Connective Tissue and Related Disorders and Preterm Birth: Clues to Genes Contributing to Prematurity

doi:10.1016/j.placenta.2008.12.007

Placenta. Author manuscript; available in PMC 2010 March 1.

Published in final edited form as:

Placenta. 2009 March; 30(3): 207–215.

Published online 2009 January 18. doi: 10.1016/j.placenta.2008.12.007

PMCID: PMC2673455

NIHMSID: NIHMS100830

Connective Tissue and Related Disorders and Preterm Birth: Clues to Genes Contributing to Prematurity

Emmanuel A. Anum,^§ Lori D. Hill,^§ Arti Pandya,^¶ and Jerome F. Strauss, III^§^*

^§Department of Obstetrics & Gynecology, Virginia Commonwealth University, Richmond, VA 23298

^¶Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298

^* Address all correspondence to: Jerome F. Strauss III, M.D., Ph.D., MCV Campus, Sanger Hall, 1^st Floor, Room 1-071, 1101 East Marshall Street, PO Box 980565, Richmond, VA 23298; Tel.: 804-828-9788; Fax: 804-828-7628; Email: jfstrauss/at/vcu.edu

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Abstract

To identify candidate genes contributing to preterm birth, we examined the existing literature on the association between known disorders of connective tissue synthesis and metabolism and related diseases and prematurity. Our hypothesis was that abnormal matrix metabolism contributes to prematurity by increasing risk of preterm premature rupture of membranes (PPROM) and cervical incompetence. Based on this review, we identified gene mutations inherited by the fetus that could predispose to preterm birth as a result PPROM. The responsible genes include COL5A1, COL5A2, COL3A1, COL1A1, COL1A2, TNXB, PLOD1, ADAMTS2, CRTAP, LEPRE1 and ZMPSTE24. Marfan syndrome, caused by FBN1 mutations, and polymorphisms in the COL1A1 and TGFB1 genes have been associated with cervical incompetence. We speculate that an analysis of sequence variation at the loci noted above will reveal polymorphisms that may contribute to susceptibility to PPROM in the general population.

Keywords: Connective tissue, Genes, Preterm Birth, PPROM, Cervical incompetence

Introduction

Preterm birth has multiple etiologies but among these, preterm premature rupture of membranes (PPROM) is the leading identifiable cause, occurring in 1% of all pregnancies [1]. The human fetal membranes are composed of an inner layer, the amnion, and an adherent outer layer, the chorion. The amnion has five distinct layers (the epithelium, basement membrane, compact layer, fibroblast layer, and an intermediate layer), while the chorion is made up of a reticular layer, basement membrane, and trophoblast cells. Although the chorion is thicker than the amnion, the amnion is the main contributor to structural integrity [1-3]. The strength of the fetal membranes is thought to be influenced by both synthesis and degradation of the components of the extracellular matrix [4,5]. The fibrillar collagens (type I, III and V), are presumed to be the critical components lending tensile strength to the amnion [5,6]. However, other extracellular membrane proteins are also present including type IV collagen, type VI collagen, elastic components, fribronectin and laminin [6-8]. Consequently, connective tissue disorders that involve defects in fibrillar collagen synthesis or altered collagen or other extracellular matrix protein structure may affect fetal membrane tensile strength and result in preterm birth from unscheduled rupture. Cervical incompetence is another cause of preterm birth [9]. Since the extracellular matrix is critical to cervical function, and its remodeling, a necessary event in normal parturition, abnormalities in maternal matrix metabolism affecting cervical integrity could also contribute to prematurity.

Women with connective tissue disorders and related diseases are at an increased risk for complications during pregnancy. These complications include rupture of maternal viscera, including blood vessels, bowel and uterus, defects in fetal connective tissue formation, recurrent miscarriage and PPROM leading to preterm delivery. Heritable disorders associated with preterm delivery include Ehlers-Danlos syndrome, osteogenesis imperfecta and restrictive dermopathy. Some of these disorders are caused by mutations that affect fibrillar collagen synthesis or structure.

