Preterm prelabor rupture of membranes: Management and outcome

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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

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2023. | This topic last updated: Jul 18, 2022.

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:

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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

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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
"Acute placental abruption: Pathophysiology, clinical features, diagnosis, and
consequences" and "Intraamniotic infection (clinical chorioamnionitis)" 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
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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 to antenatal corticosteroids more than 14 days earlier [8]. At least two trials
including pregnancies with PPROM demonstrated that a repeat course 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]. However, multiple courses
(ie, more than a single rescue course) should be avoided as they do not provide significant
added benefit and can be harmful. Regimens for rescue steroids, benefits and potential
harms of antenatal corticosteroids, 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 treated as appropriate. In some cases, the
prophylactic antibiotic therapy administered to prolong latency will provide adequate
treatment.

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● (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 individuals 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
'Clinical laboratory 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: Clinical manifestations and diagnosis", section on 'Diagnostic

evaluation'.)
● (See "Bacterial vaginosis: Clinical manifestations and diagnosis", section on 'Clinical
consequences of BV' and "Bacterial vaginosis: Initial treatment", section on 'Pregnant
or lactating 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. Guidelines for diagnosis of maternal GBS
colonization and chemoprophylaxis are discussed in more detail separately. (See
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"Prevention of early-onset group B streptococcal disease in neonates", section on 'Special

populations'.)

For patients being managed expectantly, 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 prophylaxis for GBS-colonized
women. 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 (eg, penicillin) should be
resumed when the patient subsequently goes into labor [14]. (See 'Administer prophylactic
antibiotic therapy' below.)

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

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)".)

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).

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● 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].

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The optimal regimen for antibiotic prophylaxis in PPROM was unclear in a 2020 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 or better efficacy;
this substitution is also endorsed by ACOG [7]. In a 2022 meta-analysis of five observational
studies comparing azithromycin with erythromycin for prophylaxis in nearly 1300
pregnancies with PPROM, azithromycin was associated with a lower rate of clinical
chorioamnionitis (14.5 versus 24.4 percent; OR 0.53 95% CI 0.39-0.71) [21]. Most patients
received a single dose of azithromycin versus a multiday erythromycin regimen. 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 [22]. 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

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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 [23]. 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 [24].

Ongoing studies to determine the optimal prophylactic antibiotic regimen are needed,
given changes in bacterial sensitivities over time [25]. 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 [16,26]. Others have reported that antibiotic
prophylaxis regimens based on a third-generation cephalosporin are associated with
improved newborn survival without severe morbidity when compared with amoxicillin, and
without an increase in neonatal sepsis related to third-generation cephalosporin-resistant
pathogens [27].

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

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• 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. They
also may be used to reduce the risk of delivery while a patient is being transported to a
facility with a higher level of neonatal care. 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" and "Inter-facility maternal transport", section on
'Preterm prelabor rupture of membranes'.)

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 [28]. 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
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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. The method of
thromboprophylaxis may be sequential compression devices and/or enoxaparin, 40 mg
subcutaneously daily for most patients at low to average risk of thrombosis. (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 [29,30]. The smaller trial included only 21
women with PPROM as part of a larger study of antenatal day care versus in-hospital care
[30]. 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 [29]. 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 [31].
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) [32]. 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 [32,33].

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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 [29,34]. 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 [35]. 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 [36]).

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 [37]. 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 [36].

● 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
[38].

● Fetal growth – Periodic ultrasound evaluation of fetal growth is reasonable [7] as

pathologic processes responsible for PPROM may also interfere with fetal growth
[39,40]. As a general rule, growth assessments should be performed no more often
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than every two to three weeks. (See "Fetal growth restriction: Evaluation".)

● Umbilical artery Doppler – Doppler surveillance is not useful for monitoring fetal
status in PPROM, unless growth restriction (FGR) is also present [41-43]. In this
setting, the key abnormal umbilical artery Doppler finding would be absent or
reversed end-diastolic flow. (See "Fetal growth restriction: Evaluation", section on
'Umbilical artery Doppler'.)

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 [44].

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)".)

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)".)

