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Preterm prelabor rupture of membranes: Management and outcome

Preterm prelabor rupture of membranes: Management and outcome
Author:
Patrick Duff, MD
Section Editor:
Charles J Lockwood, MD, MHCM
Deputy Editor:
Vanessa A Barss, MD, FACOG
Literature review current through: Nov 2021. | This topic last updated: Aug 17, 2021.

INTRODUCTION — Prelabor rupture of membranes (PROM) refers to membrane rupture before the onset of uterine contractions. Preterm PROM (PPROM) refers to PROM before 37+0 weeks of gestation. It is responsible for, or associated with, approximately one-third of preterm births and is the single most common identifiable factor associated with preterm delivery.

The management of PPROM is among the most controversial issues in perinatal medicine. Points of contention include:

Accurate diagnosis in problematic cases

Expectant management versus intervention

Use of tocolytics

Duration of administration of antibiotic prophylaxis

Timing of administration of antenatal corticosteroids

Methods of testing for maternal/fetal infection

Timing of delivery

Management and outcome of PPROM from 23+0 to 36+6 weeks of gestation will be discussed here. Issues specifically relating to management of PPROM before the limit of viability and term PROM are reviewed separately. (See "Prelabor rupture of membranes before and at the limit of viability" and "Prelabor rupture of membranes at term: Management".)

The epidemiology, pathogenesis, clinical manifestations, diagnosis, and clinical course of PPROM from 23+0 to 36+6 weeks of gestation are also reviewed separately. (See "Preterm prelabor rupture of membranes: Clinical manifestations and diagnosis".)

ANTEPARTUM MANAGEMENT

Overview — The management of pregnancies complicated by PPROM is based upon consideration of several factors, which are assessed upon presentation:

Gestational age

Presence or absence of maternal/fetal infection

Presence or absence of labor

Fetal presentation

Fetal well-being

Expectation of fetal lung maturity based on gestational age

Cervical status (by visual inspection)

Availability of an appropriate level of neonatal care

Some tests that can be useful in this assessment are listed in the table (table 1). Screening for infection by standard methods is useful for guiding antibiotic therapy, but vaginal culture is not helpful since the vaginal flora is normally polymicrobial. (See 'Screen for infection' below and 'Administer prophylactic antibiotic therapy' below.)

The key decision is whether to induce labor (or perform cesarean delivery) or to manage the pregnancy expectantly. The early preterm fetus (ie, <34+0 weeks) who is otherwise stable will benefit by prolonging the time it remains in the uterus if the duration is sufficient to allow a significant reduction in gestational age-related morbidity [1-3]. The late preterm fetus (34+0 to 36+6 weeks) may benefit as well, although there is less consensus at this gestational age. However, this benefit needs to be balanced with the risks of PPROM-associated complications and their sequelae in expectantly managed pregnancies: intrauterine infection, placental abruption, and cord prolapse/compression.

Expeditious delivery of women with PPROM is appropriate in the setting of intrauterine infection, placental abruption, or nonreassuring fetal testing [4]. In each of these conditions, fetal well-being can deteriorate rapidly with expectant management, and there are no therapeutic interventions available other than delivery. For the same reason, an unstable lie with a high risk of cord prolapse is an indication for delivery rather than expectant management, but the balance between the risks of cord prolapse and birth of a very or extremely preterm birth also needs to be considered on a case-by-case basis. (See "Placental abruption: Pathophysiology, clinical features, diagnosis, and consequences" and "Intraamniotic infection (clinical chorioamnionitis or triple I)" and "Umbilical cord prolapse".)

In the absence of complications, there is a consensus that patients with PPROM before 34+0 weeks should be monitored closely and managed expectantly at least until 34+0 weeks of gestation. We believe that well-dated pregnancies initially managed expectantly should be delivered at 34+0 weeks of gestation, but continuing expectant management until 37 weeks is also a reasonable approach. A more detailed discussion of delivery timing is provided below. (See 'Timing of delivery' below.)

Components of expectant management

Administer antenatal corticosteroids — A course of corticosteroids should be administered to pregnancies that present with PPROM between 23+0 and 33+6 weeks of gestation. Data supporting this recommendation were provided by systematic reviews of randomized trials that showed neonatal death, respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and duration of neonatal respiratory support were significantly reduced by antenatal corticosteroid treatment without an increase in either maternal or neonatal infection [5,6]. Mean risk reduction for these adverse events ranged from 30 to 60 percent.

A course of corticosteroids can be considered for patients who present with PPROM at 34+0 to 36+6 weeks of gestation who are going to be managed expectantly, have not received a previous course of steroids, and who are scheduled for delivery in >24 hours and <7 days [7]. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on 'Candidates for a first ACS course by gestational age'.)

Administration of antenatal steroids for pregnancies that present with PPROM in the 22nd week of gestation is also reasonable if delivery in the next seven days is anticipated and the family desires aggressive neonatal intervention after thorough consultation with maternal-fetal medicine and neonatology specialists. Data regarding outcomes of these pregnancies are reviewed separately. (See "Prelabor rupture of membranes before and at the limit of viability", section on 'Pediatric outcomes' and "Periviable birth (limit of viability)" and "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on '22+0 to 22+6 weeks' and "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on '23+0 to 33+6 weeks'.)

The author also administers a single rescue course of betamethasone to pregnancies up to 34 weeks of gestation that meet standard criteria: high risk of delivery within 7 days and prior exposure more than 14 days earlier [8]. At least two trials including pregnancies with PPROM demonstrated that repeat courses of betamethasone produced short-term benefits compared with a single course and no long-term adverse effects in children followed up to six to eight years of age [9,10]. Regimens for rescue steroids and guidelines for use are available separately. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on 'Use of rescue (salvage, booster) ACS' and "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on '34+0 or more weeks'.)

The effect of PPROM on fetal pulmonary maturation is unclear as studies have reported inconsistent results. This discordancy may be due to failure to adjust for factors that affect neonatal respiratory function, such as mode of delivery and presence or absence of labor, as well as gestational age, duration of latency, and comorbidities [11].

