, aggressive fluid resuscitation with crystalloid solu- of renal infection (e.g., perinephric abscess) should be undertaken.tions such as lactated Ringer solution or normal saline is critical. Fluid Once hospitalized patients are afebrile and asymptomatic for 24 toresuscitation must be balanced with the risk of pulmonary edema, so 48 hours, they may be discharged to complete a 14-day course ofclose monitoring of respiratory status with pulse oximetry is impera- therapy.tive. Blood cultures should be obtained from patients who have Administration of aminoglycosides requires particular caution.evidence of sepsis or septic shock or who fail to respond to initial Although they are rare with the dosage and duration of aminoglyco-therapy. sides used in the treatment of acute uncomplicated pyelonephritis, Vital signs, including respiratory rate, and urine output should be both maternal and fetal nephrotoxicity and ototoxicity have beenclosely monitored. Tachypnea, hypotension, and oliguria are signs of reported, especially with prolonged use. The more frequent occurrenceimpending sepsis or septic shock. In gestations beyond 24 weeks, of renal dysfunction in pregnant women with acute pyelonephritisuterine activity and fetal heart rate should be monitored closely. If should raise additional concerns regarding the use of aminoglycosides4uterine contractions persist despite rehydration, tocolytic therapy Therefore, unless the causative microorganism is resistant to othershould be considered, with due consideration to the synergistic cardio- antimicrobials or the patient is allergic to other agents, aminoglycosidevascular effects of tocolytics and sepsis. Use of a cooling blanket or use is best avoided. A possible exception is the pregnant womanacetaminophen or both reduces cardiovascular stress. This is impor- with severe septic shock, for whom an aminoglycoside should betant in early pregnancy, secondary to possible teratogenic effects of used to provide coverage against more resistant gram-negative entero-hyperthermia.104 Similarly, if preterm labor is a concern, untreated bacteria such as Pseudomonas aeruginosa, Enterobacter species., orhyperthermia increases the metabolic needs of the fetus. Citrobacter species. In pregnant women receiving an aminoglycoside, A number of antimicrobial regimens may be used to treat acute serum levels should be monitored to ensure adequate serum concen-pyelonephritis in pregnancy (Table 38-11). Given the high incidence trations and prevent toxicity. Either multidose gentamicin (3-5 mg/kg/of resistance by E. coli to ampicillin and first-generation cephalospo- 24 hours in 3 divided doses) or single-dose gentamicin daily regimenrins (cephalexin, cefazolin), these agents are not recommended.4 is appropriate.Ceftriaxone, 1 to 2 g IV as a single daily dose, is effective and, givenits extended spectrum, provides excellent coverage against the major Preventionuropathogens (except Enterococcus). After discharge, ceftriaxone can be Both secondary and tertiary prevention strategies are critical to preventcontinued as a single daily dose of 1 to 2 g as home parenteral therapy. acute pyelonephritis during pregnancy. As previously noted, the majorAlternatively, an oral cephalosporin or trimethoprim-sulfamethoxazole factors associated with development of acute pyelonephritis in preg-can be given, depending on the results of susceptibility studies. Some nancy are the presence of ASB which antedates the pregnancy and theauthors favor an initial combination of ampicillin plus gentamicin.104 physiologic changes of pregnancy that predispose to ascent of bacteriaPatients should respond within 48 hours. For patients who do not to the upper urinary tract. There are no known methods of primary prevention for acute pyelonephritis. However, screening for, and eradication of, bacteriuria early in pregnancy substantially reduces the incidence of acute TABLE 38-11 ANTIMICROBIAL TREATMENT OF pyelonephritis. Daily nighttime suppressive therapy after treatment ACUTE PYELONEPHRITIS IN of acute pyelonephritis significantly reduces the risk for recurrent PREGNANT WOMEN acute pyelonephritis during pregnancy or immediately after delivery. Agent Dosage After completion of therapy for acute pyelonephritis during preg- Outpatient Regimens (14 days) nancy, 30% to 40% of women have recurrent bacteriuria. If this is left Amoxicillin 500 mg tid untreated, approximately 25% develop recurrent pyelonephritis. Harris Amoxicillin-clavulanate 875/125 mg bid and Gilstrap139 reported that, among patients not receiving suppressive Trimethoprim-sulfamethoxazole DS 160/800 mg bid antimicrobial regimens for the duration of pregnancy, 60% had a recurrent episode of acute pyelonephritis. In the group maintained on Parenteral Regimens suppressive therapy, the recurrence rate was only 2.7%. Other studies Ceftriaxone 1-2 g q24h have reported a similar high rate of recurrence in pregnant women Cefepime 2 g q8h after an episode of acute pyelonephritis if they did not receive suppres- Cefotetan 2 g q12h sive therapy.161 Cefotaxime 1-2 g q8h Trimethoprim-sulfamethoxazole 2 mg/kg q6h The recommended drug for suppression after treatment of acute Ampicillin 2 g q6h pyelonephritis in pregnancy is nitrofurantoin, 100 mg at bedtime PLUS Gentamicin 3-5 mg/kg/day (qd or in 3 for the duration of the pregnancy. Alternatively, trimethoprim- divided doses) sulfamethoxazole 160/800 mg daily at bedtime may be given, recogniz- Cefazolin 1-2 g q8h ing that the sulfa moiety in the sulfamethoxazole confers a small risk PLUS Gentamicin 3-5 mg/kg/day in 3 divided of kernicterus in the newborn if given in the third trimester. An accept- doses or 7 mg/kg of ideal able alternative to daily suppressive therapy is to obtain urine cultures body weight q24h every 2 weeks for the duration of pregnancy in order to detect and OR Aztreonam 1-2 g q8 to 12h (in lieu of promptly treat recurrent bacteriuria.162 Although recurrent or persis- gentamicin) tent bacteriuria was found to be more common with this latter Ampicillin-sulbactam 1.5 g q6h Piperacillin-tazobactam 3.75 g q6-8h approach, the rates of acute pyelonephritis were similar in the urine culture group and the suppressive therapy group. Daily suppressive DS, double strength. therapy is more cost-effective than frequent reculturing.
  • 19. CHAPTER 38 Maternal and Fetal Infections 757 (25%), G. vaginalis (24%), GBS (12%), other aerobic streptococci (13%), E. coli (10%), and other aerobic gram-negative rods (10%).170Chorioamnionitis A role for genital mycoplasmas has been suggested by case reports of their isolation from amniotic fluid of clinically infected patients andBacterial infection of the amniotic cavity is a major cause of perinatal by a controlled study reporting that 35% of fluid specimens frommortality and maternal morbidity. Indeed, in the last few years, signifi- patients with chorioamnionitis yielded M. hominis, whereas only 8%cant associations between clinical intra-amniotic infection and long- of matched control fluids had this organism (P < .001).171term neurologic development in the newborn, including cerebral palsy, Present evidence suggests a small role, if any, for C. trachomatis inhave been reported (see Chapter 58). amniotic fluid infections. This organism rarely is isolated in cases of A number of terms for this infection have been used, including clinical chorioamnionitis, and no significant antibody changes to C.“clinical chorioamnionitis,” “amnionitis,” “intrapartum infection,” trachomatis have been noted in sera of women with this infection.“amniotic fluid infection,” and “intra-amniotic infection.” The term Pregnant women with cervical C. trachomatis infections do not haveclinical chorioamnionitis is invoked to distinguish the clinical syndrome higher rates of intrapartum fever.72,172of fever and uterine tenderness from ASB colonization, subclinicalinfection of the amniotic cavity, or histologic inflammation of theplacenta and fetal membranes in the absence of maternal symptoms. Diagnosis Clinical chorioamnionitis occurs in 0.5% to 10% of pregnancies.163 The clinical diagnosis of chorioamnionitis requires a high index ofHistologic chorioamnionitis occurs more frequently than does clini- suspicion. Usual laboratory indicators of infection, such as positivecally evident infection, being present in up to 20% of term deliveries stains for organisms or leukocytes and positive cultures, are foundand more than half of preterm deliveries. much more frequently than is clinically evident infection. Diagnosis typically is based on the signs of maternal fever, maternal or fetal tachycardia, uterine tenderness, foul odor of the amniotic fluid, andPathogenesis leukocytosis. Bacteremia occurs in approximately 10% of the cases.With the onset of labor or with rupture of the membranes, bacteria Because peripheral blood leukocytosis occurs commonly in normalfrom the lower genital tract are able to ascend into the amniotic cavity. labor, a high white blood cell count (>15,000/mL) supports, but is notThis is the most common pathway for development of clinical chorio- diagnostic of, infection.amnionitis. Occasional cases occurring in the absence of membrane Direct examination of the amniotic fluid, via amniocentesis orrupture or labor support a less frequent hematogenous or transplacen- aspiration through an intrauterine pressure catheter, may providetal route of infection. For example, fulminating clinical chorioamnio- important diagnostic information. Positive amniotic fluid Gram stainsnitis with intact membranes may be caused by Listeria monocytogenes. for bacteria or leukocytes occur significantly more often in womenLess commonly, the infection may develop as a consequence of obstet- with clinical chorioamnionitis than in matched controls.170 In patientsric procedures, such as cervical cerclage, amniocentesis, or percutane- with suspected amnionitis, low amniotic fluid glucose levels are a goodous umbilical blood sampling. The absolute risk of chorioamnionitis predictor of a positive amniotic fluid culture but a poorer predictor ofis low with all of these procedures, occurring in 2% to 8% of patients clinical chorioamnionitis. If the amniotic fluid glucose concentrationafter cerclage, in fewer than 1% after amniocentesis, and in up to 5% is greater than 20 mg/dL, the likelihood of a positive culture is less thanafter intrauterine transfusion. Bacteria also may reach the amniotic 2%. If the glucose level is less than 5 mg/dL, the likelihood of a positivecavity from extragenital sources such as the urinary tract or periodon- culture rises to approximately 90%.173,174 Although the test is not readilytal tissue. available to the clinician, an elevated concentration of interleukin 6 (IL-6) in the amniotic fluid is the most sensitive and specific marker for predicting a positive amniotic fluid culture.174EpidemiologyClinical chorioamnionitis is a leading risk factor for neonatal sepsis.Yancey and coworkers164 found this infection to have by far the highest Managementodds ratio (OR, 25) for suspected or proven neonatal sepsis, compared If acute chorioamnionitis is strongly suspected, most experts agree thatwith other obstetric risk factors such as preterm delivery, rupture of prompt institution of intravenous antibiotics and delivery of the fetusmembranes more than 12 hours, postpartum endometritis, or mater- are required. However, specific points of management details remainnal carriage of GBS. unresolved. Risk factors for clinical chorioamnionitis are largely obstetric con- Regarding the timing of delivery, excellent maternal-neonatalditions in patients experiencing protracted labor. They include outcome has been reported without the use of arbitrary time limits. Gibbs and colleagues170 reported on a policy in which cesarean delivery Low parity was performed only for standard obstetric indications and not for the Prolonged labor presence of clinical chorioamnionitis alone. The mean time from diag- Prolonged rupture of membranes nosis to delivery was between 3 and 5 hours, and more than 90% Multiple vaginal examinations in labor of patients were delivered within 12 hours after diagnosis. Those Internal fetal monitoring who were delivered vaginally had lower rates of morbidity. No critical Maternal BV165-169 interval from diagnosis of chorioamnionitis to delivery could be Microbiology identified. Three studies demonstrated a significant advantage for intrapar- As with other pelvic infections, clinical chorioamnionitis is usually tum rather than immediate postpartum antibiotic treatment (Tablepolymicrobial in origin. The most common organisms found in the 38-12). In a nonrandomized trial, Sperling and coworkers175 reportedamniotic fluid of women with chorioamnionitis are Bacteroides species a lower incidence of neonatal sepsis when antibiotic treatment was
  • 20. 758 CHAPTER 38 Maternal and Fetal Infections TABLE 38-12 RATES OF NEONATAL SEPSIS TABLE 38-13 META-ANALYSIS OF AFTER INTRAPARTUM VERSUS CHORIOAMNIONITIS AS A RISK NEONATAL ANTIBIOTIC FACTOR FOR CEREBRAL PALSY TREATMENT IN CASES OF AND CYSTIC PERIVENTRICULAR INTRA-AMNIOTIC INFECTION LEUKOMALACIA Rate of Neonatal Sepsis (%) Diagnosis N RR (95% CI) Intrapartum Neonatal Preterm Infants Study N Treatment Treatment P Cerebral Palsy Clinical chorioamnionitis 11 1.9 (1.4-2.5) Sperling et al, 1987 257 2.8 19.6 .001 Histologic chorioamnionitis 5 1.6 (0.9-2.7) Gibbs et al, 1988 45 0 21 .03 Cystic PVL Gilstrap et al, 1988 273 1.5 5.7 .06 Clinical chorioamnionitis 6 3.0 (2.2-4.0) Histologic chorioamnionitis 7 2.1 (1.5-2.9) Term Infantsbegun at the time of diagnosis, compared with treatment begun imme- Cerebral Palsydiately after delivery. Gilstrap and colleagues176 found an almost four- Clinical chorioamnionitis 2 4.7 (1.3-16.2)fold reduction in neonatal sepsis with use of intrapartum treatment Histologic chorioamnionitis 1 8.9 (1.9-40)(5.7% versus 1.5%, P = .06). In a randomized trial, Gibbs and CI, confidence interval; PVL, periventricular leukomalacia; RR, relativecolleagues177 used ampicillin (2 g intravenously every 6 hours) risk.plus gentamicin (1.5 mg/kg every 8 hours), initiating treatment either Data from Grether JK, Nelson KB: Maternal infection and cerebralintrapartum or immediately postpartum. In addition, clindamycin was palsy in infants of normal birth weight. JAMA 278:207, 1997; Wu YW,used after umbilical cord clamping if cesarean delivery was performed, Colford JM Jr: Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. JAMA 284:1417, 2000.because of the high failure rate of ampicillin and gentamicin alone inwomen delivered abdominally. Maternal outcome was improved, andconfirmed neonatal sepsis was decreased by intrapartum treatment.Other regimens employing an extended-spectrum penicillin (e.g., Preterm neonates born to mothers with clinical chorioamnionitisampicillin plus a β-lactamase inhibitor) or other agents with similar experience a higher frequency of complications than do those born toactivity may be equally effective, but no comparative trials have been mothers without this disorder. Garite and Freeman180 noted that theperformed. perinatal death rate was significantly higher in 47 preterm neonates The duration of postpartum antibiotic therapy needed for patients with chorioamnionitis than in 204 uninfected neonates with similarwith clinical chorioamnionitis was addressed in a randomized clinical birth weights (13% versus 3%, P < .05). The group with chorioamnio-trial by Edwards and Duff.178 They showed that one additional dose nitis also included a significantly higher number with respiratory dis-of a broad-spectrum combination of antibiotics (ampicillin plus tress syndrome (34% versus 16%, P < .01) and infection (17% versusgentamicin) was sufficient postpartum therapy for women with clini- 7%, P < .05).cal chorioamnionitis. As mentioned previously, it is imperative that a Patients with clinical chorioamnionitis are more likely to requiredrug with excellent anaerobic coverage (e.g., clindamycin, metronida- cesarean delivery, often for uterine dysfunction, inadequate uterinezole) be given intraoperatively to women undergoing cesarean response to oxytocin, or abnormal labor progress even when uterinedelivery. activity is adequate. And, when the combination of prematurity and chorioamnionitis occurs, the risk of serious sequelae in the neonate isShort-Term Outcome increased.Since 1979, reports from systematically collected data on the outcomeof mothers and neonates in pregnancies complicated by intra-amniotic Long-Term Outcomeinfection have shown a vastly improved perinatal outcome compared There is increasing evidence that intrauterine infection is associatedwith older studies. Maternal outcome is excellent, with no deaths, few with increased risks of respiratory distress syndrome, periventricularcases of septic shock, and rare pelvic abscesses. The cesarean delivery leukomalacia, and cerebral palsy. The unifying hypothesis for theserate is increased twofold to threefold in all studies, usually because of varying morbidities is that intra-amniotic infection leads to fetal infec-dystocia. Perinatal mortality is increased in cases of clinical chorioam- tion and to an overexuberant fetal production of cytokines, whichnionitis, but little of the excess mortality can be attributed to infection leads in turn to pulmonary and brain cell damage. The “fetal inflam-per se. Among term infants born after clinical chorioamnionitis, peri- matory response syndrome” has been likened to the systemic inflam-natal mortality is less than 1%. matory response syndrome in adults. Several studies have linked Yoder and colleagues179 published a case-control study of 67 patients maternal infection with cerebral palsy and with cystic necrosis of thewith microbiologically confirmed clinical chorioamnionitis at term. white matter in preterm and term infants. Intrauterine exposure toThere was only one perinatal death, which was unrelated to infection. maternal infection is associated with an increased risk of cerebral palsyCerebrospinal fluid cultures were negative in all 49 infants sampled, (OR, 9.3) in infants of normal birth weight.181 The results of a recentand there was no clinical evidence of meningitis. Chest radiographs meta-analysis are summarized in Table 38-13.were interpreted as “possible” pneumonia in 20% and as “unequivocal” Amniotic fluid concentrations of the inflammatory cytokines, IL-pneumonia in only 4%. Neonatal bacteremia was documented in 8%. 1β, IL-6, and tumor necrosis factor are higher in preterm infants withThere was no significant difference in the frequency of low Apgar periventricular leukomalacia than in those without such lesions.182 Inscores between the chorioamnionitis and control groups. addition, the presence of cerebral palsy at 3 years of age is more
  • 21. CHAPTER 38 Maternal and Fetal Infections 759common in infants delivered preterm with funisitis or elevated amni-otic fluid concentrations of IL-6 or IL-8.183 Among preterm infants,respiratory distress syndrome has been significantly associated with Episiotomy Infectionhigh levels of tumor necrosis factor in amniotic fluid, with positivecultures of amniotic fluid, and with severe histologic chorioamnionitis, Although episiotomy and vaginal laceration repair are commonly per-even after adjustment for birth weight, infant gender, race, and mode formed after a vaginal delivery, infection is an infrequent complication.of delivery. These observations collectively have aroused renewed inter- Shy and Eschenbach196 classified episiotomy infections according to theest in the importance of the long-term effects of intrauterine infection, extent of the structures involved (Fig. 38-5). The same classificationas well as strategies to avoid their serious complications.184 These issues may be used for infections of perineal lacerations.also are addressed in Chapter 58. Simple Episiotomy InfectionPrevention A localized infection may involve only the skin and subcutaneousNumerous approaches have been tested as preventive techniques. tissue (including the Camper fascia of the perineum) adjacent to theChlorhexidine vaginal washes during labor185,186 and selected infection- episiotomy. Signs are local edema and erythema with exudate; morecontrol measures168 have been ineffective. Antepartum treatment extensive findings should raise the suspicion of a deeper infection.of BV has not been shown to decrease the rate of chorioamnionitis.187 Treatment consists of opening, exploring, and débriding the perinealUse of broad-spectrum antibiotics in patients with preterm labor wound. Drainage alone usually is adequate, but appropriate antibioticsbut intact membranes appears to be ineffective overall in decreasing should be given if there is marked superficial cellulitis or isolation ofchorioamnionitis.188 group A streptococci. The episiotomy incision should not be immedi- Intrapartum prophylaxis to prevent neonatal GBS sepsis decreases ately resutured. Most episiotomy wounds heal by granulation. Woundsthe frequency of chorioamnionitis. Use of a screening-based strategy involving the external anal sphincter or rectal mucosa may be repaired(which results in more women receiving antibiotics) compared with a after the field is free of infection.risk-based strategy produces lower rates of chorioamnionitis.189 In Recently, there has been considerable interest in early repair ofaddition, active management of labor,190 induction of labor (compared episiotomy dehiscence. Such dehiscence usually is associated withwith expectant management) after PROM at term,191 and use of anti- infection. Early repair requires prompt and meticulous débridementbiotics in selected patients with PROM192-195 have each been shown to at the time of diagnosis, followed by antibiotics and frequent cleansing.decrease the rate of chorioamnionitis. When the tissue appears healthy (usually after about 1 week or longer), Rectus abdominis Deep fasciae 1. Rectus sheath 2. Inferior fascia of urogenital diaphragm 3. Inferior fascia of levator ani Superficial fasciae 1. Camper’s 2. Scarpa’s 3. Colles’ Levator ani Urogenital diaphragm Perineal External anal Area of body sphincter Episiotomy FIGURE 38-5 Structures potentially involved in episiotomy. Paramedian sagittal section of the fascial layers of the perineum. (From Shy KK, Eschenbach DA: Fatal perineal cellulitis from an episiotomy site. Obstet Gynecol 54:292, 1979. Reprinted with permission of the American College of Obstetricians and Gynecologists.)
