PRETERM PREMATURE RUPTURE OF THE MEMBRANES; PPROM

Preterm premature rupture of the membranes is defined as rupture of membranes before 37 weeks of gestation, which occurs in approximately 3% of all pregnancies and accounts for about one-third of spontaneous preterm births (ACOG Practice Bulletin, 1998). Srinivas and Macones (2005) reviewed the pathophysiology of PPROM and noted that familial clustering and ethnic differences in the incidence of PPROM suggest possible genetic influences.

▼ Pathogenesis

Maymon et al. (2000) measured levels of MMP1, a key enzyme in the degradation of interstitial collagens, in amniotic fluid from 353 women, including those with intact membranes, in term or preterm labor or not in labor, and those with term and premature rupture of the membranes, with or without microbial invasion of the amniotic cavity. MMP1 was detectable in 81.3% (287 of 353) of amniotic fluid samples, and the concentration increased with increasing gestational age. PPROM was associated with a significant increase in the median amniotic fluid concentration of MMP1, both in the presence and absence of infection, whereas neither term nor preterm parturition was associated with a significant increase in the concentration of MMP1, with rupture of membranes at term being associated with a significant decrease in amniotic fluid MMP1 concentration. Analysis of the matrix metalloproteinase profile of amniotic fluid in term and preterm rupture of membranes showed that patterns were similar for every enzyme except MMP1 and MMP8, suggesting different molecular pathophysiologic mechanisms for extracellular matrix degradation of rupture of membranes in term and preterm gestations. Maymon et al. (2000) concluded that MMP1 is implicated in the mechanisms of membrane rupture.

▼ Molecular Genetics

Fujimoto et al. (2002) analyzed G-1607GG promoter polymorphism in the MMP1 gene (120353.0001; rs1799750) in 75 African American infants who were born after preterm premature rupture of the membranes (PPROM) and 235 controls, and found a significant association between fetal carriage of a 2G allele and PPROM (OR = 2.29; p = 0.028).

In a case-control study of African American neonates and 3 SNPs in the MMP8 gene (120355.0001), Wang et al. (2004) found a statistically significant association between the 3-minor-allele haplotype, which displayed the highest MMP8 promoter activity in trophoblast cells, and preterm premature rupture of the membranes, with an odds ratio (OR) of 4.63 (p less than 0.0001). Homozygosity for the major allele promoter haplotype appeared to be protective (OR = 0.52, p less than 0.0002).

In 2 case-control studies of African American neonates from pregnancies complicated by PPROM and a -656C-T SNP in the promoter of the SERPINH1 gene (600943.0001), Wang et al. (2006) found a significant association between the -656T allele and PPROM (p less than 0.0000045 for the combined studies). Wang et al. (2006) noted that SERPINH1 is located on chromosome 11q22.2 at approximately 27 Mb from the MMP8 gene, which has also been associated with PPROM, but stated that they found no evidence for linkage disequilibrium between the -656C-T SERPINH1 SNP and the previously studied MMP8 alleles.

Wang et al. (2008) identified an MMP1 promoter SNP, 3447T-C (numbering based on AF007878.1; rs2075847) and observed that the minor C allele was always methylated in vivo; functional studies demonstrated reduced promoter activity of the C allele. In a case-control study involving 284 African American neonates from pregnancies complicated by PPROM and 361 African American neonates from normal term pregnancies, Wang et al. (2008) found the minor C allele to be protective against PPROM (OR = 0.7451; p = 0.0326), consistent with its reduced promoter function. Neonates homozygous for the major T allele had 3.51-higher risk for PPROM compared to CC homozygotes (p = 0.007). Wang et al. (2008) concluded that in addition to genetic variation, DNA methylation plays a role in controlling MMP1 expression and risk of PPROM.