Screen for infection — The Centers for Disease Control and Prevention (CDC) recommends screening for STIs (eg, HIV, syphilis, chlamydia, gonorrhea) in the third trimester in women with risk factors for acquiring an STI (table 2) [12].

In women with PPROM, we perform this screening, as well as screening for group B Streptococcus (GBS), on admission since these pregnancies are at high risk of preterm delivery. Women with positive results are managed, as appropriate. In some cases, the prophylactic antibiotic therapy administered to prolong latency will provide adequate treatment.

(See "Treatment of uncomplicated Neisseria gonorrhoeae infections", section on 'Pregnant women'.)

(See "Treatment of Chlamydia trachomatis infection", section on 'Pregnant women'.)

(See "Antiretroviral selection and management in pregnant women with HIV in resource-rich settings".)

(See "Hepatitis B and pregnancy".)

(See "Vertical transmission of hepatitis C virus".)

The author also screens women with PPROM for bacterial vaginosis (BV) and Trichomonas vaginalis; however, screening for these infections is controversial. Testing for BV using Amsel criteria (which includes pH) is problematic since amniotic fluid in the vagina will interfere with pH-based diagnosis of these entities; a positive Gram stain is predictive of BV but has low sensitivity [13]. A commercial test using nucleic acid amplification testing (NAAT; eg, Affirm VPIII or OSOM BVBlue) is the most sensitive option for diagnosis of BV in this setting. (See "Bacterial vaginosis: Clinical manifestations and diagnosis", section on 'Commercial tests'.)

The author's rationale for screening is that there are potential maternal consequences from these infections, which may be prevented by standard treatment:

(See "Trichomoniasis", section on 'Women' and "Trichomoniasis", section on 'Initial treatment'.)

(See "Bacterial vaginosis: Clinical manifestations and diagnosis", section on 'Consequences of infection' and "Bacterial vaginosis: Treatment", section on 'Pregnant persons'.)

The author does not screen for Mycoplasma species because the azithromycin in the prophylactic antibiotic regimen to prolong latency covers these organisms, so there is no need to specifically test for them. Furthermore, most hospital microbiology laboratories are not prepared to culture these organisms, and NAATs are not available in most hospital diagnostic laboratories (in the United States, there are no approved nucleic acid-based assays for these organisms). (See "Mycoplasma hominis and Ureaplasma infections", section on 'Microbiologic confirmation'.)

GBS — Chemoprophylaxis specifically for GBS is indicated if GBS test results are positive or unknown and delivery is imminent. The intravenous portion of the prophylactic antibiotic regimen to prolong latency described below (ampicillin 2 grams intravenously every 6 hours for 48 hours) should provide adequate treatment for GBS-colonized women who are in labor at the time of admission or who go into labor within 48 hours of admission.

As noted below, this regimen of intravenous ampicillin, followed by oral amoxicillin, combined with a single 1 gram dose of azithromycin, is usually given for seven days. After completion of this regimen, antibiotics should be discontinued. If the patient's GBS culture is positive, specific prophylaxis for GBS colonization should be resumed when the patient subsequently goes into labor [14].

Regimens for women with penicillin allergy are described below. (See 'Women with penicillin allergy' below.)

Guidelines for diagnosis of maternal GBS colonization and chemoprophylaxis are discussed in more detail separately. (See "Early-onset neonatal group B streptococcal disease: Prevention", section on 'Special populations'.)

Administer prophylactic antibiotic therapy

Rationale — Infection can be a cause or a consequence of PPROM. The goal of antibiotic therapy is to reduce the frequency of maternal and fetal infection and thereby delay the onset of preterm labor (ie, prolong latency) and the need for indicated preterm delivery. The importance of reducing infection is underscored by studies suggesting a relationship between chorioamnionitis, duration of membrane rupture, and development of cerebral palsy or neurodevelopmental impairment. (See "Intraamniotic infection (clinical chorioamnionitis or triple I)".)

A 2013 systematic review of 22 placebo-controlled randomized trials involving over 6800 women evaluated the use of antibiotics following PPROM before 37 weeks of gestation [15]. Compared with placebo/no treatment, antibiotic use was associated with significant reductions in:

Chorioamnionitis (relative risk [RR] 0.66, 95% CI 0.46-0.96).

Infants born within 48 hours (RR 0.71, 95% CI 0.58-0.87) and seven days (RR 0.79, 95% CI 0.71-0.89) of randomization.

Neonatal infection (RR 0.67, 95% CI 0.52-0.85).

Use of surfactant (RR 0.83, 95% CI 0.72-0.96).

Neonatal oxygen therapy (RR 0.88, 95% CI 0.81-0.96).

Abnormal cerebral ultrasound scan prior to hospital discharge (RR 0.81, 95% CI 0.68-0.98).

Data were insufficient to determine whether any antibiotic regimen (drug, dose, duration) was better than another, but amoxicillin-clavulanate appeared to be associated with an increased risk of neonatal necrotizing enterocolitis (RR 4.72, 95% CI 1.57-14.23). The validity of this association requires further investigation in large trials, given the wide confidence interval.

Based on these and other data, the American College of Obstetricians and Gynecologists (ACOG) recommended antibiotic prophylaxis to prolong latency in pregnancies with PPROM <34+0 weeks of gestation but not for expectantly managed PPROM ≥34+0 weeks [7].

Drug regimen — We recommend administering a seven-day course of prophylactic antibiotics to all women with PPROM <34+0 weeks of gestation who are managed expectantly.