  • 22. 760 CHAPTER 38 Maternal and Fetal Infectionsa definitive repair can be undertaken. For fourth-degree lacerations, abowel preparation should be given before the repair. Such repair is an Pathogenesisattractive option compared with the delay of 2 to 3 months recom- Endometritis is a polymicrobial infection caused by microorganismsmended in older literature.197-200 that are part of the normal vaginal flora. These aerobic and anaerobic bacteria gain access to the upper genital tract, peritoneal cavity, and bloodstream as a result of vaginal examinations during labor andNecrotizing Fasciitis manipulations during surgery. The most common pathogens are GBS,With necrotizing fasciitis, both layers of the superficial perineal fascia anaerobic gram-positive cocci (streptococci and peptostreptococci(i.e., the Camper and Colles fascias) become necrotic, and infection species), anaerobic gram-negative bacilli (predominantly E. coli, K.spreads along the fascial planes to the abdominal wall, thigh, and/or pneumoniae, and Proteus species), and anaerobic gram-negative bacillibuttock. Typically, the deep perineal fascia (i.e., inferior fascia of the (principally Bacteroides and Prevotella species). C. trachomatis is noturogenital diaphragm) is not involved. Skin findings are variable but a common cause of early-onset puerperal endometritis but has beeninitially include edema and erythema without clear borders. Later, implicated in late-onset infection. The genital mycoplasmas, M. hoministhere is progressive, brawny edema of the skin. The skin becomes blue and Ureaplasma urealyticum, may be pathogenic in some patients, butor brown, and bullae or frank gangrene may occur. As the infection they usually are present in association with other, more highly virulentprogresses, there may be either loss of sensation or hyperesthesia. bacteria.201,202 Associated findings include marked hemoconcentration, although The principal risk factors for endometritis are cesarean delivery,often after fluid replacement the patient is anemic. Hypocalcemia also young age, low socioeconomic status, extended duration of labor,may develop, because of the saponification of fatty acids. Traditionally, extended duration of ruptured membranes, and multiple vaginalthis infection has been associated with group A streptococci, but anaer- examinations. Preexisting infection of the lower genital tract due toobic bacteria also play an important role. gonorrhea, GBS, or BV also predisposes to ascending infection after For therapy to be effective, appropriate antibiotics must be com- delivery.203bined with adequate débridement. Indications for surgical explorationinclude extension beyond the labia, unilateral or markedly asymmetricedema, signs of systemic toxicity or deterioration, and failure of Diagnosisthe infection to resolve within 24 to 48 hours. At surgery, necrotizing Patients with endometritis typically have a fever of 38° C or higherfasciitis may be recognized by separation of the skin from the deep within 36 hours after delivery. Associated findings include malaise,fascia, absence of bleeding along incision lines, and a serosanguineous tachycardia, lower abdominal pain and tenderness, uterine tenderness,discharge. Dissection must be wide enough to remove all necrotic and malodorous lochia. A small number of patients have a tender,tissue. indurated, inflammatory mass in the broad ligament, posterior cul-de- sac, or retrovesical space. The initial differential diagnosis of puerperal fever should includeMyonecrosis endometritis, atelectasis, pneumonia, viral syndrome, pyelonephritis,Myonecrosis is an infection that involves the muscle beneath the deep and appendicitis. Distinction among these disorders usually can befascia. It often is the result of a myotoxin elaborated by C. perfringens, made on the basis of physical examination and selected laboratory testsbut it occasionally can result from an extension of necrotizing fasciitis. such as a peripheral white blood cell count, urinalysis and culture, and,Onset may be early and typically is accompanied by severe pain. in some patients, chest radiography. Blood cultures are indicated forTreatment of this condition also consists of extensive débridement patients who have a poor initial response to therapy or for those whoand high-dose antibiotics, including penicillin, if clostridia infection are immunocompromised or are at increased risk for bacterial endo-is suspected. carditis. Cultures of the lower genital tract and endometrium are rarely Clinicians should recognize that not all puerperal vulvar edema indicated. Such cultures are difficult to obtain without contaminationsignifies serious perineal infection. In fact, most cases of vulvar edema from lower genital tract flora. In addition, by the time these cultureresult from less serious causes, such as hematoma, prolonged bearing- results are available, most patients already have responded to treatmentdown in labor, generalized edema from preeclampsia, allergic reac- and have been discharged from the hospital.tions, or trauma. In these instances, however, the edema usually isbilateral, does not extend to the buttock or abdominal wall, and is notaccompanied by signs of systemic toxicity. Treatment The most commonly used regimen for treatment of puerperal endo- metritis is the combination of clindamycin (900 mg IV every 8 hours) plus gentamicin (7.5 mg/kg of ideal body weight every 24 hours). AnPuerperal Endometritis alternative regimen is metronidazole (500 mg IV every 12 hours) plus penicillin (5 million units IV every 6 hours) or ampicillin (2 g IV everyEpidemiology 6 hours) plus gentamicin (7 mg/kg of ideal body weight every 24The frequency of endometritis in women after planned cesarean hours). Both of these combination regimens provide excellent coveragedelivery ranges from 5% to 15%, depending on maternal socioeco- against all of the potential pelvic pathogens. Broad-spectrum singlenomic status. If cesarean delivery is performed after an extended agents such as cefotetan (2 g IV every 12 hours), ticarcillin plus clavu-period of labor and ruptured membranes, the incidence of endome- lanic acid (3.1 g IV every 6 hours), ampicillin plus sulbactam (3 g IVtritis is approximately 30% to 35% without antibiotic prophylaxis every 6 hours), piperacillin plus tazobactam (3.375 g IV every 6 hours),and approximately 15% with prophylaxis. In highly indigent patient imipenem-cilastatin (500 mg IV every 6 hours), or ertapenem (1 g IVpopulations, the frequency of postcesarean endometritis may be even every 24 hours) may be used for treatment of endometritis. However,higher.201 in most hospital formularies, these broad-spectrum single agents
  • 23. CHAPTER 38 Maternal and Fetal Infections 761are more expensive than the generic combination regimens listed Although these antibiotics are used for treatment of overt infections,earlier.204 their administration still is warranted in penicillin-allergic patients Once intravenous antibiotics are begun, approximately 90% to 95% who are at high risk for postoperative infection.204,205of patients experience defervescence within 48 to 72 hours. Once the Another important method for preventing endometritis is topatient has been afebrile and asymptomatic for approximately 24 remove the placenta by gentle traction on the umbilical cord ratherhours, parenteral antibiotics should be discontinued, and the patient than manually. Several investigators206,207 have confirmed that, whenshould be discharged. As a general rule, an extended course of oral other factors are controlled, manual removal of the placenta signifi-antibiotics is not necessary after discharge.205 There are at least two cantly increases the frequency of postcesarean endometritis.exceptions to this general rule. First, patients who have had a vaginaldelivery and who defervescence within 24 hours are candidates forearly discharge. In these individuals, a short course of an oral antibioticsuch as amoxicillin-clavulanate (875 mg orally every 12 hours) may be Wound Infectionsubstituted for continued parenteral therapy. Second, patients whohave had a staphylococcal bacteremia may require a more extended Epidemiology and Pathogenesisperiod of administration of parenteral and oral antibiotics.204 Wound infection after cesarean delivery usually occurs in association Patients who fail to respond to the antibiotic therapy outlined here with endometritis rather than as an isolated condition. Approximatelyusually have one of two problems. The first is a resistant organism. In 3% to 5% of women with postcesarean endometritis have a concurrentpatients who are treated with clindamycin plus gentamicin, the prin- wound infection. The principal risk factors for this complication arecipal resistant organism is enterococcus. This organism can be ade- low socioeconomic status, extended duration of labor, extended dura-quately covered by adding ampicillin or penicillin to the treatment tion of ruptured membranes, preexisting infection such as chorioam-regimen. For those who are taking a broad-spectrum single agent, nionitis, obesity, insulin-dependent diabetes, an immunodeficiencypotential weaknesses in coverage include some aerobic and some disorder, corticosteroid or immunosuppressive therapy, and poor sur-anaerobic gram-negative bacilli. These patients should be changed to gical technique. The major organisms that cause postcesarean woundthe triple-drug regimen (clindamycin or metronidazole, plus penicillin infection are S. aureus, aerobic streptococci, and aerobic and anaerobicor ampicillin, plus gentamicin). gram-negative bacilli.208 The second major cause of treatment failure is an abdominalwound infection. Some patients have an actual incisional abscess. Inthese cases, the wound should be opened to effect drainage, and an Diagnosisantibiotic that has excellent antistaphylococcal coverage should be The diagnosis of wound infection should be of paramount consider-added to the treatment regimen. Most experts prefer an agent such as ation in a woman who has had a poor initial clinical response to anti-nafcillin (2 g IV every 6 hours). Some women do not have frank pus biotic therapy for endometritis. Clinical examination usually showsin the incision but rather an extensive cellulitis in the soft tissue around erythema, induration, and tenderness at the margins of the abdominalthe incision. In these patients, the wound does not have to be opened. incision and pus exudes from within the incision. Some patients haveHowever, an antistaphylococcal antibiotic should be added to the treat- an extensive cellulitis without actual purulent drainage.ment regimen.204 Clinical examination usually is sufficient to establish the correct Other possible causes of a poor response to treatment include diagnosis. Culture of the wound exudate should be performed rou-pelvic abscess, septic pelvic vein thrombophlebitis, and drug reaction. tinely because of the possibility of a methicillin-resistant Staphylococ-The management of pelvic abscess and septic pelvic vein thrombophle- cus aureus (MRSA) infection.209bitis is discussed in the following sections. Drug reaction should besuspected if the patient has a peripheral blood eosinophilia and if thetemperature elevation corresponds with the time of drug administra- Treatmenttion. In these individuals, discontinuation of the antibiotic usually If frank pus or significant serosanguineous effusion is present in theresults in prompt resolution of fever. incision, the wound must be opened and drained completely. Antibi- otic therapy should be modified to provide coverage against staphylo- cocci. Nafcillin, 2 g IV every 6 hours, is an appropriate drug for thisPrevention purpose. In patients who are allergic to β-lactam antibiotics, vancomy-Ideally, the best approach to endometritis is prevention of infection. cin, 1 g IV every 12 hours, is an acceptable alternative.204In this regard, prophylactic antibiotics clearly are of proven value in Once the wound is opened, it should be repacked two to three timesreducing the frequency of postcesarean endometritis, particularly in daily with gauze dampened with saline. A clean dressing shouldwomen having surgery after an extended period of labor and ruptured be applied, and the wound should initially be allowed to heal by sec-membranes. The most appropriate agent for prophylaxis is a limited- ondary intention. After all signs of infection have resolved and healthyspectrum (first-generation) cephalosporin such as cefazolin. Cefazolin granulation tissue is apparent, a secondary closure may be considered.should be administered in an intravenous dose of 1 g immediately after Antibiotics should be continued until the base of the wound is cleanthe neonate’s umbilical cord is clamped. Although extended-spectrum and all signs of cellulitis have resolved. Patients usually can be treatedpenicillins and cephalosporins are effective for prophylaxis, they offer on an outpatient basis once the acute signs of infection haveno advantage over cefazolin and are several times more expensive. In subsided.addition, widespread use of these drugs for prophylaxis ultimately may Necrotizing fasciitis is an uncommon but extremely serious com-limit their usefulness for treatment of an established infection. Patients plication of abdominal wound infection. It has also been reported inwho have an immediate hypersensitivity reaction to β-lactam antibiot- association with infection of the episiotomy site (see earlier discus-ics should receive a single dose of clindamycin (900 mg IV) plus gen- sion). This condition is particularly likely to occur in patients who havetamicin (1.5 mg/kg IV) immediately after the umbilical cord is clamped. insulin-dependent diabetes, cancer, or an immunodeficiency disorder.
  • 24. 762 CHAPTER 38 Maternal and Fetal InfectionsMultiple bacterial pathogens, particularly anaerobes, have been iso- is the combination of penicillin (5 million units IV every 6 hours) orlated from patients with necrotizing fasciitis. ampicillin (2 g IV every 6 hours), plus gentamicin (7 mg/kg of ideal This condition should be suspected if the margins of the wound body weight every 24 hours), plus clindamycin (900 mg IV every 8become discolored, cyanotic, and devoid of sensation. When the wound hours) or metronidazole (500 mg IV every 12 hours). If the patient isis opened, the subcutaneous tissue is easily dissected free of the under- allergic to β-lactam antibiotics, vancomycin (1 g IV every 12 hours)lying fascia, but muscle tissue is not affected. If the diagnosis is uncer- can be substituted for penicillin or ampicillin. Aztreonam (1 g IV everytain, a tissue biopsy specimen should be performed and examined 8 hours) can be used in lieu of gentamicin if the patient is at risk forimmediately by frozen section. nephrotoxicity. Alternatively, broad-spectrum agents, such as one of Necrotizing fasciitis is a life-threatening condition that requires the carbapenems—imipenem-cilastatin (500 mg IV every 6 hours),aggressive medical and surgical management. Broad-spectrum antibi- meropenem (1 g IV every 8 hours), or ertapenem (1 g IV every 24otics with activity against all potential pathogens should be adminis- hours)—provide excellent coverage against the usual pathogenstered. The patient’s intravascular volume should be maintained with responsible for an abscess. Intravenous antibiotics should be continuedinfusions of crystalloid, and electrolyte abnormalities should be until the patient has been afebrile and asymptomatic for a minimumpromptly corrected. Of greatest importance, the wound must be com- of 24 to 48 hours. Thereafter, the patient should be treated with apletely débrided and all necrotic tissue removed. In many instances, combination of oral antibiotics that cover the major pathogens.204 Onethe required dissection is extensive and is best managed in consultation appropriate regimen is ofloxacin (400 mg every 24 hours) or levofloxa-with an experienced general or plastic surgeon. cin (750 mg every 24 hours) plus metronidazole (500 mg twice daily) to complete a total treatment course of 10 to 14 days.12Pelvic Abscess Septic ShockEpidemiology and PathogenesisWith the advent of modern antibiotics, pelvic abscesses after cesarean Epidemiology and Pathogenesisor vaginal delivery have become extremely rare. As with wound infec- The term “severe sepsis” refers to infection-induced organ dysfunctiontions, pelvic abscesses, when they do occur, usually develop in women or hypoperfusion abnormalities. Septic shock implies hypotension thatwho initially had postcesarean endometritis. The frequency of pelvic is not reversed with fluid resuscitation and which is associated withabscess as a complication of endometritis is less than 1%.201 multiorgan dysfunction.208 In obstetric patients, the most common Pelvic abscesses typically are located in the anterior or posterior predisposing conditions for septic shock are septic abortion, acutecul-de-sac or within the leaves of the broad ligament. The bacteria pyelonephritis, chorioamnionitis, and puerperal endometritis. Fewerusually isolated from abscess cavities are anaerobic gram-positive than 2% of patients with any of these conditions develop septic shock.organisms such as Peptococci and Peptostreptococci species, anaerobic The most common pathogenic organisms are E. coli, K. pneumoniae,gram-negative bacilli (particularly Bacteroides and Prevotella species), and Proteus species. Highly virulent, drug-resistant organisms such asand aerobic gram-negative bacilli such as E. coli, Klebsiella, and Proteus Pseudomonas, Enterobacter, and Serratia species are uncommon exceptspecies.202,203 in immunosuppressed patients.209 Aerobic gram-negative bacilli such as E. coli have a complex lipo- polysaccharide in their cell wall, termed endotoxin. When released intoDiagnosis the systemic circulation, endotoxin causes a variety of immunologic,Patients who have a pelvic abscess typically experience persistent fever hematologic, neurohormonal, and hemodynamic derangements thatdespite appropriate antibiotic therapy for endometritis. In addition, ultimately result in multiple-organ dysfunction.211-213they usually have malaise, tachycardia, tachypnea, lower abdominal In the early stages of septic shock, patients usually are restless, dis-pain and tenderness, and a palpable pelvic mass. The peripheral white oriented, tachycardic, and hypotensive. Although hypothermia may beblood cell count usually is elevated (>20,000/mm3), and there is a shift present initially, most patients subsequently have a high fever. The skintoward immature cell forms. The diagnosis of pelvic abscess may be may be warm and flushed owing to a preliminary phase of vasodila-confirmed by ultrasound, computed tomographic (CT) scanning, or tion. Later, extensive vasoconstriction occurs, and the skin becomesmagnetic resonance imaging (MRI).210 The latter two tests are slightly cool and clammy. Cardiac arrhythmias may develop, and signs of myo-more sensitive, but more expensive, than ultrasound. cardial ischemia may occur. Jaundice, typically due to hemolysis, may be evident. Urinary output decreases, and spontaneous bleeding from the genitourinary tract or venipuncture sites may occur as a result ofTreatment a coagulopathy. ARDS is a common complication of sepsis and isPatients who develop an abscess after delivery usually require surgical usually manifested by dyspnea, stridor, cough, tachypnea, bilateraldrainage in addition to broad-spectrum antibiotic therapy. If the rales, and wheezing. In addition to these systemic signs and symptoms,abscess is located in the posterior cul-de-sac, colpotomy drainage may affected patients also may have specific findings related to their primarybe feasible. For abscesses located anterior or lateral to the uterus, drain- site of infection, such as uterine tenderness in women with endo-age may be accomplished by CT- or ultrasound-guided placement of metritis or chorioamnionitis or flank tenderness in patients witha catheter drain. If access to the abscess cavity is limited by the inter- pyelonephritis.212,213position of bowel, or if the abscess is extensive, open laparotomy isindicated.207 Patients also must receive antibiotics that have excellent activity Diagnosisagainst multiple aerobic and anaerobic pathogens. One regimen that The differential diagnosis of septic shock in obstetric patients includeshas been tested extensively in obstetric patients with serious infections hypovolemic and cardiogenic shock, diabetic ketoacidosis, anaphylac-
  • 25. CHAPTER 38 Maternal and Fetal Infections 763tic reaction, anesthetic reaction, and pulmonary embolism. Distinction The duration of antibiotic therapy should be 5 to 10 days, dependingamong these disorders usually can be made on the basis of a detailed on the rapidity of the patient’s response.204history and physical examination and selected laboratory studies. The Patients also may require surgery to evacuate retained, infectedwhite blood cell count initially may be decreased in septic shock but products of conception, to drain a pelvic abscess, or to remove ansubsequently becomes elevated. The hematocrit may be decreased if infected intravascular catheter. Indicated surgery never should beblood loss has occurred. The platelet count and serum fibrinogen delayed because the patient is unstable, because operative interventionconcentration are typically decreased. Serum concentration of fibrin may be precisely the step necessary to reverse septic shock.degradation products is usually elevated. The prothrombin time and The patient’s core temperature should be maintained as close toactivated partial thromboplastin time (aPTT) are frequently pro- normal as possible by use of antipyretics and a cooling blanket. Coagu-longed. Serum concentrations of transaminase enzymes and bilirubin lation abnormalities should be corrected. Insulin should be adminis-often are increased. The blood urea nitrogen and serum creatinine tered as needed to maintain euglycemia. Granulocyte colony-stimulatingconcentrations are also increased. factor may be indicated for severely neutropenic patients. Severely ill Septic patients should have a chest radiograph to determine whether patients should receive prophylaxis for deep venous thrombosis withpneumonia or ARDS is present. In addition, a CT scan, MRI, or either unfractionated or fractionated heparin. They also should receiveultrasound study may be of value in localizing an abscess. Patients stress ulcer prophylaxis with histamine2 (H2) blockers.211,214also require continuous electrocardiographic monitoring to detect In addition, treatment with activated protein C (24 μg/kg/min forarrhythmias or signs of myocardial ischemia. Blood samples for 96 hours) may be of value in decreasing mortality and minimizingculture should be obtained, one drawn percutaneously and one organ dysfunction in severely ill patients.214 Activated protein Cdrawn through each vascular device that has been in place longer ultimately reduces inflammation by inhibiting platelet aggregation,than 48 hours.211 neutrophil recruitment, and degranulation of mast cells. Patients should be given oxygen supplementation and observed closely for evidence of ARDS, which is one of the major causes ofTreatment mortality in patients with severe sepsis.215 Oxygenation should beThe first priority in treatment is fluid resuscitation with isotonic crys- monitored by means of a pulse oximeter or radial artery catheter. Iftalloids such as Ringer lactate solution or normal saline or colloids. evidence of respiratory failure develops, the patient should be intu-There is no firm evidence that one type of solution is better than bated promptly and supported with mechanical ventilation and posi-another, although crystalloids are used more commonly. Intravenous tive end-expiratory pressure.211,215fluid administration should be titrated in accordance with the patient’s The prognosis in patients with septic shock clearly depends on thepulse, blood pressure, and urine output. If the initial fluid infusion is severity of the patient’s underlying illness. In otherwise healthy patients,not successful in restoring hemodynamic stability, a right-sided heart mortality should not exceed 15%. The prognosis for complete recoverycatheter should be inserted to monitor pulmonary artery wedge pres- is excellent, provided that the patient receives timely therapy.215,216sure. Treatment goals of fluid resuscitation include a central venouspressure of 8 to 12 mm Hg, a mean arterial pressure of 65 mm Hg orhigher, urine output of 0.5 mL/kg or greater, and a mixed venousoxygen saturation of 70% or greater.211 Septic Pelvic Vein The “7-3 rule” is helpful in guiding fluid resuscitation. Ringerlactate or normal saline should be infused at a rate of 10 mL/min for Thrombophlebitis15 minutes. If the pulmonary capillary wedge pressure (PCWP) doesnot increase by more than 3 mm Hg, the bolus should be repeated. If Epidemiology and Pathogenesisthe PCWP increases by 7 mm Hg or more, the fluid bolus should be Like pelvic abscess, septic pelvic vein thrombophlebitis is extremelywithheld. The optimal PCWP in septic patients is 12 to 16 mm Hg.213 rare in modern obstetrics, occurring in approximately 1 of every 2000Transfusion of red blood cells is indicated to maintain a hemoglobin pregnancies overall and in fewer than 1% of patients who have puer-concentration of 7.0 to 9.0 g/L. peral endometritis.217 Septic pelvic vein thrombophlebitis occurs in If fluid resuscitation alone does not restore adequate tissue perfu- two distinct forms. The most commonly described disorder is acutesion, dopamine should be administered (starting dose, 1 to 3 μg/kg/ thrombosis of one (usually the right) or both ovarian veins (ovarianmin) to stimulate myocardial contractility and improve the perfusion vein syndrome).218 Affected patients typically develop a moderate tem-of central organs. In some patients with persistent low cardiac output perature elevation in association with lower abdominal pain duringand low blood pressure in the face of adequate fluid resuscitation, the first 48 to 96 hours after delivery. The pain usually localizes to thedobutamine should be added to the vasopressor therapy to improve side of the affected vein but may radiate into the groin, upper abdomen,cardiac output. In addition, such patients should be treated with intra- or flank. In addition, nausea, vomiting, and abdominal bloating mayvenous corticosteroids (hydrocortisone, 200 to 300 mg/day for 7 days be present.in 3 or 4 divided doses or by continuous infusion).211,214 On physical examination, the patient usually is found to have tachy- Patients in septic shock also should be treated with broad-spectrum cardia. Tachypnea, dyspnea, and even stridor may be evident if septicantibiotics. The triple combination of penicillin or ampicillin, plus pulmonary embolization has occurred. The abdomen is tender, andclindamycin or metronidazole, plus gentamicin (in the doses specified bowel sounds often are decreased or absent. Most patients have volun-earlier for treatment of pelvic abscess) is an excellent initial regimen. tary and involuntary guarding, and 50% to 70% have a tender, rope-Alternatively, a broad-spectrum antibiotic such as imipenem-cilastatin like mass that originates near one cornua and extends laterally and(500 mg IV every 6 hours), meropenem (1 g IV every 8 hours), cephalad toward the upper abdomen. The principal conditions thatertapenem (1 g IV every 24 hours), piperacillin-tazobactam (3.375 g should be considered in the differential diagnosis of ovarian vein syn-IV every 6 hours), ampicillin-sulbactam (3 g IV every 6 hours), or drome are acute pyelonephritis, nephrolithiasis, appendicitis, broad-ticarcillin-clavulanic acid (3.1 g IV every 6 hours) can be administered. ligament hematoma, adnexal torsion, and pelvic abscess.
