Preterm premature rupture of membranes (PPROM) is an event in pregnancy in which the amniotic sac spontaneously ruptures prior to the onset of labor and prior to thirty-seven weeks gestation. In the United States, approximately 3% of all pregnancies are affected by PPROM, totaling roughly 150,000 pregnancies annually (Medina & Hill, 2006; Simhan, Caritis, Krohn, & Hillier, 2005). Preterm premature rupture of membranes is the leading known cause of preterm birth affecting approximately one-third of all births delivered prior to 37 weeks gestation (Dadvand et al., 2014; Jazayeri, 2014; Zamani, Goodarzi, Lavasani, & Khosravi, 2013). This event is associated with significant increased risk of neonatal, maternal, and fetal morbidity and mortality (Furman, Shoham-Vardi, Bashiri, Erez, & Mazor, 2000; Mercer, 2003). There are many known or suspected causal pathways to preterm premature rupture of membranes (Simmons, Rubens, Darmstadt, & Gravett, 2010), but few, if any, established protective factors warranting changes to clinical guidelines. Preterm birth resulting from preterm premature rupture of membranes is not considered to be a preventable event (R. Goldenberg & Rouse, 1998).
Preterm premature rupture of membranes affects populations differently. Research shows that African American mothers are at greater risk for PPROM than their white counterparts (Goldenberg, Culhane, Iams, & Romero, 2008; Savitz, Blackmore, & Thorp, 1991; Shen, DeFranco, Stamilio, Chang, & Muglia, 2008). A study in the American Journal of Obstetrics and Gynecology reports that black mothers were more than two times more likely to experience preterm premature rupture of membranes than white mothers even when adjusting for observed risk factors (Shen et al., 2008). Black mothers were also more likely to experience recurrent PPROM in subsequent pregnancies.
Women of lower socio-economic status are also disproportionately affected by PPROM. Among a recent study of 2,244 women delivering in Rio Grande, Brazil, in which 3.1 percent experienced PPROM, researchers found a prevalence ratio of 1.94 among women with lower SES and 2.43 with lower levels of schooling (Hackenhaar, Albernaz, & Fonseca, 2014). A Canadian case control study found that women experiencing PPROM were three times more likely (OR 3.1, 95% CI 1.6–6) to be of low socio-economic status, indicated by a total household income of less than $25,000 (Ferguson, Smith, Salenieks, Windrim, & Walker, 2002). The reasons for these disparities may be found in the possible risk factors and risk markers of PPROM.
Potential Risk Factors for PPROM
Much research has been conducted on the possible risks factors and risk markers for PPROM. Studies indicate possible risk factors such as low body mass, a history of preterm birth, presence of bacterial vaginosis in pregnancy, tobacco use, and even air pollution. Other research points to chronic inflammation, procedures such as cerclage and amniocentesis, and certain genetic markers. Each of these causal pathways or associations has the potential to play a role in the onset of PPROM leading to preterm birth, maternal and neonatal morbidity, and maternal and neonatal mortality.
One mechanism of preterm premature rupture of membranes may be the presence of Group B Streptococcus (GBS). This bacteria has been shown to potentially weaken the amniotic membrane leading to PPROM. The resulting bacterial infection may cause inflammation to the chorioamnion which “is thought to play a major role in the pathogenesis of premature rupture resulting in preterm delivery” (Vanderhoeven et al., 2014). The asymptomatic GBS infection may also ascend into the uterus where it may infect the placenta, causing inflammation of the amniotic sac and surrounding fluid that leads to PPROM and preterm birth.
Bacterial vaginosis, as indicated by elevated vaginal pH levels, is associated with an increased risk of preterm premature rupture of membranes in the third trimester. Bacterial vaginosis may be asymptomatic which could cause it to go unnoticed. A secondary cohort analysis of 12,734 found that of the 169 who experienced PPROM, 12.5-17.7% were infected with bacterial vaginosis (Simhan et al., 2005). When stratifying by two gestational age categories, 24-32 weeks and 32-36 weeks, the relationship between bacterial vaginosis and PPROM at 24-32 weeks was statistically significant. However, treatment for BV with metronidazole in pregnant women has not been shown to decrease rates of preterm birth (Carey et al., 2000).
