Clin Perinatol 31 (2004) 765 – 782




 Preterm premature rupture of the membranes:
          diagnosis and management
   ...
766                 B.M. Mercer / Clin Perinatol 31 (2004) 765–782


infection, and oligohydramnios. Few conditions carry ...
B.M. Mercer / Clin Perinatol 31 (2004) 765–782              767


possible approaches to the care of these patients. Indiv...
768                  B.M. Mercer / Clin Perinatol 31 (2004) 765–782


urinary incontinence, vaginitis, cervicitis, mucous ...
B.M. Mercer / Clin Perinatol 31 (2004) 765–782                       769

                        Confirm the Diagnosis of...
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later in this article for women with bPROM remote fr...
B.M. Mercer / Clin Perinatol 31 (2004) 765–782                            771

                        Previable PROM (<23...
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may be helpful in assisting the patient in the deci...
B.M. Mercer / Clin Perinatol 31 (2004) 765–782               773

              Preterm PROM remote from term (230 - 31 6 ...
774                  B.M. Mercer / Clin Perinatol 31 (2004) 765–782


cord. Color flow ultrasound may be helpful in differ...
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biotic availability have necessitated them. Oral ampici...
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cerclage retention, despite brief pregnancy prolonga...
B.M. Mercer / Clin Perinatol 31 (2004) 765–782                          777

                                    Preterm P...
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subset of women. However, the following principl...
B.M. Mercer / Clin Perinatol 31 (2004) 765–782                          779

 [2] Tucker JM, Goldenberg RL, Davis RO, Copp...
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       membranes by identification of beta-HCG ...
B.M. Mercer / Clin Perinatol 31 (2004) 765–782                          781

[46] Pattinson RC, Makin JD, Funk M, Delport ...
782                     B.M. Mercer / Clin Perinatol 31 (2004) 765–782

[66] Russell JC, Cooper CM, Ketchum CH, Torday JS,...
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Mercer Clin Perinatol 2004, Rpm Diagnosis And Management

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Mercer Clin Perinatol 2004, Rpm Diagnosis And Management

  1. 1. Clin Perinatol 31 (2004) 765 – 782 Preterm premature rupture of the membranes: diagnosis and management Brian M. Mercer, MDa,b,* a Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH, USA b Department of Obstetrics and Gynecology, MetroHealth Medical Center, Suite G240, 2500 MetroHealth Drive, Cleveland, OH 44109, USA Premature rupture of the membranes (PROM) complicates approximately 8% of pregnancies: 3% of pregnancies deliver from PROM before term. Defined as membrane rupture before the onset of labor, preterm PROM is responsible for approximately one third of preterm deliveries. Preterm PROM can result from various mechanisms, including physiologic weakening associated with apoptosis (programmed cell death) near term; dissolution of the amniochorionic matrix exacerbated by contraction-induced shearing forces; ascending genital tract colonization/infection initiating a cytokine cascade that enhances membrane apoptosis; protease production and dissolution of the extracellular matrix; placental abruption with decidual thrombin expression triggering thrombin–thrombin receptor interactions and increasing chorio- decidual protease production; and membrane stretch that may increase amnio- chorionic cytokine and protease release. Clinical risk factors for preterm PROM include low socioeconomic status, low body mass index, prior preterm birth, cigarette smoking, urinary tract infection, sexually transmitted disease, cervical conization or cerclage, uterine overdistention, amniocentesis in the current pregnancy, and prior preterm labor or symptomatic contractions in the current pregnancy. In many cases, the ultimate cause of membrane rupture cannot be determined [1–10]. The hallmarks of premature rupture of the membranes include brief latency from membrane rupture to delivery, increased risk of intrauterine and neonatal * Suite G240, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109. 0095-5108/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2004.06.004