  • 26. 764 CHAPTER 38 Maternal and Fetal Infections The second presentation of septic pelvic vein thrombophlebitis has percentage of patients, an actual abscess forms within the affectedbeen termed “enigmatic fever.”219 These patients usually have been breast.224treated initially for presumed puerperal endometritis. Subsequently, The diagnosis of mastitis is usually established on the basis of thethey experience some subjective improvement, with the exception of patient’s symptoms and clinical examination findings. Culture of milkpersistent fever. They do not appear to be seriously ill, and positive from the infected breast is not helpful. However, if an abscess is sus-findings are limited to persistent fever and tachycardia. Disorders that pected on physical examination, the contents should be drained andmust be considered in the differential diagnosis of enigmatic fever are cultured, particularly in light of the recent increase in methicillin-drug reaction, viral syndrome, recrudescence of connective tissue resistant staphylococcal infections.disease, and pelvic abscess. TreatmentDiagnosis Mastitis usually can be treated successfully with oral antibiotics thatCT and MRI are the diagnostic tests of greatest value in confirming have excellent coverage against staphylococci and streptococci. Initially,the diagnosis of pelvic vein thrombophlebitis.220 These tests are most sodium dicloxacillin, 500 mg orally four times daily, is preferable. In asensitive in detecting large thrombi in the major pelvic vessels. They woman with a history of a mild allergic reaction to penicillin, cepha-are not as useful in identifying thrombi in smaller vessels. In some lexin, 500 mg orally four times daily, may be substituted for sodiumcases, the diagnosis is one of exclusion and is confirmed by observing dicloxacillin. With a history of a serious immediate hypersensitivitythe patient’s response to an empiric trial of heparin.217 reaction to penicillin, clindamycin, 300 mg orally every 6 hours, is an appropriate alternative. The duration of antibiotic therapy depends on the patient’s response to treatment but usually should extend forTreatment approximately 7 to 10 days.204The traditional treatment for patients with presumed septic pelvic vein There are no reports to suggest that nursing from the infectedthrombophlebitis is therapeutic anticoagulation with intravenous breast is contraindicated. Therefore, the patient should be encouragedheparin. The dose of heparin should be adjusted to maintain the aPTT to continue nursing once the tenderness in the affected breast hasat approximately two times normal. Alternatively, medication may be decreased.adjusted to achieve a serum heparin concentration of 0.2 to 0.7 IU/mL. Hospitalization and treatment with intravenous antibiotics shouldIntravenous heparin should be continued for 7 to 10 days, depending be considered for immunosuppressed patients and for those who areon the response to treatment. Long-term anticoagulation with oral at particular risk for having complications should staphylococcal bac-agents probably is unnecessary unless the patient has massive clotting teremia develop (e.g., patients with prosthetic heart valves). In addi-throughout the pelvic venous plexus or has sustained a pulmonary tion, women with a breast abscess should be hospitalized for intravenousembolism. Patients should be given broad-spectrum antibiotics, such antibiotic therapy and surgical drainage. Appropriate intravenousas those used for treating pelvic abscess, throughout the period of drugs include nafcillin (2 g every 6 hours), cefazolin (1 g every 8heparin administration.217,221 hours), or vancomycin (1 g every 12 hours). Other agents with excel- Once medical therapy is initiated, there is usually objective evidence lent antistaphylococcal coverage include linezolid (600 mg every 12of a response within 48 to 72 hours. If no improvement is noted, surgical hours) and quinupristin/dalfopristin (7.5 mg/kg every 8 hours). Theseintervention may be considered. The surgical approach should be tai- latter two drugs are extremely expensive and should not routinely belored to the specific intraoperative findings. In most instances, treatment used as first-line agents.204requires only ligation of the affected vessels. Extension of the thrombosisalong the vena cava to the point of origin of the renal veins may requireembolectomy. Excision of the infected vessel and removal of the ipsilat- Preventioneral adnexa and uterus are indicated only in the presence of a well- In an effort to prevent mastitis, lactating women should be advised todefined abscess. Consultation should be obtained from an experienced take measures to prevent drying and cracking of the nipples. Specifi-vascular surgeon if surgical intervention becomes necessary.221 cally, they should avoid the use of alcohol-based products for cleaning the nipples and should apply a moisturizing agent such as lanolin to the nipple and areola after nursing.MastitisEpidemiology and Pathogenesis Cytomegalovirus Infection 223Mastitis occurs in 5% to 10% of lactating women. The principalcausative organisms are S. aureus and Viridans streptococci. These Epidemiology and Pathogenesis oforganisms are part of the mother’s skin flora and are introduced into Maternal and Fetal Infectionthe milk ducts when the infant suckles.222,223 Cytomegalovirus (CMV) is a DNA virus that is a member of the her- pesvirus family. Like other members of this family, CMV may remain latent in host cells after the initial infection. Recurrent infection isDiagnosis usually caused by reactivation of an endogenous latent virus ratherAffected women initially experience malaise, followed by a relatively than reinfection with a new viral strain.225,226high fever (39° C or higher) and chills. Thereafter, an erythematous, CMV is not highly contagious; close personal contact is requiredtender area appears in the affected breast. In addition, patients for infection to occur. Horizontal transmission may result from trans-also may experience pain and tenderness in the ipsilateral axilla, plantation of an infected organ or transfusion of infected blood, sexualand the milk from the infected breast may be discolored. In a small contact, or contact with contaminated saliva or urine. Vertical trans-
  • 27. CHAPTER 38 Maternal and Fetal Infections 765mission may occur as a result of transplacental infection, exposure to of breastfeeding. However, when the virus is acquired in one of thesecontaminated genital tract secretions during delivery, or breastfeeding. ways, infants rarely have major abnormalities.The incubation period of CMV ranges from 28 to 60 days.227 Among young children, the most important risk factor for infectionis close contact with playmates (e.g., from handling toys that are con- Diagnosis of Congenital Infectiontaminated by infected saliva).228,229 Most children who acquire CMV The most sensitive and specific test for diagnosing congenital CMVinfection are asymptomatic. When clinical manifestations are present, infection is the identification of CMV in amniotic fluid by eitherthey include malaise, low-grade fever, lymphadenopathy, and hepato- culture or PCR.234,235 This test is of greater accuracy than cordocentesissplenomegaly. Most immunocompetent adults with CMV also are for two major reasons. First, it can be performed at gestational agesasymptomatic or have only mild symptoms suggestive of a flulike when sampling of cord blood is technically not possible (<20 weeks).illness. However, in an immunosuppressed patient, CMV infection can Second, fetal anti-CMV–specific IgM antibody is usually not apparentbe quite serious. until 23 weeks’ gestation or later, which may be many weeks after infec- The diagnosis of CMV infection is confirmed by viral culture. The tion occurred.highest concentrations of virus are in urine, seminal fluid, saliva, and Identification of the virus in amniotic fluid by culture or PCRbreast milk, with most cultures becoming positive within 72 to 96 does not necessarily delineate the severity of fetal injury. Fortunately,hours. PCR methodology permits identification of viral antigen within sonography is invaluable in providing information about the con-24 hours.225,227 dition of the fetus. The principal sonographic findings suggestive Serologic methods also are of value in establishing the diagnosis of of serious fetal injury are microcephaly, ventriculomegaly, inter-CMV infection. Positive IgM titers usually decline rapidly over a period cerebral calcification, fetal hydrops, growth restriction, and oligohy-of 30 to 60 days, but they can remain elevated for many months. There dramnios. Less common findings include fetal heart block, echogenicis no single IgG titer that clearly differentiates acute from recurrent bowel, meconium peritonitis, renal dysplasia, ascites, and pleuralinfection. However, a fourfold or greater change in the IgG titer over effusions.2 weeks usually is consistent with recent acute infection. Anotheruseful test for differentiating acute from recurrent infection is assess-ment of the avidity of IgG antibody. Low- to moderate-avidity IgG Treatmentantibody, combined with the presence of IgM antibody, is consistent Until recently, no consistently effective therapy for congenital CMVwith acute infection. If high-avidity IgG antibody is present, the patient infection was available. However, in 2005, Nigro and colleagues236 pub-typically has recurrent infection.230,231 lished a prospective cohort study from eight medical centers describing Approximately 50% to 80% of adult women in the United States the use of hyperimmune globulin as treatment and prophylaxis forhave serologic evidence of past CMV infection. However, the presence congenital CMV infection. Of 157 women with confirmed primaryof antibodies is not perfectly protective against either reinfection or CMV infection, 148 were asymptomatic and were identified by routinevertical transmission of infection from mother to fetus. Therefore, serologic screening; 8 women had symptomatic viral infection, and 1pregnant women with either recurrent or primary infection pose a risk was identified because her fetus had abnormal ultrasound findings.to their fetus.229,232 Forty-five women had had a primary infection longer than 6 weeks Antepartum (congenital) infection results from hematogenous dis- before enrollment, underwent amniocentesis, and had CMV detectedsemination of virus across the placenta and poses the greatest risk to in amniotic fluid by PCR or culture. Thirty-one of these womenthe fetus. Dissemination is much more likely in the presence of a received intravenous treatment with CMV-specific hyperimmuneprimary maternal infection. Among women who acquire primary globulin (200 U/kg of maternal body weight). Nine of the 31 receivedCMV infection during pregnancy, approximately half will infect their one or two additional infusions into either the amniotic fluid or thefetus. The overall risk of congenital infection is greatest when maternal umbilical cord because their fetuses had persistent abnormalities oninfection occurs in the third trimester, but the probability of severe ultrasound. Fourteen women declined treatment; 7 of these womenfetal injury is highest when it occurs in the first trimester. had infants who were acutely symptomatic at the time of delivery. In Approximately 5% to 15% of infants who develop congenital CMV contrast, only 1 of the 31 treated women had an infant with clinicalinfection as a result of primary maternal infection are symptomatic at disease at birth (adjusted OR, 0.02, P < .001).birth. The most common clinical manifestations of severe neonatal In this same investigation,236 84 additional women did not have aninfection are hepatosplenomegaly, intracranial calcifications, jaundice, amniocentesis because their infection occurred within 6 weeks beforegrowth restriction, microcephaly, chorioretinitis, hearing loss, throm- enrollment, their gestational age was less than 20 weeks, or theybocytopenia, hyperbilirubinemia, and hepatitis. Approximately 30% of declined amniocentesis. Thirty-seven of these women received hyper-severely infected infants die, and 80% of survivors have major morbid- immune globulin, 100 U/kg every month until delivery, and 47 declinedity. Among the 85% to 90% of infants with congenital CMV infection treatment. Six of the treated women delivered infected infants, as didwho are asymptomatic at birth, 10% to 15% subsequently develop 19 of the untreated women (adjusted OR, 0.32, P = .04). No adversehearing loss, chorioretinitis, or dental defects within the first 2 years effects of hyperimmune globulin were noted in either group receivingof life.229,232 immunotherapy. Pregnant women who experience recurrent or reactivated CMV This report by Nigro and colleagues had several shortcomings.237infection are much less likely to transmit infection to their fetus. If The design of the study was neither randomized nor controlled. Thererecurrent infection develops in pregnancy, approximately 5% to 10% are at least some biologic reasons to question whether the remarkableof infants become infected; however, none of these neonates will be success reported by the authors will be maintained in larger, random-symptomatic at birth. The most common sequelae are hearing loss, ized studies. The authors also did not address the financial and logisticvisual deficits, and mild developmental delays.232-235 issues associated with screening large obstetric populations for CMV Perinatal infection can occur during delivery as a result of exposure infection, triaging the inevitable patients with false-positive results,to infected genital tract secretions. Infection also can occur as a result offering amniocentesis and targeted sonography to women who
  • 28. 766 CHAPTER 38 Maternal and Fetal Infectionsseroconvert, and then treating at-risk patients with hyperimmune surprisingly high percentage of neonates with GBS sepsis (perhapsglobulin. Nevertheless, the authors’ observations are extremely inter- 25%) are born to women with light colonization. Therefore, focusingesting and offer the best available therapy for this dangerous perinatal solely on heavily colonized women in preventive approaches isinfection. inadequate. The documented colonization rate for GBS has been far higher than the attack rate in terms of neonatal infection. Overall, sepsis developsPrevention in only 1% of infants of colonized mothers. The following are riskIdeally, preventive measures should be employed to ensure that women factors for GBS neonatal sepsis242:do not contract CMV infection during pregnancy. One simple measureis using CMV-negative blood products when transfusing pregnant Prematurity (or low birth weight as its surrogate)women or fetuses. In addition, women should be encouraged to Maternal intrapartum fever (presumably as a result ofuse careful hand washing techniques after handling infant diapers chorioamnionitis)and toys. They also should adopt safe sexual practices if they Membrane rupture for longer than 18 hoursare not already engaged in a mutually faithful, monogamous sexual A previous infant infected with GBS diseaserelationship.225,228,237 GBS bacteriuria in this pregnancy Because of the preponderance of term infants overall, 70% to 80% of cases of neonatal GBS infection in the United States occur in infantsGroup B Streptococcal born after 36 weeks’ gestation.243,244 Today, approximately half of casesInfection are early in onset (first week of life). Previously, before implementation of intrapartum antibiotic prophylaxis (IAP), at least three quarters ofThe hemolytic streptococci cause a variety of infections and are cases were of the early-onset variety.243,244 The most common diagnosissignificant causes of perinatal morbidity and mortality. In 1933, with early-onset disease is bacteremia (89%); meningitis but notLancefield used serologic techniques to subdivide β-hemolytic strep- bacteremia is diagnosed in 10%, and both bacteremia and meningitistococci into specific groups, designated A, B, C, D, and E. Only groups in 1%.243A, B, and D commonly are involved in human disease. Group A β-hemolytic streptococcus (Streptococcus pyogenes) longhas been recognized as a major pathogen in perinatal sepsis.238 Several Clinical Manifestations in the Neonatecase series have documented fulminant puerperal infection, with mul- Two clinically distinct neonatal GBS infections have been identified:tisystem dysfunction, resulting from group A streptococci.239 early- and late-onset disease.245 The Lancefield group B streptococci, GBS (Streptococcus agalactiae)can be classified into five major serotypes on the basis of antigenic Early-Onset Infectionstructure. They originally were thought to be commensal organisms. Early-onset infection appears within the first week of life, usuallyBy the 1960s GBS had been linked to neonatal infections, and by the within 48 hours. It is characterized by rapid clinical deterioration and1970s they had emerged as the leading cause of neonatal sepsis. Today, a high mortality rate. The association between gestational age andGBS still are among the leading organisms in perinatal sepsis and have early-onset GBS infection is shown in Table 38-14. In its most fulmi-become the focus of national prevention strategies. In 1995, in surveil- nant form, early-onset GBS infection manifests as septic shock accom-lance areas set up by the CDC, the rate of perinatal sepsis was 1.3 per panied by respiratory distress and leads to death within several hours1000 liveborn infants, accounting for an estimated 7000 to 8000 cases despite appropriate antibiotic therapy. In less severe disease, the clinicalper year in the United States.240 Outcome has improved dramatically findings are similar to those seen in respiratory distress syndrome.in recent years, but morbidity still is substantial, particularly in preterm Although pulmonary disease predominates in early-onset disease,infants. One data set showed an overall case fatality rate of 4%, 2% in meningitis may be present in 10% to 30% of cases. The case fatalityterm infants but 16% in preterm infants. rate for early-onset disease is now approximately 4.5%.243 Current GBS have been reported to cause 1% to 5% of UTIs in pregnancy. nationwide prevention strategies have decreased the number of casesIn addition, a characteristic early onset of puerperal endometritis has of early-onset GBS sepsis by an estimated 3900 per year and thebeen associated with these organisms. number of deaths by 200 per year.246EpidemiologyAsymptomatic rectovaginal colonization with GBS occurs in approxi- TABLE 38-14 EARLY-ONSET GROUP Bmately 20% of pregnant women. The choice of culture medium is acrucial determinant of the prevalence of GBS. The highest yield occurs STREPTOCOCCAL DISEASE, BYwhen a selective medium, such as LIM or Trans-Vag broth, is used as GESTATIONAL AGE, 1993-1998an enriching step before plating on sheep’s blood agar. Gestational Age (Wk) % of Cases Case Fatality Rate (%) The single greatest risk factor for colonization with GBS in anewborn is being born to a colonized mother. Without intervention, ≤33 9 30more than half of infants born to colonized mothers will become colo- 34-36 8 10nized.241 Also, 16% to 45% of nursery personnel are carriers of GBS ≥37 83 2infection, and nosocomial acquisition in newborns is common. There Data from Schrag SJ, Zywicki S, Farley MM, et al: Group Bclearly is an association between heavy growth of GBS in the maternal streptococcal disease: The era of intrapartum antibiotic prophylaxis. Ngenital tract and the development of GBS sepsis in neonates. Yet, a Engl J Med 342:15, 2000.
  • 29. CHAPTER 38 Maternal and Fetal Infections 767Late-Onset Infection genital tracts are colonized with GBS. Strategies can be classified asLate-onset infection with GBS occurs more insidiously, usually after antepartum, intrapartum, neonatal, and immunologic.the first week of life. In the majority of infants, meningitis is the pre-dominant clinical manifestation. Although the mortality rate in late- Antepartum Strategiesonset GBS infection is lower (2%) than with early-onset disease, up to Antepartum strategies to reduce maternal carrier rates generally have50% of babies with meningitis subsequently demonstrate neurologic been unsuccessful owing to recolonization and are therefore notsequelae. Late-onset disease may result in localized infections involving recommended.the middle ear, sinuses, conjunctiva, breasts, lungs, bones, joints, orskin. Meningitis appears to be related to the serotype of GBS. More Intrapartum Strategiesthan 80% of early-onset GBS infections in which meningitis is present Intrapartum strategies have been the most attractive to date from bothare caused by Lancefield type III organisms; in late-onset disease, 95% clinical and cost-effectiveness perspectives.of meningitis is attributable to this subtype. To standardize a national approach, in 1996, the CDC published Although early-onset disease is acquired mainly via transmission recommendations that were also endorsed by the ACOG. These recom-from the mother’s genital tract either before or during parturition, mendations have been disseminated widely and have resulted in dra-such a route of transmission is not implicated in late-onset disease. matic decreases in early-onset neonatal GBS sepsis.244,246 In 2002, theseNosocomial transmission of GBS can occur in the nursery from colo- guidelines were revised, based on several studies, including a largenized nursing staff or from other infants. Current prevention strategies case-control series.246,247 The main changes in the 2002 guidelines arehave not decreased the number of cases of late-onset GBS disease in recommendation of the screen-based approach only, a change in thenewborns.243,246 recommended alternative antibiotics for penicillin-allergic patients, and provision of more specific recommendations for selected clinical scenarios. These guidelines are summarized here (Fig. 38-6).Clinical Manifestations in the MotherGBS is a major cause of puerperal infection. Features of GBS puerperal 1. All pregnant women should be screened at 35 to 37 weeks’ gestationinfection include the development of a high fever within 12 hours after for vaginorectal GBS colonization. IAP should be given at the timedelivery, tachycardia, abdominal distention, and endometritis. Some of labor or rupture of membranes to those identified as GBS carri-patients have no localizing signs early in the course of the infection. ers. GBS colonization in a previous pregnancy does not obviate need for screening in subsequent pregnancies; colonization in a previous pregnancy is not an indication for IAP in subsequent deliveries.Diagnosis 2. GBS bacteriuria: Give IAP to women with GBS in urine in anyThe diagnosis of maternal asymptomatic genitourinary or gastrointes- concentration.tinal colonization with GBS can be confirmed by culture. Several rapid a. Prenatal screening at 35 to 37 weeks is not necessary in thesediagnostic tests are available for detection of GBS from maternal patients.sources, but most methods are insufficiently sensitive. Some newer b. Treat bacteriuria by usual standards of care.PCR-based tests seem to be an exception to that statement.247,248 3. Women with previous birth of infant with GBS disease should Most colonized neonates are asymptomatic, and the clinical mani- receive IAP; prenatal screening is not necessary for these women.festations of neonatal infection are not sufficient for diagnosis in the 4. If the result of the GBS culture is not known at the time of labor,absence of a positive culture. The diagnosis should be suspected if give IAP under any of the following circumstances:the clinical manifestations occur in the setting of a risk factor for a. Less than 37 weeks’ gestationinfection. b. Rupture of membranes at least 18 hours earlier c. Temperature at or greater than 100.4° F (38.0° C) 5. In cases of onset of labor or rupture of membranes earlier than 37Treatment weeks with “significant risk for imminent preterm delivery,” treatPenicillin G remains the drug of choice for symptomatic GBS infection as follows:in both mother and neonate if the infecting organism has been identi- a. If the patient had a negative screening culture for GBS withinfied. In most instances, however, treatment must be initiated before the the past 4 weeks, IAP is not indicated.availability of culture results. In these instances, a broad-spectrum b. If colonization status is unknown at admission, perform screen-approach for empirically treating the mother with chorioamnionitis or ing culture and initiate IAP; if the culture is negative, stop IAP.puerperal sepsis and the neonate with sepsis is required. Ampicillin fre- 6. Specimensquently is used in such situations and provides adequate treatment forGBS infection. Alternative drugs for patients with a contraindication to Collectionpenicillin are a cephalosporin in those not at risk for immediate penicil- a. Collect specimen from distal vagina and the anorectum.lin hypersensitivity or vancomycin in patients who are at risk (e.g., those b. Specimen may be collected by patient or provider.with immediate urticaria or bronchospasm as manifestations of penicil- c. Do not use a speculum.lin allergy). Because of rising resistance, clindamycin and erythromycin d. Transport medium is acceptable.no longer can be relied upon to treat GBS infection unless susceptibility e. Label the specimen “GBS culture.”to these antibiotics has been demonstrated for a given isolate. Laboratory processing f. Inoculate into selective broth medium (e.g., LIM, Trans-Vag)Prevention g. Methods have been provided for susceptibility testing to clinda-Because of the severity of early-onset GBS neonatal infection, major mycin and erythromycin for GBS isolates from penicillin-efforts have been directed toward use of IAP in gravid women whose allergic women.