Our preference is:

Azithromycin 1 gram orally upon admission, plus

Ampicillin 2 grams intravenously every 6 hours for 48 hours, followed by

Amoxicillin 875 mg orally every 12 hours or 500 mg orally every 8 hours for an additional five days

Ampicillin and amoxicillin specifically target GBS, many aerobic gram-negative bacilli, and some anaerobes. Azithromycin specifically targets Ureaplasma, which can be an important cause of chorioamnionitis in this setting [16]. Azithromycin also provides coverage of Chlamydia trachomatis, which is an important cause of neonatal conjunctivitis and pneumonitis. In addition, in patients with PPROM with either intraamniotic infection or sterile intraamniotic inflammation, administration of intravenous clarithromycin has been associated with a reduction in the intensity of the intraamniotic inflammatory response [17].

The optimal regimen for antibiotic prophylaxis in PPROM was unclear in a network meta-analysis of randomized trials [18]. Our regimen has reasonable activity against the major genital tract pathogens and is similar to that shown to be effective in the National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network trial on antibiotic therapy for reduction of infant morbidity after PPROM (intravenous ampicillin 2 grams every 6 hours and erythromycin 250 mg every 6 hours for 48 hours followed by oral amoxicillin 250 mg every 8 hours and erythromycin 333 mg every 8 hours for five days) [19], which is recommended by ACOG [20]. We give azithromycin in lieu of a multiple-day course of erythromycin because of its ease of administration, improved gastrointestinal tolerance, favorable cost profile, and similar efficacy; this substitution is also endorsed by ACOG [7]. In retrospective studies of women with PPROM given prophylaxis with erythromycin versus azithromycin as part of the antibiotic regimen, both drugs had similar pregnancy and neonatal outcomes (latency length; mean birth weight; rates of chorioamnionitis, low Apgar score, neonatal sepsis, and neonatal respiratory distress syndrome) [21-24]. For amoxicillin, the author prefers the 875 mg twice daily dose for patient convenience. He uses a higher dose than that used in the NICHD-MFMU trial to reduce rectovaginal GBS colonization, if present, although data regarding efficacy are not available.

An animal model investigation illustrates the importance of genital mycoplasmas in the pathogenesis of preterm labor and helps to explain why drugs such as erythromycin and azithromycin may be valuable both in prolonging the latent period and reducing the frequency of infection and injury in the baby [25]. In this study, 16 chronically instrumented rhesus monkeys underwent intra-amniotic inoculation with Ureaplasma parvum. Uterine contractions began soon after inoculation, at which time six monkeys received no treatment, five received intravenous azithromycin for 10 days, and five received azithromycin plus dexamethasone and indomethacin for 10 days. Azithromycin significantly prolonged gestation by approximately seven days, significantly decreased the Ureaplasma colony count in the amniotic fluid, decreased the amniotic fluid concentration of proinflammatory mediators, and decreased the magnitude of histologic lung injury. Interestingly, dexamethasone and indomethacin did not further enhance the treatment effect of azithromycin.

Prophylactic antibiotics may exert selective pressures for emergence of drug-resistant microorganisms. In addition, there is a theoretical concern that clinical infection may be more difficult to recognize or treat in patients who have received prophylactic antibiotics. These problems have not been observed in women with PPROM receiving antibiotic prophylaxis. Long-term adverse effects of antepartum prophylactic antibiotics for PPROM have not been observed in children followed to age seven years [26]. This finding is in contrast to the observation from the same authors that, in patients with spontaneous preterm labor and intact membranes, the rate of cerebral palsy was increased in children exposed to antibiotics in utero [27].

Ongoing studies to determine the optimal prophylactic antibiotic regimen are needed, given changes in bacterial sensitivities over time [28]. One expanded-spectrum alternative regimen that has been suggested is ceftriaxone, clarithromycin, and metronidazole [16]. This regimen has been associated with successful eradication of intra-amniotic inflammation/infection in two studies: one in women with PPROM and the other in women with preterm labor with intact membranes [16,29].

Women with penicillin allergy

Low risk for anaphylaxis – If the patient's history suggests a low risk for anaphylaxis (algorithm 1), we suggest (see "Penicillin allergy: Immediate reactions"):

Azithromycin 1 gram orally upon admission, plus

Cefazolin 1 gram intravenously every 8 hours for 48 hours, followed by

Cephalexin 500 mg orally four times daily for five days

The cephalosporins provide coverage for both GBS and Escherichia coli, the two major causes of neonatal infection.

High risk for anaphylaxis – If the patient's history suggests a high risk for anaphylaxis (algorithm 1), we suggest (see "Penicillin allergy: Immediate reactions"):

Azithromycin 1 gram orally upon admission, plus

Clindamycin 900 mg intravenously every 8 hours for 48 hours, plus

Gentamicin 5 mg/kg actual body weight intravenously every 24 hours for two doses, followed by

Clindamycin 300 mg orally every eight hours for five days

This regimen is appropriate for patients with a positive GBS culture and laboratory-documented GBS susceptibility to clindamycin.

High risk for anaphylaxis and GBS resistant to clindamycin – If the patient has a history of a severe penicillin allergy and the GBS culture shows resistance to clindamycin or susceptibility results are not available, we suggest:

Azithromycin 1 gram orally upon admission, plus

Vancomycin 20 mg/kg every 8 hours (maximum single dose 2 grams) for 48 hours

Indications for tocolysis — The principal indication for tocolysis in the setting of PPROM is to delay delivery for 48 hours to allow administration of a course of corticosteroids. As a general rule, tocolytics should not be administered for more than 48 hours. They also should not be administered to patients who are in advanced labor (>4 cm dilation) or who have any findings suggestive of subclinical or overt chorioamnionitis. Other potential contraindications to tocolysis include nonreassuring fetal testing (eg, nonreactive nonstress test [NST]), abruptio placentae, and significant risk of cord prolapse (eg, dilated cervix and fetal malpresentation). (See "Inhibition of acute preterm labor".)

