By Mingione, Matthew J; Pressman, Eva K; Woods, James R
Our understanding of the pathophysiologic processes leading to preterm premature rupture of membranes (PPROM) has grown tremendously in recent years. Evidence suggests that there may be a genetic susceptibility to PPROM and that genetic and environmental elements are important cofactors in its development. A number of risk-based protocols have been proposed in an attempt to identify those women at highest risk for PPROM. While we have made advances in the area of predicting PPROM, treatments based on current risk- based systems have failed to distinguish a specific, effective preventive therapy for PPROM. The concept that genetic factors increase susceptibility or decrease resistance to disease has stimulated new work in the field of PPROM. Several maternal and fetal gene polymorphisms have been identified that are associated with an increased risk for PPROM. Patients with ‘susceptible’ genotypes may also have clinical risk factors for PPROM resulting in a synergistic increase in the risk for PPROM, a so-called gene- environment interaction. The concept that these gene-environment interactions represent new targets for our efforts to prevent PPROM is explored.
Keywords: PPROM, prevention, polymorphism, genetics, gene- environment interaction
For the practicing clinician, preterm premature rupture of membranes (PPROM) continues to be one of the most frustrating and devastating complications of pregnancy. Our understanding of the pathophysiologic processes leading to PPROM has grown tremendously in recent years and, as a result, has led to advances in the delivery of obstetric and neonatal care. Yet despite these advances, the incidence of PPROM has not changed and PPROM remains a major cause of perinatal morbidity and mortality. Successful strategies for the prevention of PPROM are needed.
Recent evidence suggests that there may be a genetic susceptibility to PPROM and that genetic and environmental elements are important cofactors in its development. In this era of ‘-omics’- based research, we have many new tools for deciphering the pathways that lead to PPROM. In this review we discuss current modalities for the prevention of PPROM. We also consider how gene-environment interactions offer opportunities to improve the efficacy of these preventive efforts by tailoring therapy to suit a patient’s risk profile.
The pathogenesis of PPROM
In the USA, Preterm premature rupture of membranes complicates 140 000 pregnancies annually [I]. The scope of this problem is not difficult to appreciate. Like many obstetric diseases, the etiology of PPROM appears to be multifactorial. A number of clinical risk factors for predicting PPROM have been identified (Table I) [2-6].
Recently, subclinical intrauterine infection has been implicated as the major etiologic factor contributing to the pathogenesis of PPROM . Subclinical infection is the presence of pathogens in tissues that are not producing clinical evidence of overt infection. Most subclinical infections are believed to have ascended from the lower genital tract. The initiating event is likely a change in the normal vaginal flora or introduction of pathogens from an exogenous source into the cervix leading to an inflamed vaginal milieu . The pathogens ascend into the decidua and enter the fetal membrane where they generate a cascade of maternal and fetal inflammatory events that culminate in membrane weakening and rupture.
Table I. Risk factors for PPROM.
Damage to type I collagen, the primary supporting element in the chorioamnion, is believed to represent the final step in the sequence leading to membrane rupture. Normally collagen deposition and degradation in the fetal membranes are balanced continuously until term. Collagen is laid down by fibroblasts and degraded by a family of enzymes called matrix metalloproteinases (MMPs). In anticipation of term labor and delivery, the membrane weakens in response to an up-regulation of matrix metalloproteinase-9 . The action of MMPs is normally held in check by tissue-specific inhibitors of their activity (TIMPs). In the case of PPROM, disruption of the balance between MMP and TIMP activity is the terminal event that results in collagen degradation and eventual membrane rupture.
The clinical risk factors generate PPROM through different pathways that up-regulate the inflammatory process. Infection leads to recruitment of activated neutrophils and macrophages. These cells are capable of killing bacteria by releasing reactive oxygen species (ROS) that destroy the bacterial cell wall. The primary ROS released, hypochlorous acid, is also capable of damaging the fetal membrane directly and acts as a signal for the up-regulation of MMPs.
