Just Accepted by The Journal of Maternal-Fetal & Neonatal Medicine Maternal periconceptional alcohol consumption and the risk of neural tube defects in offspring: a meta-analysis Li-Yun Leng, Jian-Wei Wang, Shuang-Shuang Cao, Meng Wang doi: 10.3109/14767058.2015.1059807 Abstract

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Objective Several studies have been conducted to examine the association between alcohol consumption during pregnancy and risk of neural tube defects (NTDs), while the results are inconsistent. In the present study, we aimed to clarify the relationship between maternal periconceptional alcohol consumption and NTDs risk in offspring. Methods PubMed, Springer Link, and Elsevier databases were searched up to November, 2014. All case-control and cohort studies of maternal alcohol consumption during pregnancy with risk of NTDs were included. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) for highest vs. lowest category of alcohol consumption were calculated using a fixed- or random-effects model. Results The pooled ORs of maternal periconceptional alcohol consumption were 1.01 (95% CI: 0.71-1.45) for total NTDs and 1.03 (95% CI: 0.65-1.64) for NTDs subtype of spina bifida. Specifically, the pooled ORs of maternal alcohol consumption in the first trimester and binge drinking were 1.01 (95% CI: 0.71-1.43), and 1.07 (95% CI: 0.81-1.41), respectively. Conclusions Our findings suggested no association between maternal periconceptional alcohol consumption and NTDs risk in offspring.

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Maternal periconceptional alcohol consumption and the risk of neural tube defects in offspring: a meta-analysis Li-Yun Leng, Jian-Wei Wang, Shuang-Shuang Cao, Meng Wang* Li-Yun Leng : Yidu Central Hospital of Weifang. 4138 Linglong Road, Qingzhou City, Shandong Province. [email protected]

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Jian-Wei Wang (M.D): Yidu Central Hospital of Weifang. 4138 Linglong Road, Qingzhou City, Shandong Province. [email protected] Shuang-Shuang Cao (M.D) Yidu Central Hospital of Weifang. 4138 Linglong Road, Qingzhou City, Shandong Province. [email protected] * Correspondence to Meng Wang, Zhejiang Provincial Center for Disease Control and Prevention, 3399 Binsheng Road, Hangzhou, 310051, China. [email protected] Tel: +86-0571-87115164 Li-Yun Leng and Jian-Wei Wang contributed to the article equally.

Abstract Objective Several studies have been conducted to examine the association between alcohol consumption during pregnancy and risk of neural tube defects (NTDs), while the results are inconsistent. In the present study, we aimed to clarify the relationship between maternal

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periconceptional alcohol consumption and NTDs risk in offspring. Methods PubMed, Springer Link, and Elsevier databases were searched up to November, 2014. All case-control and cohort studies of maternal alcohol consumption during pregnancy with risk of NTDs were included. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) for highest vs. lowest category of alcohol consumption were calculated using a fixed- or random-effects model. Results The pooled ORs of maternal periconceptional alcohol consumption were 1.01 (95% CI: 0.711.45) for total NTDs and 1.03 (95% CI: 0.65-1.64) for NTDs subtype of spina bifida. Specifically, the pooled ORs of maternal alcohol consumption in the first trimester and binge drinking were 1.01 (95% CI: 0.71-1.43), and 1.07 (95% CI: 0.81-1.41), respectively. Conclusions Our findings suggested no association between maternal periconceptional alcohol consumption and NTDs risk in offspring. Key words Alcohol, neural tube defects, pregnancy, meta-analysis. Introduction Alcohol consumption among pregnant women remains a common occurrence and has become a worldwide public concern. Data from Behavioral Risk Factor Surveillance System (BRFSS) between 2006 and 2010 estimated that 7.6% of pregnant women used alcohol in USA and among them, 1.4% was reported binge level drinking [1]. Including over 15000 women, the UK Infant Feeding Survey (IFS) in 2010 revealed that 40% of women drank alcohol during pregnancy [2]. In addition, a study conducted in Australian population also indicated as high as 34.8% of women reported drinking

alcohol during pregnancy in 2011[3]. For pregnant women, alcohol can easily cross the placenta and result in nearly equal levels of concentrations in fetal and maternal, leading to lower birthweight, preterm birth, fetal mortality and a range of birth defects [2, 4-7]. Neural tube defects (NTDs) are one of the most common human birth defects, with a worldwide prevalence ranging from 1.0 to 10.0 per 1,000 births [8]. NTDs are complex disorders and appear to be affected by multiple factors, with both genetic and environmental contributions [9]. In recent decades, studies on the association between

