27 CME REVIEWARTICLE

Volume 59, Number 9 OBSTETRICAL AND GYNECOLOGICAL SURVEY Copyright 2004 by Lippincott Williams & Wilkins

CHIEF EDITORS NOTE: This article is part of a series of continuing education activities in this Journal through which a total of 36 AMA/PRA category 1 credit hours can be earned in 0. Instructions for how CME credits can be earned appear on the last page of the Table of Contents.

An Evidence-Based Approach to the Evaluation and Treatment of Premature Rupture of Membranes: Part II
Timothy P. Canavan, MD, FACOG,* Hyagriv N. Simhan MD, MSCR, and Steve Caritis, MD
*Fellow, MaternalFetal Medicine, Assistant Professor, and Director of MaternalFetal Medicine, Magee Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania Preterm premature rupture of membranes (PPROM) occurs in 3% of pregnancies and is responsible for one third of all preterm births. In part I of this series, the definition, pathophysiology, and diagnosis of PPROM was reviewed. In this part, treatment is discussed. Adjunctive antibiotic and corticosteroid therapy has the strongest evidence for improving neonatal outcome. Treatment is gestational age-dependent and will be influenced by local neonatal intensive-care unit (NICU) survival statistics. This review presents the available evidence and grades it according to the U.S. Preventative Task Force recommendations. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to summarize the data on the use of labor inhibition in the setting of PPROM, list potential antibiotics regimens that are recommended for prophylaxis in patients with PPROM, to describe the benefits of corticosteroid administration in patients with PPROM, and to outline potential management strategies for patients with PPROM based on gestational age.

The perinatal complications of preterm premature rupture of membranes (PPROM) change with gestational age at rupture requiring a gestational age approach to treatment. There is little maternal benefit to conservative management, but there can be significant neonatal benefit, especially in the late second and early third trimester. The benefits of conservative management are mainly in pregnancy prolongation that has the potential to decrease gestational
Reprint requests to: Timothy P. Canavan, MD, FACOG, Magee Womens Hospital, Department of Obstetrics, Gynecology & Reproductive Sciences, 300 Halket Street, Pittsburgh, PA 15213. E-mail: tcanavan@mail.magee.edu The authors have disclosed no significant financial or other relationship with any commercial entity. The authors have disclosed that Betamethasone, Dexamethasone, Magnesium sulfate, and Terbutaline are not approved by the FDA for use during pregnancy.

age-related morbidity from prematurity. This must be balanced with the risks of conservative management, which include cord prolapse, abruptio placentae, perinatal infection, emergent delivery for a nonreassuring fetal status, and fetal death.

LABOR INHIBITION Labor-inhibiting agents have been evaluated in the conservative management of PPROM and found to have limited value. Two studies evaluated the benefits of ritodrine. Christensen and associates performed a randomized double-blind study among women with PPROM between 28 and 36 weeks. Ritodrine was compared with placebo, and although pregnancy was prolonged for 24 hours longer with ritodrine than with placebo, there was no obvious

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clinical benefit (duration of pregnancy after 24 hours from PPROM, Apgar scores, birth weight, and respiratory distress syndrome) (1). Levy and Warsof performed a prospective, randomized trial comparing ritodrine with no tocolysis in patients at 25 to 34 weeks with PPROM without any evidence of labor and found an increase in latency (10 vs. 3.5 days, P 0.033) with 47.6% of the treated patients versus 14.2% of those untreated having a latent period of more than 1 week (2). They did not evaluate neonatal outcome and had no evidence that the increased latency had any clinical benefit (neonatal or maternal). Weiner and associates evaluated the cost-effectiveness of tocolysis with ritodrine, terbutaline, or magnesium sulfate in patients with PPROM at less than 34 weeks and reported a nonsignificant prolongation of pregnancy (105.2 157 vs. 62.1 77 hours, P 0.06), but there was no significant reduction in cost or improvement in perinatal outcome (3). A prospective, randomized trial comparing magnesium sulfate tocolysis with no tocolysis in patients with PPROM between 24 and 34 weeks by How and associates (4) found no significant improvement in perinatal outcomes. In this study, both groups received corticosteroids and antibiotics (4). Thus, labor-inhibiting agents can prolong pregnancy in women with PPROM, but there are no data to indicate that this prolongation has any benefit in terms of perinatal outcome. This lack of evidence is in part the result of limited sample size because most studies were not powered to address this assertion. Based on the evidence stated here and the evidence forthcoming on corticosteroid therapy, patients with PPROM at 32 weeks or less could be offered initial acute labor inhibition to achieve 48 hours of corticosteroid benefit. This should only be considered in the absence of clinically apparent or subclinical amniotic fluid infection, abruptio placentae, nonreassuring fetal status, or other maternal/fetal contraindications to labor inhibition. Figure 1 presents this option. The literature currently does not support the use of maintenance or prophylactic labor-inhibiting agents beyond the initial 48 hours to provide corticosteroids. In the setting of recurrent labor in PPROM in the extremely preterm (less than or equal to 28 weeks) gestation, amniocentesis could be performed for the detection of amniotic fluid infection in light of the high frequency of amniotic fluid infection among women with PPROM (see part I of this review). In the absence of any evidence to the contrary, labor inhibition could be considered in this group in the absence of subclinical amniotic fluid infection.

