Premature (Prelabor) Rupture of the Membranes

Physiology and Pathophysiology of Membrane Rupture

The fetal membranes consist of the amnion, which lines the amniotic cavity, and the chorion, which adheres to maternal decidua. Initially, the amnion and chorion are separate layers, and the amniotic sac is visible on ultrasound until it fuses with the chorion by the end of the 14th week of gestation. Subsequently, the amnion and chorion become connected by a collagen-rich connective tissue layer, with the amnion consisting of a single cuboidal epithelial layer with subjacent compact and spongy connective tissue layers and the thicker chorion consisting of reticular and trophoblastic layers. Together the amnion and chorion form a stronger unit than either layer individually. With advancing gestational age, physiologic membrane remodeling occurs as a result of changes in collagen content and type, changes in the intercellular matrix, and progressive cellular apoptosis. These changes lead to structural weakening that is more evident in the membranes near the internal cervical os—the typical location of spontaneous membrane rupture. Membrane weakening can be stimulated by thrombin-mediated exposure to local matrix metalloproteinases (MMPs), decreased levels of membrane tissue inhibitors of matrix metalloproteinases (TIMPs), and increased poly(ADP-ribose) polymerase cleavage. ^{, ,} Uterine contractions can also lead to membrane rupture through increased bursting pressure from increased intraamniotic pressure. If the fetal membranes do not rupture before labor, the work necessary to cause membrane rupture at the internal cervical os decreases with advancing cervical dilation because of the loss of anchoring support to the decidua.

Preterm PROM can arise through a number of pathways that ultimately result in accelerated membrane weakening. Ascending bacteria may secrete collagenases and proteases that directly weaken the fetal membranes. An increase in local host cytokines or an imbalance in the interaction between MMPs and TIMPs in response to microbial colonization can have similar effects. There is evidence linking urogenital tract infection and colonization with preterm PROM. Amniotic fluid cultures after PROM are frequently positive (25% to 35%), and histologic evaluation in the setting of preterm birth often demonstrates acute inflammation and bacterial contamination along the choriodecidual interface. Although these findings may reflect ascending infection after membrane rupture occurs, it is likely that ascending bacterial colonization is directly involved in the pathogenesis of preterm PROM in many cases. Specific genital tract pathogens that have been associated with PROM include Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, and group B β-hemolytic Streptococcus (GBS). Although GBS bacteriuria has been associated with preterm PROM and low birth weight and an association between cervical GBS colonization and preterm PROM is plausible, it does not appear that vaginal GBS carriage is associated with preterm PROM. ^, Though an association between bacterial vaginosis and preterm birth, including preterm birth due to PROM, ^, has been established, it remains unclear whether bacterial vaginosis merely identifies those women with a predisposition to abnormal genital tract colonization and inflammation, facilitates ascent of other bacteria to the upper genital tract, or directly causes pathologic membrane rupture.

Physical effects related to preterm contractions and prolapsing membranes with premature cervical dilation can predispose the fetal membranes to rupture, as can the increased intrauterine pressure seen with polyhydramnios. ^, It is likely that certain connective tissue disorders (e.g., Ehlers-Danlos syndrome) can also result in intrinsic weakening of the membranes and early membrane rupture.

Clinical associations with preterm PROM include low socioeconomic status, lean maternal body mass (<19.8 kg/m ² ), nutritional deficiencies (e.g., copper, ascorbic acid), and prior cervical conization. Maternal cigarette smoking during pregnancy, the presence of a cervical cerclage, second- and third-trimester bleeding, acute pulmonary disease, prior episodes of preterm labor or contractions, and uterine overdistention from polyhydramnios or multiple gestations have also been linked to preterm PROM. ^, Although one or more factors may lead to membrane rupture, the ultimate clinical cause is often not evident in individual cases.

In some cases, the factors leading to membrane rupture are subacute or chronic in nature. Women with a prior spontaneous preterm birth have an increased risk for preterm birth due to PROM in subsequent pregnancies, especially if the prior preterm delivery resulted from PROM. Asymptomatic women with a short cervical length (<25 mm) remote from delivery are also at increased risk for preterm birth due to preterm labor or PROM. Some women may have polymorphisms for inflammatory proteins that alter their inflammatory response and increase the risk for preterm birth. ^,

Prediction and Prevention

Considerable attention has been focused on the prediction and prevention of preterm PROM because infants delivered from these pregnancies are at high risk for complications related to preterm birth. Examples of potentially modifiable risk factors for preterm PROM include cigarette smoking, poor nutrition, urinary tract and sexually transmitted infections, acute pulmonary diseases, and severe polyhydramnios. Other than monitoring for and treatment of acute infections, it is unknown whether correction of these factors can avert this complication.

