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Author

Patrick Duff, MD

Section Editor

Charles J Lockwood, MD, MHCM

Deputy Editor

Vanessa A Barss, MD, FACOG

Preterm premature (prelabor) rupture of membranes

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

Literature review current through: Dec 2015. | This topic last updated: Jan 04, 2016.

INTRODUCTION — Premature rupture of membranes (PROM) refers to membrane rupture before the onset of

uterine contractions (also known as prelabor rupture of membranes); preterm PROM (PPROM) refers to PROM

before 37 weeks of gestation.

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

include:

Risk factors, diagnosis, and management of PPROM at 23 to 37 weeks of gestation will be discussed here. Issues

specifically relating to management of PROM prior to 23 weeks of gestation and at term are discussed separately.

(See "Midtrimester preterm premature rupture of membranes" and "Management of premature rupture of the fetal

membranes at term".)

INCIDENCE — Preterm premature rupture of membranes (PPROM) occurs in 3 percent of pregnancies and is

responsible for, or associated with, approximately one-third of preterm births [1].

PATHOGENESIS — The pathogenesis of spontaneous membrane rupture is not completely understood. The

strength and integrity of fetal membranes derive from extracellular membrane proteins, including collagens,

fibronectin, and laminin. Matrix metalloproteases (MMPs) decrease membrane strength by increasing collagen

degradation [2]. Tissue inhibitors of MMPs (TIMMPs) bind to MMPs and shut down proteolysis, thereby helping to

maintain membrane integrity [2,3]. A variety of pathologic events can disrupt this homeostasis and initiate a

cascade of biochemical changes that culminate in PROM. Although the pathway varies depending on the initiating

event, it is likely that all pathways lead to a final common pathway ending in membrane rupture. (See

"Pathogenesis of spontaneous preterm birth".)

CLINICAL FINDINGS

Risk factors — Mater nal physiologic, genetic, and environmental factors likely predispose to development of

preterm premature rupture of membranes (PPROM) in many cases. These risk factors are similar to those for

preterm labor (table 1), but most patients have no identifiable risk factors. (See "Risk factors for preterm labor and

delivery".)

A history of PPROM in a previous pregnancy, genital tract infection, antepartum bleeding, and cigarette smoking

have a particularly strong association with PPROM [4].

®

®

0/7ths

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●

Previous PPROM — Studies have consistently reported that a history of PPROM is a strong risk factor for

recurrence. As an example, the Preterm Prediction Study, a large prospective study conducted by the

National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU)

●

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In addition, several genetic polymorphisms of genes related to infection, inflammation, and collagen degradation

have been identified as potential risk factors for PPROM.

Patient presentation — The classic clinical presentation of PPROM is a sudden "gush" of clear or pale yellow

fluid from the vagina. However, many women describe intermittent or constant leaking of small amounts of fluid or

just a sensation of wetness within the vagina or on the perineum.

Findings on physical examination — Direct observation of amniotic fluid coming out of the cervical canal or

pooling in the vaginal fornix is pathognomonic of PPROM. If amniotic fluid is not immediately visible, the woman can

be asked to push on her fundus, Valsalva, or cough to provoke leakage of amniotic fluid from the cervical os.

For patients who are not in active labor, examination of the cervix and vagina is performed using a sterile speculum.

Digital examination should be avoided because it may decrease the latency period (ie, time from rupture of

membranes to delivery) and increase the risk of intrauterine infection [12-14]. The cervix may appear dilated and/or effaced and, rarely, prolapse of a fetal part or the umbilical cord may be detected.

Findings on ultrasonography — Fifty to 70 percent of women with PPROM have low amniotic fluid volume on

initial sonography [15].

Clinical course — The majority of pregnancies with PPROM deliver within one week of membrane rupture. In a

randomized trial of PPROM at 24 to 32 weeks, the median time to delivery of 239 group B streptococcal (GBS)

negative patients managed expectantly with prophylactic antibiotics was 6.1 days; 27 percent delivered within 48

hours, 56 percent delivered within 7 days, 76 percent delivered within 14 days, and 86 percent delivered within 21

days [16]. However, the duration of the latency period inversely correlates with gestational age at membrane rupture

Network, observed that women with a history of PPROM had a 13.5 percent rate of PPROM in a subsequent

pregnancy compared to 4.1 percent in women with no such history (RR 3.3, 95% CI 2.1-5.2) [5]. Others have

reported recurrence rates at high as 32 percent [6]. Women with a history of PPROM are at risk for recurrent

PPROM or preterm birth without PPROM [7,8].

Genital tract infection — Genital tract infection is the single most common identifiable risk factor for

PPROM. Three lines of epidemiologic evidence strongly support this association: (1) women with PPROM are

significantly more likely than women with intact membranes to have pathogenic microorganisms in the

amniotic fluid, (2) women with PPROM have a significantly higher rate of histologic chorioamnionitis than

those who deliver preterm without PPROM, and (3) the frequency of PPROM is significantly higher in women

with certain lower genital tract infections (particularly bacterial vaginosis) than in uninfected women [3]. (See

"Bacterial vaginosis".)