ANTIBIOTICS The benefits of group B streptococcal (GBS) prophylaxis are well established (5,6). Intrapartum prophylaxis should be initiated in any patient with an unknown GBS status or a history of a positive culture during the present pregnancy (treatment is not indicated if there was a negative anovaginal culture in the past 2 weeks). Therapeutic options include a 5-million-unit bolus of intravenous penicillin followed by 2.5 million units every 4 hours; or a 2-g bolus of intravenous ampicillin followed by 1 g every 4 hours; or 500 mg intravenous erythromycin every 6 hours; or 900 mg intravenous clindamycin every 8 hours (penicillin allergy) (6). The Centers for Disease Control and Prevention has recommended that a 2-g intravenous loading dose of cefazolin (Ancef; SmithKline Beecham, Philadelphia, PA) followed by 1 g every 8 hours be used in patients with an uncertain penicillin allergy or with a minor allergic reaction (rash) (6). Adjunctive antibiotic therapy has been recommended in the conservative management of PPROM with the goal to prevent or treat ascending intrauterine infection thereby prolonging pregnancy and decreasing maternal and neonatal infection. Numerous studies have been performed to evaluate the benefit of antibiotics and have found significant evidence that adjunctive antibiotics are beneficial in the conservative management of PPROM. Table 1 provides a summary of those studies that were placebo-controlled. Therapies have varied by antibiotic choice, route of delivery, and duration of treatment. The National Institute of Child Health and Human Development MaternalFetal Medicine Unit Network (NICHD MFMU) study found that published evidence and expert opinion supported starting with intravenous therapy for 48 hours using ampicillin and erythromycin. This was followed by a limited course of oral therapy of both drugs. This trial found that antibiotics improved neonatal health by reducing the risk of respiratory distress syndrome (RDS), early sepsis, severe intraventricular hemorrhage (IVH), and severe necrotizing enterocolitis (NEC) (composite morbidities down from 53% to 44%, P 0.04) (7). There was a decrease in amnionitis and an increase in the likelihood of latency for longer than 1 week. Several studies have evaluated ampicillinsulbactam followed by amoxicillinclavulanic acid, but Kenyon and associates (8) raised concern for this regimen as a result of an increased risk of NEC in their

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Fig. 1. Algorithm for the management and treatment of PPROM. Abx antibiotics; Amnio amniocentesis; D&E dilatation and evacuation; FLM fetal lung maturity testing; GBS group B streptococcus; GC gonorrhea; LEA leukocyte esterase; OCT oxytocin challenge test; PPROM preterm premature rupture of membranes; WBC white blood cell count.