  2. 2. 766 B.M. Mercer / Clin Perinatol 31 (2004) 765–782 infection, and oligohydramnios. Few conditions carry a higher risk of delivery soon after their onset. However, of those women with preterm PROM who are amenable to conservative management, approximately half will remain pregnant for at least 1 week after membrane rupture [11]. The median and mean latency periods increase with decreasing gestational age at membrane rupture, with approximately 25% remaining undelivered at least 1 month after membrane rupture when preterm PROM occurs before or near the limit of viability. A small number of women (2.6% to 13%) [12,13], especially those with preterm PROM subsequent to amniocentesis, can anticipate spontaneous resealing of the mem- branes and restoration of a normal amniotic fluid volume. Clinical chorioamnio- nitis is common after preterm PROM and, like latency, increases with decreasing gestational age at membrane rupture. Abruptio placentae, amnionitis, and endo- metritis complicate 4% to 12%, 13% to 60%, and 2% to 13% of pregnancies, respectively, when membrane rupture occurs remote from term [14–21]. Although amnionitis and endometritis generally respond to delivery and par- enteral antibiotic therapy, rare but serious complications such as maternal sepsis and death can occur (b1%). Neonatal complications relate primarily to the gestational age at which membrane rupture and delivery occur. Respiratory distress syndrome (RDS) is the most common serious complication after preterm PROM at any gestational age. Other serious morbidities, including necrotizing enterocolitis, intraven- tricular hemorrhage, sepsis, bronchopulmonary dysplasia, and retinopathy of prematurity, decrease with advancing gestational age at delivery and are uncommon with delivery after approximately 32 weeks, particularly if fetal pulmonary maturity is present. Infants delivered preterm after PROM have a twofold higher risk of sepsis than those delivered after preterm labor with intact membranes [22]. Although perinatal death is assured with delivery before the limit of viability, perinatal mortality rapidly declines with each advancing week of gestation at delivery until approximately 32 weeks’ gestation [23]. After this point there is little additional gain in neonatal survival with brief pregnancy prolongation. Stillbirth resulting from umbilical cord compression, intrauterine infection, or placental abruption complicates 1% to 2% of conservatively managed cases. Persistent oligohydramnios, particularly when PROM occurs before the limit of viability, inhibits alveolar development. With previable PROM occurring before 18 to 20 weeks of gestation, lethal pulmonary hypoplasia may ensue despite prolonged successful conservative management. Nonlethal pulmonary hypoplasia leading to pulmonary complications such as pneumo- thorax, pneumomediastinum, and high ventilatory pressures can occur with prolonged membrane rupture and oligohydramnios after pre- or periviable PROM. Prolonged oligohydramnios may also lead to restriction deformities similar to those seen with Potter’s syndrome. Although recent studies have been encouraging, there remains no reliable method for predicting and preventing preterm PROM. Hence the focus of clini- cal practice remains the diagnosis and treatment of this condition. The clinical assessment and management algorithms offered in this article are provided as
  3. 3. B.M. Mercer / Clin Perinatol 31 (2004) 765–782 767 possible approaches to the care of these patients. Individual circumstances should also be considered when making management decisions after preterm PROM. Diagnosis The diagnosis of membrane rupture is generally made clinically based on a suspicious history, combined with physical examination and adjunctive laboratory information as needed. The initial steps in confirming the diagnosis of membrane rupture after a suspicious history are to perform a sterile speculum examination to confirm the diagnosis, to evaluate cervical dilatation and effacement visually, and to obtain appropriate cervical cultures (Chlamydia trachomatis and Neisseria gonorrhea). In most cases membrane rupture can be confirmed by documentation of fluid passing from the cervical os with visualization of a pool of fluid in the posterior vaginal fornix, or with a high vaginal pH (nitrazine test: N6.0 to 6.5) or arborization (ferning) of vaginal secretions from the posterior fornix when observed on low-power microscopy. Although they are usually helpful, nitrazine and ferning tests are not always accurate. A false-positive nitrazine test may occur if there is blood, semen, alkaline antiseptics, or bacterial vaginosis present in the vagina. Alternatively, if membrane rupture is chronic and little amniotic fluid is present, the nitrazine test can be falsely negative. Causes of false-positive and false-negative ferning tests include cervical mucus and prolonged leakage. Alternate adjunctive tests such as vaginal prolactin, alpha-fetoprotein, human chorionic gonadotropin (HCG), and fetal fibronectin have been suggested [24–29]. These tests may be helpful if negative. However, a positive test is not specific to the diagnosis of membrane rupture. Digital examination should be avoided unless delivery is anticipated, because of the increased risk of infection and the scant additional clinical information obtained with this procedure [30]. Anal vaginal cultures for group B Streptococcus (GBS) should be obtained during initial assessment for PROM if they have not been obtained within 6 weeks. These are best obtained from immediately inside the hymeneal ring and anal canal, rather than from the cervix and posterior fornix at speculum examination. Cervical and high vaginal group B Streptococcus cultures are less likely to be positive in the setting of maternal anovaginal carriage [31]. Should initial speculum examination be negative and a clinical suspicion of membrane rupture persists, it may be helpful to repeat the speculum examination after prolonged recumbency or to consider alternative measures. Ultrasound evaluation may provide supportive information with the presence of oligohy- dramnios without evident fetal urinary tract abnormalities or growth restriction. The diagnosis of membrane rupture can be made unequivocally through ultrasound-guided amnio-infusion of indigo carmine (1 mL in 9 mL of sterile normal saline) followed by observation for passage of blue dye per vaginum onto a perineal pad or at repeat speculum examination. A normal amniotic fluid volume on ultrasound cannot exclude the diagnosis of membrane rupture. Should testing be negative, other plausible causes of abnormal vaginal discharge such as
  4. 4. 768 B.M. Mercer / Clin Perinatol 31 (2004) 765–782 urinary incontinence, vaginitis, cervicitis, mucous show, early labor, semen, and vaginal douches should be considered. On occasion, women with a normal amniotic fluid volume will present with a suspicious history for membrane rupture but have negative speculum examina- tion findings, only to return subsequently with gross membrane rupture. Whether these women had initial transudation of a small amount of fluid across a weakened membrane or minimal leakage around a firmly applied fetal presenting part is unknown. However, women presenting with a suspicious history and negative physical findings should be encouraged to return for re-evaluation should their symptoms persist or recur. Management considerations If the diagnosis of membrane rupture is confirmed, ultrasound should be performed to assess gestational age (if needed), amniotic fluid volume, and fetal growth and presentation and to evaluate for fetal malformations that could lead to polyhydramnios and membrane rupture, if this evaluation has not been previously performed (Fig. 1). The patient should initially be evaluated for evidence of labor. Continuous uterine contraction monitoring is appropriate after 20 weeks but may not be feasible before this gestation. Should the limit of viability have been reached, fetal monitoring should be performed to assess for evident distress due to umbilical cord compression, unless an active decision has been made not to intervene for fetal benefit. Subsequent management considerations will be dependent on the presence or absence of factors necessitating delivery, the gestational age at membrane rupture, and the presence of documented fetal pulmonary maturity. If the fetus is potentially viable and clinical amnionitis, placental abruption, fetal death, a nonreassuring fetal heart rate, or advanced labor are present, the patient is best served by expeditious delivery, with cesarean delivery reserved for appropriate clinical indications (see Fig. 1). Intrapartum group B Streptococcus prophylaxis (penicillin unless the patient is allergic) should be given in the absence of a recent negative anal vaginal culture, to reduce the risk of neonatal GBS sepsis [31]. In the presence of suspected chorioamnionitis, broad-spectrum intravenous antibiotics (generally ampicillin and gentamicin) should be initiated before delivery. When the diagnosis of amnionitis is unclear, amniocentesis can be helpful. A positive gram stain, glucose value of less than 16 to 20 mg/dL, or positive amniotic fluid culture is suggestive of intrauterine infection [32–34]. Amniotic fluid cytokines (eg, interleukin-2, interleukin-6) are associated with intrauterine infection; however, such testing is not currently routinely available for clinical practice. In the absence of amnionitis, placental abruption, fetal death or distress, or advanced labor, conservative management of the patient with preterm PROM may be appropriate. In this circumstance, a gestational age–based approach to management should be considered. The care-giver should be apprised of current data regarding neonatal morbidity and mortality according to gestational age at
  5. 5. B.M. Mercer / Clin Perinatol 31 (2004) 765–782 769 Confirm the Diagnosis of Membrane Rupture Fluid seen passing per cervical Os, or vaginal pool with positive Nitrazine/Ferning test, or positive Indigo-carmine amnio-infusion test Cervical cultures: Chlamydia, Gonorrhea Ano-vaginal culture: Group B streptococcus Urine culture Ultrasound for gestational age, amniotic fluid assessment, Fetal growth, and anomalies as appropriate Initial continuous monitoring for labor, and for fetal distress if fetus is potentially viable Diagnosis of: No evident diagnosis of: Amnionitis, Abruptio placentae, Amnionitis, Abruptio placentae, Fetal death, Non-reassuring testing, Fetal death, Non-reassuring testing, or Advanced labor or Advanced labor Deliver Gestational Age based approach to management Intrapartum group B streptococcus prophylaxis if no recent negative ano-vaginal culture Broad spectrum antibiotics if amnionitis See Figures 2, 3, and 4 Fig. 1. Algorithm for initial assessment and management of women presenting with preterm PROM. delivery to make appropriate decisions about the potential benefits of conserva- tive management as opposed to expeditious delivery [23]. Previable PROM (b23 weeks’ gestation) The term bmidtrimester PROM,Q referring to delivery at or before 26 weeks’ gestation, has been used in the past and at one time appropriately denoted membrane rupture before viability. Currently, however, women with membrane rupture between 23 and 26 weeks’ gestation carry fetuses that have the potential for survival. These patients are best cared for by following the scenario delineated