We reasoned that a critical analysis of the existing literature on pregnancy outcomes in disorders affecting extracellular matrix, particularly those involving known matrix components of the fetal membranes and cervix, could be informative in that disorders of matrix metabolism with known genetic causes would implicate or exclude the respective genes as candidates for PPROM and cervical incompetence [9]. Indeed, studies on pregnancy outcome in women with Ehlers-Danlos syndrome have reported an increased risk of PPROM and preterm birth if the fetus is affected [10,11]. Case reports of pregnancies in which the fetus is affected with restrictive dermopathy [12-14] and epidermolysis bullosa [15-17] have also described instances of PPROM or preterm birth. However, studies that reported on pregnancy outcome in women with Marfan syndrome, another heritable connective tissue disorder, found no increase in risk of PPROM or preterm birth whether or not the fetus was affected [18,19].

The purpose of this work was to assess the effect that heritable connective tissue disorders and related diseases in pregnancy have on preterm birth, and derive, based on the established genetics of these conditions, a list of candidate molecules and genes critical to fetal membrane and cervical integrity and risk of preterm birth. Many of the mutations in these disorders are newly identified, and the list may expand as more information regarding these diseases becomes known. The list of candidate genes for preterm birth derived from our analyses is based on what is currently known about these collagen and related disorders and does not preclude the involvement of other genes and pathways such as mutations in pro-inflammatory cytokine and matrix degrading metalloproteinases genes that are associated with preterm birth.

Methods

Medline and Google Scholar searches of studies and case reports on pregnancy outcome in heritable connective tissue disorders and related diseases were conducted. Disorders examined were Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, epidermolysis bullosa, restrictive dermopathy and cutis laxa. For each condition different combinations of the search words ‘in pregnancy’, ‘preterm birth’, ‘prematurity’ and ‘case reports’, in addition to the name of the condition were used.

Results

Ehlers-Danlos syndrome

Ehlers-Danlos syndrome encompasses a group of heritable connective tissue disorders characterized by hyperelasticity of the skin, joint hypermobility, tissue fragility and cardiac valvular defects [20]. There are six major types of Ehlers-Danlos syndrome – Classical (types I and II) in which there is a defect in type V or rarely type I collagen; Hypermobility (type III) in which the cause is still largely considered unknown, however a defect in the extracellular matrix protein tenascin X (TNXB) has been reported in a subset of patients; Vascular (type IV) where there is defect in type III collagen; Kyphoscoliosis (type VI) where there is deficiency of lysyl hydroxylase; Arthrochalasia (a subgroup of type VII) where there is deficiency of type I collagen caused by mutations in the COL1A1 and COL1A2 genes that affect recognition sites for the processing enzyme ADAMTS2; and Dermatosparaxis (also a subgroup of type VII) in which there is deficiency of the enzyme ADAMTS2, which excises the N-propeptide of type I, type II and type V procollagens [21-23] (Table 1). The prevalence for all types of Ehlers-Danlos syndrome is estimated to be 1 in 5000 [24]. People of all racial backgrounds are equally affected [25].

Table 1

Ehlers-Danlos syndrome subtypes, pregnancy outcome and gene mutations.

Data collected from members of Ehlers-Danlos Associations/Foundations have consistently revealed higher rates of preterm birth and PPROM [11,26,27] (Table 1). A 1966 study of birth outcome among mothers with Ehlers-Danlos syndrome provided strong evidence of an increased risk for PPROM and preterm delivery, if the fetus is affected [10]. Among 18 patients with Ehlers-Danlos syndrome whose birth histories were available 14 (77.8%) were born prematurely. In 13 of the 14 preterm births, labor was preceded by PPROM [10].