In a 2014 systematic review of randomized trials evaluating pregnancy outcomes of women with PPROM who received or did not receive tocolytic therapy (prophylactic or therapeutic), tocolysis for pregnancies <34 weeks resulted in fewer births within 48 hours (RR 0.59, 95% CI 0.34-1.00; four trials, n = 243 women), but an increase in chorioamnionitis (RR 1.79, 95% CI 1.02-3.14; three trials, n = 168 women) and no significant improvement in perinatal morbidity or mortality [30]. There are several limitations to these data, including the small number and size of the trials and the fact that patients did not consistently receive antenatal corticosteroids to reduce neonatal morbidity or antibiotics to prolong latency, which diverges with current standards of care and may explain the lack of improvement in clinically important outcomes.

Hospitalization versus home care — Most clinicians hospitalize women with PPROM who have a viable fetus from the time of diagnosis until delivery. The author limits activity to using the restroom and sitting up in a bedside chair as a prudent approach, although the effect of type and degree of activity on the course of PPROM has not been studied. He also administers thromboprophylaxis because of the potential for deep vein thrombosis and pulmonary embolism in sedentary hospitalized patients. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention", section on 'Administration'.)

There have been only two randomized trials evaluating the safety of outpatient versus inpatient management of women with PPROM [31,32]. The smaller trial included only 21 women with PPROM as part of a larger study of antenatal day care versus in-hospital care [32]. The larger trial, which included 67 women with PPROM, randomly assigned one group to expectant management at home and the other to expectant management in the hospital [31]. Both groups were managed similarly with bedrest, recording of temperature and pulse every six hours, daily charting of fetal movements, twice-weekly NSTs and complete blood count, and weekly ultrasound and visual examination of the cervix. Only 18 percent of the women met the strict safety criteria used for inclusion (table 3), and three women managed at home delivered unexpectedly at outside hospitals. A meta-analysis of these trials found no significant differences in maternal or neonatal outcomes between the hospital and home care groups, although the home group had lower maternal costs [33]. However, these small trials did not have sufficient statistical power to detect meaningful differences between groups.

In a retrospective study of 187 women with PPROM managed as outpatients, 12 had a severe complication (fetal death, placental abruption, umbilical cord prolapse, delivery outside of a maternity hospital, neonatal death) [34]. PPROM occurring before 26 weeks, noncephalic fetal presentation, and oligohydramnios significantly increase the risk for a severe complication, especially when more than one factor is present; therefore, these factors are an indication for hospitalization rather than outpatient management [34,35].

Further study is needed to determine the safety of outpatient management. In particular, the possibility and risks of a delay in diagnosis of maternal infection, cord prolapse, and precipitous labor and delivery need to be addressed [31,36]. Until we have definitive evidence supporting the safety of outpatient management in carefully selected individuals, we strongly recommend managing all patients in the hospital.

Fetal monitoring

Nonstress test and biophysical profile – Some type of fetal surveillance is generally employed (eg, kick counts, NSTs, biophysical profile [BPP]) to provide the clinician and patient some assurance of fetal well-being [37]. At our center, we perform a daily NST. If the NST is not reassuring, we perform a BPP. However, none of these tests have good sensitivity for predicting fetal infection, even when performed daily (sensitivity of daily NST and BPP: 39 and 25 percent, respectively [38]).

PPROM does not alter the way the BPP is calculated or interpreted. A low BPP score (0, 2, or 4) should be managed in standard fashion. The predictive value for infection is low since the low score may be due to infection or to oligohydramnios and absent fetal breathing related to PPROM. (See "Biophysical profile test for antepartum fetal assessment".)

There is no consensus among experts regarding the optimum type and frequency of testing. Three randomized trials (n = 275 women) that attempted to determine whether testing leads to an improvement in perinatal outcome did not report convincing evidence of improvement or harm but were of low quality [39]. In the largest trial (n = 135 women), women with PPROM were randomly assigned to either a daily NST or a BPP, and neither test had good sensitivity for predicting maternal or fetal infection [38].

Amniotic fluid volume – Oligohydramnios is associated with an increased risk of umbilical cord compression and shorter latency, but, as with other tests, the value of this finding alone for prediction of adverse fetal/neonatal outcome in PPROM is low [40].

Fetal growth – Periodic ultrasound evaluation of fetal growth is reasonable [7] as pathologic processes responsible for PPROM may also interfere with fetal growth [41,42]. As a general rule, growth assessments should be performed no more often than every two to three weeks. (See "Fetal growth restriction: Evaluation and management".)

Umbilical artery Doppler – Doppler surveillance is not useful for monitoring fetal status in PPROM, unless growth restriction (FGR) is also present [43-45]. In this setting, the key abnormal uterine artery Doppler finding would be absent or reversed end-diastolic flow. (See "Fetal growth restriction: Evaluation and management", section on 'Umbilical artery'.)

Maternal monitoring — Women with PPROM should be monitored for signs of infection; however, there is no consensus as to the best approach. At a minimum, routine clinical parameters (eg, maternal temperature, presence of uterine tenderness, frequency of contractions, maternal and fetal heart rate) should be monitored.

Periodically monitoring white blood cell counts or other markers for inflammation/infection has not been proven to be useful [46].

Amniocentesis to obtain amniotic fluid for Gram stain, culture, leukocyte esterase, glucose concentration, and interleukin-6 (IL-6, where available) is more controversial. We do not routinely perform amniocentesis to screen for intra-amniotic infection in asymptomatic women. If the clinical diagnosis of chorioamnionitis is uncertain and we need more information to decide whether to recommend expectant management, then we perform amniocentesis to rule out infection. An in-depth discussion of the diagnosis and management of intraamniotic infection can be found separately. (See "Intraamniotic infection (clinical chorioamnionitis or triple I)".)

If there is insufficient amniotic fluid to sample, which occurs in up to 50 percent of patients, then the diagnosis of chorioamnionitis will have to be based on clinical examination and indirect testing such as identification of an abnormal peripheral white blood cell count. The clinical findings, criteria for diagnosis, and treatment of chorioamnionitis are reviewed in detail separately. (See "Intraamniotic infection (clinical chorioamnionitis or triple I)".)