  6. 6. 770 B.M. Mercer / Clin Perinatol 31 (2004) 765–782 later in this article for women with bPROM remote from term.Q When delivery occurs immediately after previable PROM, intrapartum or neonatal death is assured. Conservative management may lead to stillbirth or to the birth of a live infant before or after the limit of potential neonatal viability. When PROM occurs before the limit of viability, gestational age assignment is of particular importance. Because the likelihood of error in ultrasound estimation of gestational age increases as pregnancy advances, the earliest available ultrasound should be obtained for confirmation of gestational dating. A bbest gestational ageQ determination should be made based on the earliest available ultrasound and menstrual history. These patients should be counseled with a realistic appraisal of potential neonatal outcomes and made aware of the availability of obstetric monitoring and neonatal intensive care facilities should delivery occur after the limit of potential viability. Because neonatal survival and morbidity in the periviable period continue to improve, attempts should be made to provide the most up-to-date information about potential perinatal outcomes. As for maternal morbidity, conservative management of midtrimester PROM is associated with a high risk of chorioamnionitis (39%), endometritis (14%), abruptio placentae (3%), and retained placenta with postpartum hemorrhage requiring curettage (12%) [13,35]. The risk of stillbirth during conservative management of midtrimester PROM is approximately 15%, higher than the 1% to 2% risk seen later in pregnancy. This greater risk may reflect fetal susceptibility to umbilical cord compression and intrauterine infection, or it may reflect nonintervention for fetal distress in the previable period. Although there are currently inadequate data to provide estimates of maternal morbidity and fetal mortality related to conservative management of PROM at less than 23 weeks’ gestation, the risks are probably higher than those stated above. Given the grave fetal and neonatal prognosis, some women will not wish to assume the maternal risks associated with conservative management of previable PROM. Expeditious delivery can be accomplished by labor induction with high dose oxytocin or with vaginal prostaglandin E2 or oral or vaginal prostaglandin E1 (Misoprostol), or by dilatation and evacuation (Fig. 2). Intracervical laminaria placement before oxytocin therapy or prostaglandin induction may be helpful. The optimal treatment approach to achieve delivery in this circumstance will depend on patient factors (eg, gestational age, evident amnionitis, prior cesarean delivery), as well as on physician experience and facilities available for induction or dilatation and evacuation. Should the patient elect conservative management, she should be monitored initially for the development of infection, labor, or placental abruption. Strict pelvic rest and modified bed rest with bathroom privileges should be encouraged, to enhance the potential for membrane resealing and reduce the potential for ascending infection. Given the current lack of data establishing the superiority of either approach, initial inpatient or outpatient monitoring may be appropriate, depending on clinical circumstances. For those women with previable PROM remote from the limit of viability, serial ultrasound is recommended to evaluate for fetal pulmonary growth and for persistent oligohydramnios. Fetal pulmonary
  7. 7. B.M. Mercer / Clin Perinatol 31 (2004) 765–782 771 Previable PROM (<23 weeks gestation) Initial monitoring for development of Infection, Labor, Abruptio placentae Initial bed-rest to encourage resealing Evaluate for persistent oligohydramnios and pulmonary hypoplasia with serial ultrasound Induction with Oxytocin, PgE2 or Re-counsel based on clinical course and available Misoprostol ultrasound findings regarding persistent or oligohydramnios and pulmonary hypoplasia Dilatation & Evacuation If discharged before viability and remains pregnant, consider readmission at limit of fetal viability for ongoing conservative management Conservative management Modified bed-rest and pelvic rest to encourage resealing, reduce infection Administer Antenatal Corticosteroids for Fetal Maturation Serial evaluation for Amnionitis, Labor, Abruption, Fetal well-being, Growth Deliver for Amnionitis, Non-reassuring Fetal Testing, Abruption, Advanced labor Consider Delivery at 34 weeks gestation Intrapartum group B streptococcus prophylaxis if no recent negative ano-vaginal culture Broad spectrum antibiotics if Amnionitis Fig. 2. Management algorithm for women presenting with preterm PROM before the current limit of potential viability (b23 weeks, 0 days of gestation). growth can be estimated by a variety of techniques, including measurement of the thoracic/abdominal circumference ratio, chest circumference, and pulmonary length. A declining thoracic/abdominal circumference ratio in the setting of persistent oligohydramnios is highly predictive of lethal pulmonary hypoplasia in this setting [36–39]. When this finding is identified before the limit of viability, it