The association between bacterial colonization of the lower genital tract and PPROM is not surprising. Many

of the microorganisms that colonize the lower genital tract have the capacity to produce phospholipases,

which can stimulate the production of prostaglandins and thereby lead to the onset of uterine contractions. In

addition, the host's immune response to bacterial invasion of the endocervix and/or fetal membranes leads to

the production of multiple inflammatory mediators that can cause localized weakening of the fetal membranes

and result in PPROM [3]. Genetic regulation of the host's immune and inflammatory response appears to play

a role in susceptibility and response to infections associated with PPROM. (See "Pathogenesis of spontaneous preterm birth" and "Risk factors for preterm labor and delivery".)

●

Antepartum bleeding — Antepartum bleeding in the first trimester is associated with a small but

statistically significant increase in the risk of PPROM [9]. Antepartum bleeding in more than one trimester

increases the risk of PPROM three- to seven-fold [4,10,11].

●

Cigarette smoking — The risk of PPROM among smokers is increased two- to four-fold compared to

nonsmokers. The risk persists even after adjustment for other known risk factors for PPROM, including

infection. (See "Cigarette smoking and pregnancy".)

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[17].

Cessation of fluid leakage is rare, except in women with PPROM related to amniocentesis. Sealing of membranes

is associated with a more favorable prognosis [18]. (See "Diagnostic amniocentesis", section on 'Leakage of

amniotic fluid'.)

The fetus and neonate are at greater risk of PPROM-related morbidity and mortality than the mother (table 2).

Prematurity-related morbidity varies with gestational age and is higher in the setting of chorioamnionitis [19]. Fetal

exposure to intrauterine inflammation has been associated with an increased risk of neurodevelopmental

impairment. (See "Incidence and mortality of the premature infant" and "Short-term complications of the prematureinfant" and "Intraamniotic infection (chorioamnionitis)".)

Approximately one-third of women with PPROM develop potentially serious infections, such as intraamniotic

infection (chorioamnionitis and funisitis), endometritis, or septicemia. Endometritis is more common after cesarean

than vaginal delivery. The incidence of infection is higher at earlier gestational ages [20,21]. (See "Intraamniotic

infection (chorioamnionitis)" and "Postpartum endometritis".)

PPROM is also associated with increased risks of abruptio placentae and prolapse of the umbilical cord. Placental

abruption occurs in 2 to 5 percent of pregnancies complicated by PPROM [22-25]. The risk is increased seven- to

nine-fold in PPROM pregnancies in which intrauterine infection or oligohydramnios is present [23,24]. Placental

abruption may be the precipitating event for or a consequence of PPROM. (See "Placental abruption: Clinical

features and diagnosis", section on 'Pathogenesis and pathophysiology'.)

Fetal malpresentation is common, given the preterm gestational age and the frequent occurrence of reduced

amniotic fluid volume. The risk of cord prolapse is especially high (11 percent in one study [26]) in the setting of

both nonvertex fetal presentation and PPROM. Non-cephalic presentation may also increase the risk of abruption,

infection, and fetal death in utero [27]. (See "Umbilical cord prolapse" and "Placental abruption: Clinical features

and diagnosis".)

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 "Midtrimester preterm premature rupture of membranes", section on 'Pediatric outcomes'.)

DIAGNOSIS — The diagnosis of preterm premature rupture of membranes (PPROM) is clinical, and is generally

based on visualization of amniotic fluid in the vagina of a woman who presents with a history of leaking fluid.

Laboratory tests are used to confirm the clinical diagnosis when it is uncertain.

Laboratory confirmation of clinically suspected PPROM

Nitrazine and fern tests — If PPROM is not obvious after visual inspection, the diagnosis can be confirmed by

testing the pH of the vaginal fluid, which is easily accomplished with Nitrazine paper. Amniotic fluid usually has a

pH range of 7.0 to 7.3 compared to the normally acidic vaginal pH of 3.8 to 4.2 ( picture 1) [28].

False-negative and false-positive Nitrazine test results occur in up to 5 percent of cases [ 29,30]. False negative test

results can occur when leaking is intermittent or the amniotic fluid is diluted by other vaginal fluids. False positiveresults can be due to the presence of alkaline fluids in the vagina, such as blood, seminal fluid, or soap. In addition,

the pH of urine can be elevated to near 8.0 if infected with Proteus species.

A second confirmatory test is the presence of arborization (ferning). Fluid from the posterior vaginal fornix is

swabbed onto a glass slide and allowed to dry for at least 10 minutes. Amniotic fluid produces a delicate ferning

pattern, in contrast to the thick and wide arborization pattern of dried cervical mucus (picture 2 and picture 3). Well-

estrogenized cervical mucus or a fingerprint on the microscope slide may cause a false-positive fern test; false

negatives can be due to inadequate amniotic fluid on the swab or heavy contamination with vaginal discharge or

blood.