Special situations

Women with HSV, HIV, or cerclage — Expectant management of women with PPROM and genital herpes simplex virus (HSV) or HIV infection is controversial, and opinions about the best course of action diverge widely. These patients are discussed separately. (See "Genital herpes simplex virus infection and pregnancy" and "Intrapartum management of pregnant women with HIV and infant prophylaxis in resource-rich settings", section on 'Preterm premature rupture of membranes'.)

Expectant management of women with PPROM and a cerclage is also reviewed elsewhere. (See "Transvaginal cervical cerclage", section on 'Removal of cerclage after PPROM'.)

Meconium-stained fluid — Patients with PPROM and meconium-stained amniotic fluid should be evaluated for signs of chorioamnionitis. In the absence of these signs, meconium alone is not an indication for intervention.

Studies of term and preterm PROM patients have generally reported that those with meconium-stained amniotic fluid have higher rates of both overt and subclinical chorioamnionitis and positive amniotic fluid cultures [47-49]. Meconium release predisposes to infection by enhancing the growth of bacteria and lowering phagocytic capacity of neutrophils [50]. However, it is also possible that, in some cases, meconium-like staining is actually pigment associated with decidual hemorrhage (abruption).

Twin pregnancy — We manage twin pregnancies with PPROM in the same way as singleton pregnancies with PPROM based on clinical experience and generally accepted practice patterns. Some PPROM studies have included both singleton and twin pregnancies, but no studies have specifically evaluated management of twin PPROM except at previable gestational ages [51] or in the setting of delayed-interval delivery. (See "Prelabor rupture of membranes before and at the limit of viability" and "Multifetal gestation: Role of delayed-interval delivery".)

Unproven interventions

Supplemental progesterone — In a meta-analysis of randomized trials, initiation of progesterone supplementation after PPROM did not prolong the latency period or increase the gestational age at delivery [52].

In women who were already on supplemental progesterone because of a prior pregnancy with preterm delivery related to preterm labor or PPROM, we discontinue the medication upon diagnosis of PPROM. In particular, if the patient had been using vaginal progesterone, continuing vaginal administration may increase the risk for ascending infection. (See "Progesterone supplementation to reduce the risk of spontaneous preterm labor and birth", section on 'After preterm prelabor rupture of membranes'.)

Tissue sealants — A variety of tissue sealants (eg, fibrin glue, gelatin sponge) have had some success in stopping leakage in case reports. Neither the safety nor the efficacy of these sealants has been established. Tissue sealants are discussed in more detail separately. (See "Prelabor rupture of membranes before and at the limit of viability", section on 'Repair of leaks'.)

Amnioinfusion — We recommend against performing antepartum amnioinfusion on patients with PPROM. A 2014 systematic review and meta-analysis compared pregnancy outcome in patients who received antepartum transabdominal amnioinfusion versus those who received usual care for management of PPROM in the third trimester (five randomized trials, n = 241 pregnancies) [53]. Transabdominal amnioinfusion resulted in statistically significant reductions in neonatal death, sepsis/infection, and pulmonary hypoplasia, but data for each outcome were limited to one to two very small trials of low to moderate quality.

To more fully understand whether amnioinfusion is beneficial in PPROM, more and better information is needed about the effects of specific amnioinfusion protocols, selection of patients (eg, gestational age at rupture of membranes), and other interventions (type, dose, and duration of antibiotics; use of corticosteroids) on perinatal outcome.

TIMING OF DELIVERY

Our approach — Expeditious delivery of women with PPROM is indicated if intrauterine infection, placental abruption, nonreassuring fetal testing, or a high risk of cord prolapse is present or suspected. If the mother and fetus are stable, the pregnancy is ≥34 weeks of gestation, and dating is optimal, we discuss the advantages and disadvantages of delivery versus expectant management with the patient, and we suggest delivery, usually by induction of labor.

If the pregnancy is suboptimally dated, we continue to manage the pregnancy expectantly until 36 to 37 weeks of gestation (by best estimate), at which time we recommend delivery.

There are no high-quality data to clearly inform the point at which the potential benefits of ongoing expectant management to achieve a more advanced gestational age at delivery are offset by the potential risks associated with prolonged PPROM: infection, placental abruption, cord prolapse/compression. The optimal time for intervention varies among institutions and depends on the balance between morbidity related to prematurity and morbidity related to complications of PPROM, which can differ in different populations. In our population, we are particularly concerned about morbidity related to complications of prolonged PPROM (eg, chorioamnionitis, antepartum bleeding).

The American College of Obstetricians and Gynecologists (ACOG) suggests delivery for all patients with PROM ≥37+0 weeks of gestation, either expectant management or immediate delivery for those 34+0 to 36+6 weeks, and expectant management before 34+0 weeks [7]. Although we believe delivery at 34 weeks of gestation is preferable to expectant management in optimally dated pregnancies, some patients may choose expectant management based on the data presented below. Expectant management until term has been advocated by the perinatal group at the University of Sydney [54] and endorsed by the Royal College of Obstetricians and Gynaecologists [55].

Comparative trials of timed delivery versus expectant management — The authors of a 2017 meta-analysis of randomized trials of management of women with PPROM prior to 37 weeks concluded that, in the absence of either fetal or maternal compromise, expectant management until 37 weeks of gestation was preferable to timed early delivery (n = 12 trials, 3617 women, 3628 neonates) [54].

Compared with expectant management until 37 weeks, planned early birth increased the risk of several adverse newborn outcomes:

Respiratory distress syndrome (relative risk [RR] 1.26, 95% CI 1.05-1.53)

Need for mechanical ventilation (RR 1.27, 95% CI 1.02-1.58)

Admission to the neonatal intensive care unit (RR 1.16, 95% CI 1.08-1.24)

Neonatal death (RR 2.55, 95% CI 1.17-5.56)

It did not reduce the risk of some outcomes of concern, such as neonatal sepsis (RR 0.93, 95% CI 0.66-1.30), positive neonatal blood cultures (RR 1.24, 95% CI 0.70-2.21), overall perinatal mortality (RR 1.76, 95% CI 0.89-3.50), or fetal death (RR 0.45, 95% CI 0.13-1.57).