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maternal alcohol consumption during pregnancy and NTDs risk in offspring have been extensively investigated, while the conclusions are inconsistent [10-14]. Therefore, more high-quality evidence is needed and we propose to perform a meta-analysis study to address this issue. Methods Literature and search strategy We collected human studies on the association between maternal alcohol consumption during pregnancy and NTDs (anencephaly, spina bifida and encephalocele) risk in offspring. PubMed, Springer Link, and Elsevier databases were searched up to November 30, 2014. The literature search was limited to the English language. To identify maternal alcohol consumption exposure, we used the main search terms of “prenatal alcohol exposure”, “alcohol intake”, “alcohol consumption”, “alcohol drinking”, “alcohol”, “binge drinking” with OR; Relevant outcomes were identified by searching terms of “neural tube defects” “NTDs”, “anencephaly”, “spina bifida”, “encephalocele”, “malformations”, “anomalies”, “defects” and combining these with OR. This systematic review was planned, conducted, and reported in adherence to standards of quality for reporting meta-analysis [15]. Eligibility criteria Studies included in the meta-analysis met the following criteria: (1) on the association between maternal alcohol consumption during pregnancy and NTDs (anencephaly, spina bifida and encephalocele) risk in offspring; (2) a case-control or cohort study design; (3) reported the odds ratio

(OR) or relative risk (RR) with 95% confidence intervals (CIs) for highest vs. lowest category of alcohol consumption. Data extraction Included articles were assessed and relevant information was extracted from by the same two investigators independently, with disagreements resolved through discussion. The main information

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included first author’s last name, year of publication, study design, countries where the study conducted, time period of each study, number and subtypes of case population, ORs or RRs with 95% CI for highest versus lowest alcohol intake, data collection period, and study quality. As most included studies were case-control studies, we chose the OR as the principal measure. The quality of each study was assessed by the 9-star Newcastle-Ottawa Scale [16], which is a validated scale for observational and non-randomized studies in meta-analysis. This scale assessed the selection of the study sample (for case-control or cohort studies, maximum of 4 points); the comparability of the sample groups (maximum of 2 points); and the ascertainment of outcome (for cohort studies, maximum of 3 points). Statistical analysis Heterogeneity between studies was assessed using Q-test and the I2 statistic [17]. If there was significant heterogeneity (P25%), a random-effects model would be used to assign the weight of each study according to the DerSimonian-Laird method [18]. If there was an evidence of no heterogeneity, we used a fixed-effects model with effect estimates were given equal weight to the inverse variance of the study. In the main analysis examining the association between maternal alcohol consumption and the risk of NTDs, a sensitivity analysis was performed. Publication bias was assessed by Egger’s regression asymmetry test [19] and Begg’s rank correlation test [20] (P2 drinks / week to 2 drinks / day) during the first trimester was not associated with increased risk of fetal malformations (RR=1.01, 95%CI: 0.94-1.08). Recently, including 33 studies (23 case-control and 10 cohort studies), Bell et al [23] conducted a systematic review and findings suggested neither maternal “any alcohol intake” nor “binge level drinking” during pregnancy was associated with the occurrence of orofacial clefts, which was also a common birth defects in infants. However, in the