  • 30. 768 CHAPTER 38 Maternal and Fetal Infections Risk factors: Previous infant with invasive GBS disease? Give intrapartum Yes GBS bacteriuria this pregnancy? penicillin Delivery 37 weeks of gestation?* No Collect rectal and vaginal swab for Offer intrapartum GBS culture at 35–37 weeks of gestation GBS penicillinFIGURE 38-6 Algorithm for prevention ofearly-onset group B streptococcal (GBS) GBS Not done, incomplete,disease in neonates, with prenatal or results unknownscreening at 35 to 37 weeks. *If membranesrupture before 37 weeks’ gestation and themother has not begun labor, collect GBS Risk factors:culture and administer antibiotics until cultures Intrapartum fever 38°C (100.4°F)? Give intrapartum Yesare completed and the results are negative. Membrane rupture 18 hours? penicillin†† Broader-spectrum antibiotics may beconsidered at the physician’s discretion, basedon clinical indications (e.g., ampicillin plusgentamicin to treat clinical chorioamnionitis). No(Adapted from Centers for Disease Controland Prevention: Prevention of perinatal groupB streptococcal disease: A public healthperspective. MMWR Morb Mortal Wkly Rep No intrapartum prophylaxis needed45[RR-7]:1, 1996.) h. Laboratories “should report results to site of delivery and 12. Other items: provider.” a. Consider establishing surveillance. 7. Inform patients of results and recommend IAP. b. Improve laboratory protocols for isolation and reporting. a. In the absence of GBS bacteriuria, do not treat GBS genital c. Ensure communication. colonization before the intrapartum period. d. Educate staff. 8. For cesarean delivery before rupture of membranes and before labor, IAP is not indicated. The guidelines suggest penicillin G as the drug of choice for IAP 9. Penicillin G is the drug of choice. and list ampicillin as an “acceptable alternative.” Concern about ampi- a. The recommended dose for penicillin G is 5 million units ini- cillin’s broader spectrum of activity is the reason for this recommenda- tially, then 2.5 million units every 4 hours intravenously until tion. However, when evaluated in a randomized clinical trial, IAP with delivery. either ampicillin or penicillin significantly increased the likelihood of b. Ampicillin remains an alternative. recovery of ampicillin-resistant gram-negative organisms from the c. When ampicillin is used, the dose is 2 g intravenously initially, lower genital tract, and there was no difference between the two drugs followed by 1 g every 4 hours until delivery. for this effect.249 Because of these data, we believe that the choice of d. For penicillin allergy, clindamycin is no longer a drug of choice, whether to use penicillin or ampicillin for IAP should be based on cost unless susceptibility has been documented. Erythromycin no and availability. longer should even be considered as an alternate drug because Another caveat involves the technique for collection of the screen- of the high rate of resistance. ing culture. The guidelines call for sampling the vagina and rectum.10. For patients with penicillin allergy, treat as follows: However, two thirds of women report at least mild pain associated with a. If not at high risk for anaphylaxis, the drug of choice is cefazo- collection of the rectal sample.250 Furthermore, Jamie and colleagues251 lin, 2 g intravenously, then 1 g every 8 hours until delivery. evaluated whether there was any advantage to sampling the vagina and b. If at high risk for anaphylaxis and GBS is susceptible: The drug rectum, compared with sampling the vagina and perianal skin. They of choice is clindamycin, 900 mg intravenously every 8 hours. found no difference in culture positivity in a cohort of 200 women. c. If at high risk for anaphylaxis and GBS is resistant to clindamy- Therefore, it seems reasonable to obtain samples for screening cultures cin or of unknown susceptibility: The drug of choice is vanco- for GBS colonization from the distal vagina and perianal skin. mycin, 1 g every 12 hours.11. Routine use of prophylaxis for newborns whose mothers received Neonatal Strategies IAP is not recommended. Antibiotics should be given to infants Measures to prevent GBS infection in the newborn have focused on only if sepsis is suspected clinically. the reports of decreases in neonatal early-onset disease when penicillin
  • 31. CHAPTER 38 Maternal and Fetal Infections 769is given at birth. Although initial reports were encouraging, most trials asymptomatically.257 This observation represents a major changein low-birth-weight infants have not found this approach to be effec- from previous concepts.tive. These results are not surprising in view of Boyer and Gotoff’s 2. First-episode nonprimary genital herpes is the initial clinicalobservation252 that up to 40% of neonates in whom GBS sepsis devel- episode with either HSV-1 or HSV-2 in a patient who has anti-ops are already bacteremic at birth, suggesting that a single dose of bodies to the other viral serotype. Because the antibody responsepenicillin after delivery may be “too little and too late.” is directed against epitopes within areas of homology in the glycoprotein G expressed by each viral type, there is some cross-Immunologic Strategies reactivity. Therefore, the presentation is more similar to recur-The immunologic approach is appealing, but a vaccine has not yet been rent episodes.developed. Such a vaccine would need to be polyvalent to cover all sero- 3. Recurrent genital herpes infections are much milder and shorter,types involved in early-onset sepsis. One limitation of this approach is with lesions lasting 3 to 10 days. The course of the infection isthat it would not be optimally protective for infants born before 32 weeks shorter, owing to the preexisting presence of antibody to theof gestation because of modest placental transfer of maternal antibody viral serotype causing the recurrent infection.before that time. Thus, the most vulnerable infants would be left withminimal protection. Nevertheless, it is estimated that a vaccine approach When primary genital herpes occurs in pregnancy, there is a highwould prevent up to 90% of cases of neonatal GBS infection.253 risk of fetal and neonatal involvement, but this risk mainly exists with infection late in pregnancy. Brown and coworkers258 found that seriousSummary morbidity occurred in 6 of 15 infants born to women with primaryNo current approach is foolproof. However, the application of IAP has infection in pregnancy and in 4 of 5 born to mothers with primaryresulted in a significant reduction in the rate of early-onset neonatal infection in the third trimester. However, the same group showed that,GBS infection. In 2004, the rate was 0.34 per 1000 live births, less than overall, maternal seroconversion to HSV-2 during pregnancy does nota third of the rate only 10 years before. result in greater risks of low birth weight, preterm delivery, fetal growth restriction, stillbirth, or neonatal death.259 When recurrent episodes occur during pregnancy, there appears to be no increase in abortionHerpes Simplex Infection or low-birth-weight infants.257 Transplacental infection of the fetus resulting in congenital infec-Herpes simplex virus (HSV) may infect the mother, the newborn, or, tion is a rare complication of maternal infection, presumably arisingon rare occasions, the fetus. In the adult, typical lesions are vesicular from primary infections with viremia. Only a few such documentedor ulcerative, involving only the skin and mucous membranes. More cases have been reported.260widespread infection involving the central nervous system (CNS) is an A major perinatal problem is neonatal herpes infection. Exact esti-extremely unusual adult complication and most often develops in mates of its frequency are subject to error, because up to 50% of infantspeople with underlying debilitating disease. On the other hand, because with culture-proven fatal disease do not show typical lesions on theof an incompletely developed immune system, the newborn is subject skin or mucous membranes. In addition, recent treatment recommen-to systemic, and frequently lethal, disease. dations probably have decreased the incidence of neonatal disease. The disease manifests at the end of the first week of life. The presentation may include skin lesions, cough, cyanosis, tachypnea, dyspnea, jaun-Epidemiology dice, seizures, and DIC.In adults, the virus commonly causes infection of the oral cavity, skin, Neonatal herpes is acquired perinatally from an infected lowerand lower genital tract. In the past, HSV type 1 (HSV-1) was said to maternal genital tract, most commonly during a vaginal delivery. In abe responsible for infection of the mouth and of the skin above the study by Brown and colleagues,259 only those women with very recentwaist, and HSV-2 was implicated in infection of the genitalia and of infection (i.e., presence of virus in the genital tract but without devel-the skin below the waist. However, both viruses can cause either genital opment of type-specific antibody) had infected infants. In that situa-or oropharyngeal lesions, which are indistinguishable clinically. Fur- tion, the risk was high (four of nine cases). The risk is considerablythermore, in some populations, HSV-1 has been reported to account lower among women with recurrent, clinically evident infection—infor 30% to 40% of new cases of genital herpes,254 but genital HSV-1 the range of 1% to 2%. In one study, the incidence of infection inrecurs much less commonly than genital HSV-2.254,255 infants born vaginally to women with asymptomatic recurrent infec- Genital herpes is spread by sexual contact. The prevalence of serum tion was 0 in 34 cases.261 However, asymptomatically infected patientsantibodies to HSV-2 is increasing in the United States. Between 1988 can give birth to seriously infected neonates. In a referral nursery, 70%and 1994, 21.9% of the population age 12 years or older was found to of mothers of infected infants had asymptomatic infections. Amongbe seropositive, representing a 30% increase since the period 1976 to infants with disseminated herpes, the risk of death or serious sequelae1980 and corresponding to 45 million cases of infection.256 The disease exceeds 40%, even with antiviral therapy.262does not appear to be more severe or more protracted in pregnancy. Clinically, there are three syndromes of genital herpes: Diagnosis 1. First-episode primary genital herpes is the clinical presentation in The clinical diagnosis of genital herpes is based on the typical painful a patient without antibodies to either HSV-1 or HSV-2. Its clini- crops of vesicles and ulcers in various stages of progression. With cal manifestations include severe local symptoms, with lesions primary infection, tender inguinal adenopathy, fever, and other, more lasting 3 to 6 weeks, regional adenopathy, constitutional symp- marked constitutional symptoms may occur. Primary genital herpes toms, and, in a small percentage of cases, viral meningitis. lesions resolve without scarring after 3 to 6 weeks. The frequency of However, it should be noted that as many as two thirds of clinically detectable recurrences varies widely among individuals, but women with HSV-2 antibodies have acquired the infection about 50% of patients have recurrent disease within 6 months. Recur-
  • 32. 770 CHAPTER 38 Maternal and Fetal Infectionsrences are milder, with fewer lesions, fewer constitutional symptoms, lower genital tract by means of cesarean delivery. Accordingly, cesareanand a shorter course (usually 3 to 10 days). delivery is recommended when typical herpes lesions are present at Because many patients present with genital herpes infection after labor, regardless of the time since membrane rupture.12,270,271the vesicles have evolved into ulcers, clinical diagnosis based on the In 1986, Arvin and colleagues272 reported HSV cultures in a series ofclassic presentation of grouped, painful vesicles has a low sensitivity 515 pregnant women with recurrent herpes infection. Seventeen womenand specificity. Furthermore, making the diagnosis of genital herpes had positive antepartum cultures, but none was positive at delivery. Ofhas social and future implications. Therefore, first-episode infections 354 asymptomatic mothers, 5 (1.4%) had positive results at delivery, butshould be confirmed by laboratory tests. none had positive antepartum cultures. The likelihood of asymptomatic The “gold standard” diagnostic test to detect the presence of herpes shedding at delivery was 1.3%. Brown and colleagues259 published avirus infection has been the viral culture. The virus grows rapidly, and cohort study that included more than 40,000 women. Testing for HSVmost positive cultures are identifiable at 48 to 72 hours. Culture of included both culture and PCR. From the 202 women from whom HSVvesicular fluid has the highest yield, and the sensitivity of culture was isolated at the time of labor, 10 infants developed HSV infection.decreases with increasing duration of active lesions. The diagnosis of Those born by cesarean delivery were less likely to develop HSV infec-herpes infection can be made using the Tzanck smear or Papanicolaou tion than those born vaginally (1.2% versus 7.7%; P = .047).smear. However, neither of these tests can differentiate among HSV-1, For gravidas with recurrent genital herpes, treatment with acyclovirHSV-2, and varicella-zoster virus infection, and neither of them has a (400 mg three times daily) starting at 36 weeks’ gestation decreases thehigh sensitivity or specificity. proportion of patients with clinical lesions at the time of labor and PCR to detect HSV DNA probably is the most useful diagnostic test lessens the need for cesarean delivery.273 Such an approach has beenavailable. Results are available in a matter of hours, and PCR exceeds shown to be cost-effective.274culture in identifying positive cases. With the use of PCR, the frequency There are no data supporting a risk to the fetus from maternalof asymptomatic viral shedding of HSV particles has been shown to administration of acyclovir, valacyclovir, or famciclovir. However, webe eight times higher than previously reported using culture.263-265 believe that acyclovir should be the drug of choice for suppression of Previously, HSV antibody tests could not discriminate infection recurrent genital herpes during the third trimester, because this drugwith HSV-1 from that with HSV-2. Newer IgG assays that are specific has been the most extensively studied.to the respective glycoprotein G of each type now allow clinicians to Current recommendations for prenatal and intrapartum caredistinguish between these infections.266 However, the role of serologic include the following:testing in making the diagnosis of genital herpes is controversial.Furthermore, cost-effectiveness analyses regarding whether pregnant 1. Obstetricians should ask all pregnant women about a history ofwomen should be screened for serologic evidence of prior HSV-2 genital herpes.infection have had mixed results.267,268 2. If the diagnosis of genital herpes has not been previously con- firmed by culture or PCR, specimens should be obtained during an active episode of apparent HSV infection.Treatment 3. Serial cultures beginning at 34 to 36 weeks are not recommendedDuring clinically evident episodes, treatment consists of supportive for asymptomatic women with a history of herpes infection.measures such as oral analgesics, hygiene, and topical anesthetics. Sec- 4. The patient with a history of genital herpes should be instructedondary infections such as candidiasis also should be treated. Many to come to the hospital early in labor or immediately if PROMwomen find that frequent bathing, followed by thorough drying of the has occurred. The patient also should be informed of the lowaffected area with a hair dryer, provides temporary relief. risk of asymptomatic infection at delivery (1%) and the low risk Acyclovir, an antiviral agent with excellent activity against herpes of neonatal infection after delivery through an asymptomaticallyinfection, is a specific inhibitor of viral thymidine kinase. It is available infected genital tract.in topical, oral, and intravenous preparations. In nonpregnant indi- 5. When the patient arrives in labor or with membrane rupture, aviduals, all of these forms have been of value in decreasing the duration careful pelvic examination should be performed. If no lesionsof symptoms and of viral shedding in primary genital infection, but are present, the delivery can be managed normally. If lesions areoral therapy seems to be superior to topical therapy and equivalent to observed, cesarean delivery is recommended to prevent neonatalintravenous therapy for treatment of non–life-threatening infections. herpes.The oral form is effective in shortening recurrences significantly(400 mg orally three times daily for 5 days) and in suppressing frequent Women with nongenital herpes do not require any special precau-recurrences (400 mg orally twice daily). Such suppressive therapy with tions during labor and delivery, apart from barrier isolation of theacyclovir has been demonstrated to be safe and effective for 6 years or infected skin, gown and glove precautions, and proper disposal of linenmore.269 and dressings. Precautions should be taken to avoid contact of the For treatment of genital herpes, valacyclovir (Valtrex) and famciclo- newborn with the infected maternal skin. After the lesions have becomevir (Famvir) have the advantage of better absorption and a longer half- encrusted, the mother may handle and feed her infant.life than acyclovir. Both are indicated for the treatment of recurrentgenital herpes, and valacyclovir is indicated for the treatment of first-episode infections. Both drugs are more expensive than acyclovir. Human ImmunodeficiencyManagement of Herpes Infection Virus Infectionin PregnancyBecause of the severity of neonatal herpes infection and the lack of Epidemiologysatisfactory therapy, the only current way of preventing neonatal infec- HIV infection is caused by an RNA retrovirus. Two major strains oftion is to avoid contact between the fetus and the infected maternal the virus have been identified, HIV-1 and HIV-2; each major strain has
  • 33. CHAPTER 38 Maternal and Fetal Infections 771several substrains. HIV-1 infection is more widely prevalent through- than 2%.280 Most cases of transmission occur at the time of delivery.out the world. HIV-2 infection is uncommon in the United States Antenatal transmission is possible, typically as a result of invasiveexcept among patients who have traveled to areas of the world where antepartum procedures such as amniocentesis or chorionic villusthis infection is endemic (e.g., sub-Saharan Africa) or who have shared sampling. Postnatal transmission also can occur from breastfeeding.needles with, or had sex with, someone from that area of the The principal risk factors for perinatal transmission of HIV infectionworld.275 are In the United States, HIV infection is more common in African-American and Hispanic women than in Caucasians. The most common History of previously affected infantmechanism of transmission of infection is heterosexual contact. Intra- Severe maternal diseasevenous drug use also is an extremely important mechanism of trans- Preterm deliverymission. Transmission through organ donation, artificial insemination, Intrapartum blood exposure as a result of events such as vaginalor blood transfusion is exceedingly rare. Important risk factors for lacerations, episiotomy, or instrumental deliverysexual transmission of HIV infection include multiple sexual partners; Time since rupture of membranes greater than 4 hoursreceptive anal intercourse; unprotected intercourse; concurrent STDs, Invasive antepartum proceduresespecially those that cause genital ulcers; sexual contact with an Chorioamnionitisuncircumcised male; severe illness in the infected partner; sex during Concurrent STDsmenstruation; and bleeding during intercourse (e.g., from sexual Vaginal delivery in the presence of an elevated viral loadassault).276 At the time of her first prenatal appointment, the HIV-infected patient should have a CD4+ count and viral load measurement to assessPathogenesis her degree of immunosuppression. She should be screened for all otherHIV infection typically evolves through four major stages. The first STDs, such as gonorrhea, chlamydia, syphilis, hepatitis B, and hepatitisstage of infection is the acute retroviral illness.277 Within several weeks C. She also should be tested for tuberculosis. If her CD4+ count isafter exposure, the patient typically develops a severe flulike illness greater than 200 cells/mm3, the purified protein derivative (PPD)characterized by malaise, poor appetite, weight loss, low-grade fever, should be a reliable screening test. If the CD4+ count is less thanand generalized lymphadenopathy. Over a period of several weeks, this 200/mm3, a negative test may be the result of anergy, and suchphase of the illness gradually resolves, and the patient enters the latent patients should have a chest radiograph to be certain that tuberculosisphase of infection. In this phase of the infection, the viral load in the is not present. Patients should be tested for toxoplasmosis andplasma tends to be relatively low, and the virus is primarily concen- CMV infection as well, because both can cause serious perinatal infec-trated in lymphatic tissue, where it replicates at a slow rate. With tion, which can be successfully treated with either antibiotics orappropriate anti-retroviral therapy and supportive care, the latent immunotherapy.phase of illness may extend beyond 10 years in many patients. Over In an effort to prevent opportunistic infections, the HIV-positivetime, however, the viral load progressively increases, and patients enter pregnant woman should be vaccinated for pneumococcal infection,a symptomatic phase of the infection. Eventually, all infected patients influenza, hepatitis A and B, and meningococcal infection. She alsodevelop acquired immunodeficiency syndrome (AIDS), albeit at a much should receive prophylactic antibiotics to protect against other patho-slower rate than in the early years of the HIV epidemic. gens.278 If her CD4+ count is less than 200/mm3 and she previously has had an infection with P. jiroveci, she should receive trimethoprim- sulfamethoxazole-DS, 1 tablet daily. This medication also providesDiagnosis protection against toxoplasmosis infection. If her tuberculin skin testOpportunistic diseases are the hallmark of HIV infection. The most is positive and her chest radiograph shows no evidence of activecommon serious opportunistic disease in women is Pneumocystis disease, she should receive prophylaxis with isoniazid (INH), 300 mgjiroveci pneumonia; second most common is Mycobacterium avium- orally each day, plus pyridoxine, 50 mg daily. The latter drug is admin-intracellulare infection. Other important opportunistic diseases include istered to prevent peripheral neurotoxicity from isoniazid. If thetuberculosis, toxoplasmosis, CMV infection, candidiasis, and non- patient’s CD4+ count falls to a range of 50 to 75 cells/mm3, she shouldHodgkin lymphoma.278 receive prophylaxis against M. avium-intracellulare with azithromycin, The initial screening test for HIV infection should be the enzyme 1200 mg orally each week. If a patient has recurrent candidiasis, sheimmunoassay (EIA) for HIV-1 and HIV-2. If this test is positive, a can be treated with fluconazole, 150 mg orally, each day. If her CD4+confirmatory test such as the Western blot or immunofluorescent assay count falls to less than 50/mm3, she also should receive prophylaxis(IFA) should be performed. If both tests are positive, the probability with fluconazole to prevent cryptococcal infection. A patient withof a false-positive sequence is extremely low. recurrent herpes simplex infection should receive prophylaxis with The CDC now recommends universal screening for HIV infection acyclovir, 400 mg PO twice daily.in pregnant women. The “opt out” strategy is the one most likely to The single most important intervention is treatment with highlyensure compliance with screening. With this strategy, HIV testing is active antiretroviral therapy (HAART).281,282 The ACTG-076 trial279 wasconsidered part of the routine prenatal laboratory panel. Patients must the first to demonstrate that treatment of pregnant women with pro-specifically decline the screening test; otherwise, it is routinely phylactic zidovudine is highly effective in reducing the rate of perinatalperformed. transmission of HIV infection. In that trial, the observed frequency of transmission was reduced from 26% in the placebo group to 8% in those patients who received zidovudine. Subsequent uncontrolledTreatment studies showed that treatment of the mother with combination chemo-In the absence of any intervention, the risk of perinatal transmission therapy reduces the rate of perinatal transmission to less than 2%.280of HIV infection is approximately 25%.279 With the interventions out- The antiretroviral agents currently available are summarized inlined in this section, perinatal transmission should be reduced to less Table 38-15. The combination of zidovudine (300 mg) and lamivudine
  • 34. 772 CHAPTER 38 Maternal and Fetal Infections TABLE 38-15 DRUGS FOR TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION Agent Usual Adult Dose Major Adverse Effects Nucleotide Analogue Tenofovir (Viread) 300 mg qd GI irritation, elevation in transaminase concentrations, decrease in serum carnitine, nephrotoxicity Nucleoside Analogues Abacavir (Ziagen) 300 mg bid Hypersensitivity reaction Didanosine (DDI, Videx) or Videx EC 200 mg bid Pancreatitis and peripheral neuropathy 400 mg qd Emtricitabine (Emtriva) 200 mg qd Headache, diarrhea, nausea, rash, hyperpigmentation, hepatitis Lamivudine (3TC, Epivir) 150 mg bid or 300 mg qd Marrow suppression Stavudine (d4T, Zerit) 40 mg bid Peripheral sensory neuropathy Zalcitabine (ddC, Hivid) 0.75 mg q8h Peripheral neuropathy, pancreatitis Zidovudine (AZT, Retrovir) 300 mg bid Marrow suppression Combination Nucleoside Analogues Combivir (zidovudine + lamivudine) 1 tablet bid Marrow suppression Trizivir (zidovudine + lamivudine + abacavir) 1 tablet bid Marrow suppression Non-nucleoside Reverse Transcriptase Inhibitors Delavirdine (Rescriptor) 400 mg tid Rash, hepatitis Efavirenz (Sustiva) 600 mg qd Rash, CNS changes. Drug is teratogenic and should not be used in pregnancy. Nevirapine (Viramune) 200 mg bid Rash, hepatitis Unique Triple Combination Atripla (efavirenz + emtricitabine + tenofovir) Single daily dose: Lactic acidosis, severe hepatomegaly, steatosis 600/200/300 mg Protease Inhibitors Amprenavir (Agenerase) 1200 mg bid Rash and GI irritation Atazanavir (Reyataz) 400 mg qd Hyperbilirubinemia, prolonged Q-T interval, hyperlipidemia Darunavir (Prezista)—must be given with 600/100 mg bid Diarrhea, nausea, headache, increased transaminase activity, ritonavir) increased serum lipids Indinavir (Crixivan) 800 mg tid Nephrolithiasis, GI upset Lopinavir/ritonavir (Kaletra) 3 gelatin capsules Diarrhea, nausea, fatigue, headache, asthenia (133.3/33.3 mg) bid Nelfinavir (Viracept) 1250 mg bid Diarrhea, fatigue, poor concentration Ritonavir (Norvir) 100-400 mg bid GI irritation, seizures, hepatitis, diabetes, marrow suppression Tipranavir (Aptivus)—must be given with 500/200 mg bid Hepatitis, diarrhea, nausea, vomiting, abdominal pain ritonavir Saquinavir: GI irritation, peripheral neuropathy, headache, rash Hard gel cap (Invirase) 400 or 1000 mg bid Soft gel cap (Fortovase) 1200 mg tid Fusion Inhibitor Enfuvirtide (Fuzeon) 90 mg bid GI irritation, rash, hypotension, injection site reaction CNS, central nervous system; GI, gastrointestinal tract.(150 mg) (Combivir, twice daily) plus ritonavir (400 mg) and lopinavir mucous membranes and contaminated maternal blood and genital(100 mg) (Kaletra, twice daily) is recommended. The patient’s response tract secretions. Specifically, amniotomy, scalp monitoring, scalp pHto treatment should be evaluated by obtaining serial measurements of assessment, episiotomy, and instrumental delivery should be avoidedviral load. If a clear response to treatment has not occurred within 12 if at all possible. Although all of these agents have potentially seriousto 16 weeks, the patient should have viral genotyping to determine side effects in the mother, only efavirenz is clearly teratogenic in thewhether she has a resistant organism. If resistance is identified, the fetus.entire antiviral regimen should be changed in accordance with the If the patient does not have an optimal response to therapy and hersusceptibility pattern identified. viral load remains greater than 1000 copies/mL, she should be deliv- If the therapy reduces the patient’s viral load to less than 1000 ered by cesarean at approximately 38 weeks’ gestation, before the onsetcopies/mL, vaginal delivery is acceptable, provided that there are no of labor and rupture of membranes. Amniocentesis should not beother indications for cesarean delivery. During labor, every precaution routinely performed before this procedure, because it poses a small riskshould be taken to minimize contact between the infant’s skin and of transmitting HIV infection to the infant.
