Review Article: GENETICS
Genetic Risk Factors for Placental Abruption: A HuGE Review and Meta-Analysis
Zdoukopoulos, Nikos*; Zintzaras, Elias*†
From the *Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece; and †Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Department of Medicine, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts.
Submitted 30 June 2007; accepted 23 August 2007.
Correspondence: Elias Zintzaras, Head, Department of Biomathematics, University of Thessaly School of Medicine, Papakyriazy 22, 41222 Larisa, Greece. E-mail: firstname.lastname@example.org.
Background: Although the precise pathophysiology that leads to placental abruption is unknown, there is evidence supporting a genetic etiology.
Methods: We searched PubMed and systematically reviewed all case-control studies that investigated the association between genetic variants and placental abruption. Pooled genetic risks were estimated using fixed and random effects odds ratios.
Results: Twenty-two articles, examining a total of 14 gene polymorphisms were identified. Seven polymorphisms (F5 Arg506Gln, F5 Met385Thr, F2 G20210A, MTHFR A1298C, MTHFD1 Arg653Gln, NOS3 Glu298Asp, AGT Met235Thr) show significant association in individual studies. Six of the 7 (all except F5Met385Thr) were studied more than once and we therefore included them in our meta-analyses. A positive association under the dominant model was found for the F5 Arg506Gln and F2 G20210A polymorphisms. The random-effects odds ratio for the F5 Arg506Gln polymorphism was 3.4 (95% confidence interval = 1.4–8.3) and the fixed-effects odds ratio for the F2 G20210A polymorphism was 6.7 (3.2–13).
Conclusion: Considering the multifactorial etiology of abruption and the relatively small numbers of studies and participants, this review provides only the first clues of possible genetic causes. Larger case-control studies that include gene-gene and gene-environment interactions may help to elucidate the genetics of placental abruption further.
Placental abruption is a dangerous obstetric condition in which the placenta separates prematurely from the uterus.1 The classic signs and symptoms of placental abruption include vaginal bleeding, back pain, fetal distress, and hypertonic uterus or tetanic contractions.2,3 The diagnosis of abruption is clinical, with ultrasonography and other tests being of limited value.4 Placental abruption complicates about 1% of deliveries.5–9 Perinatal mortality in the United States is about 120 per 1000 births complicated with abruption, compared with 8.2 per 1000 other births.5 Approximately 25%–30% of fetal and neonatal deaths are associated with placental abruption.10 Risk factors include abruption in a prior pregnancy, multiparity, advanced maternal age, maternal hypertensive disorders, polyhydramnios, chorioamnionitis, premature rupture of membranes, uterine leiomyomas, cocaine and tobacco use, poor nutrition, trauma, and possibly thrombophilias.10–20
The high recurrence rate of placental abruption21–24 and the high prevalence of thrombophilia among women with abruption25,26 support the possibility of a genetic contribution to risk. Moreover, abruption risk appears higher in families having an index patient with recurrent placental abruption.27 Genetic studies involving candidate genes have led to inconsistent results. We searched the literature for genetic studies on associations of genetic variation with risk of developing placental abruption.
Selection of Studies
We searched PubMed for all English-language articles published up to September 2007 related to placental abruption and genetic polymorphisms. We used combinations of the following terms as search criteria: “placental abruption,” “abruptio placentae,” “polymorphism,” “gene variant,” “genetic variant,” “susceptibility,” “genetic association study.” Bibliographies in articles provided further references.
Our review comprised human genetic association studies fulfilling the following inclusion criteria: (1) cases with clinically diagnosed placental abruption and controls free of placental abruption, (2) information on genotype frequency or risk estimates, and (3) validated molecular methods for genotyping. We focused on case-control genetic association studies investigating susceptibility to placental abruption. Case reports, editorials, and review articles were excluded.
The following information was extracted for each study: first author, journal, year of publication, ethnicity of study population, demographic characteristics, definition of cases and controls, matching criteria, genotyping procedure, presence or absence of masked genotyping, validity of genotyping method, and number of cases and controls for each genotype. The frequencies of the alleles and the genotypic distributions were extracted or calculated, for both cases and controls. Two investigators independently extracted data, discussed all disagreements, and reached consensus on all items.