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study, authors indicated that the effects of alcohol might be confounded by various factors (e.g. exposure measurement, outcomes ascertainment). Since neural-tube formation is completed very early in pregnancy, we choose the first trimester to approximately determine effect of alcohol on NTDs at the critical window with an independent metaanalysis study. The results show that the risk effect is non-significant and almost unchanged (OR=1.01, 95%CI: 0.71-1.43). Considering the limited number of included studies, population-based cohort or case-control studies are urgently needed to confirm the findings. Besides, a higher risk effect of binge drinking during pregnancy on birth defects is also suggested in studies [7, 14]. Without study heterogeneity, our meta-analysis reported a greater effect value (1.07 vs. 1.01), although the CI includes the null. Several limitations must be considered in our study. Firstly, with case-control and retrospective cohort design of the included articles, recall bias is inevitable in this meta-analysis. Secondly, alcohol consumption during pregnancy is likely to be underestimated out of stigma mainly by maternal selfreporting. Thirdly, other information of alcohol types and the frequency of alcohol drinking are not collected in our study, which may confound the final results. Finally, we are unable to further determine a dose-response association between maternal alcohol consumption during pregnancy and the risk of NTDs due to the limits of the collected information. In conclusion, our results show that maternal periconceptional alcohol consumption is not associated with NTDs risk in offspring. However, considering the facts that there is no known safe level of alcohol consumption in the fetus and the worldwide large proportion of women using alcohol during

pregnancy, we advise that the pregnant women should avoid alcohol consumption at least during the first trimester. Acknowledgments This study was supported by “Zhejiang Provincial Major Special Project of Science and Technology (2011C13032-1)”.

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Author contributions L.Y. L conceived, designed the study. C.S.S collected, analyzed the data with J.W W. M.W gave much advice and directions in both study design and preparing of the manuscript. All the authors have read and approved the final submitted version. Additional information Competing financial interests: The authors declare no competing financial interests. Reference [1] Centers for Disease Control and prevention (CDC). Alcohol use and binge drinking among women of childbearing age—United States, 2006-2010. MMWR Morb Mortal Wkly Rep 2012; 61:5348. [2] Nykjaer C, Alwan NA, Greenwood DC, et al. Maternal alcohol intake prior to and during pregnancy and risk of adverse birth outcomes: evidence from a British cohort. J Epidemiol Community Health 2014; 68:542-9. [3] Cameron CM, Davey TM, Kendall E, et al. Changes in alcohol consumption in pregnant Australian women between 2007 and 2011. Med J Aust 2013; 199:355-7. [4] Andersen AM, Andersen PK, Olsen J, et al. Moderate alcohol intake during pregnancy and risk of fetal death. Int J Epidemiol 2012; 41:405-13.

[5] Richardson S, Browne ML, Rasmussen SA, et al. Associations between periconceptional alcohol consumption and craniosynostosis, omphalocele, and gastroschisis. Birth Defects Res A Clin Mol Teratol 2011; 91:623-30. [6] Yang W, Zeng L, Cheng Y, et al. The Effects of Periconceptional Risk Factor Exposure and Micronutrient Supplementation on Birth Defects in Shaanxi Province in Western China. PLoS

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One 2012; 7:e53429. [7] O’Leary CM, Nassar N, Kurinczuk JJ, et al. Prenatal alcohol exposure and risk of birth defects. Pediatrics 2010; 126:e843-50. [8] Au KS, Ashley-Koch, A, Northrup, H. Epidemiologic and genetic aspects of spina bifida and other neural tube defects. Dev Disabil Res Rev 2010;16:6-15. [9] Milunsky A, Milunsky J. Genetic disorders and the fetus: diagnosis, prevention and treatment. 6th ed. West Sussex, UK: John Wiley& Sons Ltd 2010; [10] Mills JL, Graubard BI. Is moderate drinking during pregnancy associated with an increased risk for malformations? Pediatrics 1987; 80:309-14. [11] Suarez L, Felkner M, Brender, JD, Canfield, M, Hendricks, K. Maternal exposures to cigarette smoke, alcohol, and street drugs and neural tube defect occurrence in offspring. Matern Child Health J 2008;12:394-401. [12] Shaw G.M, Nelson V, Carmichael SL, et al. Maternal periconceptional vitamins: interactions with selected factors and congenital anomalies ? Epidemiology 2002; 13:625-30. [13] Shaw GM, Velie EM, Morland KB. Parental recreational drug use and risk of neural tube defects. Am J Epidemiol 1996; 144:1155-60. [14] Grewal J, Carmichael, SL, Ma, C, et al. Maternal periconceptional smoking and alcohol consumption and risk for select congenital anomalies. Birth Defects Res A Clin Mol Teratol 2008; 82:519-26.

