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
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.
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,
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.
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.
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-
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
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-
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
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
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
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
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