In a survey of patients in the Ehlers-Danlos Foundation, Ainsworth and Aulicino [26] reported premature rupture of membranes rates of 26-75%, depending on the type of Ehlers-Danlos syndrome. Ehlers-Danlos syndrome types I and III had the highest and lowest incidences, respectively. Premature rupture of membrane rates for types II and IV were 40% and 58%, respectively. The incidence of PPROM in these subjects exceeds the prevalence of PPROM in the general population of 1-3%, supporting the notion that the defects in extracellular matrix predispose to unscheduled fetal membrane rupture [1].

Lind and Wallenburg 2002 [11] reported a preterm birth rate of 22% among 45 Dutch women affected with Ehlers-Danlos syndrome. In cases where both mother and fetus were affected with Ehlers-Danlos syndrome, 35% of the deliveries were preceded by PPROM. In affected women with a non-affected fetus, the preterm delivery rate was 12.5%. Among non-affected mothers who delivered an infant with Ehlers-Danlos syndrome, the preterm delivery rate was 40%, with one-half of all preterm cases preceded by PPROM.

In a clinical survey of obstetric histories of 43 women affected with Ehlers-Danlos syndrome, Sorokin et al. [27] reported a preterm delivery rate of 23.1% (22/95). Fifteen of the infants (15.7%) were small-for-gestational age. Yen et al. [28] reviewed the medical records of 16 Ehlers-Danlos patients and reported a preterm delivery rate of 19% (3/16). The prevalence of premature rupture of membranes was also 19% (3/16).

Most articles on pregnancy outcome in Ehlers-Danlos patients are case reports or reviews of case reports. These case reports are prone to publication bias yet, review of the articles listed in Table 1 shows that a pregnancy with an unaffected child [29-40] may proceed to term whereas offspring affected with Ehlers-Danlos syndrome [41-44] are more likely to be born preterm following PPROM. Table 1 also lists reports where the diagnosis in the offspring was either unknown at time of delivery or confirmed to be Ehlers-Danlos syndrome, and yet the pregnancy proceeded to term [33,45]. Cases where maternal complications necessitated earlier delivery [46,47] are also reported. Morales-Roselló et al. [34] reviewed the obstetric outcome in 39 published cases of Ehlers-Danlos syndrome type III and reported a preterm/premature rupture of membranes rate of 15% (6/39).

In 32 out of 36 healthy women who presented with recurrent miscarriage following PPROM, using immunohistochemical and electron microscopic studies, changes in the dermal collagen architecture similar to those in patients with Ehlers-Danlos syndrome were found [48]. A control group that comprised of 33 women with uneventful pregnancies and 33 non-pregnant women showed no differences in dermal matrix structure. The findings, according to the authors, suggest a link between recurrent preterm premature rupture of membranes and connective tissue abnormalities.

Based on the observations that PPROM rates are highest when the fetus is affected with classical Ehlers-Danlos syndrome (types I and II) and type IV, the COL5A1, COL5A2 and COL3A1 genes are implicated as contributors to PPROM risk. Mutations leading to a nonfunctional COL5A1 allele, leading to haploinsufficiency of type V collagen, or mutations that result in a structural alteration in the type V collagen proteins are among the more common causes of classical Ehlers-Danlos syndrome [49]. Mutations in the COL3A1 gene causing type IV (vascular) Ehlers-Danlos syndrome encompass multiple exon deletions, skipping of a single exon or a point mutation resulting in the substitution of a glycine by another amino acid [50]. While PPROM appears to be a significant obstetrical complication when the fetus s affected, maternal Ehlers-Danlos syndrome is widely thought to facilitate vaginal delivery due to more compliance of the birth canal.

