Prelabor Rupture of Membranes

Ali Alhousseini

Dotun Ogunyemi

Marta Szymanska

Sun Kwon Kim

Ray Oliver Bahado-Singh

Definitions

Prelabor or premature rupture of membranes (PROM) refers to rupture of the chorioamniotic membranes before the onset of labor.¹ It is a leading clinically identifiable cause of preterm birth (Chapter 49) and related complications, neonatal sepsis, respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC).²^,³^,⁴^,⁵ Preterm PROM occurs before 37 weeks of gestation.¹ The interval between PROM and the onset of labor called the “latency period” has been proposed to last from 1 to 12 hours.⁶^,⁷^,⁸^,⁹^,¹⁰^,¹¹^,¹² If the latency period exceeds 24 hours, it is referred to as “prolonged” PROM.⁷^,¹³^,¹⁴ If PROM occurs before 23 weeks of gestation, it is referred to as “previable” PROM.¹^,¹⁵ “Midtrimester” preterm PROM has been described as occurring before 28 weeks of gestation.¹⁶ “Late preterm” PROM refers to PROM occurring after 34 and before 37 weeks of gestation.¹

Frequency, Timing, and Site of Membrane Rupture

Frequency

Preterm PROM affects around 2% to 3.5% of pregnant women, whereas term PROM (≥37 weeks) occurs in approximately 10% of patients.¹^,⁹^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²² Midtrimester preterm PROM (before 28 weeks) affects 0.4% to 0.7% of pregnancies and often leads to extreme preterm deliveries.¹⁵^,¹⁶^,²² Preterm PROM accounts for 30% to 40% of preterm birth. It is the number one cause of neonatal morbidity and mortality.⁷^,⁹^,¹⁶^,¹⁷^,¹⁸^,²⁰^,²¹ In the United States, preterm PROM accounts for around 150,000 live births annually.⁵^,²³^,²⁴

Timing: When Do Membranes Normally Rupture?

In normal term spontaneous deliveries, more than 80% of women have spontaneous rupture of membranes (ROM) at or after cervical dilation of 8 cm in the absence of iatrogenic rupture.⁵^,²⁵ Therefore, prelabor ROM occurs at a premature timing; hence, PROM stands for premature or prelabor rupture of membranes.

Site of Membrane Rupture

It is believed that spontaneous ROM occurs at the most dependent part of the uterine cavity and in close proximity to the cervix. This is consistent with the results of a study that utilized endoscopy in patients with preterm PROM.²⁶ Invasive procedures, such as fetoscopy, are associated with ruptured membranes away from the cervix. In spontaneous ROM, the frequency of rupture away from the cervix (high leak) is not known.

Fetal Membranes and Biophysical/Biochemical Changes That Lead to PROM

The anatomic structure that includes amnion, chorion, and superficial layer of decidua represents “fetal membranes”⁵^,¹⁶^,²³ (Figure 50.1). The amnion and chorion are of fetal origin, whereas the decidua is of maternal origin.⁵^,¹⁶^,²⁷^,²⁸^,²⁹ The amnion is made up of an epithelium facing the amniotic cavity, a compact layer, and a spongy layer in contact with the chorion.⁵^,¹⁶^,²⁷^,²⁸^,²⁹ The chorion is thicker than the amnion and contains connective tissue layers and trophoblasts and is in direct contact with decidua capsularis.⁵^,¹⁶^,²⁹ At the level of the cervix, fetal membranes interact with potential ascending triggers of infection or inflammation (eg, bacteria), mainly ascending from the vagina. At the level of the placenta, the amnion, chorion, and villous tree (originating from the fetus) interact with a different microenvironment mainly related to the maternal hematogenous perfusion. Not only placental but also fetal membranes play an important role in sustaining an appropriate environment for full-term fetal growth and development.²³

Figure 50.1 The anatomic structure that includes amnion, chorion, and superficial layer of decidua represents “fetal membranes.”

Changes in Fetal Membranes During Spontaneous Rupture

A weakening of a local area opposed to the cervix and referred to as “zone of altered morphology” (ZAM) is thought to be the site of rupture.³⁰^,³¹^,³²^,³³^,³⁴^,³⁵ Causes of “altered membranes” or “changes in ZAM” are thought to include one or more biophysical or biochemical changes:

Increased apoptosis (programmed cell death), thinning of the trophoblast layer, and disruption of the connective tissue of the decidua³¹;
Decrease in the density of collagen types I, III, and IV, with associated decrease in tensile strength²⁹;
Weakening of the membranes from biophysical stress related to stretch from contractions or polyhydramnios²⁹; and/or
Biochemical changes induced by infection or bleeding (see below).

