Pregnancies hosting a fetus with Ehlers-Danlos syndrome, restrictive dermopathy or osteogenesis imperfecta Type II are associated with an increased risk of preterm birth and PPROM. Women affected by Marfan syndrome have PPROM rates similar to rates in the general population, but appear to be at greater risk for pregnancy complications associated with cervical function. When the mother or fetus is affected with cutis laxa there is no apparent increase in risk for preterm birth. Pregnancies in which the fetus is affected with epidemolysis bullosa and pyloric atresia commonly end prematurely. This may possibly be a result of multiple factors, but epidemolysis bullosa per se does not seem to increase the risk for preterm delivery. These observations create a menu of genes that contribute to prematurity. Collectively, these epidemiologic observations strongly suggest a fetal role in risk of PPROM and an excessive risk for PPROM when extracellular matrix structure or metabolism is abnormal in the fetus.
Gene mutations in Ehlers-Danlos syndrome include defects in the COL5A1, COL5A2, COL3A1, and COL1A1 and COL1A2 genes. Other mutations reported to cause Ehlers-Danlos syndrome include defects in the TNXB, PLOD1 and ADAMTS2 genes. Among the known genetic mutations in osteogenesis imperfecta type II are defects in COL1A1, COL1A2, CRTAP and LEPRE1 genes. Mutations in the ZMPSTE24 gene have been identified in cases of restrictive dermopathy, but the pathogenetic mechanism resulting in the high rate of premature rupture of fetal membranes and preterm birth in these cases is largely unknown.
Conversely, mutations in the FBN1, FBNL5, TGFBR1
genes do not appear to be significant contributors to risk of PPROM. Of equal interest are certain other genes that are not implicated in prematurity, in particular ELN
. Elastic fibers are found in the cervix and there is some debate about their presence in the fetal membrane and their contribution to the integrity of these structures [7
]. Hieber et al. [7
] detected tropoelastin in the fetal membranes, whereas Malak and Bell [8
] could not identify elastin, but instead reported fibrillin-containing microfibrils. As noted above, fetuses affected with mutations in FBN1
gene are not evidently at risk of preterm birth from PPROM, but the exact role that defects in molecules that provide elastic properties to tissues have on PPROM is not known.
Among the deficiencies in the existing literature on collagen and related extracellular matrix disorders is the absence of information on the specific mutations that are associated with preterm birth. This is due, in part, because the diagnosis of the disorders is frequently made on a clinical basis and specific mutations are not identified. Thus, it is not possible to define genotype-phenotype relationships, or specify the genes that are most responsible for preterm birth when a syndrome is caused by mutations in more than one gene (e.g., Ehlers-Danlos syndrome types I and II and osteogenesis imperfecta type II). This is unfortunate since the knowledge of the relative contribution of each causative gene and the nature of the mutation would inform the search for genetic variants that increase risk of non-syndromic preterm delivery.
In addition, there is little information on the physical or structural abnormalities in the fetal membranes when a fetus is affected by Ehlers-Danlos syndrome, osteogenesis imperfecta or restrictive dermopathy. Consequently, we cannot construct a more refined pathophysiological mechanism other for PPROM risk in the different disease contexts. For example, it would be of interest to know how defects in type I collagen, as opposed to type V collagen influence the histological organization and physical properties of the fetal membranes.
Instances where cervical incompetence has complicated pregnancies in women with Ehlers-Danlos syndrome [41
] and Marfan syndrome [109
] have been reported. In a case-control study, Warren et al. [131
] reported that 27.2% of women with cervical insufficiency had at least one first-degree female relative with cervical insufficiency. The authors also found polymorphisms in the COL1A1
genes to be associated with cervical insufficiency.
The candidate genes for preterm birth gleaned from our analyses of the collagen and related disorders literature does not preclude the involvement of other genes and pathways. Indeed, genetic variations in the SERPINH1
gene, a molecular chaperone essential for fibrillar collagen synthesis and polymorphisms in matrix metalloproteinase genes which include enzymes that degrade fibrillar collagens, type IV collagen and other matrix molecules have been associated with preterm birth due to PPROM as suggested from our previously published work [1
]. The variants identified to date in these genes that are associated with preterm birth may interact with those in the candidate genes identified in this review to compound the risk of prematurity. Additionally, environmental factors that trigger matrix turnover, including those than engender inflammation, are likely to collaborate to increase the likelihood of structural changes in the fetal membranes and cervix, precipitating preterm birth.
In summary, based on the review of the incidence of preterm birth, it can be argued that there is a significant fetal contribution to PPROM when the fetus carries mutations in genes encoding fibrillar collagens and other genes linked to classical types of Ehlers-Danlos syndrome, osteogenesis imperfecta type II and restrictive dermopathy (e.g., COL1A1, COL1A2, COL5A1, COL5A2, CRTAP, LPRE1, ZMPSTE24
). These observations reveal the importance of the extracellular matrix in the maintenance of the integrity of the fetal membranes and reveal the propensity of those membranes with an abnormal fibrillar collagen to rupture prematurely. The recent discovery of significant natural variation in human collagen genes across ethnically diverse populations, including more than 200 novel single nucleotide polymorphisms, indicates that a comprehensive resequencing program of the genes listed above may reveal new candidate variants that predispose the pregnancies to preterm delivery as a result of PPROM [137
]. Variants in these genes with different ancestral frequencies may also help explain disparities in preterm birth among populations (e.g., COL1A1
: rs1800215, rs1057297, rs1800215; COL1A2
: rs17122498, rs1793947; COL3A1
: rs35830636). These variations may result in a phenotype that selectively affects fetal membrane structure and function, perhaps only in the context of certain environmental factors like infection/inflammation, while not resulting in gross pathology in other connective tissues. This notion is supported by the observations of Hermanns-Lê and colleagues, which suggest a link between PPROM and Elhers-Danlos-like histological changes in the dermis, in keeping with the idea that genetic variation which does not cause an overt clinical syndrome exists in the population and could contribute to preterm birth [48