HIGH-RISK PREGNANCY SERIES: AN EXPERTS VIEW

We have invited select authorities to present background information on challenging clinical problems and practical information on diagnosis and treatment for use by practitioners.

Preterm Premature Rupture of the Membranes

Brian M. Mercer, MD
Preterm premature rupture of membranes (PROM) affects over 120,000 pregnancies annually in the United States and is associated with signicant maternal, fetal, and neonatal risk. Management of PROM requires an accurate diagnosis as well as evaluation of the risks and benets of continued pregnancy or expeditious delivery. An understanding of gestational age dependent neonatal morbidity and mortality is important in determining the potential benets of conservative management of preterm PROM at any gestation. Where possible, the treatment of pregnancies complicated by PROM remote from term should be directed towards conserving the pregnancy and reducing perinatal morbidity due to prematurity while monitoring closely for evidence of infection, placental abruption, labor, or fetal compromise due to umbilical cord compression. Current evidence suggests aggressive adjunctive antibiotic therapy to reduce gestational age dependent and infectious infant morbidity. Similarly, review of evaluable data indicates that antenatal corticosteroid administration in this setting enhances neonatal outcome without increasing the risk of perinatal infection. It is not clear that tocolysis in the setting of preterm PROM remote from term reduces infant morbidity. When preterm PROM occurs near term, particularly if fetal pulmonary maturity is evident, the patient is generally best served by expeditious delivery. (Obstet Gynecol 2003;101:178 93. 2003 by The American College of Obstetricians and Gynecologists.)

INTRODUCTION Incidence and Clinical Importance Preterm premature rupture of membranes (PROM) occurs in 3% of pregnancies and is responsible for approximately one third of all preterm births. Preterm PROM is an important cause of perinatal morbidity and mortality, particularly because it is associated with brief latency from membrane rupture to delivery, perinatal infection, and umbilical cord compression due to oligohydramnios. Even with conservative management, 50 60% of women with preterm PROM remote from term will deliver within 1 week of membrane rupture. Amnionitis (13 60%) and clinical abruptio placentae (4 12%) are commonly associated with preterm PROM. The risk of these complications increases with decreasing gestational age at membrane rupture. The frequency and severity of neonatal complications after preterm PROM vary with the gestational age at which rupture and delivery occur, and are increased with perinatal infection, abruptio placentae, and umbilical cord compression. Respiratory distress syndrome (RDS) is the most common serious complication after preterm PROM at any gestation. Other serious acute morbidities including necrotizing enterocolitis, intraventricular hemorrhage, and sepsis are common with early preterm birth but relatively uncommon near term. Remote from term, serious perinatal morbidity that may lead to long-term sequelae or death is common. Figures 1 through 3 present recent gestational age dependent morbidity and mortality curves from a prospective community-based evaluation of 8523 consecutive women delivering at six hospitals in Shelby County, Tennessee between July 1997 and March 1998. In this evaluation, we found that 33% of live-born and resuscitated infants delivered at 23 weeks survived to discharge from hospital (Figure 1). One-week increments in gestational age were associated with impressive improvements in survival when delivery occurred between 23 and 32 weeks

From the Department of Obstetrics and Gynecology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio. Support: The Prematurity Center of The Partnership for Womens and Childrens Health (University of Tennessee, Memphis; Methodist Healthcare Foundation; LeBonheur Childrens Hospital; and the Tennessee Coordinated Care Network). We would like to thank the following individuals who, in addition to members of our Editorial Board, will serve as referees for this series: Dwight P. Cruikshank, MD, Ronald S. Gibbs, MD, Gary D. V. Hankins, MD, Philip B. Mead, MD, Kenneth L. Noller, MD, Catherine Y. Spong, MD, and Edward E. Wallach, MD.

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0029-7844/03/$30.00 PII S0029-7844(02)02366-9

Figure 1. Survival by gestational age among live-born resuscitated infants. Results of a community-based evaluation of 8523 deliveries, 19971998, Shelby County, Tennessee. Curves smoothed by 2-point average.
Mercer. Treatment of Preterm PROM. Obstet Gynecol 2003.

gestation. Among infants surviving to discharge, RDS (more than 24 hours oxygen requirement or ventilation in the absence of other evident cause of respiratory compromise) was the most common acute morbidity at any gestational age (Figure 2). Among surviving infants, intraventricular hemorrhage and necrotizing enterocolitis were rare when delivery occurred after 32 weeks. Blood- or cerebrospinal cultureproven sepsis declined rapidly among those delivering between 27 and 30 weeks, with a modest decline in sepsis for each week gained thereafter. Although this study did not have the opportunity to measure long-term morbidity, retinopathy of prematurity and bronchopulmonary dysplasia occurred almost uniformly among survivors born at 23 weeks, and were almost never seen with delivery at or after 32 weeks (Figure 3). These ndings were similar to a recent multicenter observational study of women delivering infants who weighed less than 1000 g.1 In that study, 15 of 40 live-born singletons delivered at 23 weeks gestation survived (37.5%). However, two thirds

of survivors suffered major morbidities potentially associated with long-term morbidity (any of the following: grades 3 to 4 intraventricular hemorrhage, grades 3 to 4 retinopathy of prematurity, necrotizing enterocolitis requiring surgery, oxygen dependence at 120 days or at discharge, or seizures). Current data specic to infants delivering after preterm PROM are not available. However, it has been found that perinatal sepsis is two-fold more common in the setting of preterm PROM than preterm birth after preterm labor with intact membranes.2 Denitions Premature rupture of the membranes is dened as spontaneous membrane rupture that occurs before the onset of labor. When spontaneous membrane rupture occurs before 37 weeks gestation, it is referred to as preterm PROM. The term latency refers to the time from membrane rupture to delivery. Conservative management is dened as treatment directed at continuing the