TABLE 1 Prospective randomized placebo-controlled studies evaluating adjunctive antimicrobial treatment for PPROM GA (wk) Antibiotics EES 250 mg, Co-amoxiclav, both, placebo q6X10d Outcomes 37

Authors

Sample Size

Kenyon 2001

4826

Mercer 19977 24 32

614

Amp 2 gm IV EES 250 mg q6hX48h then amox 250 mg po EES 33 mg po q 8hX5d

Ovalle Salas 199732 24 34

88

Clindamycin 600 mg IV Gent 4 mg/kg/d X 48h then Clindamycin 300 mg po q6h Gent 2 mg/kg/d IM q12h X5d 1. Amp-sul 1.5 gm IV q6hX72h then amox-cla 500 mg po q8h to del; 2. Amp 2 gm IV q6hX72h then amox 500 mg po q8h to del 3. placebo

Lovett 199733 2335

112

Lockwood34 Johnston 199035 24 34 20 34

75 85

Piperacillin 3 gm IV q6h X 72h Mezlocillin IV X 48h then amox po until del (doses not given) vs. placebono steroids or tocolytics

EES assoc w 2neonatal death, 2lung dz, 2major cerebral abnormality on us. Co-amoxiclav same as placebo with 1 NEC. Both prolonged pregnancy. Abx: 2RDS, 2IVH, 2NEC, 2fetal death, 2fetal sepsis (composite outcome 44.1% vs. 52.9%, P .04). In GBS negative women pregnancy prolonged (6.1 vs. 2.9 days, P .001) 1latency (10.5 vs. 4d, P .05); 2 maternal infection (4.8% vs. 28.9%, P .01); 2 RDS (9.5% vs30.2%, P .05); 2 NICU admissions (54.8 vs. 86%, P .01). No tocolytics or steroids used Grp1 vs. Grp3: 2neonatal death, sepsis & RDS (26.3 vs. 48.6%, P .05), 1 MBW (P .02), 1 latency (13.1/-1.9 vs. 6.8/-1.9 days, P .025), 1 Apgars @ 1 & 5 min grp1 & grp2, P .05, 2chorio (grp1: 10.5% vs. grp2:18.9% vs. grp3:32.4%, P 0.05) Abx: 1latency (11 vs. 6d, P .001) 1latency 7d (45 vs. 18%, P .01); 2chorio (7 vs. 35%, P .01); 2endo (12 vs. 33%, P .05); 1MBW (1897 vs. 1587 gm, P .05); 1Apgar 1 min (6.9 vs. 5.4, P .05); 2sepsis, IVH & hospital stay30d (P .05)

Evaluation and Treatment of Premature Rupture of Membranes Y CME Review Article 681

Amp ampicillin; Amox amoxicillin; chorio chorioamnionitis; cla clavulanate; Co-amoxiclav amoxicillin 250 mg clavulanic acid 125 mg; d days; del delivery; dz disease; EES erythromycin; endo endometritis; Gent gentamicin; GBS group B streptococcus; IVH intraventricular hemorrhage; MBW mean birth weight; NEC necrotizing enterocolitis; RDS respiratory distress syndrome; sul sulbactam; US ultrasound.

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patients. Until this is substantiated or refuted in future trials, these drugs should be avoided. Azithromycin can be considered as an alternative to erythromycin in view of its improved patient tolerance (less gastrointestinal upset and vascular sclerosis) and similar mechanisms of action. A reasonable dose equivalent would be 500 mg orally on day 1 followed by 250 mg daily for 6 days.

ANTENATAL FETAL SURVEILLANCE Antenatal fetal surveillance (AFS) is recommended during conservative management of PPROM. Regimens vary and are usually based on expert opinion. The 2 most common testing modalities are the nonstress test (NST) and the biophysical profile (BPP). The goal of testing is to predict untoward fetal outcome from the 2 major sources of fetal compromise: umbilical cord compression (secondary to oligohydramnios or anhydramnios) and chorioamnionitis.