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

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separately. (See "Genital herpes simplex virus infection and pregnancy" and "Intrapartum
and postpartum 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 [45-47]. Meconium release
predisposes to infection by enhancing the growth of bacteria and lowering phagocytic
capacity of neutrophils [48]. 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 [49] 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 [50].

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

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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) [51]. 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

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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 [52] and endorsed by
the Royal College of Obstetricians and Gynaecologists [53].

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) [52].

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)

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Preterm prelabor rupture of membranes: Management and outcome
● 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) [54]. 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 [55], 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
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Preterm prelabor rupture of membranes: Management and outcome

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 [56]. 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 [57]. 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 [58]. There is no evidence that its use

increases the risk of infection in women with PROM [59-61]. (See "Induction of labor:
Techniques for preinduction cervical ripening", section on 'Prostaglandin E2'.)

We do not use an intracervical balloon catheter for cervical ripening as data suggest that

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Preterm prelabor rupture of membranes: Management and outcome

introducing a foreign body probably increases the risk of infection. 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
neonates", 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 [62]. The type and frequency of
prematurity-related morbidity depend on the gestational age at birth and whether
chorioamnionitis is present [63]. Fetal exposure to intrauterine inflammation has been
associated with an increased risk of neurodevelopmental impairment. (See "Preterm birth:
Definitions of prematurity, epidemiology, and risk factors for infant mortality" and "Short-
term complications of the preterm infant" and "Intraamniotic infection (clinical
chorioamnionitis)", 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 [64,65]. (See "Intraamniotic infection (clinical
chorioamnionitis)" and "Postpartum endometritis".)

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Preterm prelabor rupture of membranes: Management and outcome

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'). Prophylactic progesterone supplementation may be offered in future pregnancies
to reduce the risk for recurrent preterm birth, but this is controversial. At our institution,
we routinely administer daily micronized progesterone (200 mg) intravaginally to patients
with a history of preterm birth due to PPROM. Evidence of efficacy and management of
progesterone supplementation are reviewed in detail separately. (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) [66]. 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 [67].
Subsequent trials have also not shown a benefit [68].

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Preterm prelabor rupture of membranes: Management and outcome

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,
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Preterm prelabor rupture of membranes: Management and outcome

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.)

REFERENCES

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Preterm prelabor rupture of membranes: Management and outcome

1. Lorthe E, Ancel PY, Torchin H, et al. 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. J Pediatr 2017; 182:47.

2. Manuck TA, Maclean CC, Silver RM, Varner MW. Preterm premature rupture of
membranes: does the duration of latency influence perinatal outcomes? Am J Obstet
Gynecol 2009; 201:414.e1.

3. Frenette P, Dodds L, Armson BA, Jangaard K. Preterm prelabour rupture of

membranes: effect of latency on neonatal and maternal outcomes. J Obstet Gynaecol
Can 2013; 35:710.

4. Roos C, Schuit E, Scheepers HC, et al. Predictive Factors for Delivery within 7 Days after
Successful 48-Hour Treatment of Threatened Preterm Labor. AJP Rep 2015; 5:e141.
5. Park CK, Isayama T, McDonald SD. Antenatal Corticosteroid Therapy Before 24 Weeks
of Gestation: A Systematic Review and Meta-analysis. Obstet Gynecol 2016; 127:715.
6. Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating
fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev
2017; 3:CD004454.
7. Prelabor Rupture of Membranes: ACOG Practice Bulletin, Number 217. Obstet Gynecol
2020; 135:e80. Reaffirmed 2022.
8. Committee on Obstetric Practice. Committee Opinion No. 713: Antenatal
Corticosteroid Therapy for Fetal Maturation. Obstet Gynecol 2017; 130:e102.
9. Crowther CA, Anderson PJ, McKinlay CJ, et al. Mid-Childhood Outcomes of Repeat
Antenatal Corticosteroids: A Randomized Controlled Trial. Pediatrics 2016; 138.
10. Crowther CA, Haslam RR, Hiller JE, et al. Neonatal respiratory distress syndrome after
repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet
2006; 367:1913.
11. Shimokaze T, Akaba K, Banzai M, et al. Premature rupture of membranes and neonatal
respiratory morbidity at 32-41 weeks' gestation: a retrospective single-center cohort
study. J Obstet Gynaecol Res 2015; 41:1193.
12. Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections
Treatment Guidelines, 2021. MMWR Recomm Rep 2021; 70:1.
13. Core La BQ, Mastrobattista JM, Bishop K, Newton ER. Gram-stain diagnosis of bacterial
vaginosis after rupture of membranes. Am J Perinatol 2000; 17:315.
- Page 23 of 28 -
Preterm prelabor rupture of membranes: Management and outcome