Genito-urinary tract infections (UTIs) may create a causal pathway to preterm premature rupture of membranes. A cross-sectional, population-based study of 5,660 singleton infants found that, when controlling for known risk factors, amniotic fluid infection and urinary tract infections “remained the independent risk factors associated with PPROM” (Furman et al., 2000). After a multivariate logistic regression analysis, genito-urinary tract infections in women with PPROM carried an odds ratio of 1.64 (95% CI 1.16–2.34) compared to women without PPROM.
Infection remains one of the most studied and most notable causal pathways to preterm premature rupture of membranes. The presence of asymptomatic bacteria or vaginal infections may cause inflammation which could weaken or otherwise compromises the amniotic sac and fluid. This infection may either originate from or become ascending infection such as chorioamnionitis which may cause further complications for both maternal and neonate health around the time of birth and in the postpartum period. Infection rates are higher among African American women than white women largely due to higher rates of bacterial vaginosis among black woman (51.4%) compared white women (23%) in the United States. (Koumans et al., 2007).
Some authors report that the rate of preterm premature rupture of membranes higher among women who smoke in pregnancy than in pregnant women who do not use tobacco products (Simmons et al., 2010). However, the mechanism by which tobacco use leads to PPROM may be unclear. Smoking has been associated with inflammation which may weaken the amniotic sac in similar ways as infection affects the membrane (Goldenberg et al., 2008). Smoking has also been associated with a 3-fold increase in bacterial vaginosis which may lead to PPROM (Simhan et al., 2005). Yet a secondary analysis of three studies including 4,205 women with singleton pregnancies found no significant association between smoking and PPROM (Andres et al., 2013).
Body Mass Index
Both high body mass index and low body mass index have been associated with preterm birth and preterm premature rupture of membranes (Capece, Vasieva, Meher, Alfirevic, & Alfirevic, 2014). However, a meta-analysis of 39 studies including over 1.7 million women concluded that high maternal BMI did “not modify the risk for PPROM” (Torloni et al., 2009). A study of 12,459 enrolled in a multi-center trial of preterm birth found that low pregravid body mass index was associated with preterm birth but not necessarily with preterm premature rupture of membranes (Hickey, Cliver, McNeal, & Goldenberg, 1997).
History of Preterm Birth
A history of prior preterm birth or PPROM may be one of the leading risk factors for PPROM in a subsequent pregnancy. One article reports that mothers with a history of PPROM carried a 13.5% higher risk of PPROM in the next pregnancy (Mercer, 2003). Another population-based study using Missouri Department of Health birth records showed, of the 1,281 women included in the study who had a history of PPROM, the recurrence frequency in subsequent pregnancies was 7.10% (95% CI, 5.70-8.51). The recurrence rate for black women with a history of PPROM was nearly three times the rate of their white counter parts. In black mothers, the recurrence rate of PPROM in was 12.85% (95% CI, 9.51-16.19) compared to a 4.53% (95% CI, 3.16-5.90) recurrence rate in white mothers (Shen et al., 2008). A study including 114 women with previous history of PPROM showed a 20-fold increase in the risk of PPROM in subsequent pregnancies (20.6; 95% CI, 4.7-90.2) with a nearly 4-fold increased risk (3.6; 95% CI, 2.1-6.4) of preterm delivery (Lee, Carpenter, Heber, & Silver, 2003).
Genetic amniocentesis may be a risk factor for preterm premature rupture of membranes by the mechanism of artificially penetrating the amniotic sac which could compromise its integrity (Goldenberg et al., 2008). However, in a study of eleven women with PPROM due to genetic amniocentesis compared to women experiencing spontaneous PPROM, the women with genetic amniocentesis had better outcomes than the comparison group (Borgida, Mills, Feldman, Rodis, & Egan, 2000). This suggests that the pathogenesis for preterm birth and perinatal morbidity following spontaneous PPROM may be different than with artificial PPROM.