CORTICOSTEROIDS The administration of antenatal corticosteroids to patients at risk for delivery of a premature infant has been clearly shown to reduce perinatal morbidity and mortality. The National Institute of Health consensus conference of 1994 recommended corticosteroid administration in patients with PPROM before 30 to 32 weeks using a single course of either betamethasone (12 mg intramuscularly every 24 hours 2 doses) or dexamethasone (6 mg intramuscularly every 12 hours 4) (9). The consensus found that corticosteroids reduced the incidence of RDS, IVH, and neonatal mortality. There was some uncertainty regarding a possible risk that corticosteroids could increase the risk of neonatal infection, but 2 randomized, controlled trials (RCTs) have not found any association. Lewis et al. (10) studied patients with PPROM between 24 and 34 weeks who received antibiotics and corticosteroids and found a reduced risk of RDS (18.4 vs. 43.6%, P 0.03) without evidence of increased neonatal infection (3% vs. 5%, P not significant). A recent metaanalysis by Harding and associates (11) found that corticosteroids administered to patients with PPROM reduced the risks of NEC (relative risk [RR], .21; 95% confidence interval [CI], 0.05.82), IVH (RR, .47; 95% CI, 0.31.7), RDS (RR, .56; 95% CI, 0.46.7) without any significant increased risk in maternal infection (RR, .86; 95% CI, 0.611.2) or neonatal infection (RR, 1.05; 95% CI, 0.661.68). This information supports the concept that a single course of antenatal corticosteroid is highly advantageous in PPROM before 32 weeks gestation. If the patient has documentation of immaturity (negative fetal maturity testing of the vaginal pool) or there is no fluid for testing, corticosteroids therapy could be considered in patients with PPROM from 32 to 34 weeks. The balance of risks and benefits of repeated corticosteroid courses has not been determined and therefore repeated courses are not recommended. NONSTRESS TESTING Moberg and associates (12) performed a study comparing the fetal heart rate patterns of 267 patients with PPROM between 28 and 35 weeks with 130 patients with preterm labor and intact membranes. Preterm premature rupture of membranes increased the incidence of cesarean section for fetal distress (7.9 vs. 1.5%, P 0.05) with or without chorioamnionitis and 76% of the fetuses with fetal distress had patterns consistent with severe cord compression. Harding and associates (13) followed 50 patients with PPROM between 23 and 34 weeks with daily NSTs and noted that variable decelerations and nonreactive NSTs predicted a significantly lower amniotic fluid index (AFI). Hoskins and associates (14) followed 3158 patients at 34 weeks with NSTs and AFI measurements and found that fetuses with spontaneous deceleration on their NSTs with an AFI less than 5 had an increased incidence of operative deliveries for fetal distress and increased incidence of neonatal acidosis and low Apgar scores. These studies suggest that the NST could be used to monitor for low AFI and cord compression in patients with PPROM. There is no evidence to guide the frequency of testing or the actual thresholds for delivery. The negative predictive value of the NST, as a means of primary fetal surveillance for stillbirth within 1 week of a negative test, is 99.8% (1.9 per 1000) (15). Expert opinions recommend a range of frequency of NSTs in women with PPROM, from daily to twice weekly (13,17). Test frequency between daily to twice weekly would seem reasonable when looking for evidence of cord compression as a result of low AFI. Vintzileos and associates (16) reviewed the records of 127 patients with PROM from 25 to 41 weeks evaluating the NST findings with the outcome of amnionitis and/or neonatal sepsis and found the sensitivity and specificity of the NST for predicting

Evaluation and Treatment of Premature Rupture of Membranes Y CME Review Article

* Not all study patients % unknown; # starting half way through study; ** at discretion of treating MD; G treated for GBS only; U unknown; $ 4 patients received steroids & 5 received tocolytics before transfer. Toco lytics (Y,N)

683

19%**

N Y** Y Y** 68%

N$

infection was 78.1% and 86.3%, respectively (see part I of this review). BIOPHYSICAL PROFILE There are presently no data to determine the frequency of biophysical profile (BPP) testing in PPROM. A reasonable course of testing could be 1) BPP twice weekly for those patients whose AFI is greater than or equal to 5 or 2) BPP daily for those patients whose AFI is less than 5 and continued expectant management as planned. TIMING OF DELIVERY Previable Preterm Premature Rupture of Membranes (24 weeks gestation) Previable PPROM presents many challenges. The major issue concerns immediate delivery that can be lethal or associated with a high risk of serious morbidity. Previable PPROM has been associated with increased perinatal infection and is frequently associated with fetal pulmonary hypoplasia (17). Fetal restriction deformities, as seen in Potters syndrome, are a risk with previable PPROM in the presence of persistent oligohydramnios or anhydramnios. Studies (see Table 2) indicate that survival increases as the gestational age at PPROM increases and as birth weight increases (18). This would indicate that latency is an important factor for neonatal survival in these patients. However, these patients face several factors that lead to fetal morbidity and mortality. Amnionitis, advanced labor, and nonreassuring fetal status usually force the clinician to affect delivery despite fetal immaturity. As noted in Table 2, 24% to 71% require delivery as a result of amnionitis and more than 50% of patients are delivered by 1 week in most studies. Perinatal mortality is high (range, 3775%) especially among newborns in the less than 24-week groups and intact survival increases as gestational age at PPROM increases. Patients with PPROM before 24 weeks should be counseled carefully about the maternal and neonatal risks and outcomes associated with PPROM before viability. Table 2 provides data on recent prospective and retrospective trials on outcomes that can be used to guide patients in their decisions. Several studies noted maternal deaths in expectantly managed patients and this should be included in counseling. Figure 1 gives guidelines for clinical management. After 24 to 48 hours of observation and appropriate counseling, patients can be monitored as outpatients

