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: email@example.com.
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.
1. Hladky K, Yankowitz J, Hansen WF. Placental abruption. Obstet Gynecol Surv
2. Gabbe SG, Niebyl JR, Simpson JL. Obstetrics: Normal and Problem Pregnancies
. 3rd ed. New York: Churchill Livingstone; 1996;505–510.
3. Hurd WW, Miodovnik M, Hertzberg V, et al. Selective management of abruption placentae: a prospective study. Obstet Gynecol
4. Oyelese Y, Ananth CV. Placental abruption. Obstet Gynecol
5. Ananth CV, Wilcox AJ. Placental abruption and perinatal mortality in the United States. Am J Epidemiol
6. Sheiner E, Shoham-Vardi I, Hallak M, et al. Placental abruption in term pregnancies: clinical significance and obstetric risk factors. J Matern Fetal Neonatal Med
7. Salihu HM, Bekan B, Aliyu MH, et al. Perinatal mortality associated with abruptio placenta in singletons and multiples. Am J Obstet Gynecol
8. Ananth CV, Oyelese Y, Yeo L, et al. Placental abruption in the United States, 1979 through 2001: temporal trends and potential determinants. Am J Obstet Gynecol
9. Rasmussen S, Irgens LM, Bergsjo P, et al. The occurrence of placental abruption in Norway, 1967–1991. Acta Obstet Gynecol Scand
10. Saftlas AF, Olson DR, Atrash HK, et al. National trends in the incidence of abruptio placentae,1979–1987. Obstet Gynecol
11. Ananth CV, Smulian JC, Demissie K, et al. Placental abruption among singleton and twin births in the U.S.: risk factors. Am J Epidemiol
12. Paterson M. The aetiology and outcome of abruptio placentae. Acta Obstet Gynecol Scand
13. Townsend RR, Laing FC, Jeffery RB. Placental abruption associated with cocaine abuse. AJR Am J Roentgenol
14. Darby MJ, Caritis SN, Shen-Schwarz S. Placental abruption in the preterm gestation: an association with chorioamnionitis. Obstet Gynecol
15. Morgan MA, Berkowitz KM, Thomas SJ, et al. Abruptio placentae: perinatal outcome in normotensive and hypertensive patients. Am J Obstet Gynecol
16. Ananth CV, Savitz DA, Williams MA. Placental abruption and its association with hypertension and prolonged rupture of membranes: a methodological review and meta-analysis. Obstet Gynecol
17. Major CA, DeVeciana M, Lewis DF, et al. Preterm premature rupture of membranes and abruptio placentae: is there an association between these pregnancy complications? Am J Obstet Gynecol
18. Voigt LF, Hollenbach KA, Krohn MA, et al. The relationship of abruptio placentae with maternal smoking and small for gestational age infants. Obstet Gynecol
19. Rice JP, Kay HH, Mahoney BS. The clinical significance of uterine leiomyomas in pregnancy. Am J Obstet Gynecol
20. Ananth CV, Smulian JC, Vintzileos AM. Incidence of placental abruption in relation to cigarette smoking and hypertensive disorders during pregnancy: a meta-analysis of observational studies. Obstet Gynecol
21. Toivonen S, Heinonen S, Anttila M, et al. Reproductive risk factors, Doppler findings, and outcome of affected births in placental abruption: a population-based analysis. Am J Perinatol
22. Rasmussen S, Irgens LM, Dalaker K. The effect on the likelihood of further pregnancy of placental abruption and the rate of its recurrence. Br J Obstet Gynaecol
23. Karegard M, Gensser G. Incidence and recurrence rate of abruptio placentae in Sweden. Obstet Gynecol
24. Rasmussen S, Irgens LM, Dalaker K. Outcome of pregnancies subsequent to placental abruption: a risk assessment. Acta Obstet Gynecol Scand
25. De Vries JIP, Dekker GA, Huijgens PC, et al. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies. Br J Obstet Gynaecol
26. Van der Molen EF, Arends GE, Nelen WL, et al. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene as a new risk factor for placental vasculopathy. Am J Obstet Gynecol
27. Toivonen S, Keski-Nisula L, Saarikoski S, et al. Risk of placental abruption in first-degree relatives of index patients. Clin Genet
28. Zintzaras E, Rodopoulou P, Koukoulis GN. BsmI
polymorphisms in the vitamin D receptor (VDR
) gene and the risk of osteoporosis: a meta-analysis. Dis Markers
29. Zintzaras E. Association of methylenetetrahydrofolate reductase (MTHFR
) polymorphisms with genetic susceptibility to gastric cancer: a meta-analysis. J Hum Genet
30. Whitehead A. Meta-Analysis of Controlled Clinical Trials.
Chichester: Wiley; 2002.