  8. 8. 772 B.M. Mercer / Clin Perinatol 31 (2004) 765–782 may be helpful in assisting the patient in the decision between continued conservative management and delivery. Although it is appealing to consider broad-spectrum antibiotic therapy for pregnancy prolongation and reduction of infection (see later discussion) after previable PROM, no specific data are available. A number of novel treatments for membrane sealing after previable PROM have been studied (eg, serial amnioinfusion, membrane plugging with Gelfoam or fibrin-platelet-cryoprecipi- tate plugs, and indwelling transcervical infusion catheter) [40–42]. However, the maternal and fetal risks and benefits associated with these interventions have not yet been determined. Further research is needed before membrane sealing is incorporated into clinical practice. Once the patient with previable PROM reaches the limit of viability, many physicians will admit her to the hospital for ongoing bed rest. The purpose of admission at this time is to allow for early diagnosis and intervention for infection, abruption, labor, and nonreassuring fetal heart rate patterns. Because these women remain at high risk for early delivery, administration of antenatal corticosteroids for fetal maturation may be appropriate at this time. It is not clear that delayed administration of broad-spectrum antibiotics for pregnancy pro- longation will assist this population. Preterm PROM remote from term (23 to 316 weeks’ gestation) General approach In the absence of evident infection, abruption, advanced labor, or fetal com- promise, the patient with preterm PROM between 23 and 31 weeks’ gestation is generally best served by conservative management to prolong pregnancy and reduce gestational age–dependent morbidity (Fig. 3). The decision whether to delay or expedite delivery should be based on the potential neonatal benefits of prolonged latency and the concurrent maternal and fetal/neonatal risks associated with conservative management. Women undergoing conservative management of preterm PROM remote from term should generally be managed in hospital to facilitate the early detection and management of amnionitis, vaginal bleeding, nonreassuring fetal heart-rate patterns, and labor. Such management should be undertaken in a facility capable of providing emergent care to the mother and newborn. Should obstetric or neonatal facilities not exist at the presenting hospital, the patient should be transferred to a facility capable of providing her with care after initial assessment and before the onset of acute complications. Digital examinations should be avoided when possible, to reduce the risk of intrauterine infection and enhanced latency. Uterine contraction and fetal heart- rate assessment should be performed at least once daily to assess for occult contractions, fetal well-being, and umbilical cord compression. Additional testing may be appropriate and necessary based on these findings. Biophysical profile testing is an alternative to fetal nonstress testing for assessment of fetal well-being
  9. 9. B.M. Mercer / Clin Perinatol 31 (2004) 765–782 773 Preterm PROM remote from term (230 - 31 6 weeks gestation) Conservative management Modified bed-rest and pelvic rest to encourage resealing, and reduce infection Administer Antenatal Corticosteroids for Fetal Maturation Serial evaluation for Amnionitis, Labor, Abruption, Fetal well-being, Growth Deliver for Amnionitis, Non-reassuring Fetal Testing, Abruption, Advanced labor Consider Delivery at 34 weeks gestation Intrapartum group B streptococcus prophylaxis if no recent negative ano-vaginal culture Broad spectrum antibiotics if Amnionitis Fig. 3. Management algorithm for women presenting with preterm PROM remote from term (23 weeks, 0 days–31 weeks, 6 days). and may be helpful if the nonstress test is not reactive. However, this test does not provide the opportunity to evaluate for periodic heart-rate changes and occult uterine activity. Because pregnancy and inactivity are risk factors for throm- boembolic complications, preventative measures such as leg exercises, anti- embolic stockings, and prophylactic doses of subcutaneous heparin may be of value during conservative management with bed rest. The combination of fever (z38.08C or 100.48F) with uterine tenderness or maternal or fetal tachycardia in the absence of another evident source of infection is suggestive of intrauterine infection and should lead to consideration of