Premature Rupture of the Membranes

Fetal Membrane Anatomy and Physiology

The fetus develops within the amniotic fluid, which is surrounded by the fetal membranes. These membranes consist of a thin amnion layer that lines the amniotic cavity and a thicker outer chorion directly apposed to the maternal decidua. The amnion fuses to the chorion near the end of the first trimester of pregnancy, and these layers are subsequently attached by a collagen-rich connective tissue zone. For the remainder of the pregnancy, the fetal membranes include a single cuboidal amnion epithelium with subjacent compact and spongy connective tissue layers, and a thicker chorion that consists of reticular and trophoblastic layers. Together, the amnion and chorion are stronger than either layer independently; individually, the amnion has greater tensile strength than the chorion.

As the pregnancy progresses, changes in collagen content and type, intercellular matrix, and cellular apoptosis result in structural weakening of the fetal membranes. Membrane remodeling, which is more evident near the internal cervical os, can be stimulated by thrombin-mediated increases in matrix metalloproteinases (MMPs), decreased levels of tissue inhibitors of matrix metalloproteinases (TIMPs) within the membranes, and increased poly (ADP-ribose) polymerase (PARP) cleavage. Contractions subject the amniochorionic membranes to additional physical strain that can lead to membrane rupture. Should the fetal membranes not rupture before labor, advancing cervical dilation decreases the work needed to cause membrane rupture over the internal cervical os. Preterm PROM likely results from a variety of factors that ultimately lead to accelerated membrane weakening. Some possible causes include: an increase in local cytokines, an imbalance in the interaction between MMPs and TIMPs, increased collagenase and protease activity, or other factors that result in increased intrauterine pressure (e.g., polyhydramnios).

Etiology of Premature Rupture of the Membranes

A number of risk factors have been associated with the occurrence of preterm PROM. Among these are: low socioeconomic status, uterine overdistension, second- and third-trimester bleeding, low body mass index (BMI), nutritional deficiencies of copper and ascorbic acid, maternal cigarette smoking, cervical conization or cerclage, pulmonary disease in pregnancy, connective tissue disorders (e.g., Ehlers-Danlos syndrome), and preterm labor or symptomatic contractions in the current gestation. Each risk factor, individually or in concert, could lead to PROM through the mechanisms outlined above. However, the ultimate clinical cause of membrane rupture is often not apparent, and many at-risk patients will deliver at term without PROM.

Preterm PROM has also been linked to infections that involve the urogenital tract. Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis have each been associated with preterm PROM. Although vaginal group B β-hemolytic Streptococcus (GBS) colonization does not appear to be associated with preterm PROM, cervical colonization may be. GBS bacteriuria is associated with preterm PROM and low-birthweight infants. Although bacterial vaginosis has been linked to spontaneous preterm births, including preterm PROM, it is unclear whether bacterial vaginosis is the inciting condition that facilitates ascent of other bacteria to the upper genital tract, or whether it is simply a marker of maternal susceptibility to abnormal genital tract colonization. Bacterial invasion can facilitate membrane rupture through direct release of proteases and also through stimulation of a host inflammatory response that results in the elaboration of local cytokines, MMPs, and prostaglandins. Histologic studies of the membranes after preterm PROM often demonstrate significant bacterial contamination along the choriodecidual interface with minimal involvement of the amnion. Further evidence that links preterm PROM and genital tract infection is that these women have a high incidence of positive amniotic fluid cultures (25% to 35%), even in the absence of clinically suspected intrauterine infection. Although some of these findings may reflect ascending infection subsequent to membrane rupture, it is probable that ascending bacterial colonization and infection are integral to the pathogenesis of preterm PROM in many cases.

Although the onset of vaginal fluid leakage is an acute event, evidence shows that the factors and events that lead to membrane rupture can be subacute or even chronic. Women with a prior preterm birth (PTB), especially because of PROM, are at increased risk for PTB due to PROM in future pregnancies. Studies have also suggested associations exist between maternal inflammatory proteins, genotype, and spontaneous preterm birth (sPTB), due to preterm labor or PROM. Furthermore, asymptomatic women with short cervical lengths, in the second trimester, are at increased risk for preterm PROM, which can occur many weeks later.