Smoking and cocaine use generate ROS that induce tissue damage and inflammation via lipid peroxidation [1O]. Subchorionic hemorrhage that is manifested as vaginal bleeding stimulates inflammation and membrane damage by at least three different pathways. First, the iron released from the lysed erythrocytes acts as a catalyst to generate the hydroxyl radical, a potent but short- lived ROS. second, thrombin in the clot directly enhances decidual cell production of MMP-3 . Lastly, platelets in the clot stimulate the release of chemoattractants, via the CD-40 ligand system, that recruit inflammatory cells to the site of bleeding .
The resultant increase in local inflammatory mediators such as interleukins-1, 6, and 8 and tumor necrosis factor-alpha (TNF- α) up-regulate MMPs and inhibit TIMPs. This tips the balance of collagen remodeling in favor of degradation and eventual membrane rupture. The interested reader is referred to two recent comprehensive reviews on the role of matrix degrading enzymes in PPROM [13,14].
Current status in the prediction and prevention of PPROM
A number of risk-based protocols have been proposed in an attempt to identify those women at highest risk for PPROM. Additionally, numerous biomarkers, especially the proinflammatory TH-I cytokines, have been associated with an increased risk for PPROM . With these predictive tools, early risk assessment and treatment to prevent PPROM and preterm birth (PTB) have been attempted. There is much debate about the distinction between PTB and PPROM and whether they represent different clinical entities with separate pathophysiologies. That argument is beyond the scope of this review. However, while there are many trials addressing the prevention of PTB there are few that focus on prevention of PPROM specifically. Given that one third of PTBs are the result of PPROM, the possibility that preventing PTB also prevents PPROM is considered .
Methods for prevention
The association between lower genital tract infection and PPROM is well documented. While no study has proved the cause and effect relationship between infection and PPROM, several recent reviews support the treatment of asymptomatic bacteria, gonorrhea and chlamydia to reduce the risk of PPROM [16,17]. The issue of whether bacterial vaginosis (BV) has a role in the pathogenesis of PPROM remains undecided . A recent metaanalysis confirms the widely held belief that there is no utility in screening for asymptomatic BV. However, treatment of symptomatic BV in patients with a history of PPROM or preterm birth (PTB) is indicated as it reduces the risk of recurrent PPROM .
Progesterone is rapidly becoming mainstream therapy for the prevention of PTB. There are no trials specifically addressing the role of progesterone in the prevention of PPROM. Evidence for prevention of PTB with the prophylactic administration of progesterone has existed for several years [20,21]. Two recent trials have renewed interest in the administration of progesterone for the prevention of PTB. Meis and colleagues published their results of 463 women randomized in a 2:1 fashion to 17α- hydroxyprogesterone caproate or placebo. All subjects had a history of prior PTB. They demonstrated a reduction in the rate of PTB by 34, 33, and 42% at less than 37, 34, and 32 weeks, respectively. All of these differences were statistically significant . da Fonseca et al. randomized 142 ‘high-risk’ subjects to daily progesterone vaginal suppositories or placebo. The rate of PTB at less than 34 weeks in the treatment group was 2.8%, compared to 18.6% in the placebo group, a statistically significant difference . Despite the fact that the mechanism by which progesterone prevents PTB is unknown, the evidence seems adequate for clinicians to prescribe progesterone therapy for the prevention of PTB, and to a lesser extent PPROM, for patients with a previous PTB.
There are no trials specifically addressing the role of cervical cerclage in preventing PPROM. Cerclage, however, is commonly used in women with a history of PTB. Investigators of four randomized trials have addressed whether PTB could be prevented with cerclage in patients with historic risk factors [24-27]. Each failed to demonstrate a reduction in PTB at less than 37 weeks. Most recently several investigators evaluated the effectiveness of cervical cerclage to prevent PTB in the setting of shortened cervical length detected at a secondtrimester ultrasound. Rust and colleagues randomized 113 women with a cervical length less than 2.5 cm to McDonald’s cerclage and bed rest \or bed rest alone . To and colleagues randomized 253 women with a cervical length less than 1.5 cm to Shirodkar cerclage or no treatment . Both of these large trials failed to demonstrate any benefit of cervical cerclage in the setting of shortened cervical length. Althuisius and colleagues enrolled women with a cervical length less than 2.5 cm who also had either a history of PTB or historic risk factors for PTB. They demonstrated a significant reduction in PTB at less than 34 weeks and a reduction in composite neonatal morbidity. There was no demonstrable benefit in a subset of patients that was randomized to prophylactic rather than therapeutic cerclage .