The associations are indicated as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). When more than 1 study investigated the same polymorphism, we carried out a meta-analysis of published results. The meta-analysis examined the overall association in a dominant model for the allele of interest. In the case of a polymorphism with 2 alleles (A and a), the dominant model is defined as: aa + Aa versus AA.28,29 Pooled ORs were estimated from the individual ORs in the individual studies. Heterogeneity among studies was tested using the Q-statistic (a weighted sum of squares of the deviations of individual study OR estimates from the overall pooled estimate).30,31 If P < 0.10, then heterogeneity was considered statistically significant. Heterogeneity was further quantified with the I2 metric, which is independent of the number of studies in the meta-analysis. I2 ranges from 0% to 100%, with higher values denoting greater heterogeneity.32,33 The pooled OR was estimated using fixed-effects (Mantel-Haenszel) and random-effects (DerSimonian and Laird) models.34 Random-effects modeling assumes a genuine diversity in the results of various studies, and incorporates a between-study variance. When there is heterogeneity between studies, it is preferable to estimate the pooled OR using the random-effects model.35 Analyses were performed using Meta-Analyst (Joseph Lau, Tufts-New England Medical Center) and Compaq Visual Fortran90 with the International Mathematics and Statistics Library (IMSL).35–37
We identified 1931 articles in PubMed that met the search criteria. The abstracts were independently assessed by 2 investigators for appropriateness for this review. Results were compared and disagreements resolved by consensus. Thirty-four were identified as potentially eligible; the full articles were then evaluated using the inclusion criteria. Data from 22 article38–59 describing 42 studies met the inclusion criteria; these were included in our review. The diagnostic criteria were similar in the reviewed studies, although not standardized (Table 1).Overall, 10 candidate genes and 14 polymorphisms had been investigated in association with placental abruption (Table 2).
Table 1 presents the study characteristics and the associations between the various polymorphisms and risk of placental abruption. Table 2 shows gene polymorphism characteristics. Table 3 provides the meta-analyses results. Seven polymorphisms (F5 Arg506Gln, F5 Met385Thr, F2 G20210A, MTHFR A1298C, MTHFD1 Arg653Gln, NOS3 Glu298Asp, AGT Met235Thr) had statistically significant associations with abruption.38–40,42–44,46,48,50,52,55,57 The genotype distribution in control subjects was in Hardy-Weinberg equilibrium in 32 studies, while in 8 studies this information was not provided. The genotyping personnel were reported to be masked to phenotype in 3 studies53,58,59 and the reliability of the genotyping procedure was controlled only in 1 study.54
A meta-analysis was performed for polymorphisms F5 Arg506Gln,38,39,41,44–48,53,57 F2 G20210A,39–41,44–46,57 MTHFR A1298C,42,50,59 MTHFR C677T,39,41,42,45,50,54,56,57,59 NOS3 Glu298Asp43,51,52 and AGT Met235Thr.52,55 In the meta-analyses, we used unadjusted risk effects estimates because only 2 studies58,59 provided ORs adjusted for confounders. Two polymorphisms (F5 Arg506Gln, F2 G20210A,) were positively associated with placental abruption in the meta-analyses, although heterogeneity was present for F5 Arg506Gln under the dominant model. The results for individual meta-analyses are described below.
Candidate Genes and Biologic Mechanisms
Genes studied in relation to placental abruption (Table 2) are of low penetrance; ie, the probability is relatively low that a woman carrying the allelic variant will present clinical manifestations. Candidate susceptibility genes can be identified by studying the biochemical or physiological pathways that may be involved in placental abruption.
During placental development in normal early pregnancy, spiral artery endothelium is replaced by trophoblast cells. The trophoblast is thereafter incorporated into the arterial wall, which loses its normal histologic characteristics. These changes free the vessels from vasomotor control, allowing vasodilatation and creating a low-resistance vascular bed.70 In placental abruption, this physiologic change in the blood vessel may not occur, and signs of vasculopathy (eg, atherosclerosis, narrowing, necrosis, and thrombosis) can be seen.71,72 Hence, genes involved in thrombophilia and hemodynamic changes of pregnancy are candidates for predisposition to placental abruption. Moreover, on the basis of the previously reported associations between placental abnormalities (such as preeclampsia and miscarriages) and oxidative stress genes,73,74 this group of genes is also a logical candidate.
The candidate genes in abruption studies to date can be classified into 3 main categories: those related to thrombophilia, to hemodynamics, and to oxidative stress. Eight of the polymorphisms in our review have functions reported in the literature (Table 2). In the 6 others, the polymorphisms were not functional (MTHFD1 Arg653Gln, MTRR A66G, BHMT G742A, F5 Arg485Lys, F5 Met385Thr, THBD Ala455Val), although even nonfunctional polymorphisms are likely to be in linkage disequilibrium with causative alleles.75 Table 2 provides the reference Single Nucleotide Polymorphism (SNP) identification (ID) numbers (rs numbers) from the database of single nucleotide polymorphisms (dbSNP),76 the chromosomal gene position, the nucleotide base change, the average heterozygosity, and the amino acid substitution for each polymorphism.