It has been proposed that two main pathophysiologic pathways lead to PROM: inflammation and oxidative stress.³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰

Inflammatory Pathway

Bacterial infection and sterile inflammation may lead to the production of proinflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs), which damage and ultimately lead to membrane rupture.³⁶^,³⁷^,³⁸^,⁴⁰^,⁴¹^,⁴²^,⁴³

Oxidative Stress Pathway

A balance between antioxidants and reactive oxygen species is needed to avoid adverse outcomes such as PROM and preterm birth.³⁸^,³⁹

Risk Factors for PROM

Harger et al⁴⁴ performed a multicenter case-controlled study analyzing risk factors for preterm PROM. Vaginal bleeding was the main clinically identifiable risk factor for preterm PROM with odds ratios (OR) of 2.38 (95% confidence interval [CI] 1.47-3.86), 4.42 (95% CI 1.62-12.03), 6.44 (95% CI 1.81-22.91), and 7.43 (95% CI 2.16-25.6) for first-trimester bleeding, second-trimester bleeding, third-trimester bleeding, and bleeding in more than one trimester, respectively. Previous preterm delivery was associated with OR 2.48 (95% CI 1.40-2.48). Previous pregnancy complicated by preterm PROM was associated with OR 4.1 (95% CI 2.0-8.7). Cigarette smoking was associated with OR 2.08 (CI 1.37-3.13). Cervical length less than or equal to 25 mm was associated with OR 9.9 (95% CI 3.8-25.9) in nulliparous women and OR 4.2 (95% CI 2.0-8.9) in multiparous women, respectively.

The following are risk factors linked to preterm PROM (Algorithm 50.1) and supporting evidence/studies.

Algorithm 50.1 Risk factors for preterm PROM. IL, interleukin; MMP, matrix metalloproteinases; PBEF, pre-B-cell colony-enhancing factor; PROM, prelabor rupture of membranes; TIMP, tissue inhibitor of metalloproteinases; TNF, tumor necrosis factor.

Previous Preterm PROM

Previous preterm PROM is a major risk factor for preterm PROM.⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰ Naeye⁴⁹ evaluated two successive singleton pregnancies in 5230 women. In women with history of term delivery without PROM, 4% had preterm PROM and 17% had term PROM in the subsequent pregnancy. In women with history of term delivery with PROM, 7% had preterm PROM and 17% had term PROM. In women with history of preterm delivery with PROM, 21% had preterm PROM and 17% had term PROM. In women with history of preterm delivery without PROM, 10% had preterm PROM and 13% had term PROM.⁴⁹ These findings were supported in other studies.¹⁵^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁵⁰

Vaginal Bleeding

Vaginal bleeding is a major risk factor for preterm PROM.⁴⁴^,⁴⁶^,⁴⁷^,⁵¹^,⁵² Vaginal bleeding in at least one trimester occurred in 17.3% of full-term pregnancies without PROM and in 41.4% of pregnancies complicated by preterm PROM.⁴⁴ Possible mechanisms explaining why vaginal bleeding leads to preterm PROM are that subchorionic hematoma weakens the membrane by increasing the production of MMPs, decreasing nutrition of the amniochorion, or acting as a nidus for ascending infection.⁵^,⁵³^,⁵⁴

Smoking

Most studies support an association between smoking during pregnancy and preterm PROM.⁵^,⁴⁴^,⁴⁶^,⁴⁷^,⁵⁰^,⁵⁵^,⁵⁶ Although Naeye⁴⁹ found no association, other studies detected significant association with preterm PROM. The risk appears to be dose dependent.⁵^,⁴⁴^,⁴⁶^,⁴⁷^,⁵⁰^,⁵⁵^,⁵⁶ Women who quit smoking during pregnancy normalize their risk,⁴⁴ whereas smoking more than 10 cigarettes is a significant predictor of preterm PROM.⁵⁵^,⁵⁶

Ethnicity

Women of African American origin are at increased risk for preterm PROM.⁵⁷^,⁵⁸ Among 32,017 women, African American women had a higher rate of preterm PROM than Caucasians (3.9% [516/13, 010] vs 1.7% [325/19,007], respectively; P < .001; controlled to confounders).⁵⁸ Another study evaluating women with low birth weight neonates found that African Americans were at a higher risk for preterm PROM compared to Caucasians (OR 1.82, 95% CI 1.45-2.28).⁵⁷ However, in a study evaluating risk of preterm PROM in women with short cervix,⁵⁹ women of African American heritage were at increased risk for preterm birth, but not of preterm PROM, compared to Caucasian women. Adams et al⁶⁰ observed that, under 28 weeks of gestation, African American women had increased risk for preterm PROM (hazard ratio [HR] 3.81, 95% CI 1.04-13.99). Several studies suggested possible genetic predisposition of African American to preterm PROM.⁶¹^,⁶²^,⁶³^,⁶⁴

