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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