Cerclage is used to help prevent preterm birth in women with an incompetent cervix or history of preterm birth. However, four randomized control trials involving high risk women found no statistical improvement in preterm birth rates for women with cervical cerclage (Simmons et al., 2010). Additionally, cerclage may increase the risk of infection when preterm premature rupture of membranes occurs. In a case-control study comparing women with cervical cerclage and PPROM to women with no cerclage, women in the cerclage group had higher rates of intrauterine infection and adverse perinatal outcomes following PPROM (Laskin, Yinon, & Whittle, 2012).
The effects of prenatal exposure to air pollutants has been studied as one potential causal pathway to preterm premature rupture of membranes. A 2013 study of 5,555 singleton births in Barcelona explored the association between maternal exposures to known air pollutants and the incidence of PPROM. Exposure to air pollutants was based on a land-use regression model. A matched case-control analysis was used to link exposure levels throughout pregnancy to rupture of membranes. Study authors found a 50% increased risk of PPROM in those exposed to nitrogen dioxide and nitrogen oxide during pregnancy. Gestational age at PPROM was also reduced by 1.3 days (95% CI −1.9, −0.6) in the exposed versus unexposed groups (Dadvand et al., 2014). These findings may suggest a link between air pollutants and a compromise of the amniotic sac due to possible inflammation or another mechanism.
Certain genetic factors may play a role in the association between inflammation and PPROM. A systemic review of genetic factors for preterm birth and PPROM separately concluded differing etiologies of spontaneous PTB and spontaneous PPROM. After a review of 15 studies including 3,600 women, 2175 single nucleotide polymorphisms, and 274 genes, the pathways implicated in PPROM include “hematologic/coagulation function disorder, collagen metabolism, matrix degradation and local inflammation” (Capece et al., 2014). The study identified specific genes which may predispose individuals to PPROM and called for validating the findings with additional research.
Another study approached the epigenomic mechanisms of long chain non-coding RNAs in relation to preterm premature rupture of membranes when examining human placentas. Certain genes such as TNFα play a role in the causal pathway to inflammation leading to PPROM due to polymorphism of the gene (Mingione, Pressman, & Woods, 2006). Results from the lncRNA study showed that “lncRNAs were identified differentially expressed from placentas of PPROM” than from the placentas of a full term birth, preterm birth, and term PROM cases (Luo et al., 2013). This research further implicates specific genetic expressions in the mechanisms of PPROM separately from other mechanisms for preterm birth.
Other research has investigated the genes related to Relaxin, a hormone involved in birth, and its potential relationship to PPROM. A case-control study of Hawaiian Filipino was conducted using 20 cases of PPROM and 20 controls. Results showed that certain genotypes of single nucleotide polymorphisms (SNR) involved in the release of Relaxin were significantly associated with PPROM compared to (SNR) associated only with preterm birth (Rocha, Slavin, Li, Tiirikainen, & Bryant-Greenwood, 2013).
Other genetic polymorphisms may play a role in the compromise of the fetal amniotic membranes. MMP9 (14 CA-repeat) has been associated with weakened collagen in the amniotic sac. Hsp70*2 has been found to increase the risk of protein degeneration of the cells, leading to weakened membranes. IL1RN*2 has been associated with a proinflammatory response which may cause PPROM. MMP8 (7799T/7381G/þ17G) and MMP1 (71607insG) are also associated with weakened collagen of the membranes resulting in the potential for PPROM (Mingione et al., 2006).
The discovery of genetic markers associated with the increased risk of PPROM may provide insight into the identification and prophylactic treatment of those individuals at increased risk of preterm birth caused by preterm premature rupture of membranes. However, identifying individuals with these genetic markers may be more difficult as prediction tools are not readily available to all pregnant women and their care providers (Mingione et al., 2006). When genetic markers are identified, prophylactics such as antibiotic therapy to reduce infection and inflammation, and vitamin C supplementation to increase the strength of the amniotic sac may be viable treatment options.
Potential Protective Factors for the Prevention of PPROM
While PPROM and preterm birth is generally considered a non-preventable event, many studies have offered explanations for the causal pathway to PPROM that may be interrupted or altered with medical interventions. Some authors have suggested that these treatments be introduced as a standard of care in order to reduce the incidence of PPROM leading to premature birth. Others have called for further research in order to qualify these possible interventions as protective measures.