Osteogenesis imperfecta

Osteogenesis imperfecta is a heterogeneous group of inherited connective tissue disorders. Among the most common signs of the disorder are increased bone fragility, blue sclera and thin skin [51]. The disease has an overall incidence of approximately 1 in 10,000 births [52]. It is usually inherited in an autosomal dominant pattern, but rare, severe forms of osteogenesis imperfecta are transmitted as autosomal recessive traits. Most patients (90%) with osteogenesis imperfecta have a mutation in COL1A1 or COL1A2, the genes encoding collagen type I. Autosomal recessive forms of osteogenesis imperfecta result from mutations in the CRTAP and LEPRE1 genes [53-56]. The prolyl 3- hydroxylase 1 (P3H1) protein is encoded by LEPRE1, which together with cartilage associated protein encoded by the CRTAP gene, and cyclophilin B forms an intracellular complex required for efficient 3-hydroxylation of the fibrillar collagen prolyl residues. Osteogenesis imperfecta has traditionally been classified into four main clinical types, Osteogenesis imperfecta I – IV [57]. This classification has recently been expanded to include four other distinct types (V, VI, VII and VIII) [58,59] (Table 2).

Table 2

Osteogenesis imperfecta subtypes, pregnancy outcome and gene mutations.

Osteogenesis imperfecta type I, the most common type, is due to a quantitative defect of collagen type I protein [51,59]. Clinical presentation in these individuals is mild with most attaining normal height, though fractures of long bones and vertebral compression fractures are common [58,59]. Osteogenesis imperfecta type II results in death in the perinatal period. These infants have multiple bone deformities and fractures and many are born prematurely [57] and are small-for-gestational age [60]. Most of the mutations that cause this form of the disease involve substitutions for one of the invariant glycine residues in the COL1A1 and COL1A2 genes, which disrupts formation of the helical structure of the molecules [61]. Cases of perinatal lethal osteogenesis imperfecta with mutations in the CRTAP gene have recently been reported [56]. Among the features that distinguish these infants from osteogenesis type II infants with a structural collagen defect is their white or light blue sclera. Osteogenesis imperfecta type III, the most severe form compatible with survival after the perinatal period, presents with multiple long bone fractures and deformities at birth. The infant’s length and birth weight are often lower than normal for gestational age [51]. Patients with osteogenesis imperfecta type IV have mild to moderate bone deformities and may not have fractures at birth. Osteogenesis imperfecta types V-VIII also present with moderate to severe bone fragility but do not have mutations in the collagen genes [59].

In a review of birth outcomes in 15 mothers affected with osteogenesis imperfecta of varying severity, Key and Horger [62] reported preterm birth in one of six infants affected with the disorder (Table 2). Table 2 also shows case reports of apparently healthy mothers delivering affected infants at term [44,63-66]. There are also cases of affected mothers with affected offspring [67], as well as affected mothers with unaffected infants [62] delivered at term. In other cases, early delivery was necessitated by maternal or fetal complications [68-70]. In two reported cases where the infant was affected with both osteogenesis imperfecta and arthrogryposis multiplex congenita one pregnancy ended in preterm delivery [71] while the other [66] proceeded to term.

In an epidemiologic and genetic study, Sillence et al. [57] reported that babies with type II osteogenesis imperfecta had many features in common, among which were prematurity, and low birth weight. A review of birth records of 16 babies and 5 stillbirths, all diagnosed with osteogenesis imperfecta type II, showed 19 instances where delivery was preterm. All had low crown-heel length at birth and the majority had low birth weight.

In a report on three pregnancies in healthy mothers carrying fetuses affected with osteogenesis imperfecta type II, Cole et al. [72] reported PPROM and preterm birth in two out of the three pregnancies. A 2008 case report [60] also reported preterm birth in a pregnancy where the fetus was affected with osteogenesis imperfecta type II. Rodriguez et al. [73] reviewed eight cases of lethal osteogenesis imperfecta, and reported a high rate of small-for-gestational age and prematurity. One-half of all the babies were born preterm (gestational ages ranging from 31-34 weeks) and six had low birth weight (weights ranging from 950 – 2150 g). Thus, there seems to be an increased risk of PPROM and premature birth when the fetus is affected with type II osteogenesis imperfecta. The impact that the CRTAP-deficient lethal osteogenesis imperfecta has on gestation is not known at this time. Mutations in the COL1A1 and COL1A2 genes result in defects in the structure of collagen in type II osteogenesis imperfecta. In osteogenesis imperfecta type I, however, the gene defects result in production of lower than normal quantities of collagen [51].