Prop Abx (Y,N)

Y Y# N G G

U 13%** 33 39 83 67 16 26 188 Moretti 198840 48

Steroid (%)

Y Y* 26.8% Y Y**

Devel Disab (%)

37 37 28 32 16

47 40 24w 32; 24w 71 63 20w 33 20 24w 50 24w 57 67 35 24 71 43 46 53 60 53 37 49 74 75 82 75 62 49 16.9 24 25 19 26 19 25 26 33 26 46 94 41 70 59 Dinsmoor 200436 Morales 199337 Rib 199318 Major 199038 Bengtson 198939

Neonatal survival (%)

Perinatal mortality (%)

Amnio nitis (%)

2 week

TABLE 2 Outcome from PPROM at <26 weeks

% Delivered by

1 week

GA (wk)

3 day

# pt

Taylor 198441

Study

53

16 25

62

72

42

23w 87 23w 50 75

25

44

N$

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and readmitted when they reach viability. There are no data to guide outpatient management at this time, but weekly to twice weekly office visits with home bedrest and temperature monitoring might be a reasonable strategy. Pulmonary Complications of Previable Preterm Premature Rupture of Membranes Pulmonary hypoplasia increases as gestational age at membrane rupture decreases below 23 weeks and increases with persistent oligohydramnios. Researchers have continued to search for an ultrasonographic sign to determine fetal pulmonary hypoplasia in patients with PPROM. So far no such conclusive indicator has been identified. Gestational age at rupture of membranes remains the best indicator of risk for pulmonary hypoplasia (17). Amniotic fluid serves many functions in the developing fetus. One of the most important in the midsecond trimester is lung development and maturity. Hydrostatic pressure from the amniotic fluid helps expand the developing lung and mature the lung buds into alveoli. The loss of amniotic fluid at this critical stage of development can irreversibly arrest lung development resulting in pulmonary hypoplastic lung disease. This is usually fatal regardless of the gestational age at birth. The most critical time period for development of pulmonary hypoplasia from PPROM is estimated to be before 22 weeks gestation (but can be as late as 25 weeks gestation). Antenatal diagnosis is critical to help counsel patients with previable/ periviable PPROM. Table 3 summarizes current literature on various ultrasound techniques used to pre-

dict fetal pulmonary hypoplasia. These studies suffer from small sample sizes and many are underpowered to provide accurate and reliable ultrasound measurements to predict pulmonary hypoplasia. The best evidence is provided by Nimrod and associates (19) (and validated by Ohlsson and associates (20)) with their data on the thoracic circumference (normalized for gestational age) that has a consistent NPV of 86% to 90%. Accurate dating is important because the normal thoracic circumference is based on gestational age. Any process that affects growth, specifically intrauterine growth restriction, can influence this value and would need to be taken into account. Studies are ongoing evaluating 3-dimensional ultrasound as a means to measure fetal lung volume and predict pulmonary hypoplasia. 24 to 31 Weeks Gestation Those patients with a reassuring fetal status who are not in advanced labor and are without signs or symptoms of abruptio placentae, clinical amnionitis, or subclinical amniotic fluid infection can be offered conservative management. Corticosteroids and antenatal antibiotics should be used as previously described and the patient should be placed on modified bedrest. Antenatal fetal surveillance should be provided as discussed previously. 32 to 33 Weeks Gestation Patients with PPROM from 32 to 33 weeks should have amniotic fluid collected through transabdominal amniocentesis for lung maturity studies and infec-