Sexual Intercourse

There is a controversy regarding sexual intercourse and increased risk for preterm PROM. Some studies showed increased risk if intercourse occurred within 9 days from the occurrence of preterm PROM.⁴⁹ Ekwo et al⁶⁵ showed increased risk if the intercourse occurred within 4 weeks of preterm PROM and in the missionary position. Other studies found no increased risk if intercourse occurred between 9 and 30 days,⁶⁶ within 1 month,⁶⁷ or at other arbitrary intervals.⁴⁴^,⁶⁸^,⁶⁹ We are left to conclude that there is insufficient evidence to support whether sexual intercourse increases the risk of preterm PROM. Jones et al⁷⁰ proposed that sexual intercourse does not increase the risk of preterm labor in low-risk pregnancies. The risk of preterm PROM may, however, be increased in women with high-risk pregnancy conditions such as cervical incompetence, preterm cervical dilation, multiple gestations, and history of preterm birth.

Vitamin C and Trace Elements

Vitamin C is a water-soluble essential vitamin that plays various important roles in the human body including collagen biosynthesis and antioxidation.⁷¹ Vitamin C supplementation was evaluated in a randomized double-blinded clinical trial that found that 100 mg/d supplementation of vitamin C reduced the rate of preterm PROM by 74% (relative risk [RR] 0.26, 95% CI 0.078-0.837, compared to placebo).⁷² This finding is supported by other research studies.⁷³ Maternal plasma concentration of less than or equal to 0.20 mg/dL was found to be associated with a higher rate of preterm PROM (14.6% [13/89]) compared to plasma concentration greater than or equal to 0.60 mg/dL (1.4% [1/69]).⁷⁴ In addition, decreased MMP activity and concentration were found in culture media in response to increased vitamin C concentrations.⁷⁵ Other studies have found decreased concentration of vitamin C in amniotic fluid of women with PROM⁷⁶ and in the fetal membranes from women with preterm PROM.⁷⁷

Supplementation with magnesium⁷⁸ and calcium⁷⁹ was not found to be effective in preventing preterm PROM. The role of copper and zinc deficiency in PROM is not well known.⁸⁰^,⁸¹^,⁸²

A Cochrane review by Rumbold et al (ref PMID: 15846696) performed a subgroup analysis that suggested vitamin C supplementation “was associated with reduced risk of preterm PROM (RR 0.66, 95% CI 0.48-0.91; 1282 participants, five studies) and term PROM (RR 0.55, 95% CI 0.32-0.94; 170 participants, one study).” Because of the limited available data, the authors concluded that further research is needed to support routine vitamin C supplementation (ref PMID: 15846696).

Elevated Maternal Serum Alpha-Fetoprotein Concentration

The association of elevated maternal serum alpha-fetoprotein concentration (MSAFP) and preterm PROM has been evaluated in three studies.⁸³^,⁸⁴^,⁸⁵ Two studies found no association.⁸³^,⁸⁴ One study, however, found that elevated MSAFP (more than 2.0 multiples of median) was associated with increased risk for developing preterm PROM.⁸⁵ More evidence is needed to support this association.

Previous Operations on the Genital Tract

Studies show conflicting results regarding the effect of genital operations on the rate of preterm PROM. Some studies found increased risk for developing preterm PROM in women with a history of cervical conization and dilatation and curettage.⁴⁹^,⁵⁵^,⁸⁶ Other studies failed to show such an association.⁴⁴^,⁸⁶^,⁸⁷^,⁸⁸

Pelvic Examinations and PROM

Two randomized trials evaluated weekly pelvic examinations after 37 weeks versus none at all.⁸⁹^,⁹⁰ The first trial showed the frequent examination increased the risk for PROM.⁸⁹ The second trial showed no difference.⁹⁰ Two studies evaluated the effect of weekly pelvic examination starting at 22 weeks and found no difference in the rate of preterm PROM compared to standard obstetric care in women with increased risk for preterm delivery.⁹¹^,⁹² Another retrospective study involving weekly pelvic examination between 20 and 37 weeks found no increase risk in preterm PROM.⁹³ Although most studies report no effect of repeated examinations on the risk of preterm PROM, a reasonable position might be to minimize elective digital examinations in favor of the use of sterile speculum examination and transvaginal ultrasound as alternatives.