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Figure 2. Acute morbidity by gestational age among surviving infants. Results of a community-based evaluation of 8523 deliveries, 19971998, Shelby County, Tennessee. Curves smoothed by 2-point average.
Mercer. Treatment of Preterm PROM. Obstet Gynecol 2003.

pregnancy. Preterm PROM that occurs at or before 26 weeks gestation complicates 0.6 0.7% of pregnancies, and has been dened as midtrimester PROM. Although the delineation of midtrimester PROM was clinically relevant in the 1970s and 1980s, the limit of fetal viability has progressively declined over the past 3 decades. As such it is currently more clinically relevant to differentiate preterm PROM into previable PROM, which occurs before the limit of viability (less than 23 weeks), preterm PROM remote from term (from viability to about 32 weeks gestation), and preterm PROM near term (approximately 3236 weeks gestation). When previable PROM occurs, immediate delivery will lead to neonatal death. Conservative management may lead to previable or periviable birth, but may also lead to extended latency and delivery of a potentially viable infant. Immediate delivery after preterm PROM remote from term is associated with a high risk of signicant perinatal morbidity and mortality that decreases with advancing gestational age at delivery. Alternatively, with preterm PROM near term, expeditious delivery of a noninfected and nonasphyxiated infant is associated with a high likelihood of survival and a low risk of severe morbidity.

Pathophysiology Premature rupture of membranes is multifactorial in nature. In any given patient, one or more pathophysiologic processes may be evident. Choriodecidual infection or inammation appears to play an important role in etiology of preterm PROM, especially at early gestational ages.3 Decreased membrane collagen content has been demonstrated in the setting of preterm PROM and with increasing gestational age.4 In support of this, increases in amniotic uid matrix metalloproteases (1, 8, and 9) as well as decreases in tissue inhibitors of matrix metalloproteases (1 and 2) have been identied among women with preterm PROM.5,6 Other factors associated with preterm PROM include lower socioeconomic status, cigarette smoking, sexually transmitted infections, prior cervical conization, prior preterm delivery, prior preterm labor in the current pregnancy, uterine distention (eg, twins, hydramnios), cervical cerclage, amniocentesis, and vaginal bleeding in pregnancy. Each of these may be associated with preterm PROM through membrane stretch or degradation, local inammation, or a weakening of maternal resistance to ascending bacterial colonization. In many cases, the ultimate cause of premature membrane rupture is unknown.

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Figure 3. Chronic morbidity by gestational age among surviving infants. Results of a community-based evaluation of 8523 deliveries, 19971998, Shelby County, Tennessee. Curves smoothed by 2-point average.
Mercer. Treatment of Preterm PROM. Obstet Gynecol 2003.

Prediction of Preterm PROM Because the clinical course of preterm PROM is often one of brief latency and increased infectious risk, it would be preferable to prevent it from occurring. In a large prospective study,7 the National Institute of Child Health & Human Development Maternal-Fetal Medicine Units Network found prior preterm birth and preterm birth due to preterm PROM to be associated with subsequent preterm birth due to preterm PROM. Those with a prior preterm birth at 2327 weeks had a 27.1% risk of preterm birth subsequently (P .001). Those with a history of preterm PROM had a 13.5% risk of preterm birth due to preterm PROM in a subsequent gestation (versus 4.1%, relative risk 3.3, P .01) and a 13.5-fold higher risk of preterm PROM at less than 28 weeks in the subsequent gestation (1.8% versus 0.13%, P .01). In a separate publication from this study the investigators found medical complications, work in pregnancy, symptomatic contractions, bacterial vaginosis, and low body mass index to be associated with preterm birth due to preterm PROM in nulliparas. Preterm PROM in multiparas was associated with prior preterm PROM, prior preterm birth due to preterm labor, and low body mass index. The presence of a short cervix (less than 25

mm by transvaginal ultrasound) was associated with preterm PROM in both nulliparas and multiparas. A positive fetal bronectin screen was also associated with preterm PROM in multiparas. Nulliparas with a positive cervicovaginal fetal bronectin and a short cervix had a 16.7% risk of preterm birth due to preterm PROM, whereas multiparas with a prior history, a short cervix, and a positive fetal bronectin had a 25% risk of preterm PROM. Multiparas with all three risk factors had a 31-fold increased risk of PROM with delivery before 35 weeks relative to those without risk factors (25% versus 0.8%, P .001).8 Unfortunately, despite our developing ability to identify women at increased risk for preterm PROM, such testing is expensive and inconvenient to the patient, and will identify only a small fraction of those ultimately delivering preterm. Because of this, our clinical efforts remain focused on treatment of preterm PROM once it has occurred, rather than its prevention. DIAGNOSTIC APPROACH The approach to the diagnosis of membrane rupture is clinical, with over 90% of cases being conrmed based

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on the presence of a suspicious history or ultrasonographic nding followed by documentation of uid passing from the cervix or the presence of a Nitrazine (Bristol-Myers Squibb, Princeton, NJ)/ferning positive vaginal pool of uid. Other plausible causes of vaginal discharge (eg, urinary incontinence, vaginitis, cervicitis, mucous show with cervical effacement and dilatation, semen, vaginal douches) should be excluded if the diagnosis is unclear. The Nitrazine test can be falsely positive if the vaginal pH is increased by blood or semen contamination or alkaline antiseptics, or if bacterial vaginosis is present. The ferning test should be performed on a sample collected from the posterior fornix or lateral vaginal sidewall to avoid cervical mucus, which may also yield a false positive result. Prolonged leakage with minimal residual uid can lead to a false negative Nitrazine or ferning test. Should initial testing be negative but a clinical suspicion of membrane rupture remain, the patient can be retested after prolonged recumbency or alternate measures can be considered. Ultrasound evaluation may prove useful if the diagnosis remains in doubt after speculum examination. The diagnosis of membrane rupture can be conrmed unequivocally with ultrasound-guided amnioinfusion of indigo carmine (1 mL in 9 mL of sterile normal saline), followed by observation for passage of blue uid per vaginum. Although oligohydramnios without evident fetal urinary tract malformations or fetal growth restriction may be suggestive of membrane rupture, ultrasound alone cannot diagnose or exclude membrane rupture with certainty. Cervicovaginal screening for fetal bronectin has been suggested as a marker for preterm PROM when the diagnosis remains in doubt after initial speculum examination. However, the impact of prolonged membrane rupture on the bronectin result has not been elucidated. Further, a positive test may reect disruption of the decidua rather than membrane rupture. As such, fetal bronectin testing for the diagnosis of preterm PROM is not recommended for routine practice. Until such time as the diagnosis of membrane rupture is excluded, it is prudent to avoid digital cervical examinations, which have been shown to decrease latency and increase infectious morbidity9,10 without adding substantial information to that obtained by careful visualization during a sterile speculum examination. The speculum examination also offers the opportunity to perform appropriate cultures (eg, endocervical chlamydia and gonorrhea), if these have not been recently performed or clinical suspicion of new infection is present. Anovaginal cultures for group B streptococcus should be obtained if these have not been performed within 5 weeks.

