Obstetrics & Gynecology:
Genetic Thrombophilias and Intrauterine Growth Restriction: A Meta-analysis
Facco, Francesca MD1; You, Whitney MD1; Grobman, William MD, MBA1
From the 1Division of Maternal–Fetal Medicine, Department of Obstetrics and Gynecology, Northwestern University School of Medicine, Chicago, Illinois.
Research for this project was done while Dr. You was a National Research Service Award postdoctoral fellow at the Institute for Healthcare Studies under an institutional award from the Agency for Healthcare Research and Quality (T-32 HS 000078-11).
Corresponding author: Francesca Facco, MD, 250 East Superior Street, Suite 05-2175, Chicago, IL, 60647; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To estimate the relationship between inherited thrombophilias and intrauterine growth restriction (IUGR) using meta-analytic techniques.
METHODS: A literature review identified case–control and cohort studies evaluating the relationship between IUGR and the following thrombophilias: homozygous or heterozygous factor V Leiden or prothrombin (PT) G20210A mutations and homozygous methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Using mixed effects and random-effects models, the association between thrombophilias and IUGR was explored. Publication bias was assessed with funnel plots and corrected for with Duval and Tweedie’s trim-and-fill method.
RESULTS: The following number of related studies were found: studies evaluating relationships between factor V Leiden mutation and IUGR, 12 case–control and four cohort; between PT mutation and IUGR, 11 case–control and 0 cohort; and between MTHFR C677T homozygosity and IUGR, 10 case–control and two cohort. The overall summary odds ratio (OR) for the association between factor V Leiden and IUGR was significant (OR 1.23, 95% confidence interval [CI] 1.04–1.44); however, this was mainly driven by the positive association seen in the case–control studies (OR 1.91, 95% CI 1.17–3.12). The association between PT and IUGR was only explored in case–control studies yielding a summary OR that was not significant (OR 1.52, 95% CI 0.98–2.35). The overall summary OR for the association between MTHFR and IUGR was not significant (OR 1.01, 95% CI 0.88–1.17), but was significant for the case–control studies alone (OR 1.35, 95% CI 1.04–1.75). For both factor V Leiden and MTHFR mutations, a funnel-plot analysis of the case–control studies suggests publication bias. When the trim-and fill-method was used to correct for the publication bias, these summary estimates were no longer significant.
CONCLUSION: The association between inherited thrombophilias and IUGR can only be discerned in case–control studies and seems to be largely because of publication bias.
LEVEL OF EVIDENCE: III
Intrauterine growth restriction (IUGR) is a familiar yet complex challenge in obstetrics. The American College of Obstetricians and Gynecologists defines IUGR as any fetus with a weight below the 10th percentile (10%) for a given gestational age.1 Research into understanding and preventing IUGR is of public health importance, because growth restriction is associated not only with fetal mortality and neonatal morbidity, but with adverse long-term consequences, such as cardiovascular disease.2–8
Multiple factors have been associated with an increased risk of IUGR. It has long been known, for example, that environmental influences, such as smoking,9–11 alcohol use,10 and poor nutrition,12 have an causative role in impaired fetal growth. The possibility of a genetic contribution is also evident given the increased risk of IUGR in the setting of multiple different chromosomal abnormalities. More recently, increasing attention has been paid to the association between IUGR and specific genetic mutations resulting in a thrombophilic state.
Inherited thrombophilic mutations have been postulated to increase the probability of IUGR due to a potential increased risk of placental thrombosis. This has been theorized to negatively affect uteroplacental blood flow and lead to poor fetal growth.13,14 However, the association between inherited thrombophilias and IUGR has not been consistently demonstrated in different investigations.15–31 One potential reason for this inconsistency is that individual studies may not have had sufficient sample sizes to detect an association, even if one were to exist. Given this inconsistency and the clinical importance of discerning an association if one were to be present, we performed a systematic review of the literature and meta-analysis to estimate the magnitude of the relationship between inherited thrombophilias and IUGR.