  • 35. CHAPTER 38 Maternal and Fetal Infections 773 Regardless of the method of delivery, the patient should receiveintravenous zidovudine during delivery (2 mg/kg for 1 hour, then Diagnosis1 mg/kg/hr until delivery). For patients scheduled for cesarean delivery, Many pregnant women with listeriosis are asymptomatic. When symp-the infusion should begin approximately 4 hours before surgery. tomatic, they present with a flulike syndrome characterized by fever,Infants delivered to infected mothers typically are treated with antiret- chills, malaise, myalgias, back pain, and upper respiratory complaints.roviral agents for at least 6 weeks after delivery.283-287 Such symptoms occur in two thirds of cases.297 The viral-like prodrome If the HIV status of the patient is unknown and she is admitted in characterizes the bacteremic stage of listeriosis. Gellin and Broome291labor, a rapid serologic screening should be performed. Current assays suggested that this is probably the time when the placenta and fetusshould yield reliable results within 1 hour. Management of seropositive are seeded with L. monocytogenes. Maternal infection tends to be mildpatients and their infants should proceed as outlined earlier until and is not associated with significant morbidity. However, diffusedefinitive testing is completed.288,289 sepsis may occur on occasion. No specific clinical manifestations have been demonstrated that help to distinguish listeriosis from other infec- tions that may occur during pregnancy. Therefore, pregnant women presenting with these symptoms in the late second or early third tri-Listeriosis mester should be evaluated for possible listeriosis. Early-onset neonatal listeriosis occurs in infants who are infectedEpidemiology and Pathogenesis in utero, often before the start of labor, and manifests during the firstListeriosis is an infection caused by L. monocytogenes, a motile, non– few hours to days of life. Late-onset neonatal listeriosis occurs in termspore-forming, gram-positive bacillus. Although seven species of Lis- infants who appear healthy at birth and manifest infection several daysteria are recognized, L. monocytogenes is the principal human pathogen. to weeks after delivery.291 Meningitis is more common than sepsis withPatients who are immunocompromised and pregnant women and late-onset disease. Either intrapartum transmission or nosocomialtheir newborns are particularly susceptible to infection with L. mono- transmission after delivery can result in late-onset infection.291cytogenes. Of concern to the obstetrician is the association between Because of the high mortality rate associated with both early- andmaternal listerial infection and stillbirth, preterm labor, and fetal infec- late-onset neonatal listerial infection, it is crucial that the obstetriciantion. High perinatal morbidity and mortality rates have been reported maintain a high index of suspicion that any febrile illness in pregnancyfor listerial infection in pregnancy.290-294 may be due to L. monocytogenes. In patients with these symptoms, As with GBS infection, neonatal listeriosis has been divided into cervical and blood cultures should be obtained for L. monocytogenestwo serologically and clinically distinct types. Early-onset disease, asso- as soon as possible. Because colonies of L. monocytogenes may be mis-ciated with serotypes Ia and IVb, takes the form of a diffuse sepsis with taken on the Gram stain for diphtheroids and therefore ignored, it isinvolvement of multiple organs, including the lungs, liver, and CNS. important to inform the microbiologist that listerial infection is aEarly-onset listeriosis is associated with a high rate of stillbirth and a concern. In febrile pregnant women, a Gram stain revealing gram-high neonatal mortality rate. It appears to occur more frequently in positive pleomorphic rods with rounded ends is highly suggestive of,low-birth-weight infants. Late-onset listeriosis manifests as meningitis, and should be presumed to be, L. monocytogenes.usually in term infants born to mothers with uneventful perinatalcourses. Neurologic sequelae, such as hydrocephalus and mental retar-dation, are common with late-onset disease. In addition, a mortality Treatmentrate approaching 40% has been reported.290-294 Penicillin G and ampicillin are effective in vivo against L. monocyto- It is possible that an ascending route of infection from cervical genes. Current opinion holds that optimal therapy includes a combina-colonization with L. monocytogenes plays a role in the pathogenesis of tion of ampicillin plus an aminoglycoside. Maternal treatment consistsneonatal infection. However, the more important and more common of ampicillin (1 to 2 g intravenously every 4 to 6 hours) and gentamicinroute of infection is hematogenous dissemination of the organism (2 mg/kg intravenously every 8 hours). For the newborn, the ampicillinthrough the placenta, which leads to placental abscesses and ultimately dosage is 200 mg/kg/day in 4 to 6 divided doses. The duration of treat-to fetal septicemia. ment is usually 1 week. A single case report has suggested that, follow- Human listeriosis manifests in both epidemic and sporadic forms. ing documentation by amniocentesis of intrauterine listerial infection,The epidemic form is associated with contamination of food and food antibiotic treatment without immediate delivery may be successful andproducts. Foods that particularly pose a risk include fresh, unpasteur- may result in a normal healthy fetus.298,299 An earlier study300 also sug-ized cheeses (e.g., Mexican “queso fresco”) and processed meats such gested that rapid diagnosis and aggressive antibiotic management inas hot dogs.295 Cherubin and colleagues293 reviewed more than 120 the antenatal patient with listeriosis may reduce the complications ofcases of listeriosis. They identified pregnancy and neonatal status as this illness. In addition, these authors reviewed reported cases of liste-two of the major risk factors for this disease. Indeed, the deaths associ- rial septicemia and antepartum antibiotic use: There was one maternalated with listeriosis occurred predominantly among premature and death, and 16 of 20 infants survived. These data compared favorablystillborn infants delivered to infected pregnant women. Moreover, the to the perinatal mortality rate of 33% to 73% observed in cases ofearlier the stage of gestation when infection manifested, the higher the untreated maternal disease.risk of fetal death. Listerial infection tends to adversely affect immu-nocompromised adults and fetuses or neonates with immature immunesystems. The sporadic form of listeriosis occurs more commonly than the Mumpsepidemic form. The incidence of listeriosis appears to be decreasing.The crude incidence in 2003 was 3.1 cases per 1 million population. The Epidemiology and Pathogenesisdecrease in the last decade is thought to be the result of a lower preva- The diagnosis of mumps is usually made on the basis of clinical exami-lence of L. monocytogenes contamination of ready-to-eat foods.296 nation. Mumps is an acute, generalized nonexanthmatous infection
  • 36. 774 CHAPTER 38 Maternal and Fetal Infectionswith a predilection for the parotid and salivary glands. The infectionalso can affect the brain, pancreas, and gonads. Mumps is caused byan RNA virus that is a member of the paramyxovirus family. It is Parvovirus Infectiontransmitted by saliva and respiratory droplet contamination and hasbeen recovered from salivary and respiratory secretions from 7 days Epidemiology and Pathogenesisbefore the onset of parotitis until 9 days afterward. The usual incuba- Parvovirus infection is a rare, but potentially extremely serious, peri-tion period is 14 to 18 days. natal complication. The infection is caused by a DNA organism, the B19 parvovirus. The virus is transmitted primarily by respiratory drop- lets and infected blood products. Immunity to parvovirus increasesDiagnosis progressively throughout childhood and young adult life. Approxi-The prodrome of mumps consists of fever, malaise, myalgias, and mately 50% to 60% of women of reproductive age have evidence ofanorexia. Parotitis follows within 24 hours and is characterized by prior infection, and immunity is long-lasting.305,306swollen and tender parotid glands. In most cases, parotitis is bilateral. The incubation period for parvovirus is 10 to 20 days. The mostThe submaxillary glands are involved less often and almost never common clinical manifestation of infection is erythema infectiosumwithout parotid gland involvement. The sublingual glands rarely are (fifth disease). Erythema infectiosum is usually manifested by a low-affected. Although mumps usually is a self-limited and complication- grade fever, malaise, myalgias, arthralgias, and a “slapped cheek” facialfree disease, it can cause aseptic meningitis, pancreatitis, mastitis, thy- rash. An erythematous, lacelike rash also may extend onto the torsoroiditis, myocarditis, nephritis, and arthritis. and upper extremities. In children, parvovirus infection also can cause transient aplastic crisis. This same disorder may occur in adults who have an underlying hemaglobinopathy.306Adverse Effects in Pregnancy When maternal parvovirus infection occurs during pregnancy, theMumps in pregnant women is generally benign and no more severe virus can cross the placenta and infect red cell progenitors in the fetalthan in nonpregnant patients. Aseptic meningitis in pregnant patients bone marrow. The virus attaches to the i antigen on red cell stem cellsis neither more common nor more severe. Mortality in association and suppresses erythropoiesis, thereby resulting in severe anemia andwith mumps is extremely rare in both pregnant and nonpregnant high-output congestive heart failure. This same antigen also is presentpatients. on fetal myocardial cells, and, in some fetuses, the viral infection causes Mumps during the first trimester is associated with a twofold a cardiomyopathy that further contributes to heart failure.306increase in the incidence of spontaneous abortion. There is no associa- The most obvious manifestation of congenital infection is hydropstion between maternal mumps infection and preterm delivery, fetal fetalis. The risk of hydrops is directly related to the gestational age atgrowth restriction, or perinatal mortality.301 which maternal infection occurs. If infection develops during the first Whether mumps infection may result in congenital disease remains 12 weeks of gestation, the risk of hydrops varies from less than 5%controversial.302 Despite animal studies in which mumps virus induced to approximately 10%. If infection occurs during weeks 13 throughcongenital malformations, definitive evidence of a teratogenic poten- 20, the risk of infection decreases to 5% or less. If infection occurstial for mumps virus in humans has not been reported. Siegal303 noted beyond the 20th week of gestation, the risk of fetal hydrops is 1%that the rate of congenital malformations in infants born to women or less.307-309who had mumps during pregnancy (2 of 117) was no different thanthe rate in infants born to uninfected mothers (2 of 123). The pre-dominant concern has been the postulated association between mater- Diagnosisnal mumps infection and the development of subsequent congenital The best way to confirm the diagnosis of maternal parvovirus infectioncardiac abnormalities, specifically endocardial fibroelastosis.304 The is through serologic testing. Table 38-16 illustrates the possible com-issue remains unresolved. binations of serologic test results that may occur in women who are being evaluated for possible parvovirus infection. Once maternal infection is confirmed, the fetus should be evaluatedTreatment for evidence of anemia. The best test for assessment of anemia is ultra-The treatment of mumps both in pregnant and nonpregnant patients sound assessment of middle cerebral artery (MCA) via Doppler velo-is symptomatic. Analgesics, bed rest, and application of cold or heat to cimetry. Serial examinations should be performed for at least 8 weeksthe parotid glands are useful. Maternal mumps is not an indication fortermination of pregnancy. The live-attenuated mumps vaccine is effec-tive in preventing primary mumps. Ninety-five percent of vaccinated TABLE 38-16 POSSIBLE RESULTS OFsusceptible subjects develop antibodies without clinically adverse reac- SEROLOGIC TESTS FORtions. The duration of protection afforded by immunization is not PARVOVIRUS AFTERknown. DOCUMENTED EXPOSURE Although mumps vaccine virus has been recovered from fetal andplacental tissue when vaccination occurred during pregnancy, there is IgM IgG Interpretationno evidence that the vaccine virus is teratogenic in humans. Neverthe-less, given the innocuous nature of mumps in pregnancy, immuniza- Negative Negative Susceptibletion with the mumps live-virus vaccine in pregnancy is contraindicated Negative Positive Prior immunity—protected against second infectionson the theoretical grounds that the developing fetus might be harmed. Positive Negative Acute infection—within previous 7 daysHowever, mumps vaccination should not be considered an indication Positive Positive Subacute infection >7 days and <120 daysfor pregnancy termination. Women vaccinated with mumps vaccineshould not become pregnant for at least 1 month. Ig, immunoglobulin.