When these studies are considered collectively, it appears that both clinical history or risk factors and a sonographically shortened cervix must be present for cervical cerclage to have any potential benefit in preventing PTB. Whether this can be extrapolated to the prevention of PPROM remains unanswered. In fact, there is evidence that a cerclage may be a risk factor for PPROM. Odibo and colleagues have published data indicating that cerclage placement in a current pregnancy is a risk factor for subsequent PPROM .
These findings further diminish the benefit-risk ratio of cerclage for the prevention of PPROM. Thus, cervical cerclage placement should be reserved for those patients with multiple predictors for PTB and likely has little role in specifically preventing PPROM.
Dietary antioxidant therapy
The primary supporting structure within the chorioamnion extracellular matrix is type I collagen. Vitamin C is essential for the formation of collagen and vitamin C deficiency has been associated with PPROM [6,31]. Low tissue concentrations of ascorbic acid have also been associated with an increased risk of PPROM . There are two randomized trials of vitamin C administration for the prevention of PPROM or PTB with disparate conclusions. Steyn and colleagues randomized subjects with a history of preterm labor in a previous pregnancy to vitamin C or placebo. They found a significantly increased rate of PTB in the treatment group and no difference in short-term neonatal outcome . Casanueva and colleagues randomized unselected subjects to vitamin C or placebo and found a significantly lower rate of PPROM in the treatment group with a trend towards lower rates of PTB . While low levels of vitamin C are associated with PPROM and PTB, the current data do not support the routine supplementation of vitamin C to prevent these adverse outcomes.
Unfortunately, treatments based on current riskbased systems have failed to distinguish a specific, effective preventive therapy for PPROM. In fact, the Maternal-Fetal Medicine Units Network has recognized such and consequently not recommended any broad-based screening programs for the prediction of PPROM .
New strategies in predicting and preventing PPROM-the role of genetic polymorphisms
The concept that genetic factors increase susceptibility or decrease resistance to disease has stimulated new work in the field of PPROM. This work may provide us with new avenues for prevention.
Individuals may have a specific genotype that places them at greater risk for disease when exposed to environmental factors than could be predicted by the presence of the genotype or exposure alone. When a combination of ‘susceptible’ genotype and the environmental exposure synergistically increase the risk for disease, a gene-environment interaction is said to exist .
Concerning PPROM, these ‘susceptible’ genotypes generally represent polymorphisms in genes known to be involved in immune regulation or collagen metabolism. Several maternal and fetal gene polymorphisms have been associated with PPROM (Table II) [36-42]. The example of a polymorphism in the TNF-α gene and symptomatic bacterial vaginosis is reviewed in detail.
Bacterial vaginosis is diagnosed in up to 20% of pregnant women. While it has been associated with PPROM, it is unlikely that such a prevalent condition represents a pathologic state in every patient, particularly when considering the comparatively low incidence of PPROM. Recent work by Macones and colleagues is lending strength to the theory that BV is a significant risk factor for PPROM under the right conditions. They have identified a subgroup of women with symptomatic BV who may have an elevated risk for infection- associated PPROM . In a case-control study, DNA from patients with PPROM was analyzed for the -308 polymorphism in the TNF- gene. This polymorphism results in an overproduction of TNF-α leading to an excessive proinflammatory response. Maternal carriers of this polymorphism had a significantly increased risk for PTB due to PPROM, OR 2.7 (1.7-4.5). When this risk was stratified for the presence or absence of symptomatic BV, those with the ‘susceptible’ genotype and BV had increased risk for PTB, OR 6.1 (1.9-21.0), compared to those without BV, OR 1.7 (1.0-3.1). Further, their multivariable analysis confirmed that the BV-TNFa-308 interaction was the only significant risk factor for PPROM in their population, indicating that there was a geneenvironment interaction. These results may explain why past studies of varied populations have failed to link BV to PPROM consistently . It also provides a plausible explanation for the failure of antibiotic treatment of BV to prevent PPROM in these mixed populations where it has been found to be linked.
Table II. Gene polymorphisms associated with increased risk of PPROM.