MATERIALS AND METHODS
A systematic search of the published literature was conducted to identify observational studies in which the association between inherited thrombophilias and IUGR was assessed. Initially, a computerized search of MEDLINE was preformed, in which the terms intrauterine growth restriction, IUGR, small for gestational age, SGA, fetal growth restriction, FGR, pregnancy complications, and pregnancy outcomes were individually crossed with each of the following terms: thrombophilia, factor V Leiden, prothrombin, MTHFR, methylene tetrahydrofolate reductase, and homocysteine. We chose to limit the thrombophilias that were assessed to the factor V Leiden, prothrombin (PT) G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T mutations because they are the most common types of inherited thrombophilias.32–34 Furthermore, these mutations are detected by identifying DNA mutations with polymerase chain reaction, and not through the testing of activity or antigen levels, which have greater interlaboratory variability and different thresholds for the diagnosis of pathology. The reference lists of all articles that were identified in the search, including review articles, were used to retrieve additional articles that were not identified in the original MEDLINE search, until the recursive searching of these lists identified no further articles.
Eligibility for inclusion in this meta-analysis was limited to peer-reviewed publications. Publications that were only in abstract form were excluded. Only studies that strictly defined IUGR as birth weight less than 10%, used this definition to identify the study group, and compared this study group to a control group of women whose fetuses did not meet this IUGR criterion were included. Studies also had to evaluate at least one of the following types of mutations: factor V Leiden (homozygous or heterozygous), PT G20210A (homozygous or heterozygous) and MTHFR C677T (homozygous). Studies were excluded if they had insufficient data reported to calculate an odds ratio, for instance studies that collectively considered IUGR with other adverse pregnancy outcomes but did not provide data specific to IUGR. Other exclusion criteria were evidence of overlapping results, thrombophilia status obtained only by self-report, or if only fetal thrombophilia status was reported with maternal status unknown. Cohort studies were only included if they examined a general obstetric population, in other words if they did not limit their cohort to a specific patient population (eg, women with a history of recurrent pregnancy loss). Once the final articles were selected for inclusion, the following information was extracted from each study: year of publication, study country, study design, descriptions of the population from which the study sample was selected, case and control group definitions, and thrombophilia definitions.
The meta-analysis was performed using Comprehensive Meta-Analysis 2 software (Biostat Inc., Englewood, NJ). The studies were divided into two subgroups by study type namely, case–control studies and cohort studies. A mixed-effect analysis, where a random-effects model is used to combine studies within each subgroup and a fixed-effect model is used to combine subgroups, was used to yield an overall summary odds ratio for the association between each thrombophilia and IUGR. Statistical heterogeneity between subgroups was assessed by deriving a Q statistic.35 In the case of summary odds ratios that were statistically significant, funnel plots were used to assess for publication bias. The Duval and Tweedie’s trim-and-fill method was used to adjust for potential publication bias. The trim-and-fill method formalizes the interpretation of any asymmetry in the funnel plot by imputing suspected missing studies and calculating an adjusted result. The adjusted result is not intended to actually find the values of missing studies or to give a better effect size estimate per se, but can be used as a form of sensitivity analysis to help ascertain the likely effect of publication bias on the meta-analysis.36–38 A further analysis was performed in which studies were subdivided by the timing of their publication to better understand the potential effect of year of publication upon the results. Given that all of the studies included in the analysis were published between January 1999 and November 2008, studies were considered to be “early” if they were published before 2004 and “late” if published during or after 2004. All tests were two-tailed and statistical significance was defined as P<.05.
One thousand twenty-four citations were initially identified through the systematic search, of which 937 were excluded due to information in their abstract that rendered them ineligible for further analysis. The 87 studies that remained were analyzed in further detail to determine whether they met inclusion criteria. We identified 14 case–control studies and five cohort studies that met these criteria and thus were included in the meta-analysis.15–28,39–43 Of the 87 studies, two were excluded because the same population was used for different reports. We excluded the Verspyck et al 200244 article because the cases and controls from this study were also subjects in a larger 2004 study28 by the same author. This later study was included in our analysis. We also excluded the Kupferminc et al45 2000 report on PT G20210A because it used 90 control subjects that been previously described in a study published in 199921 by the same author. We chose to include the earlier report because it examined multiple thrombophilias. Tables 1 and 2 list the study characteristics of the included case–control and cohort studies, respectively.