Colonization and Infection of the Lower Genital Tract With Selective Microorganisms

Studies support an increased risk of preterm PROM with colonization by Chlamydia trachomatis and Neisseria gonorrhoeae. There is no evidence for an increased risk for preterm PROM in colonization of the genital tract with group B streptococcus (GBS), genital mycoplasma, or the presence of bacterial vaginosis (BV) in low-risk populations.

BV and Vaginal Inflammation

A cohort of 10,397 low-risk pregnancies found no association between BV and preterm PROM.⁹⁴ Another study in a high-risk population showed increased risk for preterm PROM.⁹⁵ Vaginal inflammation, with or without BV, appears to increase the risk of preterm PROM.⁵^,⁹⁶^,⁹⁷ A randomized clinical trial by the Maternal-Fetal Medicine Unit (MFMU) Network concluded that treatment of asymptomatic BV using metronidazole versus placebo did not reduce either spontaneous preterm birth or spontaneous ROM.⁹⁸ A systematic review showed a protective effect against preterm PROM with the treatment of BV among women with history of preterm delivery (OR 0.14, 95% CI 0.05-0.38).⁹⁹ We conclude the treatment of BV does not appear to be beneficial in an asymptomatic low-risk population. In high-risk populations, however, the treatment of BV may reduce the risk of preterm PROM.

Group B Streptococcus

Colonization with GBS (carrier status) is not a risk factor for spontaneous preterm delivery or preterm PROM. However, once delivery is impending, colonization is a risk factor for adverse neonatal outcomes. In patients with preterm PROM, treatment with antibiotics to prolong latency, along with GBS prophylaxis if the patient is in labor, is recommended.¹⁰⁰ Maxwell et al found no difference in latency duration between patients with preterm PROM and positive GBS, N. gonorrhoeae, or both who were treated and patients preterm PROM and negative cultures.¹⁰¹ GBS colonization in patients with PROM is associated with increased incidence of neonatal infection, chorioamnionitis, and endometritis compared to women with PROM and negative GBS culture.¹⁰² If a delivery is impending, treatment with antibiotics for mothers with GBS carrier status is recommended to reduce neonatal morbidity.¹⁰⁰ If labor arrests and delivery is no longer imminent, treatment of GBS colonization should be discontinued.¹⁰⁰

Chlamydia trachomatis

Treatment is recommended for a positive endocervical C. trachomatis culture. One prospective study of 1365 enrollees reported the rate of positive chlamydia cultures in pregnancy to be 8%.¹⁰³ A positive culture on the first prenatal visit is associated with RR of 2 for preterm PROM.¹⁰⁴ Another study showed that positive C. trachomatis culture was more frequently isolated in women with preterm PROM compared to women in the control group.¹⁰⁵ Positive culture of C. trachomatis with positive serum IgM (humoral immune response) puts the pregnancy at a high risk for PROM compared to positive culture with negative serum IgM (41.1% [7/17] vs 7.0% [4/53], P < .01).¹⁰³

Neisseria gonorrhoeae

Treatment is recommended for a positive endocervical N. gonorrhoeae culture. PROM is more common in women with positive culture for N. gonorrhoeae, than in women with negative culture. N. gonorrhoeae infection is associated with an increased risk of PROM¹⁰⁶^,¹⁰⁷ and prolonged PROM (more than 24 hours).¹⁰⁸ The evidence supporting the causal effect of N. gonorrhoeae infection on preterm PROM is weak. We conclude that a positive endocervical culture of N. gonorrhoeae is an indication for treatment, even though the associated attributable risk for developing preterm PROM is unknown.

Trichomonas vaginalis

A prospective study evaluating the vaginal flora in pregnancy indicated that a positive culture of Trichomonas vaginalis on the first prenatal visit is associated with increased risk for developing PROM.¹⁰⁹ However, a randomized clinical trial of treatment of T. vaginalis with metronidazole versus placebo showed no difference in preterm delivery complicated by PROM with increased prevalence of preterm delivery with intact membranes in the metronidazole group.¹¹⁰ Klebanoff et al¹¹⁰ concluded that treatment of T. vaginalis in asymptomatic low-risk pregnant women is not recommended. Carey and Klebanoff,¹¹¹ in a subsequent analysis of the Vaginal Infections and Preterm Birth study, evaluated factors, including the presence of T. vaginalis and treatment with metronidazole before 32 weeks, and found out that the only significant risk factors associated with preterm birth were increased Escherichia coli and Klebsiella pneumonia in the vaginal flora.

We recommend that, in low-risk populations for preterm birth, only symptomatic pregnant women undergo testing and subsequent treatment if positive for T. vaginalis or BV. In asymptomatic high-risk populations for preterm birth, testing for T. vaginalis or BV may be considered.

