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Maternal Alcohol Consumption before and during Pregnancy and the Risks of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis Jian Sun, PhD,*†1 Xiaoling Chen, MD,‡1 Huajun Chen, MD,* Zhengliang Ma, PhD,§ and Jianwei Zhou, PhD* *School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China; †Department of Anesthesiology, Huai’an Maternal and Child Health Hospital, Huai’an, Jiangsu, China; ‡Department of Nephrology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, China; §Department of Anesthesiology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China ABSTRACT

Objective. Epidemiologic studies have reported conflicting results regarding maternal alcohol consumption before and during pregnancy, and the risk of congenital heart defects (CHDs). However, a systematic review and metaanalysis of the association between maternal alcohol consumption and CHDs in offspring has not been conducted. Design. We searched MEDLINE and EMBASE for articles catalogued between their inception and February 16, 2015; we identified relevant published studies that assessed the association between maternal alcohol consumption and CHD risk. Two authors independently assessed the eligibility of the retrieved articles and extracted data from them. Study-specific relative risk estimates were pooled by random-effects or fixed-effects models. Results. From the 1527 references, a total of 19 case–control studies and four cohort studies were enrolled in this meta-analysis. The summary of 23 studies related to CHDs indicated an overall pooled relative risk of 1.13 (95% confidence interval: 0.96, 1.29) among mothers drinking before or during pregnancy. Statistically significant heterogeneity was detected (Q = 196.61, P < .001, I2 = 88.8%) with no publication bias (Egger’s test: P = .157). We conducted stratified and meta-regression analyses to identify the origin of the heterogeneity among studies. Conclusion. In summary, this meta-analysis provided no positive association between maternal alcohol consumption and risk of CHDs. Key Words. Congenital Heart Defects; Pregnancy; Alcohol; Meta-analysis

Introduction

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ongenital heart defects (CHDs) are the most common group of congenital malformations, affecting almost 1% of live births throughout the world.1 CHDs represent approximately one-third of all congenital anomalies and are the leading cause of perinatal mortality.2 Although cardiovascular diagnostics and cardiothoracic surgery have achieved massive breakthroughs over the past century, leading to an increased survival of newborns with CHDs, the etiology of most CHDs is still unknown. 1

These authors equally contributed to this work.

Congenit Heart Periodicals, Dis. 2015;10:E216–E224 © 2015 Wiley Inc.

Several chromosomal anomalies, certain maternal illnesses, and prenatal exposures to specific therapeutic drugs are recognized risk factors. It is difficult to establish the role of a single factor because the cause of a defect is believed to be multifactorial in many cases, including the combination of environmental teratogens with genetic and chromosomal conditions.3 A review published in 2007 provided a summary of currently available literature on noninherited risk factors that might alter the risk of CHDs.4 Moreover, CHDs include several distinct subtypes (e.g., conotruncal defects, artioventricular septal defect, and septal defects), and there is a potential for etiologic heterogeneity. Therefore, it is not surprising that studies for C 2015 Wiley Periodicals, Inc. V Congenit Heart Dis. 2015;••:••–••

Maternal Alcohol Consumption and CHD in Offspring 2 categories of CHDs report different or opposite results. Many observational studies have been published on the topic of alcohol consumption in pregnant women and the effects on the development of their fetus and child. The association of heavy maternal alcohol consumption during pregnancy and various adverse birth outcomes has been well established.5,6 However, studies focused on the associations of low to moderate alcohol consumption during pregnancy with birth outcomes showed inconsistent results.7–9 In general, low to moderate maternal alcohol consumption is considered as one alcoholic drink at most per day on average. Some studies did not find any associations, while others found adverse or even beneficial effects. To date, mounting studies have focused on the association between maternal alcohol consumption and CHDs in offspring; however, the results have been ambiguous, possibly because of inadequate sample sizes. Therefore, we conducted a meta-analysis to quantitatively assess the relationship between the maternal alcohol consumption and the newborn’s risk of CHDs. Methods