Perhaps the strongest risk factor for preterm PROM is a history of preterm birth or preterm PROM. Those who have had an early preterm birth have the highest risk for a recurrence. A history of prior preterm birth after PROM confers a 3.3-fold increased risk for recurrent preterm birth from the same cause (13.5% versus 4.1%; P < .01) and a 13.5-fold higher risk for subsequent delivery before 28 weeks’ gestation (1.8% versus 0.13%; P < .01). Identification of a short cervical length on transvaginal ultrasound also confers an increased risk for subsequent preterm PROM in nulliparas and multiparas. Nulliparous women with a cervix length less than 25 mm and a positive cervicovaginal fetal fibronectin test at 22 to 24 weeks have a 1 in 6 (16.7%) chance of delivering preterm from PROM. In multiparous individuals with a prior preterm birth due to PROM, the combination of a short cervical length and a positive fetal fibronectin value increases the risk for delivery as a result of preterm PROM before 35 weeks’ gestation by 10.9-fold (25% versus 2.3%). However, an evaluation of 9410 nulliparas from a prospective observational cohort study of women presenting for care in the first trimester revealed routine fetal fibronectin and cervical length screening to be insensitive and to have a low positive predictive value for spontaneous preterm birth due to preterm labor or PROM. For this reason, it is unlikely that screening low-risk women will lead to interventions that are effective in preventing preterm birth due to PROM.

Broad-based preventive strategies such as progesterone supplementation can be considered for those at risk as a result of less specific risk factors, such as a history of spontaneous preterm birth (see Chapter 38 ). Research suggests that progestogens inhibit tumor necrosis factor-α (TNF-α) and thrombin-induced fetal membrane weakening, production of granulocyte-macrophage colony-stimulating factor (GM-CSF), as well as basal and TNF-α-induced apoptosis in human fetal membrane explants—providing biologic plausibility that progestogens may play a specific role in the prevention of preterm PROM. The American College of Obstetricians and Gynecologists recommends that women with a singleton pregnancy and a prior spontaneous preterm birth be offered vaginal or intramuscular progesterone. However, there is insufficient evidence as to whether or not the combination of progesterone and cerclage placement offers additive benefit in reducing the risk of preterm birth in high-risk women.

Vitamin C, known to contribute to connective tissue remodeling, has also been proposed as a potential therapeutic intervention. A meta-analysis of studies in which vitamin C was given alone or in combination with other supplements to women without prior preterm birth indicated a reduction in preterm (relative risk [RR] = 0.66; 95% confidence interval [CI], 0.48 to 0.91) and term PROM (RR = 0.55; 95% CI, 0.32 to 0.94) when given alone but an increased risk of term PROM when given in combination with vitamin E (RR = 1.73; 95% CI, 1.34 to 2.23). However, the studies included were noted to have substantial heterogeneity. Furthermore, vitamin C and E supplementation evaluated in a randomized, placebo-controlled trial did not modify membrane rupture strength, work to rupture, or MMP-9 (protein or activity), and vitamin C treatment of fetal membranes in vitro has a weakening effect. Vitamin C supplementation to prevent preterm birth resulting from PROM is thus not recommended.

Ultimately, despite knowledge of a broad range of potential risk factors, most preterm births due to preterm labor or PROM occur in women considered to be at low risk for these events. Because most cases of preterm PROM cannot be predicted or prevented, clinical efforts continue to focus on the evaluation and treatment of women who present with suspected membrane rupture.

Epidemiology and Clinical Course

PROM affects 8% of pregnancies at term. Approximately half of these women will enter active labor within 17 hours if managed expectantly, and 50% will deliver within 33 hours after membrane rupture. ^, Preterm PROM is responsible for about one-quarter of preterm births overall, but its relative contribution varies greatly in different populations (9% to 51% in singletons and 8% to 21% in twins) and in different geographic regions. Proportions as low as 9.3% and as high as 36.3% have been reported in South Africa and Ukraine, respectively. ^, Over time, the relative contribution of PROM to overall preterm birth has also varied in different populations. In a study of trends in singleton preterm birth between 1989 and 2000, Ananth and colleagues reported that preterm birth after PROM in the United States declined by nearly one-third, with 23% and 37% relative reductions in Whites and Blacks, respectively. Alternatively, Hui and associates found the frequency of preterm birth following PROM in singletons to have increased by 135% between 1995 and 2010 in a Hong Kong university hospital, whereas Schaaf and coworkers found no change in the frequency of preterm PROM in singletons or twins between 2000 and 2007. ^,

Like PROM at term, preterm PROM is associated with brief latency from membrane rupture to delivery and, on average, latency increases with decreasing gestational age at membrane rupture. With PROM near term, median latency from membrane rupture to delivery is brief, ranging from 1.5 to 5 days after conservative management. When PROM occurs before 34 weeks’ gestation, 50% to 60% of those who are managed conservatively will deliver within 1 week. ^, In contrast, with PROM before 24 weeks, median latency ranges between 13 and 39 days in various studies.

Although the likelihood of spontaneous resealing of the membranes after preterm PROM is low, it has been reported (3% to 13%). PROM is a well-described complication of amniocentesis. When PROM occurs in this setting, the prognosis is much better, with spontaneous resealing occurring in about 90% of cases, although reaccumulation of a normal fluid volume can take time (range: 8 to 51 days). ^{, ,}

Complications After Premature Rupture of the Membranes