For the mother, planned early birth resulted in:

Lower rate of chorioamnionitis (RR 0.50, 95% CI 0.26-0.95)

Shorter total length of hospitalization (mean difference -1.75 days, 95% CI -2.45 to -1.05)

Higher cesarean delivery rate (RR 1.26, 95% CI 1.11-1.44)

Higher frequency of endometritis (RR 1.61, 95% CI 1.00-2.59)

A 2018 individual participant data meta-analysis of trials of late PPROM (34+0 to 36+6 weeks) with randomization to immediate delivery or expectant management included three of the trials in the above meta-analysis (n = 2563 women) [56]. Major findings were:

The two approaches resulted in similar rates of the composite adverse neonatal outcome (probable or definitive neonatal sepsis, necrotizing enterocolitis, respiratory distress syndrome, stillbirth, or neonatal death; 9.6 percent with immediate delivery versus 8.3 percent with expectant management; RR 1.20, 95% CI 0.94-1.55).

For the mother, immediate delivery reduced the risk of antepartum hemorrhage (1.7 versus 3.0 percent, RR 0.57, 95% CI 0.34-0.95) and chorioamnionitis (1.3 versus 6.4 percent, RR 0.21, 95% CI 0.13-0.35) but modestly increased the risk of cesarean delivery (22 versus 18 percent, RR 1.26, 95% CI 1.08-1.47).

The rate of endometritis (0.2 versus 0.6 percent) and the length of hospitalization (3.45 versus 3.39 days) were not statistically different between groups.

We have reservations about routine expectant management of PPROM until 37 weeks in all patients, particularly in the United States where we practice. First, the meta-analyses summarized above are dominated by the results of one trial, the Preterm Prelabour Rupture of the Membranes close to Term (PPROMT) trial [57], which contributed almost 50 percent of the patients. Second, the trials in the meta-analyses were conducted over extended periods of time (up to nine years), and major changes occurred in both obstetric and neonatal management during this time period (notably the decreased use of endotracheal intubation and mechanical ventilation in favor of continuous positive airway pressure [CPAP]). Third, there was no uniformity in the way that corticosteroids, tocolytics, and prophylactic antibiotics were administered (given according to local protocols). Fourth, there were significant differences among trials in the interval between PROM and induction of labor in the early delivery groups. Fifth, the trials were conducted in multiple different patient populations, not all of which are similar to patients treated in the United States, and at many different facilities with different levels of resources and different management strategies. Sixth, some of the patients were treated as outpatients, a practice that is not the standard of care in the United States. Finally, and perhaps of greatest importance with respect to practice in the United States, none of the trials addressed the issue of the comparative costs of the two management options.

DELIVERY

Magnesium sulfate for neuroprotection — Magnesium sulfate is administered prior to delivery according to standard clinical protocols for fetal neuroprotection (eg, pregnancies at least 24 but <32 weeks of gestation at risk of imminent delivery). (See "Neuroprotective effects of in utero exposure to magnesium sulfate".)

Route of delivery — In the absence of contraindications to labor and vaginal birth, most patients will deliver by spontaneous or induced vaginal delivery [58]. Cesarean delivery is performed for standard indications; otherwise, labor is induced.

Cervical ripening — Once delivery is indicated, we perform a digital cervical examination to determine whether cervical ripening has occurred naturally. If the cervix is favorable (Bishop score ≥6) (table 4), oxytocin is administered for induction according to standard protocols.

If the cervix is unfavorable, we administer a prostaglandin (misoprostol) for cervical ripening; however, the value of a cervical ripening agent in pregnancies with ruptured membranes has not been established. A meta-analysis including 15 randomized trials of misoprostol versus oxytocin for labor induction in women with term PROM reported the rate of vaginal delivery in 12 and 24 hours was similar for both drugs [59]. Whether misoprostol was advantageous in the subgroup of women with an unfavorable cervix is unknown since this was not evaluated. The optimum dose and route of misoprostol administration have also not been determined. (See "Induction of labor: Techniques for preinduction cervical ripening", section on 'Prostaglandin E1 (misoprostol)'.)

Prostaglandin E2 is a reasonable alternative [60]. There is no evidence that its use increases the risk of infection in women with PROM [61-63]. (See "Induction of labor: Techniques for preinduction cervical ripening", section on 'Prostaglandin E2'.)

There is minimal information on the safety of mechanical methods of cervical ripening in PROM. We do not use these methods due to concerns that introducing a foreign body might increase the risk of infection and data from the only randomized small trial showing no reduction in the induction-to-delivery interval [64]. These data are reviewed in detail separately. (See "Prelabor rupture of membranes at term: Management", section on 'Balloon catheter'.)

MANAGEMENT OF THE NEWBORN — (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Maternal risk factors'.)

OUTCOME — The fetus and neonate are at greater risk for PPROM-related morbidity and mortality than the mother (table 5).

Fetal/neonatal — For the neonate, morbidity and mortality are primarily related to preterm birth; residual oligohydramnios also plays a role [65]. The type and frequency of prematurity-related morbidity depend on the gestational age at birth and whether chorioamnionitis is present [66]. Fetal exposure to intrauterine inflammation has been associated with an increased risk of neurodevelopmental impairment. (See "Incidence and mortality of the preterm infant" and "Short-term complications of the preterm infant" and "Intraamniotic infection (clinical chorioamnionitis or triple I)", section on 'Fetal and neonatal outcome'.)

Early, severe, prolonged oligohydramnios can be associated with pulmonary hypoplasia, facial deformation, and orthopedic abnormalities. Such complications are most likely when membrane rupture occurs at less than 23 weeks of gestation. (See "Prelabor rupture of membranes before and at the limit of viability", section on 'Pediatric outcomes'.)