Genetic Factors

There appears to be a genetic predisposition to preterm PROM.¹¹²^,¹¹³^,¹¹⁴ Two large studies showed an association of preterm PROM with genes involved in inflammation, apoptosis, collagen synthesis, inhibition of MMPs, and innate immune defense.¹¹²^,¹¹⁴ Barabas¹¹⁵ studied 39 patients with Ehlers-Danlos syndrome, a rare connective tissue disease. Preterm PROM appeared to be increased mainly in pregnancies with a fetus affected by Ehlers-Danlos syndrome. Preterm PROM was less likely to occur in pregnancies with unaffected fetuses. The study also reported that if a parent was affected and the fetus was not affected, the pregnancy was not at an increased risk for PROM.¹¹⁵ These findings are consistent with the fact that the chorioamnion is of fetal—and not maternal—origin.

Illicit Drug Use

The use of illicit drugs is a reported risk factor for preterm PROM.¹¹⁶^,¹¹⁷ It is associated with an adjusted OR of 2.4 (95% CI 1.8-3.2).¹¹⁶

Low Body Mass Index

Low body mass index was found to be associated with preterm PROM.⁴⁴^,⁴⁸^,¹¹⁷ The RR for preterm PROM in woman with low BMI (less than 19.8 kg/m²) was 1.9 (95% CI 1.3-2.8).⁴⁸

Social Determinants of Health

Health disparities affect the risk for preterm PROM. Women who have less access to health care, less support for self-care, or who are under- or uninsured will have higher risk for preterm PROM.⁴⁴^,¹¹⁶

Biophysical and Biochemical Properties of Membranes That Rupture Prematurely

Biophysical Properties

Fetal membranes have elastic properties.⁵^,³⁰^,¹¹⁸ Millar et al¹¹⁸ obtained serial longitudinal images of the uterus of women at preterm and term by ultrasonography. The ultrasound images were then analyzed with custom software to determine the in vivo surface area. They then measured the area of the expelled membranes after delivery. They concluded that fetal membranes are significantly distended in vivo. Rupture of membranes during active labor typically occurs after 8 cm of cervical dilation and repetitive contractions and stretching related to active labor,²⁵ leading to generalized weakness.²⁹^,¹¹⁹ However, premature PROM is more likely related to acute or chronic stress factors on focal weak zones in the membrane rather than generalized weakness.²⁹^,¹²⁰^,¹²¹^,¹²²^,¹²³

Biochemical Studies

Collagen Concentration of Fetal Membranes and PROM

Collagen content in the fetal membranes is thought to play a major role in their tensile strength.¹²⁴^,¹²⁵ Vadillo-Ortega et al¹²⁶ observed an increase in collagenolytic activity and collagen solubility and a decrease in collagen synthesis in membranes of women with term PROM, leading to an increase in soluble collagen content with no increase in total collagen content. Collagen breakdown is thought to play a role in the weakening and subsequent PROM.⁵^,¹²³^,¹²⁵

The Association of Proteolytic Activity in the Fetal Compartment and PROM

Several studies showed that PROM is associated with increased proteolytic activity.⁸⁰^,¹²⁴^,¹²⁷^,¹²⁸^,¹²⁹^,¹³⁰^,¹³¹^,¹³²^,¹³³^,¹³⁴^,¹³⁵^,¹³⁶^,¹³⁷^,¹³⁸^,¹³⁹^,¹⁴⁰^,¹⁴¹^,¹⁴²^,¹⁴³^,¹⁴⁴^,¹⁴⁵^,¹⁴⁶^,¹⁴⁷ The amniotic fluid of patients with PROM was reported to have higher proteolytic activity compared to women with intact membranes.¹²⁴ The extracellular matrix (ECM) is preserved by the maintenance of a balance between extracellular endopeptidases with MMPs and their inhibitors called tissue inhibitor of MMPs (TIMPs).¹⁴⁶ MMPs and TIMPs are a group of enzymes that, in concert, are responsible for the degradation of most ECM proteins during organogenesis, growth, and normal tissue turnover.¹⁴⁷ Increased levels of MMP-1, MMP-8,¹⁴⁸^,¹⁴⁹ and MMP-9¹⁵⁰ and decreased levels of TIMP-2¹⁵¹ have been observed in the amniotic fluid of women with preterm PROM. Another protease, neutrophil elastase (NE), and its inhibitors, secretory leukocyte protease inhibitor (SLPI) and proteinase inhibitor 3, are also thought to play a role in PROM. Data indicate an increase in the concentration of NE, a decrease in the concentration of SLPI, and expression of proteinase inhibitor 3 in women with PROM.¹⁵²^,¹⁵³

A Role for the Fetus in Preterm PROM

Romero et al¹⁵⁴ showed that fetuses with preterm PROM had significantly higher plasma concentration of MMP-9 compared to fetuses with preterm labor and intact membranes and proposed that the fetus may play a role in preterm PROM to speed the process of labor as a defense mechanism against insults such as infection.