Epidermolysis bullosa

Inherited epidemolysis bullosa is a clinically and genetically heterogeneous group of diseases characterized by fragility of the skin and mucous membranes. Minor trauma results in erosions and blister formation. Fragility may extend to some of the internal organs and the surface of the cornea [74]. Inherited epidemolysis bullosa has an overall incidence of 19 in every 1 million births in the United States population [74]. There are four major types of epidemolysis bullosa – intraepidermal (epidemolysis bullosa simplex (EDS)), junctional epidemolysis bullosa (JEB), dermolytic (dystrophic epidemolysis bullosa (DEB)), and mixed (Kindler syndrome) (Table 3) [75]. Each major type is further classified into major and minor subtypes, but clinical variation may occur within each subtype. Inherited epidemolysis bullosa may be transmitted as an autosomal dominant or recessive trait. The blistering tendency in inherited epidemolysis bullosa results from mutations in at least 10 distinct genes, which encode structural proteins within the epidermis or the basement membrane zone separating the epidermis from the underlying dermis [74,76].

Table 3

Epidermolysis bullosa subtypes, pregnancy outcome and gene mutations.

When the mother has the disorder but the fetus is not affected, the pregnancy usually ends in term delivery [77-81] (Table 3). There have, however been instances where the baby is delivered prematurely through caesarian section [82], or the pregnancy ends in preterm delivery following PPROM [83].

In instances where a healthy mother carried an affected fetus, the pregnancies have either proceeded to term [84-88] or ended in premature delivery [15-17,87-91]. In the rare instances where the fetus has pyloric atresia in addition to epidemolysis bullosa, the pregnancy commonly ends prematurely [15-17,87,88,90,91]. Polyhydramnios has been reported in some of these cases, which may contribute to risk of fetal membrane rupture beyond the impact of any extracellular matrix abnormality [16,17,90]. In 37 cases of JEB with pyloric atresia, Shaw et al., [16] reported the mean birth weight at the 30th percentile for gestational age.

Overall, epidemolysis bullosa, uncomplicated by pyloric atresia, does not seem to increase the risk for preterm delivery. In a study that compared birth weights of children affected by recessive DEB (N = 66) to a sibling control group (N = 44), 30% of the children with epidemolysis bullosa were found to be small-for-gestational age compared with 12% of controls (p = 0.02). There was, however no difference in gestational age. The mean gestational ages (in weeks) for the children born with epidemolysis bullosa and from the control group were 39.8, and 39.7, respectively [92].

Restrictive dermopathy

Restrictive dermopathy is a rare and lethal genetic disorder inherited in an autosomal recessive pattern. Clinical features include intrauterine growth retardation, shiny, tight and rigid skin with prominent vessels, enlarged fontanels, multiple joint contractures and characteristic facial features (small mouth, small pinched nose, and micrognathia) [12]. Affected babies are born prematurely and are either stillborn or die during the first few weeks of life from respiratory insufficiency [12-14,93-96] (Table 4).

Table 4

Restrictive dermopathy, pregnancy outcome and gene mutations.

In a review of 31 published cases of restrictive dermopathy, Mau et al. [13] found all the babies to be born prematurely (Table 4). PPROM was reported in all cases where information on spontaneous membrane rupture was provided. Most pregnancies were complicated by polyhydramnios.

A 2008 review of 58 cases of restrictive dermopathy reported PPROM in 24 of 30 cases where information on spontaneous membrane rupture was provided [96]. Polyhydramnios was reported as a complication in 21 out of 26 pregnancies with the remaining reports making no reference to the condition. Smitt et al. [97] reviewed 12 cases of restrictive dermopathy and reported polyhydramnios and premature membrane rupture rates of 50-85%. Cases of restrictive dermopathy complicated by chorioamniotic membrane separation have also been reported [98].