  • 37. CHAPTER 38 Maternal and Fetal Infections 775after documentation of maternal seroconversion, because the incuba- The rubella virus is spread by respiratory droplets. From the uppertion period for fetal infection may be longer than that observed in respiratory tract, the virus travels quickly to the cervical lymph nodeschildren and adults. and then is disseminated hematogenously throughout the body. The The most obvious ultrasound manifestation of fetal anemia is incubation period is approximately 2 to 3 weeks. The virus is presenthydrops. However, by the time sonographic evidence of hydrops is in blood and nasopharyngeal secretions for several days before appear-present, the fetal hematocrit is likely to be less than 20%. Therefore, a ance of the characteristic rash and continues to be shed from themore precise way to detect evolving fetal anemia is to assess Doppler nasopharynx for several days after appearance of the rash. Therefore,velocimetry in the fetal MCA.310 Increases in peak systolic velocity in the patient may be contagious for a period of 7 to 10 days.318this vessel correlate well with fetal hematocrit. If velocimetry indicates Antibody against rubella does not normally appear in the serumfetal anemia, a cordocentesis should be performed to determine the until after the rash has developed. Acquired immunity to rubellafetal hematocrit. If anemia is confirmed, an intrauterine blood transfu- usually lasts for life. Second infections have occurred after both naturalsion should be performed. infections and vaccination, but recurrent infections usually are not associated with serious illness, viremia, or congenital infection.TreatmentTwo retrospective studies have demonstrated that intrauterine trans- Clinical Presentationfusion is lifesaving in the setting of congenital parvovirus infection. Most infections with rubella are subclinical. Of those individuals whoThe first investigation was published by Fairley and collegues.311 They do show symptoms, most have mild constitutional symptoms such asreviewed 66 cases of fetal hydrops caused by parvovirus infection. malaise, headache, myalgias, and arthralgias. The principal clinicalTwenty-six fetuses were dead at the time of diagnosis, and two were manifestation of rubella is a widely disseminated, nonpruritic, ery-electively aborted. Twelve of the 38 live fetuses had an intrauterine thematous, maculopapular rash. Postauricular adenopathy and mildtransfusion, three of whom died. Among the 26 fetuses who did not conjunctivitis also are common. These clinical manifestations usuallyreceive an intrauterine transfusion, 13 died. The odds ratio for fetal are short-lived and typically resolve within 3 to 5 days.death in infants who received a transfusion was 0.14 (CI, 0.02 to 0.96).A second important study was published by Rodisand associates.312They surveyed specialists in maternal-fetal medicine and reported the Diagnosisoutcomes of 460 cases of parvovirus infection. Twenty-seven of 164 The differential diagnosis of rubella includes rubeola, roseola, otherfetuses who received an intrauterine transfusion died. Of the 296 viral exanthems, and drug reaction. Rubella usually can be distinguishedfetuses who did not receive an intrauterine transfusion, 138 died. The from these other conditions on the basis of the characteristic rash andobserved difference in outcome was highly significant (P < .001). serologic testing. Serum IgM antibody concentration reaches a peak 7Although cases of spontaneous resolution of fetal hydrops have been to 10 days after the onset of illness and then declines over a period ofreported, the studies presented here clearly support a firm recommen- 4 weeks. The serum concentration of IgG rises more slowly, but anti-dation for intrauterine transfusion (Level II—2 evidence, “A” body levels persist throughout the lifetime of the individual.318recommendation). Infants who survive intrauterine infection with parvovirus usuallyhave an excellent long-term prognosis.313 However, isolated case reports Congenital Rubella Infectionhave been published documenting neurologic morbidity and pro- Because of the success of rubella vaccination campaigns, the incidencelonged, transfusion-dependent anemia.314,315 More recently, Nagel and of congenital rubella syndrome (CRS) in the United States has declinedcolleagues316 reported an 8-year follow-up of 16 hydropic fetuses who dramatically. Fewer than 50 cases of congenital rubella occur each year.received intrauterine transfusions for congenital parvovirus infection However, approximately 10% to 20% of women in the United Statesand survived. Eleven (68%) of the children were normal, and 5 (32%) remain susceptible to rubella, and their fetuses are at risk for serioushad delayed psychomotor development. In light of these reports, a injury should infection occur during pregnancy.319third-trimester ultrasound to reassess fetal growth and evaluate the Rubella virus crosses the placenta by hematogenous dissemination,anatomy of the CNS, together with long-term surveillance for neuro- and the frequency of congenital infection is critically dependent on thelogic problems, seems to be a prudent course of management. time of exposure to the virus. The fetus is not at risk from infection before the time of conception. However, approximately 50% to 80% of infants exposed to the virus within 12 weeks after conception will manifest signs of congenital infection. The rate of congenital infectionRubella declines sharply with advancing gestational age, so that very few fetuses are affected if infection occurs beyond 18 weeks of gestation.320,321Epidemiology The four most common anomalies associated with CRS are deaf-Rubella (also called “German measles” or “3-day measles”) is caused ness (affecting 60% to 75% of fetuses), eye defects such as cataractsby an RNA virus. Rubella infection develops primarily in young chil- or retinopathy (10% to 30%), CNS defects (10% to 25%), anddren and adolescents and is most common in the springtime. Major cardiac malformations (10% to 20%). The most common cardiacepidemics of rubella occurred in the United States in 1935 and 1964; abnormality is patent ductus arteriosus, although supravalvular pul-minor sporadic epidemics occurred approximately every 7 years until monic stenosis is perhaps the most pathognomonic. Other possiblethe late 1960s. With licensure of an effective vaccine in 1969, the fre- abnormalities include microcephaly, mental retardation, pneumonia,quency of rubella declined markedly. In 1999, the incidence of rubella fetal growth restriction, hepatosplenomegaly, hemolytic anemia, andwas 0.1 per 100,000.317 Persistence of this infection appears to be caused thrombocytopenia.320-323by failure to vaccinate susceptible individuals rather than by a lack of A variety of tests have been proposed for the diagnosis of CRS. Fetalimmunogenicity of the vaccine.318 blood, obtained by cordocentesis, can be used to determine the total
  • 38. 776 CHAPTER 38 Maternal and Fetal Infectionsand viral-specific IgM concentration. However, cordocentesis techni- pression, and pregnancy. Precautions also are necessary in the rarecally is difficult before 20 weeks’ gestation, and fetal immunoglobulins individual with neomycin allergy.usually cannot be detected before 22 to 24 weeks. Chorionic villi, fetalblood, and amniotic fluid samples all can be tested via PCR for rubellaantigen. Because of its lower complication rate, amniocentesis is theprocedure of choice. Although these tests can demonstrate that rubella Rubeolavirus is present in the fetal compartment, they do not indicate thedegree of fetal injury. Furthermore, the possibility of false-positive test Epidemiologyresults cannot be excluded. Accordingly, detailed ultrasound examina- The measles (rubeola) virus is a single-stranded RNA paramyxovirustion is the best test to determine whether serious fetal injury has that closely is related to the canine distemper virus. The wild virusoccurred as a result of maternal rubella infection. Possible anomalies is pathogenic only for primates, and humans are the only naturaldetected by ultrasound include growth restriction, microcephaly, CNS host.abnormalities, and cardiac malformations. The virus is spread by respiratory droplets and is highly contagious. The prognosis for infants with CRS is guarded. Approximately 50% Between 75% and 90% of susceptible contacts become infected afterof affected individuals have to attend schools for the hearing-impaired. exposure. Before a measles vaccine was available, essentially all childrenAn additional 25% require at least some special schooling because of experienced natural measles infection. Since licensure of the firsthearing impairment, and only 25% are able to attend mainstream measles vaccine in 1963, the incidence of infection has decreased byschools.322 almost 99%. As expected, children younger than 10 years of age have shown the greatest decline in incidence. During the mid-1980s, almost 60% of reported cases affected children older than 10 years of age,Prevention of Rubella Infection compared with only 10% of cases occurring during the period fromIdeally, women of reproductive age should have a preconception 1960 to 1964.325appointment when they are contemplating pregnancy. At that time, In recent years, two major types of measles outbreaks have occurredthey should be evaluated for immunity to rubella. If serologic testing in the United States. One type has developed among unvaccinateddemonstrates that they are susceptible, they should be vaccinated with preschoolers, including children younger than 15 months of age.rubella vaccine before conception occurs. If preconception counseling Another type has occurred among previously vaccinated school-ageis not possible, patients should have a test for rubella at the time of children and college students. Approximately one third of the cases intheir first prenatal appointment. Women who are susceptible to rubella the latter type of outbreak have been in individuals who were previ-should be counseled to avoid exposure to other individuals who may ously vaccinated. Presumably, these cases result from either primaryhave viral exanthems. failure to respond to the first vaccine or secondary failure, a situation If a susceptible woman subsequently is exposed to rubella, serologic in which an adequate serologic response develops initially but immu-tests should be obtained to determine whether acute infection has nity wanes over time.325,326occurred. If acute infection is documented by identification of IgM The clinical manifestations of measles usually appear within 10 toantibody, the patient should be counseled about the risk of CRS. The 14 days after exposure. The most common signs and symptoms arediagnostic tests for detection of congenital infection should be reviewed, fever, malaise, coryza, sneezing, conjunctivitis, cough, photophobia,and the patient should be offered the option of pregnancy termination, and Koplik spots (blue-gray specks on a red base that develop on thedepending on the assessed risk of serious fetal injury. buccal mucosa opposite the second molars). Patients typically develop Pregnant women who are susceptible to rubella should be vacci- a generalized nonpruritic maculopapular rash that begins on the facenated immediately after delivery. The rubella vaccine is available in and neck and then spreads to the trunk and extremities. It usually lastsmonovalent, bivalent (measles-rubella), and trivalent (measles- for approximately 5 days and subsequently recedes in the same sequencemumps-rubella) forms. Approximately 95% of patients who receive in which it appeared. The duration of illness is approximately 7 to 10rubella vaccine seroconvert, and antibody levels persist for at least 18 days (hence, the name, the “10-day measles”). Patients are contagiousyears in more than 90% of vaccinees. from 1 to 4 days before the onset of coryza until several days after Adverse effects of vaccination are minimal, even in adults. Fewer appearance of the rash. Immunity to measles should be lifelongthan 25% of patients experience mild constitutional symptoms such after wild virus infection and is mediated by both humoral and cell-as low-grade fever and malaise. Fewer than 10% of vaccinees have mediated mechanisms.arthralgias, and fewer than 1% develop frank arthritis. Other com- Although measles is typically a minor illness, some patients developplaints, such as pain and paresthesias, have been rare. Women who serious sequelae. Otitis media occurs in 7% to 9% of infected patients;have received the vaccine cannot transmit infection to susceptible bronchiolitis and pneumonia affect 1% to 6%. A severe form of hepa-contacts, such as young children in the home, and vaccinated women titis also may occur. In a report by Atmar and associates,327 7 (54%) ofmay breastfeed their infants. In addition, the vaccine can be adminis- 13 pregnant women with measles developed hepatitis.tered in conjunction with immunoglobulin preparations such as Encephalitis occurs in approximately 1 in every 1000 cases ofRh immune globulin.319,323 Women who receive rubella vaccine measles. It results from both viral infection of the CNS and a hyper-should practice secure contraception for at least 1 month after sensitivity reaction to the systemic viral infection. Measles encephalitisvaccination.324 may lead to permanent neurologic impairment, including mental To decrease the occurrence of rubella, recommended public health retardation; the mortality rate from this complication is approximatelypolicies include vaccinating all children aged 12 to 15 months or older 15% to 33%. Another unusual, but extremely serious, complication ofand all adolescents and adults not known to be immune, unless they measles is subacute sclerosing panencephalitis. This complicationare pregnant or have other contraindications to vaccination. Also, all occurs in 0.5 to 2 cases per 1000. It usually develops about 7 years afterprenatal patients should be screened as early as possible in pregnancy.318 the acute measles infection and is more common in children who hadContraindications to vaccination include febrile illness, immunosup- measles before the age of 2 years. The disorder is characterized by
  • 39. CHAPTER 38 Maternal and Fetal Infections 777progressive neurologic debilitation and has an almost uniformly fatal Committee on Immunization Practices (ACIP) recommends that alloutcome.325,327 individuals who have not been infected with the live virus receive a A final complication is atypical measles. This disorder is a severe second dose of the vaccine at 4 to 6 years of age. If this second dose isform of measles reinfection that affects young adults previously not administered in childhood, it should be administered before avaccinated with the formalin-inactivated killed measles vaccine that woman plans her first pregnancy. There are only three contraindica-was distributed in the United States from 1963 to 1967. Affected tions to use of the live measles vaccine: pregnancy, severe febrile illness,patients have extremely high antibody titers to measles, and they and history of anaphylactic reaction to egg protein or neomycin.332experience high fever, pneumonitis, pleural effusion, and a coarse If a susceptible pregnant woman is exposed to measles, she shouldmaculopapular, hemorrhagic, or urticarial rash. Although the disease immediately receive passive immunoprophylaxis with immune globu-usually is self-limited, atypical measles can lead to hepatic, cardiac, and lin, 0.25 mL/kg intramuscularly, up to a maximum dose of 15 mL. Ifrenal failure. Interestingly, affected patients are not contagious to she develops measles despite immunoprophylaxis, she should beothers.325,328 observed for evidence of serious complications such as otitis media, Five clinical criteria should be present to establish the diagnosis of hepatitis, encephalitis, and pneumonia. Secondary bacterial infectionsmeasles: fever of 38.3° C or higher, characteristic rash lasting longer should be treated promptly with antibiotics. Administration of aero-than 3 days, cough, coryza, and conjunctivitis. Although the virus can solized ribavirin may be of benefit to patients with severe viralbe cultured, the mainstay of diagnostic tests is detection of antibody pneumonitis.333to measles. The hemagglutination inhibition assay and the enzyme- The affected patient should be counseled that the risk of injury tolinked immunosorbent assay (ELISA) are the most useful serologic her fetus is very low. The most effective method of evaluating the fetustests for determination of a patient’s susceptibility to measles and for for in utero infection is detailed ultrasound examination. Findingsconfirmation of infection. The serologic confirmation of acute measles suggestive of in utero infection include microcephaly, growth restric-virus infection is based on detection of IgM-specific antibody or a tion, and oligohydramnios. If the mother developed measles within 7fourfold change in the IgG titer in acute and convalescent sera. The to 10 days of delivery, the neonate should receive intramuscular immu-acute titer for IgG antibody should be obtained within 3 days after the noglobulin in a dose of 0.25 mL/kg. These infants subsequently shouldonset of the rash, and the convalescent titer should be obtained 10 to receive the live measles vaccine when they are 15 months of age.33320 days later.Obstetric Considerations SyphilisSeveral reports have documented an increase in maternal mortality Syphilis is a chronic systemic infection resulting from the spirocheteassociated with measles infection during pregnancy; most deaths have Treponema pallidum. It has been recognized for several centuries thatbeen caused by pulmonary complications. In one of the earliest inves- primary, secondary, and early latent syphilis in pregnant women causetigations, Christensen and colleagues329 described an epidemic of infection of the fetus, with resultant stillbirths, congenital abnormali-measles in Greenland in 1951. Four (4.8%) of 83 pregnant women who ties, and active disease at birth. Because of this significant morbidity,developed measles died. An unspecified number of these women also great emphasis has been placed on routine screening of all pregnanthad active tuberculosis. In the report by Atmar and associates,327 one women for syphilis. Acquisition is usually through sexual contact.(8%) of 13 pregnant women with measles died because of severerespiratory infection. Eberhart-Phillips and coworkers330 evaluated 58pregnant women with measles. Thirty-five (60%) required hospitaliza- Epidemiologytion, 15 (26%) developed pneumonia, and 2 (3%) died. Since the startling prediction in 1937 by United States Surgeon General Reports also have described a slight increase in the frequency of Thomas Parran that 10% of Americans would be infected with syphilispreterm delivery and spontaneous abortion among women who devel- during their lives, the rates of primary and secondary syphilis haveoped measles during pregnancy. In the study by Eberhart-Phillips and dramatically decreased, finally reaching a nadir in 2000 (Fig. 38-7).334colleagues,330 13 (26%) of 50 women with continuing pregnancies This striking decline was associated with the institution of publicdelivered preterm. Fortunately, the frequency of congenital anomalies health control measures and the availability of penicillin. The generallyis not increased significantly in women who contract measles during downward trend in the syphilis rate was temporarily interrupted in thepregnancy. late 1970s and early 1980s when the rates of primary and secondary Although congenital anomalies are rare, infants of mothers who are syphilis began increasing, in large part due to increases among menacutely infected at the time of delivery are at risk for neonatal measles. having sex with men. After the advent of the HIV/AIDS epidemic andThis infection typically develops within the first 10 days of life and public health efforts promoting safer sex, the rates of syphilis resumedresults from transplacental transmission of the virus. The mortality their downward trend.rate in preterm and term infants with neonatal measles has been However, in the late 1980s another transient epidemic of primaryreported to be as high as 60% and 20%, respectively.331 and secondary syphilis occurred in the United States.4 Coincident with this rise was a dramatic increase in reported cases of congenital syphi- lis.335 After a low of 108 cases of congenital syphilis in 1978, there werePreventive Measures 350 cases reported in 1986, and 3850 cases in 1992, with an incidenceIdeally, all women of reproductive age should have evidence of immu- rate of 100 per 100,000 live births (Fig. 38-8). Almost 90% of congeni-nity to measles before attempting pregnancy. Originally, public health tal syphilis cases occurred among blacks or Hispanics, and 50% of theofficials thought that a single injection of live measles vaccine when a cases occurred among mothers receiving no prenatal care. Reasonschild was approximately 15 months of age provided lifelong immunity. for this dramatic upsurge include exchange of drugs (e.g., “crack”As noted previously, however, several recent outbreaks of measles have cocaine) for sex; decreased funding for syphilis control; treatment ofoccurred due to secondary vaccine failures. Accordingly, the Advisory penicillinase-producing N. gonorrhoeae with spectinomycin, which
  • 40. 778 CHAPTER 38 Maternal and Fetal Infections 25 Pathogenesis Men T. pallidum is efficiently transmitted during sexual contact, and syphilis 20 Women is acquired in 50% to 60% of partners after a single sexual exposure to an infected individual with early syphilis. Spirochetes may gain access Incidence 15 through any break in the skin or via microscopic tears in genital tract mucosal surfaces, which occur almost universally during sexual inter- 10 course. The mean incubation time is 21 days, with a range of 10 to 90 days.4 The primary stage of syphilis is characterized by the chancre, which 5 appears at the site of entry for T. pallidum. The chancre is a painless, nontender, ulcerated lesion with a raised border and an indurated base. 0 The most common site for the chancre is the genital area. In men, the 1990 1995 2000 2005 Year lesion is easily apparent, and syphilis is often diagnosed in its primary stage. In women, the lesion most commonly is on the cervix or in theFIGURE 38-7 Incidence of primary and secondary syphilis per vagina and is not recognized. Therefore, the chancre often escapes100,000 population, by sex—United States, 1990-2005. During detection in women, and it is unusual to diagnose the primary stage2004-2005, the incidence of primary and secondary syphilis in the of syphilis in females. Usually only a single chancre is present, butUnited States increased slightly, from 2.7 to 3.0 cases per 100,000 multiple chancres occur in up to 30% of cases. Painless inguinal(from 0.8 to 0.9 per 100,000 in women, and from 4.7 to 5.1 per lymphadenopathy is frequently present. The primary chancre, even100,000 in men). without treatment, heals spontaneously in 3 to 6 weeks. After resolution of the primary stage, the patient enters the second- ary or spirochetemia (bacteremia) stage of syphilis. Syphilis always disseminates during the secondary stage. Any organ can potentially be 120 infected, especially the CNS. Although the secondary stage of syphilis 110 is characterized by involvement of all major organ systems by T. 100 palladium, it manifests most commonly with skin and mucous mem- Change in surveillance 90 brane lesions. These clinical manifestations of secondary syphilis case definition 80 include a generalized maculopapular rash that begins on the trunk and proximal extremities and spreads to the entire body, especiallyIncidence 70 60 involving the palms and soles; mucous patches; condyloma latum; and generalized lymphadenopathy. These mucocutaneous lesions are 50 highly contagious. 40 Even without treatment, the manifestations of secondary syphilis 30 spontaneously clear within 2 to 6 weeks, and the latent stage of syphilis 20 is entered, in which there is no apparent clinical disease. In the era 10 before the availability of penicillin, about 25% of such patients had a 0 recrudescence of secondary syphilis. Because these relapses usually 1975 1980 1985 1990 2000 2005 occurred within 1 year, the term “early latent period” was applied toFIGURE 38-8 Incidence of congenital syphilis (per 100,000 live this time period. In the late latent stage (>1 year), patients are notbirths) among infants aged 0 to 12 months—United States, 1975- contagious by sexual transmission, but the spirochete may still be2005. The incidence of congenital syphilis has declined since 1991. transplacentally transmitted to a fetus.340,341In 2005, the rate was 8.0 cases per 100,000 live births. Without treatment, one third of patients progress and develop ter- tiary syphilis, characterized by involvement of the cardiovascular, central nervous, or musculoskeletal, and/or various organ systems with gummas (late benign tertiary syphilis).340 One half of patients withdoes not treat incubating syphilis; and the use of revised reporting tertiary syphilis develop late benign syphilis (gummas), one fourthguidelines for congenital syphilis, which were introduced in 1989. develop cardiovascular disease, and one fourth have neurologic disease. Following this latest epidemic, the rates of primary and secondary The cardiovascular manifestations of tertiary syphilis include aorticsyphilis fell from their peak in 1990 (18.4 cases per 100,000 population aneurysm and aortic insufficiency. In the CNS, tertiary disease pro-and more than 112,000 reported cases of primary and secondary syph- duces general paresis, tabes dorsalis, optic atrophy, and meningovas-ilis) to a nadir in 2000 (2.1 cases per 100,000 population and fewer cular syphilis. The Argyll-Robertson pupil (i.e., pupil does not react tothan 6000 reported cases of primary and secondary syphilis). This was light but accommodates) is virtually pathognomonic of tertiary syphi-the lowest rate since syphilis reporting began in 1941. Concomitant lis. The pathogenesis of tertiary syphilis is based on the tropism of T.with the plummeting rates of primary and secondary syphilis, the rates pallidum for arterioles, which results in obliterative endarteritis withof congenital syphilis also dramatically fell, declining from 3850 cases subsequent tissue destruction.in 1992 to 451 cases in 2002.336 As a result of this dramatic decline in syphilis rates, the CDClaunched the National Syphilis Elimination Plan in 1999. However, this Congenital Syphilisplan for elimination of syphilis in the United States has proved overly The clinical spectrum in congenital syphilis includes stillbirth, neona-optimistic.337-339 tal death, nonimmune hydrops, clinically apparent syphilis during the