TABLE 3 Criteria for the antenatal evaluation of possible fetal pulmonary hypoplastic lung Study Nimrod 198819 Fong 198842 Songster 198943 Vintzileos 198944 Ultrasound criteria TC vs. GA TC vs. FL TC vs. FL TC TA/HA (TA-HA) 100/TA DA flow w/FBM LL TC TC/AC TC-ga TC-FL TC/AC Nasal fluid flow during FBM No. pts 45 18 3 13 Sens (%) 79 88 80 33 66 85 100 92 67 100 80 80 55 100 Spec (%) 96 100 92 57 85 85 100 100 100 100 90 97 97 100 PPV (%) 94 100 90 40 80 83 80 92 86 NPV (%) 86 90 88 50 75 85 90 91 87 -

van Eyck 199045 Roberts 199046 DAlton 199247 Ohlsson 199220

13 20 16 58

Fox 199348

Pts patients; GA gestational age; Sens sensitivity; Spec specificity; PPV positive predictive value; NPV negative predictive value; TA thoracic area; TC thoracic circumference; FL femur length; LL lung length; HA heart area; AC abdominal circumference; FBM fetal breathing movements.

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tion-related studies, if possible. A vaginal pool specimen could be obtained for fetal lung maturity studies. The Amniostat-FLM (Irvine Scientific, Santa Ana, CA) is a simple slide agglutination test to evaluate the presence of phosphatidylglycerol (PG). It can be performed on vaginal pool fluid and is unaffected by blood or meconium. It has a PPV of 95% to 100% (test indicates the fetus has lung maturity) and a NPV of 35% to 51% (21,22). The TDX-FLM assay (Abbott Laboratories, Abbott Park, IL) has been found to be a very reliable and reproducible test for amniotic fluid fetal lung maturity (FLM) testing (21). It is a fluorescent polarization assay that measures the segregation of a fluorescent dye between surfactant and albumin in amniotic fluid using an automated technique. The manufacturer recommends using a level of 70 as consistent with fetal lung maturity, although lower cutoffs are supported by several investigators (23,24). It is reported to have a PPV of 96% to 100% (test is positive if FLM is present) and a NPV of 47% to 61% (21). If testing indicates lung maturity, delivery should be considered. If there is no fluid available for testing or lung maturity testing is negative, the patient can be offered expectant management with antenatal corticosteroids and antibiotics. Delivery should be considered after corticosteroid benefit has been obtained. If testing indicates amniotic fluid infection, delivery should be considered along with broad-spectrum antibiotics. Although it is not unreasonable to await 34 weeks gestation before considering delivery of patients with PPROM, the limited evidence (Table 4) would suggest that there is little benefit to conservative management after 32 weeks gestation.

34 to 36 Weeks Gestation There appears to be no role of expectant management in any patient with PPROM beyond 34 weeks gestation. Several studies (see Table 4) have evaluated expectant management with labor induction and found increased risks of chorioamnionitis, neonatal infection, and increased length of stay among patients managed expectantly. Immediate delivery is encouraged in this patient population.

HOME MANAGEMENT Patients with PPROM have the potential for a long latency period that results in a long hospitalization. This is costly and many patients find this disruptive and stressful. Carlan and associates investigated home management of patients with PPROM between 26 and 34 weeks who met specific criteria (25). Patients who had not entered labor after 72 hours of observation and met criteria (see Table 5) were randomized to hospital versus home management. Patients were monitored with a temperature and pulse recording every 6 hours, daily charting of fetal activity, twice-weekly NSTs and CBC, and weekly ultrasound and visual examination of the cervix. These investigators found no statistically significant difference between the groups with respect to clinical characteristics, latency, gestational age at delivery, infection, or perinatal outcomes. There was a significant decrease in both hospital length of stay and costs for patients managed at home. However, only 18% of patients with PPROM met the strict criteria for home management.