The cause of restrictive dermopathy has previously been reported as unknown, but mutations in the ZMPSTE24 gene have recently been implicated [95,99,100]. ZMPSTE24 encodes a zinc metalloproteinase involved in the two step post-translational proteolytic cleavage of carboxy terminal residues of farnesylated prelamin A to form mature lamin A [101,102]. Mutations in the ZMPSTE24 gene cause accumulation of prelamin A in the nuclear envelope resulting in abnormalities in nuclear architecture [101,102].

Histological examination of the skin in restrictive dermopathy cases shows a thickened epidermis, thin dermis, parallel alignment of collagen bundles and absence of elastic fibers [12,13,96]. The precise cause of premature rupture of membranes in restrictive dermopathy is uncertain but abnormal collagen structure and absence of, or reduction in elastic fibers in the fetal membranes may be contributory factors.

Other connective tissue disorders and preterm

Marfan syndrome

Marfan syndrome is an autosomal dominant connective tissue disorder with manifestations in skeletal, ocular and cardiovascular systems [103]. The disorder is caused by mutations in the FBN1 gene that encodes the extracellular matrix protein fibrillin-1 [104]. The pathophysiology underlying Marfan syndrome is now recognized to encompass excessive TGFβ signaling as a consequence of the FBN1 mutations. Marfan syndrome has an estimated prevalence that ranges between 1 in 5,000 and 1 in 10,000 [105].

Retrospective and prospective studies on pregnancy outcome in women affected by Marfan syndrome reported preterm birth and PPROM rates similar to rates in the general population [18,19,106], but a high rate of spontaneous abortion has been reported in these women [107-110], possibly associated with cervical incompetence. There are no reports of an association between preterm birth and the Loeys Dietz Syndrome, a recently discovered syndrome that is caused by mutations in the TGFBR2 and TGFBR1 genes and has many features similar to Marfan syndrome.

Congenital cutis laxa

Congenital cutis laxa is a rare heterogeneous group of connective tissue disorders characterized by loose, sagging, inelastic skin. Both autosomal dominant and recessive forms of cutis laxa have been described [111]. A form of congenital cutis laxa with deficiency in lysyl oxidase, an extracellular copper enzyme, had been reported as a X-linked trait [112] but in 1991, Hämäläinen et al. [113] mapped the lysyl oxidase gene to chromosome 5. The X-linked form is now recognized to be a disorder of copper transport [114].

Pulmonary and cardiovascular involvement, are common in the recessive form of cutis laxa [111]. The dominant form is relatively benign, and usually confined to the skin [111] but cases of dominant cutis laxa with systemic involvement have been reported [115,116]. Mutations in the FBNL5 and ELN genes have been reported in the dominant form of cutis laxa [115-118]. Mutations in the FBLN5 gene have also been identified in the recessive form of cutis laxa [114,119], but the FBNL5 and ELN gene mutations may not be the exclusive cause of the disease [116]. Preterm birth and PPROM are not common features of cutis laxa. Although instances of cutis laxa with preterm birth have been reported [117,120,121] most offsprings affected with cutis laxa have come from full-term pregnancies [111,120,122-127].

Discussion

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 and TGFBR2 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 [7,8]. 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 [41,128] and Marfan syndrome [109,110,129,130] 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 and TGFB1 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 [1,132-136]. 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].

Acknowledgments

This research was supported by National Institutes of Health grants R01 HD034612 and P60 MD002256 and the March of Dimes. LDH is supported by the VCU Physician-Scientist Training Program.

The authors thank Reed E. Pyeritz, M.D., Ph.D. (University of Pennsylvania) for his critical reading of this manuscript and his insightful comments.

Footnotes

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