deliv- ery. Some patients will not demonstrate classical symptomatology of amnionitis. Increasing uterine discomfort or menstrual cramps may be an early finding. Although maternal white blood cell count may increase in the setting of amnionitis, such test results may be artificially elevated if antenatal corticosteroids have been administered within 5 to 7 days. Alternatively, an increasing white blood cell count in the presence of suspicious clinical findings may be useful in identifying patients who require closer observation—including continuous contraction and fetal monitoring—or who require delivery. If the clinical diagnosis is not sufficiently clear, additional information can be gained with amniocentesis, provided an adequate amniotic fluid pocket is accessible. When amniocentesis is performed, care should be taken to avoid inadvertent sampling of the umbilical
  10. 10. 774 B.M. Mercer / Clin Perinatol 31 (2004) 765–782 cord. Color flow ultrasound may be helpful in differentiating a small amniotic fluid pocket from umbilical-cord arterial or venous flow. Antenatal corticosteroids Women managed conservatively with preterm PROM remote from term should be administered antenatal corticosteroids for fetal maturation if they have not previously received corticosteroids in the current pregnancy. This inter- vention has been demonstrated to reduce the risk of intraventricular hemorrhage, and it is supported by the National Institute of Health Consensus Conference and by the American College of Obstetricians and Gynecologists [43,44]. Recent randomized clinical trials have evaluated antenatal corticosteroid administration concurrent with antibiotic administration. Lewis et al [45] found a reduction in respiratory distress (18.4% versus 43.6%, P = 0.03) with antenatal corticosteroid administration. Although a second trial found no increase or decrease in infant morbidity with antenatal corticosteroids, patients who received antenatal steroids and remained pregnant for at least 24 hours had a lower incidence of perinatal death (1.3% versus 8.3%, P = 0.05) with antenatal corticosteroid administration [46]. A recent meta-analysis has supported the beneficial effects of antenatal corticosteroid administration in this setting for the reduction of respiratory distress (20% versus 35.4%), intraventricular hemorrhage (7.5% versus 15.9%), and necrotizing enterocolitis (0.8% versus 4.6%), without significant increased risks of maternal infection (9.2% versus 5.1%) or neonatal infection (7.0% versus 6.6%) [47]. Antibiotic prophylaxis and treatment The benefits of narrow-spectrum intrapartum prophylaxis against vertical transmission of group B Streptococcus before preterm birth are well established. Intrapartum treatment is recommended for known group B Streptococcus– carriers, those of unknown carrier status, and those without a recent culture (ie, within 6 weeks of delivery) [31]. Adjunctive antibiotic therapy during conservative management of preterm PROM remote from term is given to treat or prevent ascending subclinical decidual infection, to prolong pregnancy, to reduce infectious morbidity, and to offer the opportunity to reduce neonatal infectious and gestational age–dependent morbidity. This intervention has been the subject of many randomized prospective trials. Several meta-analyses have confirmed the efficacy of aggressive, limited-duration, broad-spectrum antibiotic therapy for reduction of infant morbidity in this setting. Intravenous therapy (48 hours) with ampicillin (2 g IV every 6 hours) and erythromycin (250 mg IV every 6 hours), followed by limited-duration oral therapy (5 days) with amoxi- cillin (250 mg by mouth every 8 hours) and enteric-coated erythromycin base (333 mg by mouth every 8 hours) is recommended [48]. Although alternative antibiotic treatments have not been specifically studied, recent shortages in anti-
  11. 11. B.M. Mercer / Clin Perinatol 31 (2004) 765–782 775 biotic availability have necessitated them. Oral ampicillin, erythromycin, and azithromycin, as needed, are likely appropriate alternatives to the therapy described. A recent large multicenter study suggested that broad-spectrum antibiotic therapy might increase the risk of necrotizing enterocolitis (1.9% versus 0.5%, P = 0.001) [49]. Neonates in this study were at low risk for necrotizing enterocolitis compared with neonates in other trials, partially because of the inclusion of many women near term (32 to 36 weeks’ gestation) who might have been better served by expeditious delivery. Furthermore, the findings are at variance with those of the National Institute for Child and Human Development- Maternal-Fetal Medicine Unit (NICHD-MFMU) trial indicating a reduced stage– 2 to 3 necrotizing enterocolitis with aggressive antibiotic therapy in a higher-risk population [48]. Overall, review of the literature reveals no consistent pattern to indicate an increased risk of necrotizing enterocolitis with broad-spectrum antibiotic therapy in this setting. Several recent studies have attempted to determine whether shorter-duration antibiotic treatment (b7 