Maternal — Approximately one-third of women with PPROM develop potentially serious infections, such as chorioamnionitis, endometritis, or septicemia. Endometritis is more common after cesarean than vaginal delivery. The frequency of infection is higher at earlier gestational ages at PPROM [67,68]. (See "Intraamniotic infection (clinical chorioamnionitis or triple I)" and "Postpartum endometritis".)

MANAGEMENT OF FUTURE PREGNANCIES — As discussed above, a history of PPROM is a strong risk factor for recurrence (see "Preterm prelabor rupture of membranes: Clinical manifestations and diagnosis", section on 'Risk factors'). We suggest prophylactic progesterone supplementation for these women in future pregnancies. In studies of women with prior preterm birth that included both patients with intact and ruptured membranes, progesterone supplementation in subsequent pregnancies reduced the risk for recurrent preterm birth. (See "Progesterone supplementation to reduce the risk of spontaneous preterm labor and birth", section on 'Patients with singleton pregnancy and a short cervix or previous spontaneous preterm birth'.)

PPROM may be related to cervical insufficiency in some cases. In future pregnancies, sonographic measurement of cervical length and placement of a cerclage if cervical length is <25 mm before 24 weeks of gestation can reduce the risk of recurrent preterm birth. (See "Cervical insufficiency", section on 'Ultrasound-based cervical insufficiency'.)

Neither screening for asymptomatic infection with treatment of positive results nor empiric antibiotic therapy has been proven to prevent PPROM.

A single randomized trial evaluated whether screening all pregnant women for genital tract infection (bacterial vaginosis, T. vaginalis, Candidiasis) before 20 weeks plus standard treatment of patients with positive results found that the intervention reduced the number of spontaneous preterm births compared with a control group in which test results were not given to the provider (spontaneous preterm birth 3.0 versus 5.3 percent, 95% CI 1.2-3.6) [69]. Limitations of this trial include that it did not distinguish between preterm births due to preterm labor versus PPROM and the authors only used Gram stain to diagnosis infection.

A 2015 systematic review of randomized trials concluded that antibiotic prophylaxis in the second or third trimester did not reduce the risk of PPROM (RR 0.31, 95% CI 0.06-1.49; one trial, 229 women) or preterm birth (RR 0.85, 95% CI 0.64-1.14; five trials, 1480 women); however, the included studies were of low methodological quality [70]. Subsequent trials have also not shown a benefit [71].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Prelabor rupture of membranes".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Preterm prelabor rupture of membranes (The Basics)")

SUMMARY AND RECOMMENDATIONS

Overview – The management of women with preterm prelabor rupture of membranes (PPROM) is based upon consideration of several factors, including gestational age, the availability of an appropriate level of neonatal care, the presence or absence of maternal/fetal infection (see 'Screen for infection' above), the presence or absence of labor or placental abruption, the stability of the fetal presentation, the fetal heart rate tracing pattern, and cervical status. (See 'Overview' above.)

Patients requiring expeditious delivery (unstable patients) – Expeditious delivery of women with PPROM is indicated if intrauterine infection, placental abruption, nonreassuring fetal testing, or a high risk of cord prolapse is present or suspected. (See 'Our approach' above.)

Stable patients <34 weeks – For stable patients (mother and fetus) with PPROM <34 weeks, we suggest expectant management rather than delivery (Grade 2C) (see 'Components of expectant management' above and 'Our approach' above). In addition:

We recommend administering a course of antenatal corticosteroids (Grade 1A). Antenatal corticosteroids reduce the morbidity and mortality of prematurity if preterm delivery occurs. (See 'Administer antenatal corticosteroids' above.)

We recommend administering a course of prophylactic antibiotics (Grade 1A). Our preference is ampicillin 2 grams intravenously every 6 hours for 48 hours, followed by amoxicillin 875 mg orally twice daily for an additional five days. In addition, we administer one dose of azithromycin 1 gram orally at the time of admission. (See 'Administer prophylactic antibiotic therapy' above.)

We hospitalize women during the entire period of expectant management (diagnosis of PPROM to delivery). (See 'Hospitalization versus home care' above.)

Stable patients ≥34 weeks – For stable patients (mother and fetus) with optimally dated pregnancies at ≥34 weeks, we suggest delivery rather than expectant management (Grade 2C). If gestational dating is suboptimal, we suggest expectant management with delivery when our best estimate of gestational age is 36 to 37 weeks (Grade 2C). (See 'Our approach' above and 'Comparative trials of timed delivery versus expectant management' above.)

Outcome – The fetus and neonate are at greater risk for PPROM-related morbidity and mortality than the mother (table 5). (See 'Outcome' above.)

Future pregnancy – A history of PPROM is a strong risk factor for recurrence, and prophylactic progesterone supplementation in future pregnancies may reduce this risk. Neither screening for asymptomatic infection with treatment of positive results nor empiric antibiotic therapy has been proven to prevent PPROM. (See 'Management of future pregnancies' above.)

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Topic 120959 Version 23.0

References

1 : Impact of Latency Duration on the Prognosis of Preterm Infants after Preterm Premature Rupture of Membranes at 24 to 32 Weeks' Gestation: A National Population-Based Cohort Study.

2 : Preterm premature rupture of membranes: does the duration of latency influence perinatal outcomes?

3 : Preterm prelabour rupture of membranes: effect of latency on neonatal and maternal outcomes.

4 : Predictive Factors for Delivery within 7 Days after Successful 48-Hour Treatment of Threatened Preterm Labor.

5 : Antenatal Corticosteroid Therapy Before 24 Weeks of Gestation: A Systematic Review and Meta-analysis.

6 : Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.

7 : Prelabor Rupture of Membranes: ACOG Practice Bulletin, Number 217.

8 : Committee Opinion No. 713: Antenatal Corticosteroid Therapy for Fetal Maturation.

9 : Mid-Childhood Outcomes of Repeat Antenatal Corticosteroids: A Randomized Controlled Trial.

10 : Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.

11 : Premature rupture of membranes and neonatal respiratory morbidity at 32-41 weeks' gestation: a retrospective single-center cohort study.