In the United Kingdom, an absorbent pad (AmnioSense) that changes color at pH >5.2 is used as a panty liner and

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marketed to pregnant women. In a study of 157 pregnant women, the sensitivity and specificity of this device for

diagnosis of membrane rupture were 98 and 65 percent, respectively [31].

AmniSure and Actim PROM — Placental alpha microglobulin-1 protein assay (PAMG-1 [AmniSure]) and

insulin-like growth factor binding protein 1 (IGFBP-1 [Actim PROM]) are commercially available tests for diagnosis

of ROM. A 2013 meta-analysis of prospective observational or cohort studies investigating IGFBP-1 and PAMG-

1 tests for diagnosis of ROM concluded PAMG-1 (AmniSure) was more accurate than IGFBP-1 (Actim PROM) for

diagnosis of ROM in all patient populations (eg, known rupture status, uncertain rupture status) [32]. A subsequent

randomized trial reported similar findings [33].

Placental alpha microglobulin-1 protein assay (AmniSure) — AmniSure is a rapid slide test that uses

immunochromatography methods to detect trace amounts of placental alpha microglobulin-1 protein in vaginal fluid.

An advantage of this test is that it is not affected by semen or trace amounts of blood.

The test is done by the provider at the point of care using a commercially available kit. A sterile swab is inserted

into the vagina for one minute, then placed into a vial containing a solvent for one minute, and then an AmniSure

test strip is dipped into the vial. The test result is revealed by the presence of one or two lines within the next 5 to

10 minutes (one visible line means a negative result for amniotic fluid, two visible lines is a positive result, no visible

lines is an invalid result). In large studies, sensitivity ranged from 94.4 to 98.9 percent and specificity ranged from

87.5 to 100 percent [34-38]. In one study, the authors hypothesized that false positive results in three patients

might have been due to a small leak that sealed over [35].

Given the relatively high cost of this test, we suggest limiting its use to cases where the diagnosis remains

uncertain after physical examination and Nitrazine and fern tests.

Insulin-like growth factor binding protein 1 (Actim PROM) — Identification of insulin-like growth factor

binding protein 1 (IGFBP-1) also may be of value in confirming the diagnosis of PPROM in problematic cases. This

protein is secreted by decidual and placental cells and has a very high concentration in amniotic fluid compared to

other body fluids. An easy-to-use, immunochromatography dipstick method (eg, actim Prom) is available in some

countries for use at the bedside to detect IGFBP-1 in vaginal secretions. This test is popular in Europe, but is not

widely used in the United States. A positive test is denoted by the presence of two blue lines on the dipstick. The

test is not affected by the presence of infected vaginal secretions, urine, semen, or small amounts of blood.

The test is most accurate when applied as soon as possible after rupture of membranes. Sensitivity in detecting

ruptured membranes ranges from 95 to 100 percent, specificity ranges from 93 to 98 percent, and positive predictive

value approaches 98 percent [37,39-42]. The test is particularly helpful in identifying those women likely to deliver

within seven days.

Ultrasound examination — In equivocal cases, ultrasound can be performed to look for a reduction in

amniotic fluid volume. If the patient has a normal amniotic fluid volume, it is very unlikely that she has experienced

rupture of membranes, even with a seemingly convincing history.

Other tests

Fetal fibronectin — A negative fetal fibronectin result strongly supports absence of membrane rupture, buta positive result only indicates disruption of the interface between chorion and decidua, which can occur with intact

membranes [43].

Alpha-fetoprotein — Alpha-fetoprotein (AFP) in vaginal secretions suggestions the presence of amniotic

fluid [44-47]. In a pilot study, extraction of AFP from sanitary pads differentiated amniotic fluid, which has a high

AFP concentration, from other common secretions (vaginal discharge, urine, semen), which have low AFP levels

[47]. Sensitivity was 96.2 percent and specificity was 100 percent for diagnosis of PROM at an AFP cutoff of 3.88

ng/mL. Measurement of AFP is less costly than other commercially available tests for PROM, but blood in the

vagina can give false positive results.

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Instillation of dye — In the past, clinicians performed the "tampon test" in problematic cases. Under

ultrasound guidance, 1 mL of indigo carmine dye in 9 mL of sterile saline was injected transabdominally into the

amniotic fluid, and a tampon was placed in the vagina. Twenty minutes later, the tampon was removed and

examined for blue staining, which indicated leakage of amniotic fluid. However, indigo carmine dye is no longer

available in the United States. Moreover, this invasive test is not always easy to perform in the presence of a

reduced amniotic fluid volume, and it can cause rupture of membranes. It has been replaced by non-invasive tests,

such as AmniSure and Actim PROM. (See 'AmniSure and Actim PROM' above.).

Differential diagnosis — Other causes of vaginal/perineal wetness include urinary incontinence, vaginal

discharge, and perspiration. These causes should be considered in women with negative clinical and laboratory

findings for PPROM.