Numerous studies have explored associations between abruption and thrombophilias.4 Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary form of serum folate. Nine case-control studies39,41,42,45,50,54,56,57,59 have investigated the association of the C-to-T mutation at nucleotide position 677 of the MTHFR gene60 with placental abruption. None has found an association, regardless of the ethnicity of the population. An additional polymorphism of the MTHFR gene, A1298C,61 has been genotyped by 3 case-control studies.42,50,59 A positive association was found by only one.42 In this South African “colored” population, the ORs for the allele contrast and the dominant model were 2.6 (95% CI = 1.2–5.8) and 3.2 (1.0–10), respectively. In the same study, combined heterozygosity for mutations C677T and A1298C was found in 22% of the abruption cases, providing an OR of 5.1 (1.1–24). The meta-analysis for the MTHFR C677T polymorphism showed lack of heterogeneity, overall (P = 0.89, I2 = 0), in whites (P = 0.52, I2 = 0) and in blacks (P = 0.87, I2 = 0). The respective fixed-effect ORs for the dominant model were 1.2 (0.83–1.9), 1.2 (0.59–2.5) and 1.2 (0.25–6.0) (Table 3). The meta-analysis of the 3 studies42,50,59 for the MTHFR A1298C polymorphism showed signs of heterogeneity (P = 0.18, I2 = 43) and lack of association for the dominant model, with the fixed-effect OR = 1.3(0.97–1.8) and the random-effect OR = 1.4 (0.90–2.31) (Table 3).
MTHFD1 is a trifunctional enzyme (5,10-methylenetetrahydrofolate dehydrogenase; 5,10-methenyltetrahydrofolate cyclohydrolase; and 10-formyltetrahydrofolate synthetase) involved in folate metabolism. A nonsynonymous SNP of the MTHFD1 gene, designated as Arg653Gln62 was investigated by Parle-McDermott et al.50 The estimated ORs under the allele contrast and the recessive model were 1.6 (1.0–2.4) and 2.9 (1.5–5.5), respectively.
Three nonsynonymous SNPs of the factor V gene (F5), (Arg506Gln,63,77 Met385Thr, and Arg485Lys) have been studied for their potential role in placental abruption risk. Ten case-control studies38,39,41,44–48,53,57 have assessed Arg506Gln (Leiden mutation), with a positive association in 5.38,39,44,46,57 Jaaskelainen et al48 genotyped all 3 F5 polymorphisms, with only the Met385Thr polymorphism associated with abruption under the dominant and the allele contrast model, [ORs = 0.4 (0.2–0.8) and 0.5(0.25–0.91]. The frequency of the haplotype encoding the Thr385-Arg485-Arg506 variant was lower in the patient than in the control group, giving an OR of 0.52 (0.27–0.99). A meta-analysis of the 10 published studies for the Arg506Gln polymorphism demonstrated high heterogeneity, overall (P < 0.01, I2 = 66) and among white women (P < 0.01, I2 = 76). There was a positive association under the dominant model, with the respective random-effects ORs equal to 3.4 (1.4–8.3) and 4.2 (1.3–14) (Table 3).
Factor II (prothrombin) is a coagulation factor that it is transformed into thrombin after its activation by prothrombinase complex at the site of vascular injury.78 Seven case-control studies of abruption39–41,44–46,57 have evaluated a guanine-to-adenine substitution at position 20210 (G20210A)64 of the prothrombin gene (F2); 339,40,46 showed associations. The meta-analysis for the G20210A polymorphism showed lack of heterogeneity, and a positive association under the dominant model; fixed-effects ORs were 6.7 (3.2–13) overall and 10 (3.0–36) among white women (Table 3).
Thrombomodulin is an endothelial transmembrane glycoprotein that converts the activity of thrombin from procoagulant to anticoagulant; variants have been associated with thrombotic disorders.79,80 A nonsynonymous SNP (Ala455Val) of the thrombomodulin gene (THBD) was investigated in relation to placental abruption by Hira et al45 in black South African women. No association was found, although only 3 heterozygous were found in the control cohort and none in the patient group.