There were 12 case–control and four cohort studies that assessed the relationship between the factor V Leiden mutation and IUGR. The overall summary odds ratio (OR) from these studies revealed a significant association between the factor V Leiden mutation and IUGR (OR 1.23, 95% confidence interval [CI] 1.04–1.44). These results are shown graphically in Figure 1. The Q statistic testing the difference between the case–control and cohort studies was 3.53 (P=.06), suggesting heterogeneity between these two groups of studies. When only the cohort studies were assessed, the combined OR for the association with IUGR did not reach statistical significance (OR 1.16, 95% CI 0.98–1.38). In contrast, when only the case–control studies were analyzed, there was a significant association demonstrated, with an OR of 1.91 (95% CI 1.17–3.12). Given that the case–control studies demonstrated a significant summary estimate, a funnel-plot analysis (Fig. 2A) was used to assess publication bias. This plot suggests the existence of publication bias, given the lack of smaller studies with smaller or negative effect sizes. Figure 2B is a funnel plot that includes imputed studies using Duval and Tweedie’s trim-and-fill method. Incorporating these imputed studies results in an association between factor V Leiden and IUGR that is no longer statistically significant (imputed OR 1.47, 95% CI 0.85–2.52). Also, it is of note that after stratifying all the studies into early compared with late publication date, the combined OR for the earlier studies was significant (OR 2.04, 95% CI 1.05–3.96), whereas that for the later studies was not (OR 1.19, 95% CI 0.02–2.39).
There were 11 case–control studies and no cohort studies that evaluated the relationship between the PT mutation and IUGR. The summary OR from these case–control studies did not demonstrate a significant association between the PT mutation and IUGR (OR 1.52, 95% CI 0.98–2.35). These results are shown graphically in Figure 3. When stratifying the studies by publication date, the combined OR was significant for the early studies (OR 2.29, 95% CI 1.02–5.15) but not for the late studies (OR 1.42, 95% CI 0.95–2.13).
There were 10 case–control studies and two cohort studies that evaluated the relationship between MTHFR C677T homozygosity and IUGR. The overall summary odds ratio revealed no significant association between the MTHFR mutation and IUGR (OR 1.01, 95% CI 0.88–1.17). These results are shown graphically in Figure 4. The Q statistic testing the difference between the case–control and cohort studies was 6.88 (P=.009), demonstrating significant heterogeneity between these two types of studies. The combined OR for the seven case–control studies was 1.35 (95% CI 1.04–1.75), whereas the combined OR for the two cohort studies did not show a positive association and was not statistically significant (0.89, 95% CI 0.75–1.06). A funnel-plot analysis (Fig. 5A) of the case–control studies that assessed the association between MTHFR C677T and IUGR suggests publication bias. Figure 5B is a funnel-plot analysis including imputed studies using the trim-and-fill method. When these studies were used to derive a summary measure of association, the result for the case–control data was no longer significant (imputed OR 1.19, 95% 0.88–1.60). When stratifying the studies according to timing of publication, the combined OR for the association between MTHFR and IUGR was significant in the early (OR 1.60, 95% CI 1.11–2.30) but not in the late studies (OR 0.92, 95% CI 0.79–1.08).
In this meta-analysis, the overall summary results revealed a statistically significant association only between factor V Leiden and IUGR. However, this association seems to be driven by publication bias in case–control studies. For MTHFR C677T, the summary OR did not demonstrate an association. Moreover, subgroup analysis and assessment of publication bias revealed a pattern consistent with the factor V Leiden data. The summary results of the case–control studies revealed a positive and significant association, whereas the summary results of the cohort studies did not. For PT G20210A, only case–control studies were available, and analysis of these data revealed no significant association between this mutation and IUGR.
The positive association in the case–control studies of factor V Leiden and MTHFR seems to be related to publication bias. In this type of bias, all completed studies are not published due to the disinclination either of investigators to submit negative results (ie, those that do not demonstrate an association between exposure and outcome) or of peer-reviewers to recommend manuscripts with negative findings for publication. For factor V Leiden and MTHFR, the funnel-plot analysis demonstrates the likelihood that negative studies were preferentially not published, and that if they had been, there would be no positive association noted in the meta-analysis of the case–control studies.