days) is appropriate during conservative management with preterm PROM [50,51]. These studies are of inadequate size and power to evaluate equivalency regarding infant morbidity or latency. Currently, the 7-day NICHD-MFMU protocol is recommended. Tocolysis A small number of studies exist on which to base practice regarding tocolysis during conservative management of preterm PROM remote from term [52–56]. Overall, there does not appear to be an increase in maternal or fetal risk with tocolysis during conservative management. Neither prophylactic nor therapeutic tocolysis in this setting has been demonstrated to reduce infant morbidity. Hence, tocolytic administration should not be an expected practice. However, because several of these studies have suggested that short-term tocolytic therapy may enhance initial pregnancy prolongation at 24 to 48 hours, it is worth considering that tocolytic therapy concurrent with antenatal corticosteroid treatment for fetal maturation and antibiotic treatment to suppress infection and prolong pregnancy might enhance the effects of both steroid and antibiotic treatment. This area warrants further research to determine whether the hypothesized benefits exist. Cerclage Premature rupture of the membranes complicates approximately one in four pregnancies with a cervical cerclage in situ. Retrospective studies suggest that when cerclage is removed on admission after preterm PROM, the risk of adverse perinatal outcome is no higher than for those women admitted with preterm PROM and no cerclage [57,58]. Studies comparing cerclage retention or removal after preterm PROM have been small and have yielded conflicting results [59–61]. Individually, these studies suggest trends toward increased maternal infection with retained cerclage; however, no study has reached significance. One study found increased overall infant mortality and death related to sepsis with
  12. 12. 776 B.M. Mercer / Clin Perinatol 31 (2004) 765–782 cerclage retention, despite brief pregnancy prolongation [59]. Another study comparing practices at different institutions found significant pregnancy pro- longation with cerclage retention [60]. Although they are intriguing, the results of this study may reflect patient population or practice differences, rather than differences solely related to cerclage retention. No study has found a significant reduction in infant morbidity with cerclage retention after preterm PROM. Hence, it appears prudent to remove the cerclage when PROM occurs either remote from or near term. Should a decision be made to retain the cerclage during attempts to enhance fetal maturation with antenatal steroids, concurrent antibiotic admin- istration should be considered to reduce the risk of infection. Furthermore, consideration should be given to removal of the stitch after antenatal steroid benefit has been reached at 24 to 48 hours. Preterm PROM near term (32 to 366 weeks’ gestation) When preterm PROM occurs at 34 to 36 weeks’ gestation, the risk of severe acute neonatal morbidity and mortality with expeditious delivery is low. Conversely, conservative management at 34 to 36 weeks has been associated with an eightfold increase in amnionitis (16% versus 2%, P = 0.001) and only brief prolongation of latency and maternal hospitalization (5.2 days versus 2.6 days, P = 0.006), without significant reduction in perinatal morbidity related to prematurity [62]. Hence these women are best served by expeditious delivery with labor induction, in the absence of contraindication to labor or vaginal delivery (Fig. 4). Intrapartum group B Streptococcus prophylaxis should be given in the absence of a recent negative anal-vaginal culture. Broad-spectrum antibiotics should be given intravenously if there is a suspicion of amnionitis. A number of investigators have evaluated the clinical applicability of fetal pulmonary maturity testing in the setting of preterm PROM. Shaver et al [63] found lecithin-shingomyelin (L/S) ratios to be similar whether collected from vaginal pool or at amniocentesis. Vaginally collected phosphatidylglycerol (PG) determinations have been found to be highly predictive of fetal pulmonary maturity, with a similar negative predictive value (34% RDS) to that seen from amniocentesis specimens in the face of an immature test [64]. The surfactant/ albumin ratio has also been demonstrated to be predictive of pulmonary maturity or immaturity when obtained from vaginal pool or amniocentesis specimens [65,66]. Nonpulmonary phospholipids in blood may lower a mature result to an immature value but are unlikely to increase an immature result to a mature value [67,68]. Hence, a mature L/S ratio should be reassuring if there is blood con- tamination. Blood contamination can falsely lower the TDX-FLM assay result, but a mature result reliably predicts fetal pulmonary maturity [69]. Meconium staining can falsely elevate an L/S ratio, but not the PG test [70]. Clinically, if there is blood or meconium present in the vaginal pool specimen, serious consideration should be given to delivery rather than conservative management.