  • 41. CHAPTER 38 Maternal and Fetal Infections 779early months of life (early congenital syphilis), and the classic stigmataof late congenital syphilis (see Table 38-17).4 The most severe adverse Diagnosispregnancy outcomes occur with primary or secondary syphilis. Preg- The most definitive methods for diagnosing early syphilis are dark-nant women diagnosed with syphilis are usually in the latent stage and field microscope examination or direct fluorescent antibody tests ofhave had the disease for longer than 1 year. Consequently, about two lesion exudates or tissue.12 A presumptive diagnosis can be made usingthirds of infants with early congenital syphilis are asymptomatic at serologic testing. The serologic tests are classified into two types: non-birth and do not develop evidence of active disease for 3 to 8 weeks. specific tests for reagin-type antibodies and specific antitreponemalChancres do not occur unless the disease is acquired at the time of antibody tests.passage through the birth canal. The characteristic manifestations of Nonspecific antibody tests include the Venereal Disease Researchearly congenital syphilis (onset at <2 years of age) include a maculo- Laboratory (VDRL) test and the rapid plasma reagin (RPR) test. Thesepapular rash that may progress to desquamation or formation of vesi- are used for screening. All pregnant women should be screened at thecles and bullae, snuffles (a flulike syndrome associated with a nasal initial prenatal visit. High-risk patients should be rescreened at 28discharge), mucous patches in the oral pharyngeal cavity, hepato- weeks of gestation. In areas with high rates of congenital syphilis,splenomegaly, jaundice, lymphadenopathy, pseudoparalysis of Parrot rescreening at admission in labor is also recommended. In populationsdue to osteochondritis, chorioretinitis, and iritis.341 in which prenatal care is less than optimal, RPR-card test screening is Untreated or incompletely treated early congenital syphilis will recommended at the time pregnancy is diagnosed, with treatment ofprogress to the classic manifestations of late congenital syphilis. These patients who have a reactive test. The CDC recommends that anyinclude Hutchinson teeth, mulberry molars, interstitial keratitis, woman who delivers a stillborn infant after 20 weeks of gestationeighth-nerve deafness, saddle nose, rhagades, saber shins, and neuro- should be screened for syphilis. In addition, the CDC advises that nologic manifestations (mental retardation, hydrocephalus, general infant should leave the hospital without the maternal serostatus forparesis, optic nerve atrophy, and Clutton joints). These stigmata associ- syphilis having been assessed at some time in pregnancy.12ated with late congenital syphilis are the result of scarring induced by Treponema-specific tests are employed for confirming the diagnosisearly lesions or reactions to persistent inflammation.341 of syphilis in patients who have reactive VDRL or RPR results. These T. pallidum can cross the placenta and infect the fetus as early as tests include the fluorescent treponemal antibody absorption (FTA-the 6th gestational week.342 Clinical manifestations are not apparent ABS) test and the T. pallidum particle agglutination (TP-PA) test.until after 16 weeks of gestation, when fetal immunocompetence devel- Usually the nonspecific test result becomes nonreactive after treat-ops. Therefore, the risk to the fetus is present throughout pregnancy, ment. In some patients, a low titer may persist for a long time, in someand the degree of risk is related to the quantity of spirochetes in the cases for life. Once reactive, specific treponemal tests usually remainmaternal bloodstream. Transmission may also occur intrapartum via positive for life. In pregnancy, it is best to consider all seropositivecontact with active genital lesions in the mother. Women with primary women as infected unless an adequate treatment history is documentedor secondary syphilis are more likely to transmit infection to their and sequential serologic antibody titers have declined.offspring than are women with latent disease. Maternal primary syphi- It is critical to recognize that when the syphilitic chancre firstlis and secondary syphilis are associated with a 50% probability of appears, both the nonspecific test results and the treponemal-specificcongenital syphilis and a 50% rate of perinatal death; early latent test results may be nonreactive. Therefore, lesions suspicious forsyphilis, with a 40% risk of congenital syphilis and a 20% mortality syphilis should be sampled for detection of spirochetes and submittedrate; and late latent syphilis, with a 10% risk of congenital syphilis.343,344 to the laboratory for dark-field examination and fluorescent-antibodySimilar high rates of morbidity and mortality among the infants of staining.mothers with untreated syphilis of less than 4 years’ duration were Although the CNS is involved in almost half of the patients withreported in 1959 by Inraham,345 who noted a perinatal death rate of early syphilis, fewer than 10% of patients with untreated syphilis43% (29% stillborn, and 14% neonatal); among liveborn infants, 41% progress to symptomatic late neurosyphilis. If patients are treatedhad congenital syphilis. appropriately for early syphilis, neurosyphilis should be extremely rare. Experience during the syphilis epidemic in the late 1980s and early The CDC has stated that, unless clinical signs or symptoms of neuro-1990s confirmed that untreated syphilis is associated with significant logic involvement are present, lumbar puncture is not recommendedand frequent adverse effects on pregnancy. Ricci and associates346 for routine evaluation in primary or secondary syphilis. In patientsreported that, among 56 cases of congenital syphilis, 19 (35%) were with latent syphilis, prompt CSF examination should be performed ifstillbirths, and the perinatal mortality rate was 464 per 1000 live births. any of the following conditions is present12:Preterm labor and delivery were significantly more common, infantswith congenital syphilis had significantly lower birth weights, and 1. Clinical evidence of neurologic involvement (e.g., cognitive21% had intrauterine growth restriction. McFarlin and coworkers335 dysfunction, motor or sensory deficits, ophthalmic or auditoryreviewed 253 cases of maternal syphilis. They reported a preterm symptoms, cranial nerve palsies, symptoms or signs ofdelivery rate of 28%; 10 (13.9%) of 72 cases of congenital syphilis meningitis)were stillbirths. In addition, the manifestations of congenital syphilis 2. Evidence of active tertiary syphilis (e.g., aortitis, gummas,are usually less severe in association with long-standing maternal iritis)disease than with early syphilis of less than 1 year’s duration. Coles 3. Treatment failureand colleagues,347 in a review of 322 cases of congenital syphilis in 4. HIV infection with latent syphilis or syphilis of unknownupstate New York from 1989 to 1992, reported that 31 (10%) stillbirths durationand 59 (19%) newborns with clinical evidence of congenital syphiliswere documented. Factors believed to contribute to the development Recently, it has been suggested that only HIV-infected patients withof congenital syphilis included infection late in pregnancy, treatment neurologic manifestations or a serum RPR result of 1/32 or greaterless than 30 days before delivery, misdiagnosis or inappropriate treat- require a lumbar puncture.348 Marra and colleagues349 studied 326ment of the mother, and no serologic testing during pregnancy. patients with syphilis in an attempt to define clinical and laboratory
  • 42. 780 CHAPTER 38 Maternal and Fetal Infectionsfeatures that identify patients with neurosyphilis. Sixty-five patients TABLE 38-17 CONGENITAL SYPHILIS CASE(20.1%) had neurosyphilis. In multivariate analysis, an RPR titer of DEFINITION1/32 or greater increased the odds of neurosyphilis almost 11-fold inHIV-uninfected individuals and almost sixfold among HIV-infected Confirmed Casepatients. In HIV-infected subjects, a CD4+ of 350 cells/mL or less con- Infant in whom Treponema palladium is identified by dark-fieldferred a 3.10-fold increased odds of neurosyphilis. microscopy, fluorescent antibody, or other specific stains in No single test is adequate to diagnose neurosyphilis in all patients. specimens from lesions, placenta, umbilical cord, or autopsy materialTherefore, the diagnosis is based on various combinations of tests,including reactive serologic tests, abnormal CSF cell count, elevated Presumptive Caseprotein, and/or a reactive CSF VDRL, with or without clinical mani- 1. Any infant whose mother had untreated* or inadequatelyfestations. CSF studies demonstrating pleocytosis, elevated protein treated syphilis at delivery, regardless of signs or symptoms†levels, and a reactive CSF VDRL are diagnostic of neurosyphilis. Onoccasion, however, results may be nonreactive when neurosyphilis is ORpresent. Recently, it has been suggested that increased levels of tau 2. Any infant or child who has a reactive treponemal test forprotein may be useful in discriminating neurosyphilis from syphilis syphilis and any one of the following:without nervous system involvement.350 a. Evidence of congenital syphilis on physical examination The diagnosis of reinfection or persistence of active syphilis can be b. Evidence of congenital syphilis on long-bone radiography c. Reactive CSF VDRL testmade in patients previously known to have syphilis by following the d. Elevated CSF white blood cell count (>5/mm3) or proteintiter of the quantitative VDRL. With successful therapy, the VDRL titer concentration (>5 mg/dL)should decrease and become negative or very low within 6 to 12 e. Reactive test for FTA-ABS-19S-IgM antibodymonths in early syphilis and within 12 to 24 months in late syphilis (>1year’s duration). A rising titer indicates the need for further diagnostic CSF, cerebrospinal fluid; FTA-ABS, fluorescent treponemal antibodymeasures, such as a lumbar puncture, and appropriate treatment. absorption; IgM, immunoglobulin M; VDRL, Venereal Disease Research Laboratory. The diagnosis of congenital syphilis is easily confirmed in the clini- *On penicillin therapy or penicillin given <30 days before delivery.cally apparent case in which a jaundiced, hydropic baby with florid † Clinical signs in an infant include hepatosplenomegaly, characteristicdisease and a large, edematous placenta are delivered and laboratory skin rash, condyloma lata, snuffles, jaundice, pseudoparalysis, anemia,studies confirm the presence of the disease. However, most infected thrombocytopenia, and edema. Stigmata in children older than 2 years of age include interstitial keratitis, nerve deafness, anterior bowing ofnewborns are asymptomatic at birth. Although the cord blood shins, frontal bossing, mulberry molars, Hutchinson teeth, saddlemay give a positive nonspecific test result for syphilis, the diagnosis nose, rhagades, and Clutton joints.of congenital syphilis is complicated by the transplacental transfer From Centers for Disease Control and Prevention: Congenital Syphilisof maternal nontreponemal and treponemal IgG antibodies to the Case Definition. Atlanta, GA: U.S. Department of Health and Humanfetus.12 Services, CDC, 1998. As a result, the interpretation of reactive serologic tests for syphilisin infants is difficult. Therefore, treatment decisions must be frequentlymade on the basis of (1) identification of syphilis in the mother; (2) field microscope confirmation or a fourfold rise in titer on a quantita-adequacy (or lack thereof) of maternal treatment; (3) presence of clini- tive nontreponemal test, should receive appropriate treatment.cal, laboratory or radiologic evidence of syphilis in the infant; and (4) Treatment schedules for syphilis recommended by CDC in 2006 arecomparison of maternal (at delivery) and infant nontreponemal sero- shown in Table 38-18. Penicillin administered parenterally is the pre-logic titers using the same test and same laboratory.12 Any infant with ferred treatment for all stages of syphilis.12a positive VDRL result but no clinical evidence of syphilis should have The preparation of penicillin used and the length of treatment areserial monthly quantitative VDRL tests for at least 9 months. A rising determined by the stage and clinical manifestations of the disease.titer indicates active disease and the need for therapy. Infected infants Although several alternatives to penicillin might be effective in non-may be asymptomatic and the serum VDRL may be normal if maternal pregnant penicillin-allergic patients, parenteral penicillin G is the onlyinfection occurred late in pregnancy. therapy with documented efficacy for syphilis during pregnancy. In In 1998, the CDC implemented a new case definition for congenital pregnancy, parenteral penicillin G is effective for treating maternalsyphilis surveillance (Table 38-17). A diagnosis of congenital syphilis infection, preventing transmission to the fetus, and treating establishedcan be confirmed by identifying spirochetes in suspicious lesions, fetal infection. Therefore, the CDC recommends that pregnant patientsbody fluids, or tissues with dark-field microscopy, silver staining, with syphilis in any stage who are allergic to penicillin should beimmunofluorescence, or PCR for T. pallidum DNA.351 Several new desensitized and treated with penicillin.12laboratory tests have been introduced to facilitate the diagnosis of Desensitization is a relatively safe and straightforward procedurecongenital syphilis. These include PCR and the rabbit infectivity test that can be accomplished orally or intravenously. Oral desensitization(RIT). is generally believed to be safer and easier to perform. Patients should be desensitized in a hospital setting, because serious IgE-mediated allergic reactions can occur. Desensitization can be accomplished inTreatment approximately 4 hours (Table 38-19), after which the first dose ofAll pregnant women who have a history of sexual contact with a person penicillin is administered. After desensitization, patients must bewith documented syphilis, dark-field microscope confirmation of the maintained on penicillin continuously for the duration of their thera-presence of spirochetes, or serologic evidence of syphilis via a specific peutic course.treponemal test should be treated. In addition, patients in whom the Although erythromycin was at one time considered an alternativediagnosis cannot be ruled out with certainty or those who have been to penicillin for the treatment of syphilis during pregnancy, its efficacypreviously treated but now show evidence of reinfection, such as dark- for treatment of syphilis in the fetus and for prevention of transmis-
  • 43. CHAPTER 38 Maternal and Fetal Infections 781 TABLE 38-18 CDC-RECOMMENDED TREATMENT OF SYPHILIS DURING PREGNANCY, 2006 Diagnosis Treatment 1. Primary, secondary, and early latent syphilis (<1 yr) Benzathine penicillin G, 2.4 million units IM in a single dose 2. Late latent syphilis (>1 yr), latent syphilis of unknown Benzathine penicillin G, 7.2 million units total, administered as 3 doses of 2.4 duration, and tertiary syphilis million units IM each at 1-wk intervals 3. Neurosyphilis Aqueous crystalline penicillin G, 18-24 million units per day administered as 3-4 million units IV every 4 hr or by continuous infusion for 10-14 days OR Procaine penicillin, 2.4 million units IM daily, plus probenecid 500 mg PO qid, both for 10-14 days 4. Penicillin-allergic Pregnant women with a history of penicillin allergy should have allergy confirmed and then be desensitized Modified from Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2006. MMWR Recommendations and Reports 55(RR-11):22-35, 2006. TABLE 38-19 ORAL DESENSITIZATION PROTOCOL FOR PATIENTS WITH A POSITIVE SKIN TEST FOR PENICILLIN ALLERGY* Penicillin V Suspension Dose† Amount (Units/mL)‡ mL Units Cumulative Dose (Units) 1 1,000 0.1 100 100 2 1,000 0.2 200 300 3 1,000 0.4 400 700 4 1,000 0.8 800 1,500 5 1,000 1.6 1,600 3,100 6 1,000 3.2 3,200 6,300 7 1,000 6.4 6,400 12,700 8 10,000 1.2 12,000 24,700 9 10,000 2.4 24,000 48,700 10 10,000 4.8 48,000 96,700 11 80,000 1.0 80,000 176,700 12 80,000 2.0 160,000 336,700 13 80,000 4.0 320,000 656,700 14 80,000 8.0 640,000 1,296,700 *Observation period: 30 minutes before parenteral administration of penicillin. † Interval between doses, 15 minutes; elapsed time, 3 hours and 45 minutes; cumulative dose, 1.3 million units. ‡ The specific amount of drug is diluted in approximately 30 mL of water and then administered orally. From Wendel GO Jr, Stark BJ, Jamison RB, et al: Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med 312:1229- 1232, 1985. Reprinted with permission from the New England Journal of Medicine.sion is inadequate. Although doxycycline and tetracycline are alter- ascites, hydrops, a thickened placenta) indicate a greater risk for fetalnatives for nonpregnant patients, they usually are not used in treatment failure.353pregnancy. Syphilis can involve the CNS during any stage of disease. Therefore, Concern has been raised as to whether the recommended regimens any patient with syphilis who demonstrates clinical evidence of neu-of penicillin are optimal in pregnancy. Several reports demonstrated rologic involvement should have a lumbar puncture to assess the CSFworrisome instances of treatment failures despite adherence to recom- for evidence of neurosyphilis. Patients with neurosyphilis shouldmended guidelines.335,352 A high maternal VDRL titer at the time of be treated with high doses of aqueous penicillin G, as noted indiagnosis, unknown duration of infection, treatment within 4 weeks Table 38-17.of delivery, and ultrasound signs of fetal syphilis (e.g., hepatomegaly, Obstetric caregivers should be aware that women treated for syphi-fetal hydrops, placentomegaly) are associated with failure to prevent lis during the second half of pregnancy are at risk for preterm labor orcongenital syphilis. fetal distress if the Jarisch-Herxheimer reaction occurs. The Jarisch- Because of these reports demonstrating a high failure rate for treat- Herxheimer reaction occurs commonly during the treatment of earlyment of syphilis in pregnancy, some experts recommend additional syphilis; among 33 pregnant women, the reaction complicated therapytherapy.12 A second dose of benzathine penicillin G (2.4 million units in 100% and 60% of patients treated for primary or secondary syphilis,intramuscularly) may be given 1 week after the initial dose for preg- respectively.354 The Jarisch-Herxheimer reaction characteristicallynant women with primary, secondary, or early latent syphilis. During includes fever, chills, myalgia, headache, hypotension, and transientthe second half of pregnancy, management of syphilis may be facili- worsening of cutaneous lesions. It commences within several hourstated by sonographic assessment for evidence of congenital syphilis. after treatment and resolves by 24 to 36 hours. Among pregnantSonographic signs of fetal or placental syphilis (e.g., hepatomegaly, women, the most frequent findings are fever (73%), uterine contrac-
  • 44. 782 CHAPTER 38 Maternal and Fetal Infectionstions (67%), and decreased fetal movement (67%). Transient late should be given a 10-day course of either aqueous crystalline penicillindecelerations were observed in 30% of monitored fetuses. G (50,000 units/kg IV every 12 hours for the first 7 days of life, Because of these findings, sonographic assessment of the fetus and then every 8 hours for the next 3 days) or procaine penicillinbefore initiating therapy for early syphilis in the last half of pregnancy (50,000 units/kg/day IM).12has been recommended.355 If the results are normal, ambulatory treat-ment may be initiated. If abnormal findings suggesting fetal infectionare identified, hospitalization for treatment and fetal monitoring is Preventionrecommended. Sanchez and Wendel352 demonstrated that, in the pres- Serologic screening of all pregnant women during the early stages ofence of severe fetal compromise before treatment, early delivery with pregnancy is recommended. In geographic areas with a high prevalencetreatment of the mother and neonate after delivery may yield an of syphilis and in patients at high risk, serologic testing should beimproved outcome. repeated at 28 to 32 weeks’ gestation and at delivery.12 For primary and secondary syphilis, patients should be re-exam-ined clinically and serologically at 6 months and 12 months aftertreatment. A two-dilution (fourfold) decline in the nontreponemaltiter at 1 year after treatment is used to define response.356 Patients with Toxoplasmosissigns or symptoms that persist or recur and those with a sustainedfourfold increase in the nontreponemal test titer have probably failed Epidemiology and Pathogenesistreatment or become reinfected. They should be re-treated, be assessed Toxoplasma gondii is a protozoan that has three distinct life forms:for HIV infection, and undergo analysis of the CSF. For re-treatment, trophozoite, cyst, and oocyst. The life cycle of this organism is depen-weekly injections of benzathine penicillin G 2.4 million units IM for 3 dent on wild and domestic cats, which are the only known host for theweeks is suggested.12 oocyst. The oocyst is formed in the intestine of the cat and subse- With latent syphilis, quantitative nontreponemal titers should be quently is excreted in feces. Mammals, such as cows, ingest the oocyst,repeated at 6, 12, and 24 months. Patients with a normal CSF examina- which is disrupted in the animal’s intestine, releasing the invasive tro-tion should be re-treated for latent syphilis if (1) titers increase four- phozoite. The trophozoite then is disseminated throughout the body,fold, (2) an initially high titer (≥1:32) fails to decline at least fourfold ultimately forming cysts in brain and muscle.357(i.e., two dilutions) within 12 to 24 months after therapy, or (3) signs Human infection occurs when infected meat is ingested or oocystsor symptoms of syphilis develop. There is limited information avail- are ingested via contamination by cat feces. Infection rates are highestable concerning either clinical response or follow-up in patients treated in areas of poor sanitation and crowded living conditions. Stray catsfor tertiary syphilis.12 and domestic cats that eat raw meat are most likely to carry the para- In pregnant women treated for syphilis, the CDC recommends site. The cyst is completely destroyed by heating.repeating serologic titers at 28 to 32 weeks’ gestation, and again at Approximately half of all adults in the United States have antibodydelivery, and following the recommendations described earlier for the to this organism. Immunity is usually long-lasting except in immuno-stage of disease. Alternatively, serologic titers can be checked monthly suppressed patients. The prevalence of antibody is highest in lowerin women who are at high risk for reinfection or who live in a geo- socioeconomic classes. The frequency of seroconversion during preg-graphic area where the prevalence of syphilis is high.12 nancy is approximately 5%, and about 3 in 1000 infants show evidence Congenital syphilis is unusual if the mother received adequate of congenital infection. Clinically significant infection occurs in onlytreatment with penicillin during pregnancy. Infants should be treated 1 in 8000 pregnancies. Clinical manifestations of infection are thefor presumed congenital syphilis if they were born to mothers in the result of direct organ damage and the subsequent immunologicfollowing categories: response to parasitemia and cell death. Immunity to this infection is mediated primarily through T lymphocytes.357 1. Mothers who have untreated syphilis at delivery 2. Mothers who have serologic evidence of relapse or reinfection after treatment (i.e., a rise in titer by at least fourfold) Diagnosis 3. Mothers who were treated for syphilis during pregnancy with Most infections in humans are asymptomatic. Even in the absence of nonpenicillin regimens symptoms, however, patients may have evidence of multiorgan involve- 4. Mothers who were treated for syphilis less than 1 month before ment, and clinically apparent disease can develop after a long period delivery of asymptomatic infection. Symptomatic toxoplasmosis usually mani- 5. Mothers who do not have a well-documented history of treat- fests as an illness similar to mononucleosis. ment of syphilis In contrast to infection in the immunocompetent host, toxoplas- 6. Mothers who do not demonstrate an adequate response (four- mosis can be a devastating infection in the immunosuppressed patient. fold decrease) of nontreponemal antibody titers despite appro- In these individuals, dysfunction of the CNS is the most common priate penicillin treatment manifestation of infection. Findings typically include encephalitis, 7. Mothers who were treated for syphilis appropriately before preg- meningoencephalitis, and intracerebral abscess. Pneumonitis, myocar- nancy but had insufficient serologic follow-up to ensure response ditis, and generalized lymphadenopathy also occur commonly. to treatment. Routine screening for toxoplasmosis in pregnancy is not indicated. However, immunosuppressed patients, women who have contact with Any child with symptomatic congenital syphilis should undergo a outdoor cats, and patients with suspicious symptoms should be tested.lumbar puncture, complete blood count, and long-bone radiography The diagnosis of toxoplasmosis in the mother is best confirmed bybefore treatment. If these results are normal, a single intramuscular serology. Serologic tests suggestive of an acute infection include iden-dose of benzathine penicillin G (50,000 units/kg) should be given. tification of IgM-specific antibody, demonstration of an extremelyWith abnormal results or if compliance is not ensured, the infant high IgG antibody titer, and documentation of IgG seroconversion