14. Verani JR, McGee L, Schrag SJ, Division of Bacterial Diseases, National Center for
Immunization and Respiratory Diseases, Centers for Disease Control and Prevention
(CDC). Prevention of perinatal group B streptococcal disease--revised guidelines from
CDC, 2010. MMWR Recomm Rep 2010; 59:1.
15. Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes.
Cochrane Database Syst Rev 2013; :CD001058.
16. Lee J, Romero R, Kim SM, et al. A new antibiotic regimen treats and prevents intra-
amniotic inflammation/infection in patients with preterm PROM. J Matern Fetal
Neonatal Med 2016; 29:2727.
17. Kacerovsky M, Romero R, Stepan M, et al. Antibiotic administration reduces the rate of
intraamniotic inflammation in preterm prelabor rupture of the membranes. Am J
Obstet Gynecol 2020; 223:P114.E1.
18. Chatzakis C, Papatheodorou S, Sarafidis K, et al. Effect on perinatal outcome of
prophylactic antibiotics in preterm prelabor rupture of membranes: network meta-
analysis of randomized controlled trials. Ultrasound Obstet Gynecol 2020; 55:20.
19. Mercer BM, Miodovnik M, Thurnau GR, et al. 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. JAMA 1997; 278:989.
20. Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 199: Use of
Prophylactic Antibiotics in Labor and Delivery. Obstet Gynecol 2018; 132:e103.
21. Seaman RD, Kopkin RH, Turrentine MA. Erythromycin vs azithromycin for treatment of
preterm prelabor rupture of membranes: a systematic review and meta-analysis. Am J
Obstet Gynecol 2022; 226:794.
22. Grigsby PL, Novy MJ, Sadowsky DW, et al. Maternal azithromycin therapy for
Ureaplasma intraamniotic infection delays preterm delivery and reduces fetal lung
injury in a primate model. Am J Obstet Gynecol 2012; 207:475.e1.
23. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics
to pregnant women with preterm rupture of the membranes: 7-year follow-up of the
ORACLE I trial. Lancet 2008; 372:1310.
24. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics
to pregnant women with spontaneous preterm labour: 7-year follow-up of the

- Page 24 of 28 -
Preterm prelabor rupture of membranes: Management and outcome

ORACLE II trial. Lancet 2008; 372:1319.

25. Wolf MF, Miron D, Peleg D, et al. Reconsidering the Current Preterm Premature
Rupture of Membranes Antibiotic Prophylactic Protocol. Am J Perinatol 2015; 32:1247.
26. Yoon BH, Romero R, Park JY, et al. Antibiotic administration can eradicate intra-
amniotic infection or intra-amniotic inflammation in a subset of patients with preterm
labor and intact membranes. Am J Obstet Gynecol 2019; 221:142.e1.
27. Lorthe E, Letouzey M, Torchin H, et al. Antibiotic prophylaxis in preterm premature
rupture of membranes at 24-31 weeks' gestation: Perinatal and 2-year outcomes in
the EPIPAGE-2 cohort. BJOG 2022; 129:1560.
28. Mackeen AD, Seibel-Seamon J, Muhammad J, et al. Tocolytics for preterm premature
rupture of membranes. Cochrane Database Syst Rev 2014; :CD007062.
29. Carlan SJ, O'Brien WF, Parsons MT, Lense JJ. Preterm premature rupture of
membranes: a randomized study of home versus hospital management. Obstet
Gynecol 1993; 81:61.
30. Turnbull DA, Wilkinson C, Gerard K, et al. Clinical, psychosocial, and economic effects
of antenatal day care for three medical complications of pregnancy: a randomised
controlled trial of 395 women. Lancet 2004; 363:1104.
31. Abou El Senoun G, Dowswell T, Mousa HA. Planned home versus hospital care for
preterm prelabour rupture of the membranes (PPROM) prior to 37 weeks' gestation.
Cochrane Database Syst Rev 2014; :CD008053.
32. Petit C, Deruelle P, Behal H, et al. Preterm premature rupture of membranes: Which
criteria contraindicate home care management? Acta Obstet Gynecol Scand 2018;
97:1499.
33. Point F, Ghesquiere L, Drumez E, et al. Risk factors associated with shortened latency
before delivery in outpatients managed for preterm prelabor rupture of membranes.
Acta Obstet Gynecol Scand 2022; 101:119.
34. Lewis DF, Robichaux AG, Jaekle RK, et al. Expectant management of preterm
premature rupture of membranes and nonvertex presentation: what are the risks? Am
J Obstet Gynecol 2007; 196:566.e1.
35. Hanley ML, Vintzileos AM. Biophysical testing in premature rupture of the membranes.
Semin Perinatol 1996; 20:418.