If ultrasound is performed, a mild reduction of amniotic fluid volume is a nonspecific finding related to many

etiologies, including PPROM. On the other hand, the finding of anhydramnios or severe oligohydramnios, combined

with a characteristic history, is highly suggestive of rupture of membranes, although renal agenesis, obstructive

uropathy, or severe utero-placental insufficiency also can cause marked reductions in amniotic fluid volume. (See

"Assessment of amniotic fluid volume".)

MANAGEMENT — Management of preterm premature rupture of membranes (PPROM) from 23 weeks to 37 weeks

will be discussed here. Issues specifically relating to management of previable PPROM and PROM at term are

reviewed separately. (See "Midtrimester preterm premature rupture of membranes" and "Management of prematurerupture of the fetal membranes at term".)

Initial approach — The management of pregnancies complicated by PPROM is based upon consideration of

several factors, which are assessed upon presentation:

Some tests that can be useful in this assessment are listed in the table (table 3). Screening for GBS, sexually

transmitted infections, and possibly bacterial vaginosis is useful for guiding antibiotic therapy (discussed below),

but vaginal culture is not helpful since the vaginal flora is normally polymicrobial.

The key decision is whether to induce labor (or perform cesarean delivery) or to manage the pregnancy expectantly.

The immature fetus will benefit by prolongation of pregnancy that results in a significant reduction in gestational

age-related morbidity, but this benefit needs to balance with the risks of PPROM-associated complications and

their sequelae (table 2).

Expeditious delivery of women with PPROM is clinically appropriate if intrauterine infection, abruptio placentae,

nonreassuring fetal testing, or a high risk of cord prolapse is present or suspected. In each of these conditions, fetal

well-being can deteriorate with expectant management, and there are no therapeutic interventions available other

than delivery. (See "Placental abruption: Clinical features and diagnosis" and "Intraamniotic infection

(chorioamnionitis)" and "Umbilical cord prolapse".)

In the absence of these complications, we do not intervene to effect delivery prior to 34 weeks. Our simplified

algorithm for management of women with PPROM at 26 to 36 weeks is shown in the algorithm ( algorithm 1). As

noted, most patients who are initially managed expectantly will be delivered at 34 weeks of gestation; in some,

delivery will be delayed until 36 weeks of gestation. A detailed analysis of the nuances of management is beyond

Gestational age●

Presence or absence of maternal/fetal infection●

Presence or absence of labor ●

Fetal presentation●

Fetal well-being●

Fetal lung maturity●

Cervical status (by visual inspection)●

Availability of neonatal intensive care●

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the scope of this topic review; however, several aspects of management will be discussed.

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. The American College of Obstetricians and

Gynecologists (ACOG) suggests delivery for all patients ≥34 weeks of gestation [48]. (See 'Timing of delivery for

expectantly managed pregnancies' below.)

Meta-analyses of randomized trials, and subsequent randomized trials, have not provided conclusive evidence

favoring induction or expectant management of PPROM between 28 and 37 weeks [49-53]. The complexity of

management decisions was illustrated by the Preterm Prelabour Rupture of the Membranes close to Term(PPROMT) trial [49]. This multicenter, international randomized trial (65 centers in 11 countries) was focused

specifically on patients who developed PPROM between 34 and 36 weeks of gestation and were randomly

assigned to immediate delivery (n = 924) or expectant management (n = 915). The trial found that rates of neonatal

sepsis (primary outcome) were 2 to 3 percent and did not differ significantly between the two groups. Infants in the

immediate delivery group were more likely to develop respiratory distress syndrome (8 versus 5 percent, relative risk

[RR] 1.6, 95% CI 1.1-2.3), require mechanical ventilation (12 versus 9 percent, RR 1.4, 95% CI 1.0-1.8), and spend

more time in the neonatal intensive care unit (six versus four days) than infants delivered to mothers in the

expectant management group. There was no difference between groups in the composite neonatal outcome of

sepsis, ventilation for ≥24 hours, or death. However, mothers assigned to expectant management were more likely

to develop antepartum or intrapartum bleeding (5 versus 3 percent), develop intrapartum fever (2 versus 1 percent),

and require use of therapeutic antibiotics (20 versus 16 percent). They also had a longer hospital stay (six versus

five days) and a lower frequency of cesarean delivery (19 versus 26 percent). This trial had several limitations that

preclude extrapolating these findings to contemporary populations in the United States. For example, the trial was

conducted over 10 years, during which obstetric and neonatal management has likely changed. In addition, the

study was conducted at many different facilities with different levels of resources and different management

strategies. Some patients were managed as outpatients, which is not done in the United States; there were no

clear criteria for determining the timing of delivery in the expectantly managed group; there were significant

variations in protocols for laboratory testing and administration of prophylactic antibiotics, and there were

inconsistencies in the use of corticosteroids.