TABLE 4 Expectant management compared to labor induction at 32 to 37 weeks Author Naef 1998
49

Study type RCT

GA (wks) 34 -36
0 6

No. pts 120

Findings No tocolytics, steroids or Abx given. GA @ PROM & US EFW were similar between groups - 1chorio in expectant group (16 vs. 2%, P.007) - 1 LOS in expectant group (5.2 vs. 2.6 days, P.006)neonatal sepsis 1 in expectant group (3 vs. 0, NS) No tocolytics, steroids or Abx given. BW, IVH, NEC, RDS, Sepsis, Perinatal death not improved in expectant group (P NS) - 1 chorio (15 vs. 2%, P .009) & 1 24 hr antepartum LOS in expectant group (75 vs. 3%, P .001) Note: 1neonatal death in expectant and 3 in induction group No tocolytics; no comment on steroids & Abx. Expectant group had 1 latency (36 vs. 14 hrs, P .001), 1total LOS (3.5 vs. 2.3 days, P .001), 1chorio (14.9 vs. 0%, P .01), 1abn FHR (12.8 vs. 0%, P .03), 1neo LOS (5 vs. 3 days, P .05)

Cox 199550

RCT

30 34

129

Mercer 199851

RCT

320-366 mature FLM

164

abn abnormal; Abx antibiotics; BW birth weight; grp group; LOS length of stay.

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TABLE 5 Criteria for home management of PPROM25 Criteria Cephalic presentation Cervical dilatation 4 cm by inspection Local county resident No clinical evidence of intra-amniotic infection One vertical pocket of AF 2 cm Singleton gestation AF amniotic fluid.

SPECIAL CIRCUMSTANCES Cervical Cerclage Several reviews have reported that cervical cerclage could be a risk factor for PPROM (26). There are few prospective data to guide treatment of PPROM in patients with cerclage and many of the studies are conflicting. Ludmir performed a retrospective study (27) noting that cerclage retention prolonged latency (delivery delayed 48 hours in 90% vs. 50%, P 0.05) but with a significant increase in perinatal mortality (70% vs. 10%, P 0.001). Yeast and Garite (28) followed 32 patients expectantly but compared them with patients with PPROM and no cerclage. They found no significant difference in latency, infection, or mortality. Jenkins and associates (29) found cerclage retention increased latency (10.1 vs. 5 days, P 0.001) without altering maternal or neonatal outcomes. McElrath and associates (30) performed a retrospective review comparing women with PPROM and retained cerclage to women with immediate cerclage removal and women without cerclage and found no difference in latency or perinatal outcome among the 3 groups. The disparate findings of Ludmir et al. from those of other studies could be explained by the lack of antenatal antibiotics and corticosteroids in the subjects of Ludmir et al. Based on the present evidence, it would not be unreasonable to leave a cerclage in place until the patient has received antenatal antibiotics and obtained corticosteroid benefit. Medical Complications Diabetes Diabetes presents a unique challenge when complicated by PPROM. On a review of Medline abstracts back to 1966, no studies were found evaluating the comorbidities of diabetes and PPROM. The evidence for recommendations in based solely on expert opinion. Diabetes will place the patient with PPROM at increased risk for infection, and use of

corticosteroids in these patients will result in transient hyperglycemia. Although the poor glucose control is temporary, it can result in severe hyperglycemia in brittle diabetics and theoretically increase the risk of diabetic ketoacidosis. Diabetes has been found to slow fetal lung maturity. These babies have the potential for poor respiratory function in the neonatal intensive-care unit (NICU) as compared with babies of nondiabetics with PPROM matched for gestational age. In the absence of any evidence to the contrary, it would seem reasonable to manage these patients conservatively.

Preeclampsia Preeclampsia presents its own set of diagnostic dilemmas in patients diagnosed preterm. A literature search back to 1966 using Medline did not identify any studies on the interactions between PPROM and preeclampsia. Based on expert opinion, patients with PPROM and preeclampsia must have each morbidity evaluated separately for its severity and treatment options. In the presence of mild preeclampsia, it would not be unreasonable to manage the PPROM conservatively. In the presence of severe preeclampsia, treatment options would be gestational age-dependent, but conservative management could be a reasonable course of action in some cases whereas delivery could be necessary in others. Each case would need to be evaluated on the patients risk for morbidity and mortality compared with the fetal risks of delivery versus conservative management. There is the potential that complications of preeclampsia could potentiate complications of PPROM. Ananth and associates (31) performed a metaanalysis of the risks of placental abruption and found an association between prolonged rupture of membranes (odds ratio [OR], 3.05; 95% CI, 2.16 4.32) as well as preeclampsia (OR, 1.81; 95% CI, 1.622.02). The authors made no comment on whether the effects of prolonged ROM and preeclampsia would be additive or multiplicative but did note that their analysis was limited by the variability used to make the various diagnoses. Based on this 1 study, it is unclear whether patients with PPROM and preeclampsia have an increased risk of abruption over the risk for each morbidity individually; however, it would seem likely that the risk is elevated. Close surveillance for abruptio placentae in patients with preeclampsia and PPROM seems warranted.