36. Lewis DF, Adair CD, Weeks JW, et al. A randomized clinical trial of daily nonstress
- Page 25 of 28 -
Preterm prelabor rupture of membranes: Management and outcome

testing versus biophysical profile in the management of preterm premature rupture of

membranes. Am J Obstet Gynecol 1999; 181:1495.
37. Sharp GC, Stock SJ, Norman JE. Fetal assessment methods for improving neonatal and
maternal outcomes in preterm prelabour rupture of membranes. Cochrane Database
Syst Rev 2014; :CD010209.
38. Mercer BM, Rabello YA, Thurnau GR, et al. The NICHD-MFMU antibiotic treatment of
preterm PROM study: impact of initial amniotic fluid volume on pregnancy outcome.
Am J Obstet Gynecol 2006; 194:438.
39. Bukowski R, Gahn D, Denning J, Saade G. Impairment of growth in fetuses destined to
deliver preterm. Am J Obstet Gynecol 2001; 185:463.
40. Deering SH, Patel N, Spong CY, et al. Fetal growth after preterm premature rupture of
membranes: is it related to amniotic fluid volume? J Matern Fetal Neonatal Med 2007;
20:397.
41. Leo MV, Skurnick JH, Ganesh VV, et al. Clinical chorioamnionitis is not predicted by
umbilical artery Doppler velocimetry in patients with premature rupture of
membranes. Obstet Gynecol 1992; 79:916.
42. Abramowicz JS, Sherer DM, Warsof SL, Levy DL. Fetoplacental and uteroplacental
Doppler blood flow velocity analysis in premature rupture of membranes. Am J
Perinatol 1992; 9:353.
43. Carroll SG, Papaioannou S, Nicolaides KH. Doppler studies of the placental and fetal
circulation in pregnancies with preterm prelabor amniorrhexis. Ultrasound Obstet
Gynecol 1995; 5:184.
44. Tita AT, Andrews WW. Diagnosis and management of clinical chorioamnionitis. Clin
Perinatol 2010; 37:339.
45. Romero R, Hanaoka S, Mazor M, et al. Meconium-stained amniotic fluid: a risk factor
for microbial invasion of the amniotic cavity. Am J Obstet Gynecol 1991; 164:859.
46. Duff P. Premature rupture of the membranes in term patients. Semin Perinatol 1996;
20:401.
47. Seaward PG, Hannah ME, Myhr TL, et al. 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. Am J
Obstet Gynecol 1997; 177:1024.
- Page 26 of 28 -
Preterm prelabor rupture of membranes: Management and outcome