Prediction and Prevention of Preterm Premature Rupture of the Membranes

Once preterm PROM occurs, delivery is often required or inevitable. Optimally, prevention of PROM would offer the best opportunity to avoid its complications. Both prior PTB, and especially prior preterm PROM, have been associated with preterm PROM in a subsequent pregnancy. The risk of recurrence for PTB increases with decreasing gestational age for the initial PTB. Those with a prior delivery near the limit of viability (23 to 27 weeks) have a 27.1% risk for subsequent PTB. Those with a prior history of PTB due to PROM have a 3.3-fold higher risk for PTB due to PROM (14% vs. 4.1%) and a 13.5-fold higher risk for PROM before 28 weeks’ gestation (1.8% vs. 0.13%) in a subsequent pregnancy ( P < .01 for each). In an analysis from a prospective evaluation of PTB prediction, nulliparas and women with prior deliveries were evaluated separately, since those without a prior birth lacked important historic information available to those with a prior term or preterm birth. In that study, multivariable analysis revealed medical complications (including pulmonary disease in pregnancy), work during pregnancy, recent symptomatic uterine contractions, and bacterial vaginosis to be significant markers for subsequent PTB in nulliparas when assessed at 22 to 24 weeks’ gestation ( Table 37.1 ). Among women with prior deliveries, prior PTB due to preterm labor or PROM and a positive cervicovaginal fetal fibronectin (fFN) screen were statistically significant clinical markers for subsequent preterm PROM, after controlling for other factors. Short cervical length (<25 mm), identified by transvaginal ultrasound, and low maternal BMI (<19.8 kg/m ² ) were associated with an increased risk for subsequent PROM in both nulliparas and multiparas. Nulliparas with a positive cervicovaginal fFN and a short cervix had a 17% risk for PTB due to PROM. Multiparas with a prior PTB due to PROM, a short cervix on ultrasound, and positive cervicovaginal fFN screen had a 31-fold higher risk for PROM with delivery before 35 weeks’ gestation (25% vs. 2.3%) than women without those risk factors ( Table 37.2 ).

Unfortunately, clinical risk-assessment systems identify only a small fraction of women who will ultimately deliver preterm. Although clinical and ancillary testing has increased our ability to identify women at increased risk from potentially modifiable factors—such as cigarette smoking, poor nutrition, urinary tract and sexually transmitted infections, pulmonary disease, and severe polyhydramnios—it is unknown whether modification of these in a given patient will reduce the risk for PROM. However, women at risk for PTB due to PROM, based on clinical findings, can be counseled regarding the symptoms of membrane rupture and contractions and can be encouraged to seek medical care should those symptoms occur. Regarding ancillary testing, progesterone therapy has been recommended for prevention of PTB in asymptomatic women with a short cervix, and thus cervical length (CL) screening has been both predictive and of therapeutic value. Alternatively, routine fFN screening has similar predictive value to CL measurement; however, no effective intervention can be offered based on the results of this testing. Thus, routine fFN testing after PTB due to PROM is not recommended. Current evidence supports both the use of 17-α-hydroxyprogesterone caproate (17-P) therapy for women with a prior PTB due to PROM or preterm labor and treatment with vaginal progesterone for asymptomatic women with short cervical lengths. Data regarding the value of vitamin C supplementation in preventing PROM are conflicting and are not generally supportive. In one study, such treatment was associated with a lower risk for sPTB (7.7% vs. 25%; P = .02). In contrast, secondary analysis of another study suggested that treatment with vitamin C and E did not reduce sPTB or late preterm birth due to PROM but was associated with less frequent PTB due to PROM before 32 weeks’ gestation. However, a review of studies in which vitamin C was given alone or in combination with other supplements suggests a negative impact on membrane strength and an increased risk for PTB. As a result of these conflicting findings, vitamin C supplementation to prevent preterm PROM is not recommended.

Clinical Course After Premature Rupture of the Membranes

Brief latency from membrane rupture to delivery is one of the major hallmarks of PROM. On average, latency increases with decreasing gestational age at membrane rupture. At term, half of expectantly managed gravidas deliver within 33 hours, and 95% deliver within 94 to 107 hours of membrane rupture. Of all women with PROM before 34 weeks, 93% deliver in less than 1 week. After excluding those who require delivery soon after admission, 50% to 60% of those conservatively managed and treated with antibiotics for pregnancy prolongation will deliver within 1 week of membrane rupture. While only a small proportion of women with spontaneous membrane rupture (≤5%) can anticipate cessation of fluid leakage, about 86% of those with leakage after amniocentesis will reseal.

Risks of Premature Rupture of the Membranes