A Role for Selective Cytokines in Maintaining Membrane Integrity

Two cytokines have been evaluated in relation to PROM: pre-B-cell colony-enhancing factor (PBEF) and interleukin (IL)-8. PBEF, also known as visfatin, is a highly conserved, 52-kDa protein found in living species from bacteria to humans.¹⁵⁵ IL-8 is a chemoattractant cytokine produced by a variety of tissue and blood cells.¹⁵⁶ PBEF and IL-8 gene expression is upregulated after distension of membranes both in vivo and in vitro.¹⁵⁷^,¹⁵⁸ PBEF and IL-8 have been proposed to play a role against ROM, possibly through their antiapoptotic properties.¹⁵⁷^,¹⁵⁸^,¹⁵⁹^,¹⁶⁰^,¹⁶¹

A Role for Premature Aging of Fetal Membranes

Studies have suggested a role of increased oxidative stress and telomere reduction in PROM and preterm birth. Menon et al¹⁶² evaluated telomere length in fetal membranes in three pregnancy groups: term (n = 35), preterm birth with intact membranes (n = 69), and preterm PROM (n = 28). They found out that the preterm PROM group had shorter telomere lengths compared to preterm birth with intact membranes. When compared to the term group, telomere lengths of the preterm PROM group were similar. These results suggest a premature aging of fetal membranes in preterm PROM.¹⁶² The specific mechanism behind a possible accelerated premature aging of fetal membranes leading to premature rupture is yet to be defined.

A Model for Preterm PROM

Compromise in the immune and mechanical properties of the fetal membranes allows for microbial invasion from the genital tract,¹⁶³ activation of the host inflammatory response leading to collagenolysis-mediated mechanical disruption,³⁰^,¹⁶⁴^,¹⁶⁵^,¹⁶⁶ and membrane weakening predisposing the membranes to preterm PROM.²³ Kumar et al³⁰ described an ex vivo model of treatment of fetal membranes with thrombin and tumor necrosis factor (TNF) leading to inflammation and apoptosis. This ex vivo treatment resulted in membrane weakening, increase in MMPs, and apoptosis.³⁰ Treatment with progesterone, medroxyprogesterone, or 17-hydroxyprogesterone counteracted TNF- and thrombin-induced membrane weakening,³⁰ which supports findings from clinical trials that have demonstrated the efficacy of progesterone in preventing preterm birth and suggests a possible mechanism of action.¹⁶⁷^,¹⁶⁸

Rupture of Membranes as an Obstetrical Syndrome

Obstetrical syndromes result from distinct etiologies, fetal involvement, adaptive clinical manifestations, chronic processes that lead to the condition, and a predisposition due to gene-environment interaction.¹⁶⁹ Thus, preterm PROM was classified as one of the “great obstetrical syndromes” because of the multiple pathologic processes that lead to it. Women with vaginal bleeding in the first and second trimester,⁴⁸^,⁵¹^,⁵² short cervix,⁴⁸ or positive fetal fibronectin (FFN)⁴⁸ are at increased risk for preterm PROM,⁸³ suggesting the existence of chronic processes leading to preterm PROM.⁵ The association between PROM and inflammation and infection has been well established. It has been proposed that PROM might be an adaptive response to intra-amniotic infection, as a mechanism to drain the infected amniotic cavity.⁵^,¹⁵⁴ Furthermore, environmental factors, such as smoking⁴⁴ and BV,⁹⁵ have been associated with preterm PROM. These demonstrate the multiple pathologic processes and interactions that are associated with PROM justifying the categorization as an obstetrical syndrome.

Mechanisms of Disease Implicated in Preterm PROM

Intrauterine Amniotic Infection/Inflammation

Microbial invasion of the amniotic cavity (MIAC) is associated with later development of preterm PROM.¹^,¹⁷⁰ Amniotic fluid culture in the second trimester of asymptomatic pregnancies has shown that MIAC is associated with subsequent preterm PROM. The interval from time of microbial invasion to preterm PROM varied: a few hours, days, or weeks.¹⁷¹^,¹⁷²^,¹⁷³ MIAC can also occur after ROM. Amniocentesis at the time of diagnosis of preterm PROM showed MIAC in around 30% of women.¹⁷⁴ When women with preterm PROM went into labor, amniocentesis showed microbial invasion in 75% of the cases.¹⁷⁵ Therefore, although MIAC is implicated in the development of some preterm PROM cases, not all patients demonstrate this finding.