THERAPEUTIC APPROACH General Considerations Because the risk of perinatal complications changes dramatically with gestational age at membrane rupture and delivery, a gestational age based approach to the management of preterm PROM is appropriate. Although there is no apparent neonatal benet to conservative management after membrane rupture at term, there is a potential for neonatal benet when conservative management of preterm PROM is undertaken for the immature fetus. This benet may only be accrued if conservative measures lead to pregnancy prolongation resulting in a reduction of gestational age dependent morbidity, or through prevention of perinatal infection. Management should be based on individual assessment of the estimated risk for maternal, fetal, and neonatal complications should conservative management or expeditious delivery be pursued (Figure 4). Although practice varies and there is considerable controversy regarding the optimal management of preterm PROM, there is general consensus regarding some issues. First, gestational age should be established based on clinical history and prior ultrasound assessment where available. Ultrasound should be performed if feasible to estimate gestational age (if no prior ultrasound has been performed) as well as fetal growth, position, and residual amniotic uid volume, and to evaluate for gross fetal abnormalities that may cause polyhydramnios. The woman with preterm PROM should be evaluated clinically for evidence of advanced labor, chorioamnionitis, abruptio placentae, and fetal distress. Those with advanced labor, intrauterine infection, signicant vaginal bleeding, or nonreassuring fetal testing are best delivered regardless of gestational age. If fetal malpresentation coexists with signicant cervical dilation, there is an increased risk of umbilical cord prolapse, which may increase the risk of fetal loss. This circumstance may justify early delivery given the increased fetal risk. Women with genital herpes simplex virus (HSV) infection or human immunodeciency virus (HIV) infection should generally not be managed conservatively. In certain cases (eg, recurrent HSV or HIV infection near or before the limit of viability), conservative management of preterm PROM may be justied because of the extremely high risk of mortality and chronic morbidity when immediate delivery is undertaken. These cases should be managed individually. Although there are published case series supporting conservative management in the setting of recurrent HSV infection, there are no data in this regard for women infected with HIV. Intrapartum prophylaxis against group B streptococcus is recommended for gravidas delivering preterm, unless

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Figure 4. An algorithm for evaluation and management of preterm premature rupture of the membranes (pPROM). PgE2 prostaglandin E2; NIH National Institutes of Health Maternal-Fetal Medicine Units Network.
Mercer. Treatment of Preterm PROM. Obstet Gynecol 2003.

recent anovaginal group B streptococcus cultures are negative.11 If conservative management of preterm PROM is to be pursued, the patient should be admitted to a facility capable of providing emergent delivery for abruptio placentae, fetal malpresentation in labor, and/or fetal distress due to umbilical cord compression or in utero infection. The facility should also be capable of providing 24-hour neonatal resuscitation and intensive care, as conservative management should generally be performed only in pregnancies where there is a signicant risk of neonatal morbidity and mortality should delivery occur. If adequate facilities for maternal and neonatal care do not exist, patient transfer should be undertaken early in the course of management to avoid emergent transfer once complications arise. Preterm PROM Near Term (3236 Weeks) When preterm PROM occurs at 34 36 weeks gestation, the risk of severe acute morbidity and mortality occurring is low when expeditious delivery is pursued. Corticosteroids are generally not given to accelerate fetal pulmonary maturity. Conversely, conservative management at 34 36 weeks is associated with an increased risk of amnionitis (16% versus 2%, P .001), prolonged maternal hospitalization (5.2 versus 2.6 days, P .006), and a lower mean umbilical cord pH at delivery (7.25 versus 7.35, P .009) without the benet of a signicant reduction of perinatal complications related to prematurity.12 A mature phosphatidyl glycerol, AmniostatFLM (Irvine Scientic, Santa Ana, CA), uorescence polarization TDX FLMII assay (surfactant/albumin ratio) (Abbott Laboratories, Abbott Park, IL), lecithinsphingomyelin ratio, or a lamellar body count result from uid collected from either vaginal pool uid or amniocentesis is associated with a low risk of signicant pulmonary complications after preterm PROM near term, regardless of the presence of blood or meconium contamination. The presence of blood or meconium in the setting of preterm PROM should raise the level of suspicion for abruptio placentae or fetal compromise and lead to reconsideration of the benets of conservative management. Should pulmonary maturity be evident based on vaginal pool amniotic uid or from amniocentesis at 3236 weeks gestation, it is evident that the risk of major nonpulmonary perinatal complications are low and that conservative management will prolong pregnancy only briey (36 versus 14 hours, P .001), increase the risk of amnionitis (27.7% versus 10.9%, P .06), and place the fetus at risk for occult cord compression while unmonitored, without offering a signicant reduction in neonatal morbidity.13 Thus, the woman who suffers preterm PROM at 34 36 weeks is generally best served by expeditious delivery. When preterm