Methionine synthase reductase (MTRR) and betaine-homocysteine S-methyltransferase (BHMT) regulate homocysteine metabolism. A study by Ananth et al58 focused on 2 variants of these enzymes, MTRR (A66G) and BHMT (G742A),81,82 with no associations observed. After adjusting for confounders, a positive association emerged for BHMT (G742A) polymorphism, with an OR of 2.8 (1.8–5.0) for AA versus GG.
Hemodynamic changes in pregnancy play an important role in the development of placental abruption.6,83,84 Endothelial nitric oxide synthase (NOS3) regulates endothelial nitric oxide availability, which in turn facilitates pregnancy-related vasodilatation.85–87 A nonsynonymous functional SNP of theNOS3 gene (NOS3) designated as Glu298Asp65,88 was genotyped in 3 studies.43,51,52 Two (1 in Japanese women43 and 1 in South African black women52) reported a positive association, with ORs under the dominant model of 4.1 (1.9–8.7) and 3.5 (1.8–10), respectively. A third study, by Toivonen et al51 found no association. A meta-analysis of the 3 studies showed a high degree of heterogeneity (P < 0.01, I2 = 82); in a dominant model, the random-effects OR was 2.3 (0.84–6.3) (Table 3).
Angiotensinogen (AGT) is the precursor of the hormone angiotensin II. One functional variant of the AGT gene, the nonsynonymous SNP Met235Thr,66,67 has been investigated by 2 case-control studies.52,55 Zhang et al55 reported an OR under the recessive model of 3.3 (1.8–6.0). A high level of heterogeneity (P = 0.03) was observed in the meta-analysis of the 2 studies, with little evidence of an association under the dominant model, [random-effects OR = 1.7 (0.22–14)] (Table 3).
Genes involved in oxidative stress, such as microsomal epoxide hydrolase gene (EPHX), may play a role in the development of pathologic processes in the placenta.49 Two functional nonsynonymous SNPs of EPHX gene (Tyr113His and His139Arg)68 have been analyzed in a study from Finland.49 Single-point allele and genotype distributions for both polymorphisms were not statistically different between the groups. A single haplotype association analysis showed a lower risk of abruption with the low activity haplotype (His113-His139) (0.55 [0.36–0.85]).
As with other complex traits, the development of placental abruption is likely to be affected by several genes that act collectively, with allelic variants at different genes having either additive or contrasting effects.75 There are many possible interactions among genetic polymorphisms and possible effect modifiers such as maternal age and parity, race, cigarette smoking, nutrition, prenatal care, or other environmental factors.
Two studies50,58 investigated possible gene-gene interactions. Parle-McDermott et al50 performed a combined analysis of MTHFR C677T and MTHFD1 Arg653Gln polymorphisms by the nonhierarchical logistic model analysis, with no significant effects observed (data not available).
Ananth et al58 examined a potential synergistic effect between MTRR A66G and BHMT G742A polymorphisms. Homozygotes for the BHMT mutant allele (A/A) were associated with increased risk for abruption with the wild type (A/A) and heterozygous (A/G) forms of the MTRR polymorphism [adjusted ORs = 4.8 (1.2–19) and 2.4 (1.0–8.4), respectively].
Conflicting results among studies investigating genetic polymorphisms and the risk of placental abruption may be due to lack of information on the possible interactions with environmental factors. Differences in total homocysteine, folate, and vitamin B12 concentrations between cases and controls were examined by genotypes of MTRR A66G and BHMT G742A polymorphisms by Ananth et al.58 Among women carrying the wild-type form of MTRR (A/A), homocysteine concentrations were lower in cases than controls (P = 0.011), whereas cases carrying the wild-type and heterozygous mutant form of BHMT (G/G and G/A) had higher levels of homocysteine (P = 0.031 and P < 0.001, respectively).
Ananth et al59 compared the distributions of plasma total homocysteine, folate, and vitamin B12 between cases and controls within the different genotypes of MTHFR C677T and MTHFR A1298C mutations. Elevated homocysteine and B12 concentrations were reported in cases compared with controls among women with the wild-type genotype of MTHFR C677T (P = 0.039 for homocysteine, and P = 0.048 for B12).
Genetic association studies in placental abruption have been inconsistent. The complex nature of the disease implies that for individual polymorphisms, associations are likely to be modest. To detect such modest genetic effects, stronger study designs will be necessary.