Polymorphisms in other non-immune system genes can also be linked to PPROM. Abnormal collagen is a risk factor for PPROM, as observed in patients with Ehlers-Danlos syndrome. As stated above, vitamin C availability is critical to the formation of normal collagen and it has been tested as a preventive therapy for PPROM in previous trials. Regrettably, similar to the treatment of BV, vitamin C therapy for the prevention of PPROM or PTB has yielded mixed results [33,34]. Recently, Erichsen et al. reported an increased risk for PTB among patients who carried a polymorphism in the sodium- dependent vitamin C transporter gene . Homozygotes for the polymorphism had a 2.7-fold increased risk for PTB. The authors concluded that this polymorphism might explain previous dietary associations with PPROM and PTB. If there were a difference in the allelic frequencies of the polymorphic gene in the two study populations, then this could account for the difference in outcomes. Supplementation in patients with dysfunctional or decreased numbers of vitamin C transporters may help to drive ascorbic acid into the cell. Unfortunately, no gene-environment interaction was tested to determine whether this polymorphism might interact with the clinical risk of poor nutrition or oxidant stress.
The role of progesterone for the prevention of PPROM may also be influenced by genetic factors. While there are no studies examining progesterone receptor gene polymorphisms and their possible link to PPROM, there are data that support this premise. Both term and preterm labor have been associated with decreased expression of progesterone receptors [45,46]. There are also data demonstrating that decreased progesterone receptor expression is associated with a reduction in fetal membrane fibrillar collagens . A reduction in membrane fibrillar collagens results in a weakening of the membrane whether under physiologic or pathologic conditions. If a polymorphic progesterone receptor gene results in the decreased expression of progesterone receptors or expression of faulty progesterone receptors, then a ‘weak membrane’ phenotype might be expected.
The genes discussed are primarily involved in immune regulation. As such, for the polymorphism to become clinically apparent, there must be an evoked immune response. Although these gene polymorphisms have been associated with the pathogenesis of PPROM under specific conditions, it is unlikely that possession of these genotypes alone is sufficient to result in the expression of the PPROM phenotype. More likely is the scenario that an environmental exposure (e.g., infection) results in a genotype-specific, exaggerated proinflammatory response that increases the likelihood of PPROM. Using this theory, the genotype, the exposure (clinical risk factor) or both may be used to identify patients at increased risk for PPROM. Identifying the clinical risk factors or predictors of PPROM is currently done in most centers. Genotype analysis for predicting PPROM, however, is not commercially available as a clinically useful tool. Hao and colleagues have recently reported using high- throughput genotyping technology to analyze candidate genes associated with preterm birth . Using this method they were able to identify, quickly and cost-effectively, gene polymorphisms that may be involved in the pathogenesis of PPROM.
As studies of this type continue to be published, more gene polymorphisms linked to PPROM will be discovered. Future gene- environment or genenutrient investigations are likely to reveal that distinct populations (e.g., African-Americans) have specific polymorphisms or differences in gene-linkage disequilibrium patterns that explain why they are at the highest risk for PPROM.
Preterm premature rupture of membranes may soon be considered a disease of the genome that is influenced by environmental and nutritional factors. The PPROM phenotype may be the result of interactions of environmental and genetic elements both of which are potentially identifiable in high-risk patients. If the functional analyses of genotypes susceptible to PPROM are incorporated into a 1PPROM gene chip’ and combined with clinical risk factors, then patients with the highest risk of PPROM can be identified. PPROM may then be preventable with future individualized therapy based on the particular patient’s genotype, clinical risk facto\rs, and known gene-environment interactions.
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MATTHEW J. MINGIONE, EVA K. PRESSMAN5 & JAMES R. WOODS
Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, University of Rochester, Rochester,
New York, USA
(Received 2 August 2006; revised 18 October 2006; accepted 15 August 2006)
Correspondence: Matthew J. Mingione, MD, Assistant Professor, Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, University of Rochester, 601 Elmwood Ave, Box 668, Rochester, NY 14642, USA. Tel: +1 585 273 3242. Fax: +1 585 256 1416. E-mail: [email protected]
Copyright Taylor & Francis Ltd. Dec 2006
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