PROM occurs at 32 to 33 weeks, it is recommended that fetal pulmonary maturity be assessed by vaginal pool specimen if available, and that amniocentesis by a skilled clinician be considered should there be inadequate vaginal uid for pulmonary maturity evaluation. When fetal pulmonary maturity is evident after preterm PROM at 32 to 33 weeks, there is little to be gained by continued pregnancy, and expeditious delivery is recommended. There are no studies upon which to guide practice for women in which pulmonary maturity testing is not performed or unavailable after preterm PROM at 32 to 33 weeks gestation. At this gestation, the likelihood of survival with delivery is high, but there remains signicant risk of pulmonary immaturity and other gestational age dependent morbidity should the fetus be immature. Cox et al14 evaluated the practice of immediate delivery versus conservative management in 129 unselected women with preterm PROM at 30 33 67 weeks gestation. Tocolytics and antenatal steroids were not administered, and group B streptococcus prophylaxis was not given. Conservative management of preterm PROM was associated with only a brief increase in latency to delivery (59% versus 100% delivered within 48 hours, P .001), but a signicant increase in amnionitis (15% versus 2%, P .009), and no evident reduction in gestational age dependent morbidity. There was a signicant risk of RDS in this population (35%). In addition, there was one stillbirth due to suspected occult umbilical cord compression in the conservatively managed group, and three neonatal deaths in the immediately delivered group (two from sepsis and one from pulmonary hypoplasia). Although this study does suggest that immediate delivery might reduce fetal exposure to intrauterine infection and avoid fetal loss due to cord compression, it conrms that the infant delivered at 30 33 weeks remains at risk for neonatal sepsis and other signicant gestational age dependent morbidity in the absence of documented pulmonary maturity. As such, should fetal pulmonary immaturity be suspected at 32 to 33 weeks, or should uid for testing be unavailable, an option would be to treat conservatively with close fetal monitoring, adjunctive antibiotic therapy, and antenatal corticosteroid administration for fetal maturation (see below). Alternatively, if there is no plan to either induce fetal maturation with corticosteroids or prolong pregnancy and suppress infection with concurrent antibiotics, these patients may be better served by expeditious delivery. Preterm PROM Remote From Term (2331 Weeks) Delivery before 32 weeks gestation is associated with a signicant risk of neonatal complications, including severe acute morbidity and death. Because of this, the

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stable gravida with preterm PROM remote from term is generally best served by conservative management in an attempt to prolong pregnancy and reduce the risk of gestational age dependent morbidity in the newborn. Despite conservative efforts, many women will ultimately deliver after a brief latency. However, a subset of these women will remain pregnant for an extended period of time, allowing the fetus to mature in utero. A low initial amniotic uid index has been shown to be associated with shorter latency and an increased risk of amnionitis.15,16 However, amniotic uid volume assessment does not accurately predict who will ultimately deliver quickly despite conservative measures, and thus should not be used in isolation to make decisions regarding conservative management. During conservative management, care should be directed toward the early detection of labor, abruptio placentae, amnionitis, and umbilical cord compression or occult fetal distress. This is generally best accomplished by inpatient observation unless the membranes reseal. Conservative management generally consists of initial prolonged continuous fetal and maternal monitoring combined with subsequent modied bed rest to increase the opportunity for amniotic uid reaccumulation and spontaneous membrane sealing. The fetus with preterm PROM remote from term is at signicant risk (3276%) for umbilical cord compression and fetal distress.17,18 Because abnormal fetal heart rate patterns and contractions can occur in otherwise asymptomatic women, fetal assessment should be performed at least daily on those with initially reassuring testing. Although both the nonstress test and the biophysical prole have the ability to conrm fetal well-being or identify fetal compromise in the setting of preterm PROM, fetal heart rate monitoring offers the opportunity to identify periodic heart rate changes such as variable and late decelerations, in addition to allowing concurrent assessment of uterine activity. Biophysical prole testing may be confounded by the presence of oligohydramnios but can be helpful should the nonstress test be equivocal, particularly remote from term, when the fetal heart rate pattern is less likely to be reactive. Those with intermittent umbilical cord compression but otherwise reassuring testing should undergo continuous fetal heart rate monitoring, pending reassessment upon successful attainment of antenatal corticosteroid benet (24 48 hours after initial dose). Complete pelvic rest and avoidance of digital pelvic examinations should be undertaken to reduce the risk of intrauterine infection and enhance latency. The combination of fever (temperature exceeding 38.0C or 100.4F) with uterine tenderness and/or maternal or fetal tachycardia, in the absence of another source

of infection, are suggestive of intrauterine infection and should lead to expeditious delivery. Maternal white blood cell counts may be articially elevated if antenatal corticosteroids have been administered within 57 days. Alternatively, a rising white blood cell count in the presence of suspicious clinical ndings may be useful in identifying those who require closer observation, including continuous fetal monitoring or delivery. Maternal fever is not always present early in the course of amnionitis. Should maternal symptoms, physical ndings, and/or hematological ndings be equivocal, amniocentesis may provide further suggestive information regarding the presence of intrauterine infection, including a glucose concentration of less than 16 20 mg/dL, a positive Gram stain, or a positive amniotic uid culture. Although positive amniotic uid cultures and elevated interleukin levels have been clearly associated with an increased risk of early delivery and perinatal infectious morbidity, these test results are not rapidly available in most clinical laboratories, limiting their utility in clinical practice. If amnionitis is suspected but the diagnosis is equivocal, amniocentesis should be considered with Gram stain, differential count, and glucose level used, for acute management. Should a positive amniotic uid culture become evident later, this information should be considered by the obstetrician if the patient remains pregnant, and provided to the neonatologist if the patient has delivered subsequent to the amniocentesis. Optimal treatment of the woman reaching an advanced gestational age after conservative management of preterm PROM remote from term has not been studied. In the absence of labor, abruption, nonreassuring fetal testing, or intrauterine infection, it is reasonable to consider labor induction when the pregnancy reaches 34 weeks gestation. It may also be reasonable to assess fetal pulmonary maturity at any time from 32 to 34 weeks and consider delivery once maturity has been documented. Adjunctive Treatment of PROM Remote From Term Antibiotics. The benets of narrow-spectrum intrapartum prophylaxis with intravenous penicillin or ampicillin to prevent vertical transmission and early-onset neonatal sepsis by group B streptococcus (Streptococcus agalactiae) have been well established. Intrapartum group B streptococcus prophylaxis with intravenous penicillin as a 5,000,000-U initial bolus followed by 2,500,000 U every 4 hours or ampicillin (2 g) followed by 1 g intravenously (IV) every 4 hours (erythromycin, 500 mg IV every 6 hours, or clindamycin, 900 mg IV every 8 hours, if penicillin allergic) should be administered during labor or before cesarean delivery after preterm PROM unless there is inadequate time or there is a negative anovaginal culture obtained within 5 weeks of delivery. Because of