48. Clark P, Duff P. Inhibition of neutrophil oxidative burst and phagocytosis by meconium.
Am J Obstet Gynecol 1995; 173:1301.
49. Myrick O, Dotters-Katz S, Grace M, et al. Prophylactic Antibiotics in Twin Pregnancies
Complicated by Previable Preterm Premature Rupture of Membranes. AJP Rep 2016;
6:e277.
50. Quist-Nelson J, Parker P, Mokhtari N, et al. Progestogens in singleton gestations with
preterm prelabor rupture of membranes: a systematic review and metaanalysis of
randomized controlled trials. Am J Obstet Gynecol 2018; 219:346.
51. Hofmeyr GJ, Eke AC, Lawrie TA. Amnioinfusion for third trimester preterm premature
rupture of membranes. Cochrane Database Syst Rev 2014; :CD000942.
52. Bond DM, Middleton P, Levett KM, et al. Planned early birth versus expectant
management for women with preterm prelabour rupture of membranes prior to 37
weeks' gestation for improving pregnancy outcome. Cochrane Database Syst Rev
2017; 3:CD004735.
53. Thomson AJ, Royal College of Obstetricians and Gynaecologists. Care of Women
Presenting with Suspected Preterm Prelabour Rupture of Membranes from 24+0
Weeks of Gestation: Green-top Guideline No. 73. BJOG 2019; 126:e152.
54. Quist-Nelson J, de Ruigh AA, Seidler AL, et al. Immediate Delivery Compared With
Expectant Management in Late Preterm Prelabor Rupture of Membranes: An
Individual Participant Data Meta-analysis. Obstet Gynecol 2018; 131:269.
55. Morris JM, Roberts CL, Bowen JR, et al. Immediate delivery compared with expectant
management after preterm pre-labour rupture of the membranes close to term
(PPROMT trial): a randomised controlled trial. Lancet 2016; 387:444.
56. Kunze M, Hart JE, Lynch AM, Gibbs RS. Intrapartum management of premature
rupture of membranes: effect on cesarean delivery rate. Obstet Gynecol 2011;
118:1247.
57. Lin MG, Nuthalapaty FS, Carver AR, et al. Misoprostol for labor induction in women
with term premature rupture of membranes: a meta-analysis. Obstet Gynecol 2005;
106:593.
58. ACOG Committee on Practice Bulletins -- Obstetrics. ACOG Practice Bulletin No. 107:
Induction of labor. Obstet Gynecol 2009; 114:386. Reaffirmed 2020.
59. Ray DA, Garite TJ. Prostaglandin E2 for induction of labor in patients with premature
- Page 27 of 28 -
Preterm prelabor rupture of membranes: Management and outcome

rupture of membranes at term. Am J Obstet Gynecol 1992; 166:836.

60. Hannah ME, Ohlsson A, Farine D, et al. Induction of labor compared with expectant
management for prelabor rupture of the membranes at term. TERMPROM Study
Group. N Engl J Med 1996; 334:1005.
61. Zhang Y, Wang J, Yu Y, et al. Misoprostol versus prostaglandin E2 gel for labor
induction in premature rupture of membranes after 34 weeks of pregnancy. Int J
Gynaecol Obstet 2015; 130:214.
62. Pergialiotis V, Bellos I, Fanaki M, et al. The impact of residual oligohydramnios
following preterm premature rupture of membranes on adverse pregnancy outcomes:
a meta-analysis. Am J Obstet Gynecol 2020; 222:628.
63. Soraisham AS, Singhal N, McMillan DD, et al. A multicenter study on the clinical
outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol 2009;
200:372.e1.
64. Beydoun SN, Yasin SY. Premature rupture of the membranes before 28 weeks:
conservative management. Am J Obstet Gynecol 1986; 155:471.
65. Garite TJ, Freeman RK. Chorioamnionitis in the preterm gestation. Obstet Gynecol
1982; 59:539.
66. Kiss H, Petricevic L, Husslein P. Prospective randomised controlled trial of an infection
screening programme to reduce the rate of preterm delivery. BMJ 2004; 329:371.
67. Thinkhamrop J, Hofmeyr GJ, Adetoro O, et al. Antibiotic prophylaxis during the second
and third trimester to reduce adverse pregnancy outcomes and morbidity. Cochrane
Database Syst Rev 2015; 1:CD002250.
68. Bellad MB, Hoffman MK, Mallapur AA, et al. Clindamycin to reduce preterm birth in a
low resource setting: a randomised placebo-controlled clinical trial. BJOG 2018;
125:1601.

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