A prospective cross sectional study involving 40 cases of PPROM and 40 controls examined the association between plasma vitamin C concentration and occurrence of PPROM. The authors found a significant association between low Vitamin C levels and premature rupture of membranes. It is thought that the mechanism for PPROM may be a degradation in the collagen of the amniotic sac. Higher levels of ascorbic acid seem to be a protective factor against a weakened membrane leading to PPROM (Osaikhuwuomwan, Okpere, Okonkwo, Ande, & Idogun, 2011).
Another clinical trial involving 170 pregnant women with a history of PPROM examined the effects of vitamin C supplementation on the occurrence of PPROM. Pregnant women were randomized into the intervention group which received a 100 mg dose of vitamin C beginning in the second trimester. The control group did not receive supplementation. The authors found that PPROM occurred more often in the control group than the intervention group (44.7% vs 31.8%) as did term PROM (34.1% vs 18.8%). The authors concluded that “Vitamin C supplementations after 14th weeks of gestation can prevent from PPROM in women with the history of PPROM” (Ghomian, Hafizi, & Takhti, 2013).
A randomized, double-blind control trial was conducted with 109 pregnant women to test the effects of vitamin c supplementation on the incidence of PPROM. The intervention group received 100 mg daily of vitamin C while the control group received a placebo. Authors found that the relative risk of PPROM in the intervention group was 0.26 (95% CI: 0.078, 0.837) compared to the placebo group. Authors concluded that daily Vitamin C supplementation is effective at reducing the risk of premature rupture of membranes (Casanueva et al., 2005).
Another double-blind, randomized clinical trial involving 60 women with history of PPROM examined the effects of vitamin C supplementation versus a placebo. There were no significant differences in the demographics or parity of the two groups. Women in the intervention group were given 250 mg vitamin C twice per day. Results of the study showed a significant decrease in serum levels of unconjugated estriol. The study authors concluded that consuming vitamin C may effectively reduce the incidence of PPROM by reducing serum levels of unconjugated estriol (Zamani et al., 2013).
The biological plausibility for vitamin C as a preventative measure for preterm premature rupture of membranes exists in that vitamin C is a collagen builder which can help strengthen the amniotic sac. This protection may decrease or eliminate the chance of PPROM, particularly in women with a history of PPROM or preterm birth. Medical providers should review the aforementioned research and consider routine ascorbic acid supplementation as a prophylactic protective measure guarding against the occurrence of PPROM. However, more research is necessary to determine the levels appropriate for supplementation. Current literature suggests levels ranging from 100 mg to 500 milligrams daily, but clinical recommendations would require a more precise dosage.
If genetic markers can be identified early in pregnancy, this may play a role in the potential prevention of PPROM. One pathway analysis found 17 genes “unique” to preterm premature rupture of membranes (Capece et al., 2014). Another case control study involving 225 mothers who experienced PPROM found that “DNA variants in a maternal gene involved in extracellular matrix metabolism doubled the risk of pPROM” (Romero et al., 2010). If it is possible to analyze the mother’s DNA, interventions may be used to help prevent PPROM, such as anti-inflammatory drugs to treat the genetic markers associated with inflammation and collagen-building supplements such as vitamin C to treat the early degradation of the chorioamniotic membranes. However, DNA genetic testing is costly and not readily available to clinicians. This method could be reserved for women and the highest risk such as those with multiple recurrent preterm premature rupture of membranes or other health risk factors that may cause inflammation or collagen weakening.
Preterm premature rupture of membranes is a serious perinatal event that leads to premature birth, morbidity, and mortality. PPROM disproportionately affects women of lower socio-economic status and AA mothers. It has been shown to be associated with a number of possible causes including ascending lower genital tract infection, previous preterm birth, air pollution, and genetic risk markers. It is not considered a preventable medical event in current standard practice. However, nutrition and genetic markers may play a role in lowering the incidence of PPROM. Further research is necessary to determine the efficacy of preventative treatment methods such as vitamin c and anti-inflammatory drugs on the larger population. Vitamin C is a low-risk, low-cost intervention that could be entered into the standard of care for women with a history of preterm birth, informed by the available current evidence.
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