  13. 13. B.M. Mercer / Clin Perinatol 31 (2004) 765–782 777 Preterm PROM near term (320 - 366 weeks gestation) 320 - 336 weeks 340-366 weeks gestation gestation Immature Testing or Fluid Documented fetal Unavailable pulmonary maturity Conservative Management for Antenatal Corticosteroid benefit, with Concurrent Antibiotic Therapy Delivery after Delivery at Expeditious Expeditious Expeditious 24 - 48 hours 34 weeks delivery delivery delivery Intrapartum group B streptococcus prophylaxis if no recent negative ano-vaginal culture Broad spectrum antibiotics if Amnionitis Fig. 4. Management algorithm for women presenting with preterm PROM near term (32 weeks, 0 days–36 weeks, 6 days). When preterm PROM occurs at 32 to 336 weeks’ gestation, fetal pulmonary maturity assessment can be helpful in determining the approach to management. In the presence of fetal pulmonary maturity documented by either vaginal pool sampling or amniocentesis after 32 weeks, there is little risk of severe neonatal morbidity with expeditious delivery [71]. Given the increased risk of amnionitis, the potential for occult cord compression, and the scant additional latency accrued with conservative management after preterm PROM near term, this strategy is likely to lead to more morbidity than expeditious delivery, assuming fetal pulmonary maturity is documented. Women with documented fetal pulmonary maturity after preterm PROM at 32 to 336 weeks’ gestation are best served by expeditious delivery with intrapartum antibiotic administration, as delineated earlier. When amniotic fluid testing reveals an immature result, or when amniotic fluid is unavailable after preterm PROM at 32 to 336 weeks’ gestation, conser- vative management may be appropriate. No studies specifically address this
  14. 14. 778 B.M. Mercer / Clin Perinatol 31 (2004) 765–782 subset of women. However, the following principles may be helpful. The infant delivered with documented pulmonary immaturity is at an increased risk of respiratory distress and other complications. Antenatal corticosteroids have been demonstrated to benefit populations at high risk for fetal immaturity, and antibiotic treatment in the setting of preterm PROM has been shown to reduce the risk of infectious morbidity. Given these general principles, conservative management with antenatal corticosteroid administration and concurrent anti- biotic therapy may be appropriate. Because no data address the potential risks and benefits of delaying delivery after antenatal corticosteroid benefit has been achieved, either delivery 24 to 48 hours after corticosteroid administration or conservative management to 34 weeks’ gestation should be considered accept- able. All three studies that prospectively evaluated preterm PROM near term found significant increases in perinatal infection and only brief pregnancy prolongation subsequent to conservative management [62,71,72]. Expeditious delivery should be considered unless the fetus is considered to be at significant risk for gestational age–dependent morbidity, in which case measures should be taken to reduce the risk of infection and enhance fetal maturation. If antenatal corticosteroids and antibiotics are not to be administered in this setting, the women may be better served by expeditious delivery with appropriate intra- partum antibiotic therapy. Summary Preterm PROM is a common and significant cause of preterm birth and perinatal morbidity and mortality. The obstetric caregiver has the opportunity significantly to alter pregnancy and perinatal outcome for women suffering from this complication. Although management is often predetermined by the presence of clinical infection, vaginal bleeding, labor, or nonreassuring fetal heart-rate pattern on admission, a gestational age–based approach to the management of the stable patient with preterm PROM offers the potential to reduce perinatal infectious and gestational age–dependent morbidity for patients amenable to conservative management. Gestational age–appropriate counseling, incorporating both the obstetric and the neonatal caregiver, may be helpful in preparing the patient for potential complications. Early transfer to a facility capable of providing urgent obstetric and neonatal intensive care is important should ade- quate local facilities not be available. Regardless of management approach, this population is at high risk for perinatal complications, many of which cannot be avoided with current technology and management algorithms. References [1] Meis PJ, Ernest JM, Moore ML. Causes of low birth weight births in public and private patients. Am J Obstet Gynecol 1987;156:1165 – 8.
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