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increasing resistance of group B streptococcus to erythromycin and clindamycin, some investigators have suggested careful conrmation of penicillin allergy before alternate treatment, and intravenous cefazolin for those with documented penicillin allergy.19,20 Should the latter approach be taken, the caregiver should closely observe the patient for allergy to cephalosporins. It may be prudent to restrict such alternative treatment to women with minor allergic reactions to penicillin therapy. The reader is encouraged to watch for evolving recommendations regarding intrapartum group B streptococcus prophylaxis. The goal of adjunctive antibiotic therapy during conservative management of preterm PROM remote from term is to treat or prevent ascending decidual infection in order to prolong pregnancy and offer the opportunity for reduced neonatal infectious and gestational age dependent morbidity. Over two dozen randomized, prospective, controlled trials have been undertaken to determine if there is value in the adjunctive administration of antibiotics during conservative management of preterm PROM remote from term. These studies are addressed in detail elsewhere (Svare J. Preterm delivery and subclinical uro-genital infection [thesis]. Copenhagen, Denmark: University of Copenhagen, Department of Obstetrics and Gynaecology Rigshospitalet, 1997).2124 The broad range of antibiotics administered, differing routes and duration of administration, inclusion of pregnancies at low risk for neonatal morbidity, and the variability of concurrent tocolytic and corticosteroid administration make interpretation of the ndings difcult. However, two large multicenter clinical trials with different approaches to this issue have adequate power to evaluate the utility of adjunctive antibiotics after preterm PROM in reducing infant morbidity. The combination of these studies, as well as specic details from individual smaller trials, offer valuable insights regarding the potential role of adjunctive antibiotics in this setting. The National Institute of Child Health & Human Development Maternal-Fetal Medicine Units Network elected to study women with preterm PROM from the limit of 24 32 07 weeks gestation.25 The primary goal was to see if adjunctive antibiotic therapy during conservative management of preterm PROM would reduce the number of infants who were acutely ill after birth; a secondary goal was to see if such treatment reduced individual infectious or gestational age dependent morbidities. The National Institute of Child Health & Human Development Maternal-Fetal Medicine Units Network elected to use initial aggressive IV 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 amoxicillin (250 mg

orally every 8 hours) and enteric coated erythromycin base (333 mg orally every 8 hours). These agents were chosen because of their broad-spectrum antimicrobial coverage and their demonstrated safety when used in pregnancy. The duration of therapy was limited because of concerns that prolonged therapy might lead to selective survival of resistant bacteria that might be more difcult to treat should neonatal infection occur. Once group B streptococcus carriage was identied based on initial cultures, carriers were treated with ampicillin for 1 week and then again in labor, regardless of whether they were assigned to study antibiotics or placebo therapy. Similar to other studies, this trial found that antibiotic treatment prolonged pregnancy, increasing two-fold the likelihood that patients would not have delivered after 7 days of treatment. Despite discontinuation of antibiotics at 7 days, treated women continued to be more likely to remain pregnant at up to 3 weeks after randomization, suggesting that the therapy actually successfully treated subclinical infection rather than just suppressing it. Regarding infant morbidity, the National Institutes of Health (NIH) trial found that antibiotics improved neonatal health by reducing the number of infants with one or more major infant morbidity (composite morbidity: death, RDS, early sepsis, severe intraventricular hemorrhage, severe necrotizing enterocolitis) from 53% to 44% (P .05). Additionally, aggressive antibiotic therapy was associated with signicant reductions in individual gestational age dependent morbidity including RDS (40.5% versus 48.7%), stages 3 to 4 necrotizing enterocolitis (2.3% versus 5.8%), patent ductus arteriosus (11.7% versus 20.2%), and chronic lung disease (bronchopulmonary dysplasia: 13.0% versus 20.5%) (P .05 for each). Regarding infectious morbidity, the antibiotic study group had a lower incidence of neonatal group B streptococcus sepsis (0% versus 1.5%, P .03). Amnionitis was also reduced with study antibiotics (23% versus 32.5%, P .01). Neonatal sepsis (8.4% versus 15.6%, P .009) and pneumonia (2.9% versus 7.0%, P .04) were less frequent in those who were not group B streptococcus carriers. In support of this studys ndings, Mantel-Haenszel 2 analysis of prospective randomized clinical trials with initial broad-spectrum parenteral therapy for women with preterm PROM at less than 34 weeks (Svare J. Preterm delivery and subclinical urogenital infection [thesis]. Copenhagen, Denmark: University of Copenhagen, Department of Obstetrics and Gynaecology Rigshospitalet, 1997)23-32 shows that antibiotics increase the likelihood of women remaining pregnant for longer than 1 week (odds ratio [OR] and 95% condence interval [CI]: 2.52; 1.92, 3.30), reduce amnionitis (0.60; 0.47, 0.78), reduce neonatal sepsis (0.47; 0.33, 0.67), reduce RDS (0.76; 0.60, 0.96), and reduce intra-