Vascular Pathology

Bleeding in the first and second trimesters is associated with increased risk for preterm PROM.⁴⁴ Vaginal bleeding in the first and second trimester leads to separation of the chorioamnion from the decidua, thus weakening the membranes.¹⁷⁶ In addition, increased generation of thrombin to promote clot formation in a subchorionic bleed stimulates the release of MMPs, a further risk factor for ROM.⁵³^,⁵⁴^,¹⁷⁶^,¹⁷⁷^,¹⁷⁸

Arias et al reported two common histologic lesions in the placenta of women with preterm PROM, namely vascular lesions and acute chorioamnionitis.¹⁷⁹ Vascular lesions reported included “failure of physiologic transformation of the spiral arteries” and atherosis.¹⁸⁰ These lesions are observed in other obstetrical syndromes and conditions, including preeclampsia, fetal growth restriction, abruption, and fetal death,¹⁸¹ and support the inclusion of preterm PROM in this group.

Short Cervix and Uterine Cervical Pathology

Procedures affecting cervical integrity, such as conization, are associated with an elevated risk of preterm PROM.⁴⁹^,⁵⁵ Loss of the mucus plug may play a role in weakening the innate immune defense against ascending infection.¹⁸²^,¹⁸³^,¹⁸⁴ Cervical shortening (less than or equal to 25 mm) enhances the risk for preterm PROM (Chapter 48).⁴⁸^,¹⁸⁵^,¹⁸⁶

Connective Tissue Disorders—Acquired or Congenital?

Acquired and genetic disorders that affect collagen synthesis and metabolism or other components of the connective tissue system may predispose women to preterm PROM. Vitamin C deficiency,⁷⁶ an affected fetus with Ehlers-Danlos syndrome,¹⁸⁷ and polymorphism of the MMP genes⁶¹^,⁶³^,⁶⁴ are associated with increased risk for preterm PROM.

Midtrimester Fetal Heart Rate Deceleration and Subsequent Preterm PROM

Yanagihara et al¹⁸⁸ observed that decelerations between 24 and 27 weeks of gestation were associated with increased risk of developing preterm PROM. The subsequent occurrence of preterm PROM compared to fetuses without decelerations was 60.0% versus 37.1%, P < .05. The potential mechanism that would explain the association between episodic and periodic fetal heart rate deceleration in the late second and early third trimester and preterm PROM is currently unknown.

Clinical Consequences of Preterm PROM

The main consequences of preterm PROM are spontaneous preterm birth (Chapter 49), maternal and fetal infection (Chapter 39), placental abruption (Chapter 47), the oligohydramnios sequence, fetal death (Chapters 1 and 4), and maternal death.

Preterm Labor and Delivery

Preterm birth is the number one cause of neonatal morbidity and mortality,¹⁸⁹^,¹⁹⁰^,¹⁹¹^,¹⁹² and the most common consequence of preterm PROM is preterm delivery.¹⁹³^,¹⁹⁴^,¹⁹⁵ Nelson et al¹⁹⁴ evaluated 511 women with preterm PROM followed up expectantly (without antibiotics, steroids, or tocolysis). Fifty-two percent delivered within 48 hours and 87.1% within 1 week. The perinatal death rate was 8.4% (43/511). Perinatal death occurred mainly with delivery <28 weeks (35/82). Perinatal death was strongly associated with maternal infection that occurred in 21.7% of mothers.¹⁹⁴ Other studies showed similar findings. Cox et al found that, within 48 hours of expectant management of PROM, preterm delivery occurred in 93% of women (total n = 298).¹⁹³ Another study of 143 women with preterm PROM managed expectantly found that 82% delivered within 1 week with a high neonatal death rate of 13.1% (18/137) and a maternal infection of 10% (15/143).¹⁹⁵

Latency duration is inversely related to the gestational age at ROM. A retrospective study of 905 women with preterm PROM showed that latency duration is inversely related to gestational age at ROM (HR 1.29, 95% CI 1.22-1.37), oligohydramnios (HR 1.49, 95% CI 0.52-0.83), fetal growth restriction (HR 2.94, 95% CI 1.24-6.94), and nulliparity (HR 1.28, 95% CI 1.12-1.63).¹⁹⁶ Normal amniotic fluid volume had a favorable prognostic implication.¹⁹⁷

Infection

Preterm PROM increases the risk of maternal, fetal, and newborn infection.¹⁹³^,¹⁹⁴^,¹⁹⁵ However, most women with MIAC do not have clinical evidence of infection¹⁹⁸ (Table 50.1).