Further evidence for bias in the published results is provided by the analysis of early compared with late studies. In the case of each of the mutations, the significant association with IUGR was only evident in the studies that were published in the early period. In the late period, the summary OR of association had a point estimate that was lower than that of the early period and was no longer significant. This finding is consistent with a type of bias known as “the winner’s curse,” as noted by Zollner et al46 In this type of bias, not only are significant results more likely to be published, but these results are likely to have particularly overestimated magnitudes of association in the initial published reports. As further studies are published, the strength of the association is typically degraded. This effect has been noted in other data, specifically other studies linking genetic mutations with clinical outcomes.47
In an attempt to use the best quality data available, this meta-analysis included only studies that met strict criteria. Cohort studies were limited to those that derived their study participants from the general population and not from specifically targeted and tested populations, such as women with a history of a venous thromboembolism. This type of cohort minimizes the possibility of selection bias and confounding. Compared with the cohort studies, the case–control studies varied widely in their methodology. These studies had significant heterogeneity, which included different definitions of IUGR (between less than 3% and less than 10%) and other differences in inclusion and exclusion criteria. For example, some studies excluded cases of IUGR if they occurred in the setting of gestational hypertension or preeclampsia, whereas other studies did not. Correcting for potential confounding factors was also infrequently performed. Adjusted odds ratios were available in only three of the case–control studies.18,24,39 Nevertheless, because the meta-analysis only included the highest quality studies, applied strict eligibility criteria for study inclusion, and used a random-effects analysis, we believe that these results provide the best estimate of the association (or lack thereof) between inherited thrombophilias and IUGR. Moreover, even if a relatively weak association did exist, this analysis would have the power to discern it. With regard to our negative analysis for PT and MTHFR, this meta-analysis had 80% power to detect an OR of 1.9 and an OR of 1.2 for the association of IUGR with PT and MTHFR, respectively.48
Another point of consideration when interpreting the results of this meta-analysis is the definition of IUGR that was used by the majority of the studies. Our meta-analysis included studies that defined IUGR by a birth weight of at least less than 10%. Notably, most of the studies used this exact cutoff point as their case definition. Compared with this standard definition of IUGR, a more conservative definition (eg, less than 3%) may be more clinically relevant. In our included studies, only two case controls studies and one cohort study defined IUGR as birth weight less than 3%22,23,44, and one case–control study used a less than 5% cutoff.20 Given the limited number of studies that used these more stringent criteria, a separate analysis of this subgroup was not feasible.
Determining whether an association exists between thrombophilias and IUGR is important for several reasons. If such an association exists, it would further help us to understand the physiologic events that lead to this pathology. Moreover, understanding this pathophysiology is an important step in determining therapeutic interventions. Indeed, because some of the data that exist do demonstrate an association, some clinicians have used anticoagulation to prevent the recurrence of IUGR. The efficacy of this therapy, however, has not been established, given that there are no randomized controlled trials demonstrating that anticoagulation can prevent IUGR or its related adverse perinatal events. The costs of therapy such as heparin, as well as the potential adverse effects such as bleeding, make it important to determine whether this therapy is actually of benefit. Clearly, if an association between thrombophilias and IUGR does not exist, the benefits of using anticoagulant therapy would be more difficult to understand.
As always, caution should be exercised when drawing conclusions from a meta-analysis. The conclusions from this analysis are only as strong as the studies included. In this case, because the aggregated studies were generally heterogeneous and represented diverse populations, the accuracy of the summary odds ratio may be lessened. We also recognize that conclusions of this study cannot be extrapolated to other adverse pregnancy outcomes associated with IUGR, such as preeclampsia or stillbirth. We additionally recognize the limitations of using an MTHFR mutation rather than homocysteine levels in our study. We specifically chose not to look at homocysteine because such values may vary significantly based on various clinical and laboratory conditions. Studies that measured homocysteine levels did not have uniform protocols; therefore, the ability to summarize the data in the context of a meta-analysis is limited. Nevertheless, the best summary evidence that can be obtained from the available data does not provide strong evidence for a significant association between inherited thrombophilias and IUGR. This finding further emphasizes the need for cohort studies that are adequately powered to detect an association so that we can better understand the cause, evaluation, and prevention of IUGR.
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