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ventricular hemorrhage (0.70; 0.52, 0.95), without an increase in the risk of cesarean delivery (1.00; 0.78, 1.28) or necrotizing enterocolitis (1.28; 0.84, 1.98). Because of these ndings, limited duration aggressive antibiotic therapy is recommended during conservative management of preterm PROM remote from term. Kenyon et al33 performed a large multiarm, multicenter placebo-controlled trial of oral antibiotic therapy of women with preterm PROM at less than 37 weeks. Women were randomized to receive oral erythromycin, amoxicillin clavulonic acid, both, or a placebo for up to 10 days. Over 400 presented and nonpresented statistical analyses were performed. In summary, oral erythromycin was associated with brief pregnancy prolongation (not signicant at 7 days), reduced need for supplemental oxygen (31.1% versus 35.6%, P .02), reduced positive blood cultures (5.7% versus 8.2%, P .02), but no signicant reduction in the composite primary outcome (an infant suffering one or more of the following: death, chronic lung disease, major cerebral abnormality on ultrasonography) (12.7% versus 15.2%, P .08). Subanalysis of singleton gestations revealed a reduction in oxygen dependence at 28 days (6.9% versus 8.9%, P .03), positive blood cultures (5.3% versus 7.4%, P .04), abnormal cerebral ultrasonography (3.0% versus 4.6%, P .04), and composite morbidity (11.2% versus 14.4%, P .02) with erythromycin. Oral amoxicillin clavulonic acid prolonged pregnancy (43.3% versus 36.7% undelivered after 7 days, P .005) and reduced the need for supplemental oxygen (30.1% versus 35.6%, P .05), but was associated with an increased risk of necrotizing enterocolitis (1.9% versus 0.5%, P .001) without reducing other neonatal morbidity or composite morbidity. The combination of oral amoxicillin clavulonic acid and erythromycin yielded similar ndings. Subanalysis of women with preterm PROM remote from term was not presented but was reported to reveal the same pattern of ndings. There was no analysis of the benets of oral antibiotics during conservative management at 3236 weeks. The authors concluded that oral erythromycin, when given to women with preterm PROM, has effects on the occurrence of major neonatal disease, and might therefore have a substantial health benet on the long-term respiratory and neurological function of many children. They raised concern regarding the potential negative effects of oral amoxicillin clavulonic acid because of the increased incidence of necrotizing enterocolitis. An alternate conclusion would be that oral antibiotic therapy with erythromycin reduces perinatal morbidity when given to women with preterm PROM before 37 weeks gestation, but given the small differences in the actual incidences of morbidity in the study groups, many women would need to be treated to prevent one adverse

outcome. Although the nding regarding increased necrotizing enterocolitis with oral amoxicillin clavulonic acid is concerning, it is at odds with the National Institute of Child Health & Human Development Maternal-Fetal Medicine Units Network trial nding of reduced stages 2 to 3 necrotizing enterocolitis with aggressive antibiotic therapy in a higher risk population. Further, there is no consistent trend towards a positive or negative effect of antibiotics for necrotizing enterocolitis in the literature. In summary, there appears to be a role for adjunctive aggressive antibiotic therapy with erythromycin and amoxicillin or ampicillin during conservative management of preterm PROM remote from term. If aggressive therapy is not given, oral erythromycin may offer some benet. The combination of erythromycin and extended-spectrum ampicillin clavulonic acid in a lower risk population near term does not appear to be benecial and may be harmful. This latter regimen is not recommended. Intrapartum group B streptococcus prophylaxis should be given to carriers, regardless of prior therapy. Corticosteroids. It is well established that administration of antenatal corticosteroids to women at high risk of delivering an immature preterm infant is one of the most effective obstetric interventions directed to reduce perinatal morbidity and mortality. Antenatal corticosteroids reduce the risk of RDS, intraventricular hemorrhage, and perinatal death and have been shown to have longterm neurological benets when given in a timely fashion before preterm birth. The current NIH consensus conference recommendations regarding corticosteroid administration in the setting of preterm PROM are that a single course of betamethasone (12 mg intramuscularly [IM], two doses every 24 hours) or dexamethasone (6 mg IM, four doses every 12 hours) be given during conservative management of preterm PROM before 30 32 weeks gestation because of the potential for reduction of intraventricular hemorrhage.34 There continues to be discussion regarding the efcacy of corticosteroids in the setting of preterm PROM in the prevention of RDS. It has been suggested that antenatal corticosteroids may be inappropriate in this setting because 1) women with preterm PROM will deliver too quickly to accrue the potential benets; 2) preterm PROM itself might induce fetal pulmonary maturation, thereby making corticosteroids unnecessary; and 3) antenatal corticosteroids might delay the diagnosis or increase the risk of perinatal infection through their immunosuppressive effects. It is now clear that the majority of conservatively managed women with preterm PROM remote from term will remain pregnant for at least 24 48 hours, particularly if adjunctive antibiotics are administered. Although there have been conicting reports regarding the relative risk