  • 45. CHAPTER 38 Maternal and Fetal Infections 783from negative to positive. Clinicians should be aware that serologicassays for toxoplasmosis are not well standardized. Therefore, if initiallaboratory tests suggest an acute maternal infection, additional evalu- Varicella-Zoster Virusation, as detailed in the following paragraphs, is indicated before con-cluding that the fetus is at risk for serious injury.357,358 Infection Approximately 40% of neonates born to mothers with acute toxo-plasmosis have evidence of infection. Congenital infection is most Epidemiology and Pathogenesislikely to occur when maternal infection develops during the third tri- The varicella-zoster virus (VZV) is a DNA organism that is a membermester. The risk of injury to the fetus is greatest, however, when mater- of the herpesvirus family. The organism causes varicella (chickenpox)nal infection occurs in the first trimester. and herpes zoster infection (shingles). Varicella is of great importance The usual clinical manifestations of congenital toxoplasmosis in pregnancy because it poses risks to the mother, fetus, and neonate.362include a disseminated purpuric rash, enlargement of the spleen and Herpes zoster infection can be a painful and somewhat debilitatingliver, ascites, chorioretinitis, uveitis, periventricular calcifications, ven- condition, especially in an immunosuppressed patient. However,triculomegaly, seizures, and mental retardation. Chronic or latent because it occurs in a patient who already has antibody against VZV,infection in the mother is unlikely to be associated with serious fetal herpes zoster poses essentially no risk to the fetus or neonate and isinjury. not discussed further in this chapter. The most valuable test for confirmation of congenital toxoplasmo- Varicella occurs in approximately 1 to 5 cases per 10,000 pregnan-sis is detection of toxoplasmic DNA in amniotic fluid using the PCR cies. The infection is transmitted by respiratory droplets and by directmethodology. In an important initial investigation, Hohlfeld and asso- contact with vesicular lesions. The incubation period of the organismciates359 identified 34 infants with confirmed congenital toxoplasmosis. is 10 to 14 days. Varicella is among the most highly contagious of anyAmniotic fluid specimens from all affected pregnancies were positive viral infection.363by PCR, and test results were available within 1 day after specimencollection. In a subsequent investigation, Romand and colleagues360reported that the PCR test for toxoplasmic DNA had an overall sensi- Diagnosistivity of 64% (CI, 53% to 75%). No false-positive results were noted, The typical clinical manifestation of varicella is a disseminated, pru-and the positive predictive value was 100%. Once amniocentesis has ritic, vesicular rash. The lesions typically occur in crops and evolve inconfirmed toxoplasmic infection, targeted ultrasound examination sequential fashion from vesicle to pustule, eventually crusting over tois indicated to look for specific findings suggestive of severe fetal form a dry scab. Varicella is almost always a mild, self-limited infectioninjury. in children. However, approximately 20% of infected adults develop pneumonia, and approximately 1% develop encephalitis. Both of these complications can cause serious morbidity and even mortality.Treatment The diagnosis can be confirmed by identification of anti-VZV IgMIn the immunocompetent adult, toxoplasmosis usually is an asymp- antibody.363tomatic or self-limited illness that does not require treatment. Immu-nocompromised patients should be treated with a combination of oralsulfadiazine (4-g loading dose followed by 1 g four times daily) plus Treatmentpyrimethamine (50 to 100 mg initially, then 25 mg daily). Extended All pregnant women should be questioned about prior varicella at thecourses of treatment may be necessary to cure the infection. time of their first prenatal appointment. If they have a well-defined When acute toxoplasmosis occurs during pregnancy, treatment is history of infection, they should be reassured that second infectionsindicated, because maternal therapy reduces the risk of congenital are extremely unlikely and that, should a second infection occur, theinfection and decreases the late sequelae of infection. Pyrimethamine risk to the fetus is negligible. Women who are not certain of prioris not recommended for use during the first trimester of pregnancy exposure should have an anti-VZV IgG assay. Approximately 75% ofbecause of possible teratogenicity. Sulfonamides may be used alone, individuals who are uncertain about their prior history actually havebut single-agent therapy appears to be less effective than combination definitive serologic evidence of immunity. Women who do not havetherapy. Spiramycin has been used extensively in European countries antibody against varicella should be cautioned about the need to avoidwith excellent success. It is available in the United States through exposure to people who have vesicular viral eruptions.364,365special permission from the CDC.358 If a susceptible pregnant patient is exposed to someone with vari- Aggressive early treatment of infants with congenital toxoplasmosis cella, she should be treated within 72 to 96 hours with one of twois indicated and consists of combination therapy with pyrimethamine, agents to prevent active infection. The most extensively tested regimensulfadiazine, and leucovorin for 1 year. Early treatment reduces, but is intramuscular varicella zoster immune globulin (VZIG), 1 vial perdoes not eliminate, the late sequelae of toxoplasmosis such as chorio- 10 kg of weight up to a maximum of 5 vials.366 However, the U.S.retinitis. Early treatment of the neonate appears to be comparable in company that manufactured this agent has discontinued its produc-effectiveness to in utero therapy.361 tion, and securing the product through international manufacturers is In pregnant women, prevention of toxoplasmosis is of paramount problematic. An alternative method of prophylaxis is to administerimportance. Pregnant women should be advised to avoid contact with oral acyclovir (800 mg, five times daily for 7 days) or oral valacyclovircat litter if at all possible. If they must change the litter, they should (1000 mg, three times daily for 7 days).367wear gloves and wash their hands afterward. They should always wash Pregnant women who develop varicella despite immunoprophy-their hands after preparing meat for cooking, and they should never laxis should be treated with oral acyclovir or valacyclovir in the sameeat raw or rare beef, fowl, or pork. Meat should be cooked thoroughly dose as outlined for prophylaxis. Patients who have evidence of pneu-until the juices are clear. Fruits and vegetables also should be washed monia, encephalitis, or disseminated infection and those who arecarefully to remove possible contamination by oocysts. immunosuppressed should be hospitalized and treated with intrave-
  • 46. 784 CHAPTER 38 Maternal and Fetal Infectionsnous acyclovir (10 mg/kg infused over 1 hour every 8 hours for 10 annually.374,375 Pregnant women suffer disproportionate morbidity anddays).363,366,368 mortality during influenza pandemics.376 Acute varicella infection during pregnancy has been associated with Influenza virus is characterized by low-level alterations of thespontaneous abortion, intrauterine fetal death, and congenital anoma- surface proteins of influenza A (hemagglutinin A and neuraminidase).lies. However, these complications are rare. Investigations, have shown This antigenic drift allows the virus to change enough to evade thethat the frequency of fetal anomalies was less than 1% when maternal host’s immune system response and cause the yearly epidemics. Atinfection occurred in weeks 1 through 12 of pregnancy and 2% or less approximately 20- to 40-year intervals, a more profound change of thewhen infection occurred in weeks 13 through 20.369,370 surface proteins occurs, possibly as a result of genetic recombination, The most valuable test to identify fetal injury due to congenital and leads to a substantially different surface protein configuration. Itvaricella is targeted ultrasound examination. Possible findings include is this antigenic shift that imparts the novel properties for a virulentintrauterine growth restriction, microcephaly, ventriculomegaly, echo- strain of influenza virus associated with pandemics. The aggressivegenic foci in the fetal liver, and limb anomalies.363 nature of pandemic influenza also results, in part, from the lack of Neonatal varicella, as opposed to congenital varicella infection, relevant immunity in the population to this novel surface proteinoccurs when the mother develops acute varicella during the period configuration.376from 5 days before to 2 days after delivery. If infection occurs at this Three influenza pandemics occurred in the last century: 1918, 1957,time, there is no opportunity for protective antibody to cross the pla- and 1968. Of these, two were major in nature. The pandemic of 1918centa. The manifestations of neonatal varicella include disseminated was responsible for between 30 and 50 million deaths worldwide andmucocutaneous lesions, visceral infection, pneumonia, and encephali- 500,000 deaths in the United States. The Asian influenza pandemic oftis. In the absence of timely antiviral chemotherapy, up to 30% of 1957-1958 also caused substantial morbidity and mortality.377infected infants die of complications of neonatal varicella. Infants born The influenza A strains responsible for all three of these great pan-during this window of time must avoid contact with vesicular lesions demics originated in Southeast Asia. Great concern has arisen thaton the mother’s skin. These infants, and any infants with suspected another pandemic of influenza will soon occur because of the emer-exposure in the nursery or postpartum ward also should receive immu- gence of a new influenza A strain (avian H5N1) in that region.378noprophylaxis with VZIG or treatment with antiviral agents such as According to the World Health Organization, this virus has causedacyclovir or valacyclovir.363 almost 100 deaths and has a case mortality rate of 55%.379 Although cases in humans have been reported, to date efficient human-to-human transmission has not occurred. Given the natural history of geneticPrevention shifting and evolution of the influenza virus, the ease of rapid world-In an effort to prevent the serious conditions noted here, all women of wide travel, and the crowded living conditions in many areas of thereproductive age should be vaccinated for varicella if they have not world, it may only be a matter of time before a pandemic on the scalealready acquired natural immunity. The varicella vaccine (Varivax) is of the 1918 influenza pandemic (or greater) occurs.376a live virus vaccine that is highly immunogenic. Individuals aged 1 Annually, in the United States, influenza is responsible for 82to 12 years should receive one dose of the vaccine subcutaneously. million infections and health care costs estimated at billions ofIndividuals older than 12 years of age require two subcutaneous dollars.380 Epidemics in the United States occur during the winterdoses, administered 4 to 6 weeks apart. Contraindications to the months (November through March). The rates of infection are highestvaccine include pregnancy, an immunodeficiency disorder, high-dose in children, who are a major reservoir for spread of infection to adults,corticosteroid therapy, untreated tuberculosis, severe systemic illness, including pregnant women. The rates of serious illness and death areand an allergy to neomycin, which is one component of the highest among persons 65 years of age and older, children youngervaccine.365,371,372 The CDC guidelines366 indicate that the vaccine may than 2 years of age, and people of any age who have medical conditionsbe considered in breastfeeding mothers, although there is little infor- that place them at increased risk for complications of influenza.381mation about whether the vaccine virus is excreted in breast milk.Vaccine recipients pose minimal risk of transmitting infection to sus-ceptible contacts if no rash develops after the vaccination. If a rash does Pathogenesisdevelop, there is a very small risk of transmission to susceptible The influenza virus is transmitted primarily by respiratory dropletscontacts.365 and, to a limited extent, by direct contact. The incubation period is relatively short, 1 to 5 days. Influenza occurs most commonly in the late fall and winter, and epidemics recur with regularity because the virus mutates in important ways from year to year. Immunity toViral Influenza the strains that caused infection in one year does not necessarily provide protection against strains that circulate in subsequent years.Epidemiology Influenza can range in severity from a mild respiratory infection toInfluenza is caused by an RNA virus of the myxovirus family. Three a life-threatening pneumonia. The illness typically begins abruptlyantigenically different influenza viruses have been identified.373 Type A with prodromal symptoms of malaise, myalgia, and headache in asso-influenza is responsible for most epidemics and is associated with ciation with fever. Subsequently, the patient develops a dry, nonpro-severe clinical presentation. Type B influenza is less frequently associ- ductive cough, coryza, mild dyspnea, and sore throat. On physicalated with epidemics and tends to cause milder clinical disease. Type C examination, the temperature is elevated and the pharynx is inflamed;is the least frequent type and, as a result, is not accounted for in the auscultation of the chest discloses rales and rhonchi. In some patients,annual influenza vaccine. a secondary bacterial pneumonia develops, and their cough then Influenza is of major clinical importance, both in the United States becomes productive of purulent sputum.382and worldwide. In the United States, the disease causes 30,000 to Influenza virus infects the ciliated columnar epithelial cells of the40,000 excess deaths and approximately 200,000 hospitalizations respiratory tract, with resultant cellular necrosis and sloughing. Con-
  • 47. CHAPTER 38 Maternal and Fetal Infections 785sequently, either the upper or the lower respiratory tract may be a site 5. Adults and children with chronic disorders of pulmonary orof infection. cardiovascular systems In pregnancy, the major concern is the increased risk for develop- 6. Adults and children who have required medical follow-up orment of life-threatening pneumonia.373,376 Influenza virus has not been hospitalization in the past year for chronic metabolic diseasesassociated with an increased risk of spontaneous abortion, stillbirth, (e.g., diabetes mellitus), renal dysfunction, hemoglobinopa-or congenital anomalies. However, an infant delivered to an acutely thies, or immunodeficiencyinfected patient may develop neonatal influenza as a result of close 7. Persons having any condition that compromises respiratorypersonal contact with the mother after delivery. In addition, mothers function or increases risk of aspirationwith severe respiratory infections may have an increased risk of preterm 8. Residents of nursing homes and other chronic care facilitieslabor. In previous reports of influenza pandemics, pregnant women 9. Persons living with or caring for individuals at high risk forexperienced increased morbidity and mortality compared with non- influenza-related complicationspregnant patients.383-385 10. Health care workers Neuzil and coauthors386 assessed the impact of influenza on preg-nant women during nonpandemic “flu” seasons. They reported that The vaccine contains killed, inactivated virus and is safe for use inthe relative risk for hospitalization with cardiorespiratory complica- pregnancy. Since 2004, the CDC has recommended universal vaccina-tions in pregnant women, compared with nonpregnant women, tion for all pregnant women regardless of gestational age.381 Robertswas 1.4 at 14 to 20 weeks’ gestation, rising to 4.7 in weeks 37 through and colleagues388 recently demonstrated that universal vaccination42. Moreover, women in the third trimester had a hospitalization with inactivated trivalent influenza vaccine is cost-saving in pregnantrate similar to that of nonpregnant women with high-risk medical women. The recently available live, attenuated intranasal influenzaconditions. vaccine is contraindicated during pregnancy.381,389DiagnosisThe presence of the clinical manifestations described earlier is highly Viral Hepatitissuggestive of influenza. The diagnosis can be confirmed by culture ofthe virus from respiratory secretions and by documentation of char- Hepatitis Aacteristic rises in serum antibody to influenza A and B. Chest radio- Hepatitis A is the second most common form of viral hepatitis in thegraphy also may be of great value in assessing the severity of the United States. The infection is caused by an RNA virus that is transmit-pulmonary infection. ted by fecal-oral contact. The incubation period ranges from 15 to 50 days. Infections in children are usually asymptomatic; infections in adults are usually symptomatic. The disease is most prevalent in areasTreatment of poor sanitation and close living.390The management of influenza in pregnant women is similar to that in The typical clinical manifestations of hepatitis include low-gradenonpregnant persons, consisting of symptomatic relief, with bed rest, fever, malaise, poor appetite, right upper quadrant pain and tender-analgesia, liberal fluid intake, and fever control with acetaminophen ness, jaundice, and acholic stools. The diagnosis is best confirmed by(650 mg PO every 4 to 6 hours, maximum 4 g/24 hours). Patients detection of IgM antibody specific for the hepatitis A virus.should be reevaluated immediately if signs of worsening pneumonia Hepatitis A does not cause a chronic carrier state. Perinatal trans-or preterm labor develop. In addition, if they have disabling symptoms, mission virtually never occurs, and, therefore, the infection does notthey should be offered treatment with either zanamivir (10 mg twice pose a major risk to either the mother or the baby. The exception isdaily for 5 days) or oseltamivir (75 to 150 mg PO twice daily for 5 the development of fulminant hepatitis and liver failure in the mother,days).387 Although amantidine is effective in nonpregnant patients, it but such a situation is extremely rare.390has been associated with teratogenic effects in animals and is not rec- Hepatitis A can be prevented by administration of an inactivatedommended for use in pregnancy.373 If pneumonia occurs in a pregnant vaccine. Two formulations of the vaccine are available: Vaqta andwoman with influenza, prompt hospitalization with broad-spectrum Havrix. Both vaccines require an initial intramuscular injection, fol-antibiotic coverage for bacteria that cause superinfection (e.g., S. lowed by a second dose 6 to 12 months later. The vaccine should beaureus, Streptococcus pneumoniae, Haemophilus influenzae) is required. offered to the following individuals in the following categories391:Respiratory support is indicated in the presence of inadequate oxygen-ation, retention of carbon dioxide, or excessively labored breathing. International travelers Children in endemic areas Intravenous drug usersPrevention Individuals who have occupational exposure (e.g., workers in aThe key to the prevention of influenza is vaccination. Immunization primate laboratory)is 70% to 90% effective in either preventing influenza or diminishing Residents and staff of chronic care institutionsthe severity of illness. The ACIP381,388 recommends annual vaccination Individuals with liver diseasefor Homosexual men Individuals with clotting factor disorders 1. Children aged 6 to 59 months 2. Women who will be pregnant during flu season Standard immune globulin provides reasonably effective passive 3. Persons aged 50 years or older immunization for hepatitis A if it is given within 2 weeks after 4. Children and adolescents (aged 6 months to 18 years) who are exposure. The standard intramuscular dose of immune globulin is receiving long-term aspirin therapy 0.02 mg/kg.392
  • 48. 786 CHAPTER 38 Maternal and Fetal Infections is essentially identical to that of hepatitis B. Patients with hepatitis DHepatitis E may have two types of infection. Some have acute hepatitis D andHepatitis E is caused by an RNA virus. The epidemiology of hepatitis hepatitis B (coinfection). These individuals typically clear theirE is similar to that of hepatitis A. The incubation period averages 45 infection and have a good long-term prognosis. Others have chronicdays. The disease is rare in the United States but is endemic in develop- hepatitis D infection superimposed on chronic hepatitis B infectioning countries of the world. In these countries, maternal infection with (superinfection). These women are particularly likely to develophepatitis E often has an alarmingly high mortality rate, in the range of chronic liver disease.39010% to 20%. This is probably less the result of virulence of the micro- The diagnosis of hepatitis D can be established by identifyingorganism and more related to poor nutrition, poor general health, and the delta antigen in liver tissue or serum. However, the most usefullack of access to modern medical care.390 diagnostic tests are detection of IgM and/or IgG antibody in The clinical presentation of acute hepatitis E is similar to that of serum.390hepatitis A. The diagnosis can be established with the use of electron As noted, hepatitis D can cause a chronic carrier state inmicroscopy to identify viral particles in the stool of infected patients. conjunction with hepatitis B infection. Perinatal transmission ofThe most useful diagnostic test, however, is serology. hepatitis D occurs but is uncommon. Moreover, the immunoprophy- Hepatitis E does not cause a chronic carrier state. Perinatal trans- laxis outlined for hepatitis B is highly effective in preventing transmis-mission can occur but is extremely rare.393 sion of hepatitis D.390,394Hepatitis B Hepatitis CHepatitis B is caused by a DNA virus that is transmitted parenterally Hepatitis C is caused by an RNA virus. The virus may be transmittedand via sexual contact. The infection also can be transmitted perina- parenterally, via sexual contact, and perinatally. In many patient popu-tally from an infected mother to her infant. lations, hepatitis C is as common or more common than hepatitis B. Acute hepatitis B occurs in 1 or 2 of every 1000 pregnancies in the Chronic hepatitis C infection now is the number one indication forUnited States. The chronic carrier state is more frequent, occurring liver transplantation in the United States.390,396-398in 6 to 10 of 1000 pregnancies. Worldwide, more than 400 million Hepatitis C is usually asymptomatic, at least in its initial stages. Theindividuals are chronically infected with hepatitis B virus. In the diagnosis is best confirmed by serologic testing. The initial screeningUnited States alone, approximately 1.25 million people are chronically test should be an EIA. The confirmatory test is a recombinant immu-infected.390 noblot assay (RIBA). Seroconversion may not occur for up to 16 weeks Approximately 90% of patients who acquire hepatitis B mount an after infection. In addition, although these immunologic tests haveeffective immunologic response to the virus and completely clear their been available for many years, they still do not consistently and pre-infection. Fewer than 1% of infected patients develop fulminate hepa- cisely distinguish between IgM and IgG antibody. 390titis and die. Approximately 10% of patients develop a chronic carrier In patients who have a low serum concentration of hepatitis C RNAstate. Some individuals with chronic hepatitis B infection ultimately and who do not have coexisting HIV infection, the risk of perinataldevelop severe chronic liver disease such as chronic active hepatitis, transmission of hepatitis C is less than 5%. If the patient’s serum con-chronic persistent hepatitis, cirrhosis, or hepatocellular carcinoma. centration of hepatitis C RNA is high or she is coinfected with HIV, orThis sequela is particularly likely in patients who are coinfected with both, the perinatal transmission rate may approach 25%.399,400 Severalhepatitis D or hepatitis C or both.390 small, nonrandomized, uncontrolled cohort studies (level II evidence) The diagnosis of hepatitis B is best confirmed by serologic tests. support a role for elective cesarean delivery before the onset of laborPatients with acute hepatitis B are positive for the hepatitis B surface and rupture of membranes in selected women who have detectableantigen and positive for IgM antibody to the core antigen. Patients with hepatitis C virus RNA. For women who have undetectable serum con-chronic hepatitis B are positive for the surface antigen and positive centrations of RNA, vaginal delivery appears to be a reasonable planfor IgG antibody to the core antigen. Acutely or chronically infected of management.401,402patients may or may not be positive for the hepatitis B e antigen. Ifthis latter antigen is present, it denotes active viral replication and ahigh level of infectivity.394 Hepatitis G In the absence of intervention, approximately 20% of mothers who Hepatitis G is caused by an RNA virus that is related to the hepatitisare seropositive for hepatitis B surface antigen will transmit infection to C virus. Hepatitis G is more prevalent, but less virulent, than hepatitistheir neonates. Approximately 90% of mothers who are positive for both C. Many patients who have hepatitis G are coinfected with hepatitis A,the surface antigen and the e antigen transmit infection. Fortunately, B, C, and/or HIV. Coinfection with hepatitis G does not adversely effectexcellent immunoprophylaxis for prevention of perinatal transmission the prognosis of these other infections.403-406of hepatitis B infection is now available. Infants delivered to seropositive Most patients with hepatitis G are asymptomatic. The diagnosis ismothers should receive hepatitis B immune globulin within 12 hours best established by detection of the virus on PCR and identification ofafter birth. Before their discharge from the hospital, these infants also antibody on ELISA testing.should begin the hepatitis B vaccination series. The CDC now recom- Hepatitis G can cause a chronic carrier state, and perinatalmends universal vaccination of all infants for hepatitis B. In addition, transmission has been documented. However, the clinical effectsthe vaccine should be offered to all women of reproductive age.394,395 of infection in both mother and baby appear to be minimal. Accordingly, patients should not routinely be screened for this infec- tion, and no special treatment is indicated even if infection isHepatitis D (Delta Virus Infection) confirmed.390Hepatitis D is an RNA virus that is dependant on coinfection with Table 38-20 summarizes the key features of each form ofhepatitis B for replication. Therefore, the epidemiology of hepatitis D hepatitis.
  • 49. CHAPTER 38 Maternal and Fetal Infections 787TABLE 38-20 HEPATITIS IN PREGNANCY: SUMMARY OF KEY FEATURES Mechanism of PerinatalInfection Transmission Best Diagnostic Test Carrier State Transmission Vaccine RemarksHepatitis A Fecal-oral Antibody detection No No Yes Passive immunization with immune globulinHepatitis E Fecal-oral Antibody detection No Rare No High maternal mortality in developing countriesHepatitis B Parenteral, sexual Antigen detection Yes Yes Yes Passive immunization with contact hepatitis B immune globulinHepatitis D Parenteral, sexual Antibody detection Yes Yes Prevented by Virus cannot replicate in contact hepatitis B absence of hepatitis B vaccine infectionHepatitis C Parenteral, sexual Antibody detection Yes Yes No Cesarean delivery for women contact with detectable serum hepatitis C virus RNAHepatitis G Parenteral, sexual Antibody detection Yes Yes No No clinical significance of contact infection 16. 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