To identify relevant epidemiologic studies, a computerized literature search was conducted in MEDLINE and EMBASE from their inception to February 16, 2015, by two independent investigators (J.S. and X.C.). We searched relevant studies using the following strategy: (alcohol OR ethanol OR light drinking OR moderate drinking) AND (congenital heart defect OR heart abnormality OR malformation of heart OR cardiovascular abnormality). In addition, we conducted a search for a broader range on environmental teratogens and CHDs and checked the relevant references and review articles; in this way we could identify information on other related studies. We followed standards of quality for conducting and reporting meta-analyses.10

Eligibility Criteria We selected articles that (1) were original epidemiologic studies; (2) examined the association between maternal alcohol consumption and CHDs overall or any one of the CHD subtypes in infants; (3) were published in English; (4) reported odds ratios (i.e., risk ratios or odds ratios) and associated 95% confidence intervals (CIs) or SEs or data necessary to recalculate these factors; and Congenit Heart Dis. 2015;••:••–••

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(5) defined CHDs or one of the CHD subtypes as an outcome. Articles that reported results from more than one population were considered as separate studies. As some articles assessed the same connection based on data of the same individuals, those with a greater number of participants, and those with the same number of participants were used, the article containing more detailed analytic information was also selected. The studies were decided to be listed as hierarchical: first study titles, next the abstracts, and finally the whole text was assessed. Nonpeer-reviewed articles, experimental animal studies, ecologic assessments, correlation studies, and mechanistic studies were excluded.

Data Extraction Data extraction was carried out separately by two reviewers (J.S. and X.C.) working independently. Where differences of opinion arose, these were discussed and resolved by discussion between the two or by involving a third reviewer (H.C.) for adjudication. The studies meeting the inclusion criteria were reviewed to retrieve information of interest including study characteristics (i.e., authors, year of publication, geographic region, periods of data collection, study design, population studied, exposure and outcome assessment, number of cases, number of noncases, the association measure, point estimate with their corresponding 95% CIs, and any adjustment/ stratification/matching variables). When no adjusted estimates were available, we extracted the crude estimate. If no estimate was provided in a given study, using standard equations, we recalculated odds ratios or risk ratio and 95% CI from the presented raw data. To assess the study quality, we used a 9-star system on the basis of the Newcastle–Ottawa Scale,11 in which we judged a study on three broad perspectives: the selection of study groups, comparability of study groups, and the ascertainment of either the exposure or outcome of interest for case–control or cohort studies, respectively. The highest score was 9, and we defined the highquality study as quality scores greater than or equal to 7 (Supplementary Table S1). Statistical Analysis In studies without appropriate measurement of associations, aggregated raw data (not considering matching design, where necessary), if possible, were referred to for estimation of unadjusted associations. Under the assumption of rare outcome, Congenit Heart Dis. 2015;10:E216–E224

E218 Maternal Alcohol Consumption and CHD in Offspring the inverse variance weighted method was adopted to combine odds ratios, rate ratios and for producing a pooled odds ratio. Cochran Q and I2 statistics were used to test for heterogeneity across studies.12 If there was an evidence of heterogeneity (P < .05 or I2 ≥ 50%), the random-effects model was used, which provided a more appropriate summary effect estimate among heterogeneous study-specific estimates. If the study showed no evidence of heterogeneity, the fixed-effects analysis was used, applying inverse variance weighting to calculate summary relative risk (RR) estimates.13 Finally, we conducted sensitivity analyses to explore whether a specific study strongly influenced the results by excluding one study at a time. Publication bias was assessed by visual inspection of a funnel plot with asymmetry, using both Egger’s linear regression14 and Begg’s rank correlation15 methods. Significant statistical publication bias was defined as a P value of

Maternal Alcohol Consumption before and during Pregnancy and the Risks of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis.

Epidemiologic studies have reported conflicting results regarding maternal alcohol consumption before and during pregnancy, and the risk of congenital...
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