Expectant management

Administration of antenatal corticosteroids — A course of corticosteroids should be given to pregnancies

between 23 and 34 weeks of gestation. Data supporting this recommendation were provided by systematic reviews

of randomized trials [54,55] that showed neonatal death, respiratory distress syndrome (RDS), intraventricular

hemorrhage (IVH), necrotizing enterocolitis (NEC), and duration of neonatal respiratory support were significantly

reduced by antenatal glucocorticoid treatment, without an increase in either maternal or neonatal infection. Mean

risk reduction for these adverse events ranged from 30 to 60 percent.

A single course of ‘rescue’ therapy is reasonable if the patient is clinically estimated to be at high risk of delivery

within the next seven days, at least two weeks have passed since the initial course of antenatal corticosteroids,

and the initial course was given at


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consequence of PPROM. Infection may lead to spontaneous preterm labor or may be the indication for medically-

indicated preterm delivery. 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 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 (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 [57]. Compared to placebo/no treatment, antibiotic use

was associated with significant reductions in:

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.

A 2008 meta-analysis was limited to PPROM before 34 weeks of gestation, and reported similar results [58].

Drug regimen — A regimen with reasonable activity against the major pelvic pathogens should be used,

but the optimal regimen is unclear [59]. We recommend administering a seven-day course of antibiotic prophylaxis

to all women with PPROM who are managed expectantly. Our preference is ampicillin 2 g intravenously every 6

hours for 48 hours, followed by amoxicillin (500 mg orally three times daily or 875 mg orally twice daily) for an

additional five days. In addition, we recommend giving one dose of azithromycin (one gram orally) upon admission.

Ampicillin specifically targets group B streptococcus, many aerobic gram-negative bacilli, and some anaerobes.

Azithromycin specifically targets genital mycoplasmas, which can be important causes of chorioamnionitis in this

setting, and also provides coverage of Chlamydia trachomatis, which is an important cause of neonatal

conjunctivitis and pneumonitis.

This regimen 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 g 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)

[16]. 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. In a retrospective study of women

with PPROM given prophylaxis with ampicillin plus erythromycin or ampicillin plus azithromycin, the two regimens

resulted in similar pregnancy and neonatal outcomes (latency length; mean birth weight; rates of chorioamnionitis,

cesarean delivery, low Apgar score, neonatal sepsis, neonatal respiratory distress syndrome) [60]. The powder

formulation of azithromycin is less expensive than the tablets, but may not be as well tolerated.

A basic science 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 [ 61]. In this study, 16 chronically

instrumented rhesus monkeys underwent intraamniotic inoculation with Ureaplasma parvum. Uterine contractions

Chorioamnionitis (RR 0.66, 95% CI 0.46-0.96)●

Babies born within 48 hours (RR 0.71, 95% CI 0.58-0.87) and 7 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), and●

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

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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.

Women with penicillin allergy — If the patient's history suggests a "low risk" for anaphylaxis (eg,

isolated maculopapular rash without urticaria or pruritus), then we suggest cefazolin 1 g intravenously every 8 hours

for 48 hours, followed by cephalexin 500 mg orally four times daily for five days. These drugs provide coverage for

both GBS and E Coli, the two major causes of neonatal infection. We also give a single oral dose of azithromycin 1

g. (See "Penicillin allergy: Immediate reactions".)

If the patient's history suggests a "high risk" for anaphylaxis (eg, anaphylaxis, angioedema, respiratory distress,

urticaria, particularly if these symptoms occurred within 30 minutes of drug administration), we suggest clindamycin

900 mg intravenously every 8 hours for 48 hours plus gentamicin 7 mg/kg ideal body weight for two doses 24 hours

apart, followed by oral clindamycin 300 mg every eight hours for five days. We also give a single dose of

azithromycin 1 g.

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 havereceived 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 7 years [62]. 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 [63].

Chemoprophylaxis for GBS — Chemoprophylaxis specifically for GBS disease is indicated if GBS test

results are positive or unknown and delivery is imminent, but is generally not given to women with recent (within five

weeks) negative GBS test results. The intravenous portion of the regimen described above for PPROM prophylaxis

(ampicillin 2 g 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, thisregimen of intravenous ampicillin, followed by oral amoxicillin, combined with 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 (algorithm 2) [64].

Testing to determine GBS status and guidelines for chemoprophylaxis are discussed in detail separately. (See

"Neonatal group B streptococcal disease: Prevention", section on 'Approach to threatened preterm delivery'.)

Use of tocolysis — The principal indication for tocolysis in the setting of PPROM is to delay delivery for 48

hours to allow administration 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, 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


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improvement in clinically important outcomes.

Supplemental progesterone — Progesterone supplementation is not beneficial in women with PPROM in the

current pregnancy. In two placebo-controlled, randomized trials of women with PPROM at 20 to 30 weeks of

gestation, weekly injection of hydroxyprogesterone caproate did not extend the latent period before delivery or

reduce perinatal morbidity [66,67].

In women who are 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. (See "Progesterone

supplementation to reduce the risk of spontaneous preterm birth", section on 'Preterm premature rupture of membranes'.)

