Pregnancy Loss, Recurrent, Susceptibility To, 1

A number sign (#) is used with this entry because of evidence that susceptibility to recurrent pregnancy loss-1 (RPRGL1) is conferred by variation in the coagulation factor V gene (F5; 612309) on chromosome 1q24.

Description

Miscarriage, the commonest complication of pregnancy, is the spontaneous loss of a pregnancy before the fetus has reached viability. The term therefore includes all pregnancy losses from the time of conception until 24 weeks of gestation. Recurrent miscarriage, defined as 3 or more consecutive pregnancy losses, affects about 1% of couples; when defined as 2 or more losses, the scale of the problem increases to 5% of all couples trying to conceive (summary by Rai and Regan, 2006).

Pregnancy losses have traditionally been designated 'spontaneous abortions' if they occur before 20 weeks gestation and 'stillbirths' if they occur after 20 weeks. Subtypes of spontaneous abortions can be further distinguished on the basis of embryonic development and include anembryonic loss in the first 5 weeks after conception (so-called 'blighted ovum'), embryonic loss from 6 to 9 weeks' gestation, and fetal loss from 10 weeks' gestation through the remainder of the pregnancy. These distinctions are important because the causes of pregnancy loss vary over gestational ages, with anembryonic losses being more likely to be associated with chromosomal abnormalities, for example. Possible etiologies for RPRGL include uterine anatomic abnormalities, cytogenetic abnormalities in the parents or fetus, single gene disorders, thrombophilic conditions, and immunologic or endocrine factors as well as environmental or infectious agents (summary by Warren and Silver, 2008).

Genetic Heterogeneity of Recurrent Pregnancy Loss

Susceptibility to RPRGL2 (614390) is conferred by mutation in the coagulation factor II gene (176930) on chromosome 11p11; RPRGL3 (614391) by mutation in the ANXA5 gene (131230) on chromosome 4q27; and RPRGL4 (see 270960) by mutation in the SYCP3 gene (604759) on chromosome 12q23.

Genetic variation in the conceptus itself that results in decreased viability of the embryo or fetus is discussed in the respective gene and/or phenotype entry (see, e.g., MTHFR, 607093.0004; NLRP7, 609661; hydatidiform mole, 231090).

Pathogenesis

Kwak-Kim et al. (2009) noted that thrombotic/inflammatory processes are often observed at the maternal-fetal interface as the final pathologic insult in many cases of RPRGL. They reviewed the involvement of cellular immune responses and autoimmune abnormalities in women with RPRGL.

Disorders of Coagulation

Maternal hypercoagulability has been hypothesized to be a major causative factor in RPRGL (Allison and Schust, 2009). See, e.g., antiphospholipid syndrome (107320), which involves arterial and venous thrombosis and recurrent fetal loss, and activated protein C resistance (188055).

Braulke et al. (1993) presented data suggesting that reduced levels of factor XII activity (234000) may be a risk factor for repeated spontaneous abortions. Standen and Bowen (1993) reported a woman with factor XIII deficiency (613225) who had 2 pregnancies terminate in spontaneous abortion, but 2 further pregnancies in which she was transfused with fresh frozen plasma resulted in live offspring.

Pregnancy-Specific Glycoproteins

Pregnancy-specific beta-1-glycoprotein (176390) levels have been found to correlate well with placental function and fetal well-being (Gordon et al., 1977; Bartels and Lindemann, 1988). Low pregnancy-specific glycoprotein (PSG) levels are associated with poor pregnancy outcome (Wurz et al., 1981).

Trophoblast-Lymphocyte Crossreactive Alloantigens

McIntyre et al. (1983) proposed that trophoblast-lymphocyte crossreactive alloantigens (TLXA; 191020) are central in establishing maternal recognition and protection of the blastocyst, and that lack of recognition results in implantation failure and spontaneous abortion.

P-Related IgG and IgM Antibodies

Hellberg et al. (2004) explored the molecular basis of the clinically important but rare blood group phenotypes p, P1(k), and P2(k), by analysis of the A4GALT (607922) and B3GALT3 (603094) genes, which are responsible for synthesis of the related Gb3 and Gb4 antigens, respectively. Lack of these glycolipid moieties is associated with severe transfusion reactions and recurrent spontaneous abortions but also offers immunity against infectious agents.

Other Related Factors

Salker et al. (2011) observed that SGK1 (602958), a kinase involved in epithelial ion transport and cell survival, was downregulated in midsecretory endometrial samples from women with RPRGL, whereas SGK1 was upregulated in samples from patients with unexplained infertility. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from women with RPRGL, sensitizing those cells to oxidative cell death and rendering the fetomaternal interface vulnerable to oxidative damage.

Molecular Genetics

Majerus (1994) noted that an estimated 2 to 4% of the Dutch population and 7% of the Swedish population carried a mutant R506Q allele of coagulation factor V, the 'factor V Leiden' variant (612309.0001). The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. Majerus (1994) suggested that a slight thrombotic tendency may confer some advantage in fetal implantation.

In a study of 67 women with a first episode of unexplained late fetal loss (fetal death after 20 weeks or more of gestation) and 232 women who had had 1 or more normal pregnancies with no late fetal loss, Martinelli et al. (2000) found that both factor V Leiden and a 20210G-A mutation in prothrombin (176930.0009) were associated with an approximate tripling of the risk of late fetal loss.

Associations Pending Confirmation

Associations between certain HLA polymorphisms and RPRGL have been reported; see, e.g., HLA-G (142871), HLA-DRB1 (142857), and HLA-DQB1 (604305).

For discussion of a possible association between RPRGL and variation in the NOS3 gene, see 163729.

For discussion of a possible association between RPRGL and variation in the JAK2 gene, see 147796.

For discussion of a possible association between RPRGL and variation in the NLRP7 gene, see 609661.