31. Ioannidis JP, Trikalinos TA, Zintzaras E. Extreme between-study homogeneity in meta-analyses could offer useful insights. J Clin Epidemiol
32. Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol
33. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ
34. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials
35. Fleiss JL. The statistical basis of meta-analysis. Stat Methods Med Res
36. Zintzaras E, Stefanidis I. Association between the GLUT1
gene polymorphism and the risk of diabetic nephropathy: a meta-analysis. J Hum Genet
37. Zintzaras E, Hadjigeorgiou GM. Association of paraoxonase 1 gene polymorphisms with risk of Parkinson's disease: a meta-analysis. J Hum Genet
38. Wiener-Megnagi Z, Ben-Shlomo I, Goldberg Y, et al. Resistance to activated protein C and the Leiden mutation: high prevalence in patients with abruptio placentae. Am J Obstet Gynecol
39. Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med
40. Kupferminc MJ, Peri H, Zwang E, et al. High prevalence of the prothrombin gene mutation in women with intrauterine growth retardation, abruptio placentae and second trimester loss. Acta Obstet Gynecol Scand
41. Alfirevic Z, Mousa HA, Martlew V, et al. Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynecol
42. Gebhardt GS, Scholtz CL, Hillermann R, et al. Combined heterozygosity for methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C is associated with abruptio placentae but not with intrauterine growth restriction. Eur J Obstet Gynecol Reprod Biol
43. Yoshimura T, Yoshimura M, Tabata A, et al. The missence Glu298Asp variant of the endothelial nitric oxide synthase gene is strongly associated with placental abruption. Hum Genet
44. Agorastos T, Karavida A, Lambropoulos A, et al. Factor V Leiden and prothrombin G20210A mutations in pregnancies with adverse outcome. J Matern Fetal Neonatal Med
45. Hira B, Pegoraro RJ, Rom L, et al. Polymorphisms in various coagulation genes in black South African women with placental abruption. BJOG
46. Facchinetti F, Marozio L, Grandone E, et al. Thrombophilic mutations are a main risk factor for placental abruption. Haematologica
47. Prochazka M, Happach C, Marsal K, et al. Factor V Leiden in pregnancies complicated by placental abruption. BJOG
48. Jaaskelainen E, Toivonen S, Romppanen EL, et al. M385T polymorphism in the Factor V Gene, but not Leiden mutation is associated with placental abruption in Finnish women. Placenta
49. Toivonen S, Romppanen EL, Hiltunen M, et al. Low-activity haplotype of the microsomal epoxide hydrolase gene is protective against placental abruption. J Soc Gynecol Investig
50. Parle-McDermott A, Mills JL, Kirke PN, et al. MTHFD1 R653Q polymorphism is a maternal genetic risk factor for severe abruptio placentae. Am J Med Genet
51. Toivonen S, Keski-Nisula L, Romppanen EL, et al. Endothelial nitric oxide synthase polymorphism is not associated with placental abruption in Finnish women. Fetal Diagn Ther
52. Hillermann R, Carelse K, Gebhardt GS. The Glu298Asp variant of the endothelial nitric oxide synthase gene is associated with an increased risk for abruptio placentae in pre-eclampsia. J Hum Genet
53. Dizon-Townson D, Miller C, Sibai B, et al. The relationship of the Factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol
54. Jaaskelainen E, Keski-Nisula L, Toivonen S, et al. MTHFR C677T polymorphism is not associated with placental abruption or preeclampsia in Finnish women. Hypertens Pregnancy
55. Zhang XQ, Craven C, Nelson L, et al. Placental abruption is more frequent in women with the angiotensinogen Thr235 mutation. Placenta
56. Naidu CA, Moodley J, Pegoraro R. Methylenetetrahydrofolate (MTHFR) reductase gene polymorphism in African women with abruptio placentae. Eur J Obstet Gynecol Reprod Biol
57. Jarvenpaa J, Pakkila M, Savolainen ER, et al. Evaluation of factor V Leiden, prothrombin and methylenetetrahydrofolate reductase gene mutations in patients with severe pregnancy complications in northern Finland. Gynecol Obstet Invest
58. Ananth CV, Elsasser DA, Kinzler WL, et al. Polymorphisms in methionine synthase reductase and betaine- homocysteine S- methyltransferase genes: risk of placental abruption. Mol Genet Metab
59. Ananth CV, Peltier MR, De Marco C, et al. Associations between 2 polymorphisms in the methylenetetrahydrofolate reductase gene and placental abruption. Am J Obstet Gynecol
60. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet
61. Weisberg I, Tran P, Christensen B, et al. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab
62. Konrad C, Muller GA, Langer C, et al. Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections. J Neurol
63. Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature
64. Poort SR, Rosendaal FR, Reitsma PH, et al. A common genetic variation in the 3′ untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood
65. Tesauro M, Thompson WC, Rogliani P, et al. Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci USA
66. Jeunemaitre X, Soubrier F, Kotelevtsev Y, et al. Molecular basis of human hypertension: role of angiotensinogen. Cell
67. Caulfield M, Lavender P, Farrall M, et al. Linkage of the angiotensinogen gene to essential hypertension. N Engl J Med
68. Hassett C, Aicher L, Sidhu JS, et al. Human microsomal epoxide hydrolase: genetic polymorphism and functional expression in vitro of amino acid variants. Hum Mol Genet
69. Robien K, Ulrich CM. 5,10-methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. Am J Epidemiol
70. Pijnenborg R, Robertson WB, Brosens J, et al. Review article: trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals. Placenta
71. Stone S, Pijnenborg R, Vercruysse L, et al. The placental bed in pregnancies complicated by primary antiphospholipid symdrome. Placenta
72. Kujorich JL. Thrombophilia and pregnancy complications. Am J Obstet Gynecol
73. Zusterzeel PL, Peters WH, Visser W, et al. A polymorphism in the gene for microsomal epoxide hydrolase is associated with pre-eclampsia. J Med Genet
74. Wang X, Wang M, Niu T, et al. Microsomal epoxide hydrolase polymorphism and risk of spontaneous abortion. Epidemiology
75. Risch NJ. Searching for genetic determinants in the new millennium. Nature
76. Sherry ST, Ward MH, Kholodov M, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res
77. Zoller B, Dahlback B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet
78. Kalafatis M. Coagulation factor V: a plethora of anticoagulant molecules. Curr Opin Hematol
79. Van der Velden PA, Krommenhoek-Van Es T, Allaart C, et al. A frequent thrombomodulin amino acid dimorphism is not associated with thrombophilia. Thromb Haemost.
80. Norlund L, Holm J, Zoller B, et al. A common thrombomodulin dimorphism is associated with myocardial infarction. Thromb Haemost
81. Heil SG, Lievers KJ, Boers GH, et al. Betaine- homocysteine methyltransferase (BHMT): genomic sequencing and relevance to hyperhomocysteinemia and vascular disease in humans. Mol Genet Metab
82. Morin I, Platt R, Weisberg I, et al. Common variant in betaine- homocysteine methyltransferase (BHMT) and risk for spina bifida. Am J Med Genet
83. Bernischke K, Kaufmann P. Pathology of the Human Placenta.
4th ed. New York: Springer; 2000.
84. Dommisse J, Tiltman AJ. Placental bed biopsies in placental abruption. Br J Obstet Gynaecol
85. Dorup I, Skajaa K, Sorensen KE. Normal pregnancy is associated with enhanced endothelium-dependent flow-mediated vasodilation. Am J Physiol
86. Sladek SM, Magness RR, Conrad KP. Nitric oxide and pregnancy. Am J Physiol
87. Williams DJ, Vallance PJ, Neild GH, et al. Nitric oxide-mediated vasodilation in human pregnancy. Am J Physiol
88. Yoshimura M, Yasue H, Nakayama M, et al. A missence Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese. Hum Genet
89. Nurk E, Tell GS, Refsum H, et al. Associations between maternal methylenetetrahydrofolate reductase polymorphisms and adverse outcomes of pregnancy: the Hordaland Homocysteine Study. Am J Med
90. McCarthy JJ, Parker A, Salem R, et al. Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes. J Med Genet
91. Thomas DC, Witte JS. Point: population stratification: a problem for case-control studies of candidate-gene associations? Cancer Epidemiol Biomarkers Prev
92. Pritchard JK, Rosenberg NA. Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet
93. Zintzaras E. Methylenetetrahydrofolate reductase gene and susceptibility to breast cancer: a meta-analysis. Clin Genet
94. Xu J, Turner A, Little J, et al. Positive results in association studies are associated with departure from Hardy-Weinberg equilibrium: hint for genotyping error? Hum Genet
95. Weir BS. Genetic Data Analysis II: Methods for Discrete Population Genetic Data.
Sunderland, MA: Sinauer Associates; 1996.