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SUMMARY Preterm premature rupture of membranes affects over 120,000 pregnancies in the United States annually and is associated with significant maternal morbidity and neonatal morbidity and mortality. Healthcare costs are significantly impacted by the prolonged maternal hospital stay, need for frequent testing, and the resulting neonatal costs as a result of prolonged NICU care for the newborn. Management requires an accurate diagnosis and determination of gestational age. A gestational age approach to therapy is important and should be adjusted for each hospitals NICU outcomes. Antenatal antibiotics and corticosteroid therapies have clear benefits and should be offered to all patients without contraindications. These patients are at high risk for infection, and amniocentesis can be used to evaluate early markers for infection and provide a sample of amniotic fluid for culture. Any evidence of infection by amniocentesis should be considered carefully as an indication for delivery. During conservative management, patients should be monitored closely for abruptio placentae, infection, labor, and a nonreassuring fetal status. Patients with PPROM after 32 weeks should be considered for delivery, and clearly after 34 weeks for the benefits of delivery outweigh the risks. Ultrasound can be used to evaluate those fetuses at risk for pulmonary hypoplasia to help guide patient counseling. We reviewed and evaluated published reports for quality according to the method outlined by the U.S. Preventative Services Task Force: I. Evidence obtained from at least 1 properly designed randomized, controlled trial. II-1. Evidence obtained from well-designed controlled trials without randomization. II-2. Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than 1 center or research group. II-3. Evidence obtained from multiple time-series with or without the intervention. Dramatic results in uncontrolled experiments also could be regarded as this type of evidence. III. Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees. Based on the highest level of evidence found in the data, our recommendations are provided and graded according to the following categories: Level ARecommendations are based on good and consistent scientific evidence.

Level BRecommendations are based on limited or inconsistent scientific evidence. Level CRecommendations are based primarily on consensus and expert opinion. SUMMARY TABLE OF RECOMMENDATIONS Category A (recommendations are based on good and consistent scientific evidence) 1. Antibiotics prolong the latency from PPROM to delivery and improve perinatal outcome. They could be administered by any of the reviewed protocols up to 34 weeks gestation. Ampicillin and erythromycin is 1 such regimen as recommended by the NICHD MFMU study. 2. Antenatal corticosteroids should be administered to all patients with PPROM up to 32 weeks gestation using either betamethasone or dexamethasone as described by the NIH Consensus Development Conference. 3. Patients with PPROM at greater than or equal to 34 weeks will have less chorioamnionitis and neonatal infection and a shorter hospital stay with immediate labor induction versus expectant management. 4. Home management of PPROM could be offered to those patients who meet criteria. Category B (recommendations are based on limited or inconsistent scientific evidence) 1. Maintenance tocolysis or reinhibition of preterm labor is not recommended for patients with PPROM at greater than 28 weeks gestation or with early markers of intraamniotic infection. 2. Based on the present evidence, it would not be unreasonable to leave a cerclage in place until the patient has received antenatal antibiotics and obtained corticosteroid benefit. 3. Ultrasound can be used to evaluate the fetal risk of lethal pulmonary hypoplasia. Category C (recommendations are based primarily on consensus and expert opinion) 1. Antenatal steroids could be administered to patients with PPROM between 32 and 34 weeks if fetal lung maturity is negative or uncertain. 2. Labor inhibition could be used in patients with PPROM to prolong the latency for administra-

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tion of antibiotics and to obtain antenatal corticosteroid benefit. NST testing interval for the conservative management of PPROM could range between daily to twice weekly and can be based on the practitioners preference and level of comfort. Biophysical profile is recommended daily for patients with an AFI less than 5 cm receiving conservative management. Biophysical profile is recommended twice weekly for patients with an AFI greater than or equal to 5 cm receiving conservative management. Patients with PPROM complicated by preeclampsia could be at increased risk for abruptio placentae.

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