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of RDS with preterm birth after preterm PROM, it is clear that RDS remains the most common acute morbidity after preterm birth due to preterm PROM. In the National Institute of Child Health & Human Development Maternal-Fetal Medicine Units Network trial, the incidence of RDS after conservatively managed preterm PROM was 41% when corticosteroids were not administered, despite adjunctive antibiotic administration. Regarding perinatal infection, studies performed before the era of adjunctive antibiotic administration revealed conicting results as to the risk of neonatal infection when antenatal corticosteroids were administered. There are two recent randomized clinical trials that have assessed the utility of antenatal corticosteroid administration concurrent to adjunctive antibiotic administration. In the rst, Lewis et al35 found a reduced incidence of RDS (18.4% versus 43.6%, P .03) with no obvious increase in perinatal infection (3% versus 5%, P NS) when antenatal corticosteroids were administered after initiation of ampicillin-sulbactam for preterm PROM at 24 34 weeks. In the Dexiprom multicenter trial,36 women with preterm PROM were evaluated after being allocated to either a single course of dexamethasone (12 mg IM, two doses every 24 hours) or placebo at 28 34 weeks gestation. All patients received amoxicillin and metronidazole for 5 days. Although there was no significant reduction in morbidity in the overall population, no increase in maternal or neonatal morbidity was evident in the corticosteroid group. Among those remaining pregnant at least 24 hours after study entry, newborns exposed to antenatal steroids had a lower incidence of perinatal death (1.3% versus 8.3%, P .05). The most recent meta-analysis regarding this issue37 includes data from the original trial of corticosteroid administration published by Liggins and Howie in 1972. These authors found corticosteroid administration in the setting of preterm PROM to substantially reduce the risks of RDS (20% versus 35.4%; OR 0.56; CI 0.46, 0.70), intraventricular hemorrhage (7.5% versus 15.9%; OR 0.47; CI 0.31, 0.70), and necrotizing enterocolitis (0.8% versus 4.6%; OR 0.21; CI 0.05, 0.82), without signicantly increasing the risks of maternal infection (9.2% versus 5.1%; OR 1.95; CI 0.83, 4.59) or neonatal infection (7.0% versus 6.6%; OR 1.05; CI 0.66, 1.68). The authors suggested that there was no need for additional study of this specic issue. Thus, based on current information, it is recommended that a single course of antenatal corticosteroids be administered concurrently to initial adjunctive antibiotic therapy during conservative management of preterm PROM before 32 weeks. Similar treatment should also be considered if conservative management is pursued for suspected fetal pulmonary immaturity at 3234

weeks gestation. The risks and benets of repeated corticosteroid administration after an initial course of antenatal corticosteroids near the limit of viability remain to be determined. Currently routine repeated administration of antenatal corticosteroid is not recommended. Tocolysis. There are inadequate data upon which to make rm recommendations regarding tocolytic therapy in the setting of preterm PROM. Two small studies of prophylactic intravenous or oral betamimetic therapy and a study of prophylactic betamimetic or magnesium sulfate tocolysis after preterm PROM38 40 have suggested brief pregnancy prolongation in this setting. Alternatively, a practice of expectant management with therapeutic tocolysis initiated only after the onset of contractions did not show that tocolysis prolonged latency.41 Similarly, improved neonatal outcome has not been conferred with a practice of tocolysis and serial assessment of fetal pulmonary maturity followed by delivery.42 Although no study has demonstrated tocolytics to improve or worsen neonatal outcome, studies of conservative management have not evaluated tocolysis when corticosteroids and antibiotics are given concurrently. It is plausible that short-term pregnancy prolongation with prophylactic tocolysis could enhance the potential for corticosteroid effect and allow more time for antibiotics to act against subclinical decidual infection. Given evidence of short-term pregnancy prolongation without evident risk in some studies, it is not unreasonable to initiate tocolysis in women at high risk for infant morbidity should there be concurrent attempts to prevent infection, prolong pregnancy, and induce fetal pulmonary maturity. However, this approach should not be considered an expected practice as further research is needed. Previable Preterm PROM (Less Than 23 Weeks) Approximately half of women with second-trimester PROM will deliver within 1 week of membrane rupture. Alternatively, up to 22% will reamin pregnant for at least 1 month. In addition to the high risk of chorioamnionitis (39%), maternal morbidities associated with conservative management of second-trimester PROM include endometritis (14%), abruptio placentae (3%), retained placenta, and postpartum hemorrhage necessitating dilation and curettage (12%). Maternal sepsis is a rare but serious complication, complicating 0.8% of cases. One maternal death from sepsis has been reported in 731 pregnancies complicated by second-trimester PROM (0.14%).43 The incidence of stillbirth subsequent to second-trimester PROM (15%) is higher than that seen with preterm PROM later in pregnancy ( 1%). This may

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reect increased fetal susceptibility to umbilical cord compression, hypoxia, and intrauterine infection, but may also reect a practice of nonintervention for fetal distress in the pre- or periviable fetus. Previable delivery is immediately lethal. Periviable delivery after preterm PROM may be associated with more frequent morbidity and mortality than that seen with delivery due to other causes because pre- and periviable PROM are associated with perinatal infection and pulmonary hypoplasia. Women with early previable PROM before 20 weeks, and those with persistent oligohydramnios, are at particular risk for pulmonary hypoplasia. Lethal pulmonary hypoplasia rarely occurs with membrane rupture subsequent to 24 weeks gestation, presumably because alveolar growth adequate to support postnatal development has occurred. Ultrasound estimates of interval fetal lung growth including lung length, chest circumference, chest/abdominal circumference ratio, or chest circumference/femur length ratio carry a high positive predictive value for lethal pulmonary hypoplasia.44 47 The pattern of fetal restriction deformities occurring after prolonged intrauterine crowding is similar to that seen with Potter syndrome. The nonpulmonary features include abnormal facies and limb positioning abnormalities. The ears may be low set and epicanthal folds present. The extremities may be attened and malpositioned. It is estimated that 56 84% of survivors will be neurologically intact after midtrimester PROM.43,48 52 However, developmental delay (24%), delayed motor development (23%), and other less frequent complications including cerebral palsy, chronic lung disease, hydrocephalus, and mental retardation are serious reported sequelae. The frequency of these outcomes may be biased because of the lack of follow-up in over 40% of cases. There are no available recent data regarding the outcomes of survivors delivering after conservatively managed previable preterm PROM. Women presenting with PROM before viability should be counseled regarding the impact of immediate delivery and the potential risks and benets of conservative management. Counseling should include a realistic appraisal of neonatal outcomes, including the availability of obstetric monitoring and neonatal intensive care facilities. Because of the signicant risk of adverse maternal and neonatal sequelae after previable PROM, some women will desire expeditious delivery. Depending on the experience of the caregiver and the patients wishes, this can be accomplished by dilation and evacuation, or by labor induction with high-dose oxytocin or vaginal prostaglandin therapy in the absence of contraindications. There are currently no data upon which to make recommendations regarding initial conservative man-