Hospitalization versus home care — We hospitalize women with PPROM who have a viable fetus from the

time of diagnosis until delivery, with few exceptions. Activity is limited to using the bathroom and sitting up in a

bedside chair. Thromboprophylaxis in the form of sequential compression devices should be provided to all

hospitalized pregnant women at bedrest [68]. We also administer prophylactic doses of enoxaparin (1 mg/kg/day)

to patients who have additional risk factors for deep vein thrombosis.

There have been only two randomized trials evaluating the safety of outpatient versus inpatient management of

women with PPROM [69,70]. The smaller trial included only 21 women with PPROM as part of a larger study of

antenatal day care versus in-hospital care [70]. 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

[69]. Both groups were managed similarly with bedrest, recording of temperature and pulse every six hours, daily

charting of fetal movements, twice-weekly nonstress tests (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 4) and three women managed at home delivered unexpectedly at outside hospitals.

A meta-analysis found no significant differences in maternal or neonatal outcomes between the hospital and home

care groups, although the home group had lower maternal costs [71]. However, these small trials did not have

sufficient statistical power to detect meaningful differences between groups. A small retrospective study also

observed no significant differences in maternal or neonatal outcomes for hospital versus home care, but the small

number of patients and lack of a standardized protocol are major limitations to interpreting the results [72].

Further study to determine the safety of this approach is warranted before a policy of outpatient management can

be recommended. 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 [26,69].

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, uterine

tenderness and 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 useful [73].

Amniocentesis to obtain amniotic fluid for Gram stain, culture, leukocyte esterase, and glucose concentration is

more controversial. We do not routinely perform amniocentesis to screen for intraamniotic infection inasymptomatic women. If the clinical diagnosis of chorioamnionitis is uncertain and we need more information to

decide about expectant management, then we perform amniocentesis to rule out infection. However, if there is

insufficient amniotic fluid to sample, which occurs in at least 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. An in-depth discussion of the diagnosis and management of

intraamniotic infection can be found separately. (See "Intraamniotic infection (chorioamnionitis)".)

Fetal monitoring — 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 [74]. At our center, we perform

a daily NST. If the NST is not reassuring, we perform a BPP. However, none of these tests has good sensitivity for

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http://www.uptodate.com/contents/preterm-premature-prelabor- rupture-of-membranes?topicKey=OBGYN%2F6754&elapsedTimeMs=0&source=search_resul… 10

predicting fetal infection, even when performed daily (sensitivity of daily NST and BPP: 39 and 25 percent,

respectively [75]). 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 [ 76]. 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 [ 75].

Low amniotic fluid volume is associated with an increased risk of umbilical cord compression and shorter latency,

but, as with other tests, the value of fetal heart rate testing or the BPP score for prediction of adverse fetal/neonatal

outcome in this setting is low [15].

Similarly, Doppler surveillance is not useful for monitoring fetal status in PPROM [ 77-79].

Special situations

Women with HSV, HIV, or cerclage — Expectant management of women with PPROM and genital

herpes simplex virus (HSV) or human immunodeficiency virus (HIV) infection is controversial, and opinions about

the best course of action diverge widely. These issues are discussed separately. (See "Genital herpes simplex

virus infection and pregnancy" and "Prenatal evaluation and intrapartum management of the HIV-infected woman in

resource-rich settings".)

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

Meconium stained fluid — 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 [80-82]. Meconium release predisposes to infection by enhancing the growth of bacteria and

lowering phagocytic capacity of neutrophils [83]. However, it is also possible that in some cases meconium-like

staining is actually pigment associated with decidual hemorrhage (abruption).

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.

Tissue sealants — A variety of tissue sealants (eg, fibrin glue, gelatin sponge) has shown 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 "Midtrimester preterm premature rupture of membranes",

section on 'Repair of leaks'.)

Amnioinfusion — 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) [ 84]. Transabdominal amnioinfusion

resulted in statistical reductions in neonatal death, sepsis/infection, and pulmonary hypoplasia, but the data for

each outcome were limited to one to two very small trials of low to moderate quality.

To better understand whether amnioinfusion is beneficial in PPROM, more and better information is needed aboutthe 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. Until

better data are available to support a change in practice, we recommend not performing antepartum amnioinfusion

on patients with PPROM.

Twin pregnancy — The management of PPROM in twin pregnancies is similar to that in singletons.

Diagnosis and treatment of overt infection — Overt chorioamnionitis is usually easily diagnosed clinically

because of maternal fever, particularly when associated with leukocytosis, maternal and fetal tachycardia, uterine

tenderness, and/or malodorous amniotic fluid. Diagnosis of subclinical chorioamnionitis requires amniocentesis to

identify microorganisms in the amniotic fluid (gram stain and culture) and document an abnormally low amniotic

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fluid glucose concentration. A rapid test for interleukin-6 (IL-6), which is perhaps the most sensitive marker for

microbial invasion of the amniotic cavity, is available in some countries [85]. (See "Intraamniotic infection

(chorioamnionitis)", section on 'Diagnosis of clinical chorioamnionitis'.)