What Is the Prevalence of MIAC in PROM?

Based on fluid culture, 32% (473/1462) of women with preterm PROM have MIAC,¹⁷⁴ whereas 34% (11/32) of women with term PROM have MIAC.¹⁹⁹ However, the prevalence of MIAC is likely higher than what has been reported due to two primary limitations of testing. First, use of standard bacterial culture techniques, as opposed to molecular techniques such as polymerase chain reaction (PCR), may not capture as many species and, thus, not reflect true microbial yield of fluid samples.²⁰⁰^,²⁰¹ Second, amniocentesis is performed less frequently on women with preterm PROM in labor or in women with low amniotic fluid volume; however, these groups have a higher probability of MIAC.²⁰²^,²⁰³^,²⁰⁴

The association between decreased amniotic fluid volume and increased prevalence of MIAC may be explained by two possible mechanisms.⁵ First, decreased fetal urine production may represent a hemodynamic redistribution of blood to other organs in the setting of inflammation or infection. Second, amniotic fluid has innate defense abilities, including the presence of antimicrobial peptides such as defensins.²²⁰^,²²¹^,²²²^,²²³ A decrease in fluid may also be associated with a decrease in the availability of these antimicrobial proteins.

What Microorganisms Are Typically Isolated in Women With MIAC?

The most common microorganisms isolated from preterm and term PROM are genital mycoplasmas (Ureaplasma urealyticum and Mycoplasma hominis).⁵^,¹⁷⁵^,²⁰⁶^,²⁰⁷^,²⁰⁸ Other commonly isolated bacteria include GBS, Fusobacterium species, and Gardnerella vaginalis in patients with preterm PROM⁵^,¹⁷⁵^,²⁰⁶^,²⁰⁷^,²⁰⁸ and Peptostreptococcus, Lactobacillus, Bacteroides, and Fusobacterium species in patients with term PROM.¹⁹⁹ In addition, 26.7% (43/161) of women with preterm PROM have polymicrobial infection.¹⁷⁵^,²⁰⁵^,²⁰⁶^,²⁰⁷^,²¹⁰^,²¹¹^,²¹² When quantitative microbiology has been performed, 23% (6/26) had an inoculum size greater than 10⁵ colony-forming units/mL.²⁰⁵

Does an Amniotic Fluid Microbiota Exist in Normal Pregnancy?

Currently, there is no evidence for the existence of microbiota in the amniotic fluid of normal pregnancies.²⁰⁹ Limitations of studies evaluating the existence of microbiota in potential low biomass locations, such as the amniotic cavity and the placenta, include the presence of bacterial DNA signal in reagents, need for appropriate technical controls, and the challenges of avoidance of contamination by the vaginal microbiota and the skin.²⁰¹^,²²⁴^,²²⁵^,²²⁶^,²²⁷^,²²⁸^,²²⁹ In addition, amniotic fluid has an innate immune ability against bacterial invasion and thus can suppress bacterial culture beyond measurable levels.²²⁰^,²²¹^,²²²^,²²³

Table 50.1 Frequently Asked Questions and Answers: Infection and PPROM

Question	Answer	References
What is the prevalence of MIAC in PPROM?	34% (by culture)	174,199-201
Factors associated with increased prevalence of MIAC	Low amniotic fluid volume, earlier onset of labor (decreased latency duration)	175,202-205
What are the most common isolated microorganisms?	Ureaplasma urealyticum, Mycoplasma hominis, GBS, Fusobacterium species, Gardnerella vaginalis	5,175,206-208
Does an amniotic fluid microbiota exist in normal pregnancy?	Currently, there is no evidence	209
Consequences of MIAC	Neonatal sepsis, respiratory distress syndrome, chorioamnionitis, and endometritis	137,175,205-208,210-213
Can intra-amniotic infection resolve without treatment?	No	175
Does antibiotic administration prevent or eradicate MIAC?	No	214,215
Can the fetus be infected in utero? Does this influence the latency period?	Yes. Positive fetal blood culture is associated with shorter latency period	175,216
Can the fetus mount an inflammatory response to MIAC?	Yes	37,41,154,217
Can MIAC occur before rupture of membranes?	Yes, 29%-48% of women with PPROM shortly before the onset of labor had histologic chorioamnionitis	66
Can MIAC be a consequence of PPROM?	Yes, 50% of women with PPROM and not in labor who had initial negative amniotic fluid culture had a positive culture when in labor	66,175
Is MIAC associated with histologic chorioamnionitis?	Yes	218,219
GBS, group B streptococcus; MIAC, microbial invasion of the amniotic cavity; PPROM, preterm prelabor rupture of membranes.