Placental abruption is a relatively rare pregnancy complication, occurring in only 0.5% to 1% of pregnancies.89 Past studies have been relatively small. Small studies often lack adequate representation in certain genotype groups, are unable to address gene-gene or gene-environment interactions, and are subject to publication bias.69 Larger samples would improve power; selection of cases that are genetically loaded may also aid power. The genetic component is thought to be more prominent in recurrent cases.27 Therefore, by selecting cases with a strong family history, cases may be weighted toward individuals whose disease has a strong genetic etiology.90
Lack of stratification in genetic association studies might blur the genetic effect. On the other hand, there is concern about the possible effects of population stratification in case-control studies.91 Unequal genetic admixture in the control and patient populations can result in spurious associations. One approach to minimize this problem is to measure and adjust for genetic markers that are not linked to the disease under investigation.92 Furthermore, since the prevalence of polymorphisms can vary widely across populations, stratification on ethnicity in studies with mixed populations, could help to unmask a true genetic effect.
Variability in the diagnostic criteria for placental abruption might contribute to the heterogeneity of the results. In most studies presented here, the diagnosis of abruption was a clinical one, which was then confirmed by antepartum ultrasonographic diagnosis, histologic examination, or observation of a retroplacental blood clot after delivery. Placental abruption was defined only on the basis of clinical diagnosis alone in 4 studies,39,40,45,57 and in 1 study41 diagnostic information was not provided.
Hardy-Weinberg Equilibrium and Genotyping
The lack of Hardy-Weinberg equilibrium among controls55,59 suggests genotyping errors, population stratification, or selection bias,93,94 as well as continued selection, migration, mutation, or absence of random mating.95,96 The possible lack of masking of genotyping personnel in 19 studies38–52,54–57 could also be a source of bias.
Candidate Gene Selection
Genomic or proteomic expression analyses can assist in the selection of candidate variants by ranking those genes that appear to be the most active in the disease process. This overlapping of independent sources of information has been termed “genomic convergence” and is expected to provide new insights into the cellular mechanisms involved in placental dysfunction.97,98
Because placenta is a fetal tissue, fetal genetic variants may also play a role in abruption. Family designs may be particularly useful tools in studying the effects of maternal and fetal genes on the risk of placental abruption. Moreover, family-based designs are robust against population substructure, and associations imply both linkage and association.99 Only 1 study has evaluated the impact of both maternal and fetal genotype on the risk of abruption,53 without showing a significant association between fetal factor V (Leiden) and the disease. No family-based studies have been conducted.
Gene-Environment Interactions Must be Addressed
Many environmental factors have been associated with increased risk of placental abruption. These factors include gestational hypertensive disease, maternal age and parity, multiple gestations, chorioamnionitis, cocaine and tobacco use.1 Despite difficulties in study design and assessment of the exposures, such parameters should be incorporated in future studies.100
The search for susceptibility loci has been complicated by the increasing number of contributing loci and susceptibility alleles.101 Elucidating the pathogenesis of the disorder will require simultaneous investigation of many genetic variants of genes that participate in distinct pathophysiological pathways.102
The Need for Large-Scale Genetic Association Studies and Meta-Analyses
The overall frequency of placental abruption is low in the population, which makes it more difficult to recruit large numbers of twins, sib pairs, or pedigrees of women who have already experienced placental abruption. Elucidating the genetics of abruption relies largely upon rigorous genetic association studies. Future studies should be planned with the intention of combining them with other similar studies in meta-analyses.103 The opportunities offered by meta-analysis are the enhancement of power, the ability to place each study in the context of others, (particularly early fake-positive results),104,105 and the possibility of examining the reasons why studies reach different conclusions.93,96
Given the underlying thrombotic phenomena of abruption, it is logical that mutations in genes coding for blood coagulation factors might influence the disease, either by the synthesis of a defective protein or by the enhanced production of a procoagulant protein. The former mechanism is exemplified by the factor V gene Arg506Gln SNP, which renders factor V resistant to activated protein C degradation.63 The latter is exemplified by the prothrombin gene G20210A SNP, which alters mRNA stability, resulting in higher prothrombin levels.64 By utilizing the linkage disequilibrium data from the HapMap Project, these polymorphisms can be investigated in the context of disease-associated haplotypes, to provide further insights about the role of genetic variation in these candidate genes.106 Moreover, interactions with other candidate genes involved in the thrombophilic pathway or with environmental factors should be investigated. The concomitant study of fetal DNA or fetal-maternal genetic interaction could provide an alternative avenue of research.53 Finally, a hypothesis-free approach under a genome-wide association study for placental abruption could highlight novel genetic risk factors.107–109
We thank George Kitsios for comments on the manuscript.
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