Women who develop overt infection require therapy with therapeutic, rather than prophylactic, antibiotics. (See

"Intraamniotic infection (chorioamnionitis)", section on 'Antibiotics'.)

Women with PPROM who have an identifiable genital tract infection (eg, gonorrhea, chlamydia, bacterial vaginosis)

that would not be eliminated by a prophylactic antibiotic regimen should receive antibiotics that specifically target

the infection. (See individual topic reviews on each infection).

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


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of women with prior preterm birth that included both patients with intact and ruptured membranes, progesterone

supplementation in subsequent pregnancies reduced the risk of recurrent preterm birth. (See "Progesterone

supplementation to reduce the risk of spontaneous preterm birth", section on 'Spontaneous singleton preterm birth

in prior pregnancy'.)

In addition, 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


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Use of UpToDate is subject to the Subscription and License Agreement.

Topic 6754 Version 77.0

We recommend administering a course of antenatal corticosteroids to enhance fetal lung maturation in

pregnancies less than 34 weeks of gestation (Grade 1A). (See 'Administration of antenatal

corticosteroids' above.)

•

We recommend prophylactic antibiotics (Grade 1A). Our preference is to give ampicillin 2 g

intravenously every 6 hours for 48 hours, followed by amoxicillin (500 mg orally three times daily or 875

mg orally twice daily) for an additional five days. In addition, we give one dose of azithromycin (one gram

orally) at the time of admission and repeat the dose five days later. (See 'Prophylaxis' above and

'Management' above.)

•

For patients with confirmed gestational age, we suggest delivery at ≥34 weeks of gestation without

assessment of pulmonary maturity (Grade 2C). If gestational age is uncertain, we attempt to confirm

lung maturity before delivery. If amniotic fluid cannot be obtained or the test result demonstrates lung

immaturity, we suggest delivery at 36 weeks, assuming the mother and fetus are stable (Grade 2C).

(See 'Timing of delivery for expectantly managed pregnancies' above.)

•

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GRAPHICS

Risk factors for preterm birth

No partner

Low socioeconomic status

Anxiety

Depression

Life events (divorce, separation, death)

Abdominal surgery during pregnancy

Occupational issues (upright posture, use of industrial machines, physical exertion, mental or

environmental stress related to work or working conditions)

Multiple gestation

Polyhydramnios

Uterine anomaly, including diethylstilbestrol-induced changes in uterus and leiomyomas

Preterm premature rupture of membranes

History of second trimester abortion

History of cervical surgery

Premature cervical dilatation or effacement (short cervical length)

Sexually transmitted infections

Systemic infection, pyelonephritis, appendicitis, pneumonia

Bacteriuria

Periodontal disease

Placenta previa

Placental abruption

Vaginal bleeding, especially in more than one trimester

Previous preterm delivery

Substance abuse

Smoking

Maternal age (40)

African-American race

Poor nutrition and low body mass index

Inadequate prenatal care

Anemia (hemoglobin


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Fetal anomaly

Fetal growth restriction

Environmental factors (eg, heat, air pollution)

Graphic 68992 Version 7.0


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Pregnancy complications associated with preterm premature rupture

of membranes (PPROM)

Pregnancy complicationPotential consequences

for offspring

Potential maternal

consequences

Intrauterine infection Neonatal sepsis

Long-term

neurodevelopmental

abnormalities, particularly

cerebral palsy

Postpartum endometritis

Umbilical cord compression Fetal asphyxia

Oligohydramnios Limb restriction deformities

and pulmonary hypoplasia

(primarily with severe

oligohydramnios in the early

to mid second trimester).These complications are rare

when membrane rupture

occurs after 23 weeks.

Fetal malpresentation Cesarean delivery

Umbilical cord prolapse Fetal asphyxia Cesarean delivery

Abruptio placentae Fetal asphyxia Cesarean delivery

Coagulopathy

Preterm birth Morbidity of prematurity,

including respiratoryabnormalities, intraventricular

hemorrhage, necrotizing

enterocolitis, retinopathy of

prematurity, patent ductus

arteriosus



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pH of vaginal discharge using nitrazine paper

(A) normal, (B) bacterial vaginosis, (C) pregnant woman with

premature rupture of membranes.

Reproduced with permission from Aron Schuftan, MD. Copyright © Aron

Schuftan, MD.



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Ferning of amniotic fluid

(A) Typical ferning pattern of dried amniotic fluid (400).

(B, C) Urine and amniotic fluid can be distinguished by microscopic examination of a

droplet of the fluid spread and dried on a microscope slide. The proteins in amniotic

fluid give the appearance of ferning (B) that is not observed with urine (C).

(D) Ferning pattern from amniotic fluid.

Reproduced with permission from:

(A) Courtesy of Dr. Dwight Rouse.