[15] Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283:2008-12. [16] Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 3rd Symposium on Systematic Reviews: Beyond the Basics, Oxford, UK 2000; Available at: J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 07/07/15 For personal use only.

http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm (Accessed 8 December, 2014). [17] Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21:1539-58. [18] Der Simonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1996; 7:177-88. [19] Egger M, Davey Smith, G, Schneider, M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315:629-34. [20] Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50:1088-101. [21] Friedman, JM. Can maternal alcohol ingestion cause neural tube defects? J Pediatr 1982; 101: 232-4. [22] Polygenis, D, Wharton S, Malmberg C, et al. Moderate alcohol consumption during pregnancy and the incidence of fetal malformations: a meta-analysis. Neurotoxicol Teratol 1998; 20: 61-7. [23] Bell JC, Raynes-Greenow C, Turner RM, et al. Maternal alcohol consumption during pregnancy and the risk of orofacial clefts in infants: a systematic review and meta-analysis. Paediatr Perinat Epidemiol 2014; 28: 322-32. [24] Benedum CM, Yazdy MM, Mitchell AA, et al. Risk of spina bifida and maternal cigarette, alcohol, and coffee use during the first month of pregnancy. Int J Environ Res Public Health 2013; 10:3263-81.

[25] De Marco P, Merello E, Calevo MG, et al. Maternal periconceptional factors affect the risk of spina bifida-affected pregnancies: an Italian case-control study. Child Nerv Syst 2011; 27:107381. [26] Groenen PMW. Nutritional and environmental factors in human spina bifida: an emphasis on myo-inositol. 2004; [Sl: sn].

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[27] McDonald AD, Armstrong BG, Sloan M. Cigarette, alcohol, and coffee consumption and congenital defects. Am J Public Health 1992; 82:91-3. [28] Makelarski, JA, Romitti PA, Sun L, et al. Periconceptional maternal alcohol consumption and neural tube defects. Birth Defects Res A Clin Mol Teratol 2013; 97:152-60.

Figure Legends Figure 1. Process of study selection

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Figure 2. Meta-analysis of maternal periconceptional alcohol consumption and NTDs risk

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Figure 3. Subgroup analysis of maternal alcohol consumption in the first trimester and NTDs risk (First trimester 1:Yes 0:No)

Figure 4. Meta-analysis of maternal periconceptional alcohol consumption and spina bifida risk

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Figure 5. Meta-analysis of maternal periconceptional binge drinking and NTDs risk

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Table 1. Information of the studies included in the mata-analysis

Study ID

Design

Country

Case-control

USA, Canada

Benedum 2013 [24]

Time period

1988-2012

Case population

776 spina bifida

OR (95% CI) for highest vs. lowest alcohol intake

1.2 (0.8-2.0)

Heavy drinking(≥4 drinks per drinking day);

Data collection period

Study quality

P1

7

B1-P2

7

B3-P3

7

P1

8

1st trimester

8

B3-P3

7

1st trimester

7

No heavy drinking

Makelarski 2013 [28]

Case-control

USA

1997-2005

328 anencephaly, 703 spina bifida and 129 other rare subtype

1.1 (0.7-1.6)

De Marco 2011 [25]

Case-control

Italy

2000-2008

133 spina bifida

3.05 (1.24-7.50)

>30 drinks per month; 16-30; 515; 0 More than half a liter per day; Less than half a liter per day

Grewal

116 anencephaly and Case-control

USA

1999-2003

2008 [14]

0.6 (0.3-1.4) 145 spina bifida

USA

1995-2000

175 NTDs

0.9 (0.2-3.9) for ≥1 drink daily and 1.3(0.6-2.9) for binge drinking

Case-control

Dutch

1999-2001

128 spina bifida

0.6 (0.4-1.0)

2008 [11]

Binge drinking(≥5 drinks per drinking occasion); No consumption

Case-control

Suarez

Groenen 2004 [26]

Alcohol intake categorization

Binge drinking (>3 drinks on any occasion); ≥1 drink daily;

Maternal periconceptional alcohol consumption and the risk of neural tube defects in offspring: a meta-analysis.

Several studies have been conducted to examine the association between alcohol consumption during pregnancy and risk of neural tube defects (NTDs), wh...
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