12 : Sexually Transmitted Infections Treatment Guidelines, 2021.

13 : Gram-stain diagnosis of bacterial vaginosis after rupture of membranes.

14 : Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010.

15 : Antibiotics for preterm rupture of membranes.

16 : A new antibiotic regimen treats and prevents intra-amniotic inflammation/infection in patients with preterm PROM.

17 : Antibiotic administration reduces the rate of intraamniotic inflammation in preterm prelabor rupture of the membranes

18 : Effect on perinatal outcome of prophylactic antibiotics in preterm prelabor rupture of membranes: network meta-analysis of randomized controlled trials.

19 : Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. A randomized controlled trial. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.

20 : ACOG Practice Bulletin No. 199: Use of Prophylactic Antibiotics in Labor and Delivery.

21 : A retrospective comparison of antibiotic regimens for preterm premature rupture of membranes.

22 : Azithromycin vs erythromycin for the management of preterm premature rupture of membranes.

23 : Equivalence of erythromycin and azithromycin for treatment of PPROM

24 : Comparison of Azithromycin versus Erythromycin for Prolongation of Latency in Pregnancies Complicated by Preterm Premature Rupture of Membranes.

25 : Maternal azithromycin therapy for Ureaplasma intraamniotic infection delays preterm delivery and reduces fetal lung injury in a primate model.

26 : Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial.

27 : Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial.

28 : Reconsidering the Current Preterm Premature Rupture of Membranes Antibiotic Prophylactic Protocol.

29 : Antibiotic administration can eradicate intra-amniotic infection or intra-amniotic inflammation in a subset of patients with preterm labor and intact membranes.

30 : Tocolytics for preterm premature rupture of membranes.

31 : Preterm premature rupture of membranes: a randomized study of home versus hospital management.

32 : Clinical, psychosocial, and economic effects of antenatal day care for three medical complications of pregnancy: a randomised controlled trial of 395 women.

33 : Planned home versus hospital care for preterm prelabour rupture of the membranes (PPROM) prior to 37 weeks' gestation.

34 : Preterm premature rupture of membranes: Which criteria contraindicate home care management?

35 : Risk factors associated with shortened latency before delivery in outpatients managed for preterm prelabor rupture of membranes.

36 : Expectant management of preterm premature rupture of membranes and nonvertex presentation: what are the risks?

37 : Biophysical testing in premature rupture of the membranes.

38 : A randomized clinical trial of daily nonstress testing versus biophysical profile in the management of preterm premature rupture of membranes.

39 : Fetal assessment methods for improving neonatal and maternal outcomes in preterm prelabour rupture of membranes.

40 : The NICHD-MFMU antibiotic treatment of preterm PROM study: impact of initial amniotic fluid volume on pregnancy outcome.

41 : Impairment of growth in fetuses destined to deliver preterm.

42 : Fetal growth after preterm premature rupture of membranes: is it related to amniotic fluid volume?

43 : Clinical chorioamnionitis is not predicted by umbilical artery Doppler velocimetry in patients with premature rupture of membranes.

44 : Fetoplacental and uteroplacental Doppler blood flow velocity analysis in premature rupture of membranes.

45 : Doppler studies of the placental and fetal circulation in pregnancies with preterm prelabor amniorrhexis.

46 : Diagnosis and management of clinical chorioamnionitis.

47 : Meconium-stained amniotic fluid: a risk factor for microbial invasion of the amniotic cavity.

48 : Premature rupture of the membranes in term patients.

49 : International Multicentre Term Prelabor Rupture of Membranes Study: evaluation of predictors of clinical chorioamnionitis and postpartum fever in patients with prelabor rupture of membranes at term.

50 : Inhibition of neutrophil oxidative burst and phagocytosis by meconium.

51 : Prophylactic Antibiotics in Twin Pregnancies Complicated by Previable Preterm Premature Rupture of Membranes.

52 : Progestogens in singleton gestations with preterm prelabor rupture of membranes: a systematic review and metaanalysis of randomized controlled trials.

53 : Amnioinfusion for third trimester preterm premature rupture of membranes.

54 : Planned early birth versus expectant management for women with preterm prelabour rupture of membranes prior to 37 weeks' gestation for improving pregnancy outcome.

55 : Care of Women Presenting with Suspected Preterm Prelabour Rupture of Membranes from 24+0 Weeks of Gestation: Green-top Guideline No. 73.

56 : Immediate Delivery Compared With Expectant Management in Late Preterm Prelabor Rupture of Membranes: An Individual Participant Data Meta-analysis.

57 : Immediate delivery compared with expectant management after preterm pre-labour rupture of the membranes close to term (PPROMT trial): a randomised controlled trial.

58 : Intrapartum management of premature rupture of membranes: effect on cesarean delivery rate.

59 : Misoprostol for labor induction in women with term premature rupture of membranes: a meta-analysis.

60 : ACOG Practice Bulletin No. 107: Induction of labor.

61 : Prostaglandin E2 for induction of labor in patients with premature rupture of membranes at term.

62 : Induction of labor compared with expectant management for prelabor rupture of the membranes at term. TERMPROM Study Group.

63 : Misoprostol versus prostaglandin E2 gel for labor induction in premature rupture of membranes after 34 weeks of pregnancy.

64 : Foley Plus Oxytocin Compared With Oxytocin for Induction After Membrane Rupture: A Randomized Controlled Trial.

65 : The impact of residual oligohydramnios following preterm premature rupture of membranes on adverse pregnancy outcomes: a meta-analysis.

66 : A multicenter study on the clinical outcome of chorioamnionitis in preterm infants.

67 : Premature rupture of the membranes before 28 weeks: conservative management.

68 : Chorioamnionitis in the preterm gestation.

69 : Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery.

70 : Antibiotic prophylaxis during the second and third trimester to reduce adverse pregnancy outcomes and morbidity.

71 : Clindamycin to reduce preterm birth in a low resource setting: a randomised placebo-controlled clinical trial.