(B) McClatchey KD. Clinical Laboratory Medicine, 2nd Edition. Philadelphia: Lippincott Williams &

Wilkins, 2002.

(C) McClatchey KD. Clinical Laboratory Medicine, 2nd Edition. Philadelphia: Lippincott Williams &

Wilkins, 2002.

(D) Beckmann CRB, Ling FW, Smith RP, et al. Obstetrics and Gynecology, 5th Edition.

Philadelphia: Lippincott Williams & Wilkins, 2006.



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Ferning of cervical mucus

(A) Ferning of cervical mucus.

(B) A ferning pattern of cervical mucus oc curs with high estrogen levels.

(C) Incomplete ferning during secretory phase of cyc le.

Reproduced with permission from:

(A) Lexikon Medizin, 3rd Edition. Munich, Germany: Urban & Schwarzenburg, 1993.

(B) Scott JR. Danforth's Obstetrics and Gynecology, 6th Edition. Philadelphia: J.B. Lippincott,

1990.

(C) Scott JR. Danforth's Obstetrics and Gynecology, 6th Edition. Philadelphia: J.B. Lippincott,

1990.



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Evaluation of pregnancies with preterm premature rupture of

membranes

Diagnostic tests (one of the following):

Nitrazine and fern

Placental alpha microglobulin-1 protein assay (AmniSure)

Assessments to consider after confirmation of membrane rupture:

Complete blood count

Test for fetal lung maturity (eg, lamellar body count in amniotic fluid, lecithin sphingomyelin

ratio)

Rectovaginal culture for group B streptococcus

Ultrasound examination for fetal growth, position, residual amniotic fluid volume, fetal

anatomy, and biophysical profile

Cardiotocography to monitor fetal heart rate (including a nonstress tes t) and frequency of

uterine contractions

Nucleic acid amplification test o r culture for Neisseria gonorrhoeae and Chlamydia

trachomatis



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Algorithm for management of patients with PPROM at 23 to 34

weeks of gestation



22/26



CDC algorithm for screening for GBS in PROM before

37 weeks of gestation

CDC: Centers for Disease Control and Prevention; GBS: Group B

streptococcus; PROM: premature rupture of membranes.

* If patient has undergone vaginal-rectal GBS culture within the preceding

5 weeks, the results of that culture should guide management. GBS-colonized women should receive intrapartum antibiotic prophylaxis. No

antibiotics are indicated for GBS prophylaxis if a vaginal-rectal screen

within 5 weeks was negative.

• Antibiotics given for latency in the setting of pPROM that include

ampicillin 2 g intravenous ly (IV) once, followed by 1 g IV every 6 hours for

at least 48 hours are adequate for GBS prophylaxis. If other regimens are

used, GBS prophylaxis should be initiated in addition.

Δ GBS prophylaxis should be discontinued at 48 hours for women with

pPROM who are not in labor. If results from a GBS screen performed on

admission become available during the 48-hour period and are negative,

GBS prophylaxis should be discontinued at that time.

◊ Unless subsequent GBS culture prior to delivery is pos itive.

§ A negative GBS screen is considered valid for 5 weeks. If a patient with

pPROM is entering labor and had a negative GBS screen >5 weeks prior,

she should be rescreened and managed according to this algorithm at

that time.

Reproduced from: Centers for Disease Control and Prevention. Prevention of

Perinatal Group B Streptococcal Disease. Revised Guidelines from CDC, 2010.

MMWR 2010; 59:No. RR-10.


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24/26



Suggested criteria for home management of women with PPROM

Reliable pa tient

Dependable transportation and telephone service

Lives near hospital

Evaluation in hospital for 72 hours before discharge home

Patient to check her pulse and temperature every 6 hours and notify physician if temperature

>98.6 degrees F (37 degrees C) or pulse >100 beats/minute

Fetal kick counts daily and notify physician if fewer than 10 fetal movements in a two hour

period

Nonstress test and complete blood count twice a week

Weekly ultrasound

Cephalic presentation

No evidence o f infection or labor

Presence of a vertical amniotic fluid pocket >2 cm on ultrasound

Adapted from: data in Bartfield MC, Carlan SJ. Clin Obstet Gynecol 1998; 41:503.



25/26



Corticosteroid and antibiotic management of PPROM in the absence of

labor

Week of

gestation when

PPROM occurs

Plan Corticosteroids* Antibiotics

24 to 32 weeks Expectant

management if no

evidence of

chorioamnionitis or

fetal compromise

Yes Yes and GBS

prophylaxis at

delivery if indicated

>32 but


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Disclosures: Patrick Duff, MD Nothing to disclose. Charles J Lockwood, MD, MHCM Consultant/Advisory Boards: Celula [Aneuploidy

screening (Prenatal and cancer DNA screening tests in development)]. Vaness a A Barss, M D, FACOG Nothing to disclose.

Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are addressed by vetting througha multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced

content is required of all authors and must conform to UpToDate standards of evidence.

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