96. Salanti G, Sanderson S, Higgins JP. Obstacles and opportunities in meta-analysis of genetic association studies. Genet Med
97. Hauser MA, Li YJ, Takeuchi S, et al. Genomic convergence: identifying candidate genes for Parkinson's disease by combining serial analysis of gene expression and genetic linkage. Hum Mol Genet
98. Kitsios G, Zintzaras E. Genetic variation associated with ischemic heart failure: a HuGE review and meta-analysis. Am J Epidemiol
99. Laird NM, Lange C. Family-based designs in the age of large-scale gene-association studies. Nat Rev Genet
100. Cooper RS. Gene—environment interactions and the etiology of common complex disease. Ann Intern Med
101. Cordell HJ. Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans. Hum Mol Genet
102. Zintzaras E, Kitsios G, Stefanidis I. Response to endothelial nitric oxide synthase polymorphisms and susceptibility to hypertension: genotype versus haplotype analysis. Hypertension.
103. Zintzaras E, Koufakis T, Ziakas PD, et al. A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in acute lymphoblastic leukemia. Eur J Epidemiol
104. Zintzaras E. C677T and A1298C methylenetetrahydrofolate reductase gene polymorphisms in schizophrenia, bipolar disorder and depression: a meta-analysis of genetic association studies. Psychiatr Genet
105. Zintzaras E. Brain-derived neurotrophic factor gene polymorphisms and schizophrenia: a meta-analysis. Psychiatr Genet
106. International HapMap Consortium. A haplotype map of the human genome. Nature.
107. Gibbs JR, Singleton A. Application of genome-wide single nucleotide polymorphism typing: simple association and beyond. PLoS Genet
108. Zintzaras E, Lau J. Trends in meta-analysis of genetic association studies. J Hum Genet
109. Zintzaras E, Lau J. Synthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approach. J Clin Epidemiol
. 2008; in press.
This article has been cited 11 time(s).
International Journal of EpidemiologyGenetic association studies in pre-eclampsia: systematic meta-analyses and field synopsisInternational Journal of Epidemiology
American Journal of Obstetrics and GynecologyPolymorphisms in thrombophilia and renin-angiotensin system pathways, preterm delivery, and evidence of placental hemorrhageAmerican Journal of Obstetrics and Gynecology
Molecular Human ReproductionInhibin alpha gene and susceptibility to premature ovarian failure: a data synthesisMolecular Human Reproduction
American Journal of EpidemiologyVariants of the Arachidonate 5-Lipoxygenase-Activating Protein (ALOX5AP) Gene and Risk of Stroke: A HuGE Gene-Disease Association Review and Meta-AnalysisAmerican Journal of Epidemiology
American Journal of EpidemiologyA Field Synopsis and Meta-Analysis of Genetic Association Studies in Peripheral Arterial Disease: The CUMAGAS-PAD DatabaseAmerican Journal of Epidemiology
Genetic Testing and Molecular BiomarkersGlutathione S-Transferase M1 and T1 Genes and Susceptibility to Chronic Myeloid Leukemia: A Meta-AnalysisGenetic Testing and Molecular Biomarkers
Bjog-An International Journal of Obstetrics and GynaecologyOccurrence of placental abruption in relativesBjog-An International Journal of Obstetrics and Gynaecology
Mutation Research-Fundamental and Molecular Mechanisms of MutagenesisThe integration of genome-based information for common diseases into health policy and healthcare as a major challenge for Public Health Genomics: The example of the methylenetetrahydrofolate reductase gene in non-cancer diseasesMutation Research-Fundamental and Molecular Mechanisms of Mutagenesis
Journal of Human GeneticsThe role of MTHFR gene in multiple myelomaJournal of Human Genetics
BiomarkersGenetic variants of homocysteine/folate metabolism pathway and risk of inflammatory bowel disease: a synopsis and meta-analysis of genetic association studiesBiomarkers
Journal of Medical PrimatologyAbruptio placentae in cynomolgus macaques (Macaca fascicularis): male biasJournal of Medical Primatology
© 2008 Lippincott Williams & Wilkins, Inc.