agement of the woman with previable PROM. The benets of an initial period of inpatient observation may include strict bed and pelvic rest to enhance the opportunity for resealing, and for early identication of infection and abruption. Ultrasound should be performed to exclude the presence of associated fetal anomalies. Serial ultrasound should be offered every 1 to 2 weeks initially to evaluate for reaccumulation of amniotic uid and to evaluate interval pulmonary growth. Some women will elect not to continue the pregnancy if interval ultrasound suggests a high likelihood of lethal pulmonary hypoplasia based on the presence of persistent severe oligohydramnios and/or lagging pulmonary growth. A number of novel treatments including amnioinfusion and brin/ platelet/cryoprecipitate or gel foam sealing of the membranes have been preliminarily investigated.5355 In some approaches cervical cerclage placement concurrent to attempted membrane sealing is used. The maternal risks and fetal benets of these aggressive interventions have not been adequately demonstrated, so currently they should not be incorporated into routine clinical practice. Many clinicians will discharge the patient to bed rest at home after an initial observation period, with readmission to hospital bed rest once the patient reaches a gestation at which they would intervene for fetal benet should labor, amnionitis, nonreassuring testing, or abruption occur. There are no published data evaluating the risks and benets of this strategy versus continued hospitalization in this population. CERVICAL CERCLAGE Cervical cerclage is a widely described risk factor for PROM and other adverse pregnancy outcomes. Preterm PROM complicates about one in four pregnancies with a cerclage, and about half of pregnancies after emergent cerclage. Although women undergoing cerclage placement, whether elective or emergent, are at high risk for preterm birth, a thorough discussion of the potential adverse sequelae despite cerclage placement should be undertaken before the procedure. There are no prospective studies regarding the treatment of preterm PROM subsequent to cervical cerclage in situ. A number of retrospective studies have suggested that when cerclage is removed on admission, the risk of adverse perinatal outcomes is not higher than those seen after preterm PROM without a cerclage.56,57 Alternatively, studies comparing pregnancies in which the cerclage was retained or removed have been small and have yielded conicting results.58 60 Each study found a statistically insignicant trend towards increased maternal infection with retained cerclage. One study found increased infant mortality and death from sepsis with retained cerclage,

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with the only evident benet being an decreased likelihood of delivery within 24 hours.58 One study, which largely reected differing practices at two institutions, found signicant pregnancy prolongation with cerclage retention.59 Among those with preterm PROM before 28 weeks, cerclage retention was associated with improved birth weight (942 versus 758 g, P .04). However, no controlled study has found a signicant reduction in infant morbidity with cerclage retention after preterm PROM. Given the potential risk without evident neonatal benet, the general approach to management should include early cerclage removal after preterm PROM. The role for short-term cerclage retention while attempting to enhance fetal maturation with antenatal corticosteroids in the periviable gestation has not been determined. CEREBRAL PALSY/ADVERSE NEUROLOGICAL OUTCOME It is established that preterm birth is a signicant risk factor for long-term sequelae such as chronic lung disease, neurosensory impairment, cerebral palsy, and developmental delay. There are accumulating data linking perinatal infection to neurological complications. Because preterm PROM is associated with early delivery and perinatal infection, it is a potential risk factor for long-term neurological morbidity. Cerebral palsy and cystic periventricular leukomalacia have been linked to the presence of amnionitis, which is commonly seen after preterm PROM.61 Similarly, elevated amniotic uid cytokines and fetal systemic inammation, which may accompany or reect maternal or fetal infection, have been associated with preterm PROM as well as brain lesions such as periventricular leukomalacia and/or the subsequent development of cerebral palsy.62 64 Currently there are no data to suggest that immediate delivery of the candidate for conservative management after preterm PROM will prevent these sequelae. Therefore, conservative management, with adjunctive antibiotics to reduce the risk of intrapartum infection, is recommended. However, at more advanced gestational ages, particularly if pulmonary maturity can be documented, expeditious delivery may reduce the risk of exposure to intrauterine infection and subsequent morbidity. SUMMARY Premature rupture of the membranes affects over 120,000 pregnancies annually in the United States and is associated with signicant maternal, fetal, and neonatal risk. Management of PROM requires an accurate diagnosis and evaluation of the risks and benets of continued pregnancy or expeditious delivery. An understand-

ing of gestational age dependent neonatal morbidity and mortality is important in determining the potential benets of conservative management of preterm PROM at any gestation. Where possible, the treatment of pregnancies complicated by PROM remote from term should be directed towards conserving the pregnancy and reducing perinatal morbidity due to prematurity while monitoring closely for evidence of infection, abruptio placentae, labor, or fetal compromise due to umbilical cord compression. Alternatively, when preterm PROM occurs near term, the patient is generally best served by expeditious delivery, particularly if fetal pulmonary maturity is evident. It is important that the patient be well informed regarding the potential for subsequent maternal, fetal, and neonatal complications regardless of the management approach.

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63. Yoon BH, Romero R, Kim CJ, Koo JN, Choe G, Syn HC, et al. High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol 1997;177:40611. 64. Yoon BH, Romero R, Yang SH, Jun JK, Kim IO, Choi JH, et al. Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol 1996;174:143340.

Reprints are not available. Address correspondence to: Brian M. Mercer, MD, MetroHealth Medical Center, Department of Obstetrics and Gynecology, 2500 MetroHealth Drive, Suite G240, Cleveland, OH 44109-1989.

Received May 28, 2002. Received in revised form July 18, 2002. Accepted August 8, 2002.

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