Evidence-Based Medicine Online First, published on November 26, 2013 as 10.1136/eb-2013-101556 Aetiology Cohort study

Beyond genetics: focusing on maternal environment for congenital heart disease prevention 10.1136/eb-2013-101556

Vidu Garg, Madhumita Basu Center for Cardiovascular and Pulmonary Children’s Hospital, Columbus, Ohio, USA

Research,

Nationwide

Correspondence to: Dr Vidu Garg, Center for Cardiovascular and Pulmonary Research, Nationwide Children’s Hospital, 700 Children’s Drive, Room WB4221, Columbus, OH 43205, USA; vidu.garg@ nationwidechildrens.org

Commentary on: Liu S, Joseph KS, Lisonkova S, et al. Association between maternal chronic conditions and congenital heart defects: a population-based cohort study. Circulation 2013;128:583–9.

Context Congenital heart disease (CHD) is the most common birth defect, accounting for about one-quarter of birth defects resulting in mortality.1 Aetiology for the majority of CHD remains unknown, but is thought to be multifactorial with genetic and environmental (non-genetic) contributors. Advances in molecular biology and genetic technologies have aided identification of genetic contributors for CHD. Increasing numbers of genomic abnormalities have been discovered in individuals with CHD using next-generation sequencing and array-based methodologies.2 While great strides have been made, genetic aetiologies are identified in only a subset of CHD.2 Epidemiological studies have demonstrated associations between maternal diseases, maternal exposure to environmental teratogens and CHD.3 4 However, there remains a paucity of information on their contribution to overall CHD prevalence and link to specific CHD subtypes. Liu and colleagues move towards quantifying the association between chronic maternal conditions and CHD and its subtypes.

Methods Investigators performed a large-scale population-based cohort study with 2 278 838 infants born in Canada from 2002 to 2010. Phenotypic classification of infants with CHD and maternal conditions were obtained by hospital record review. The prevalence of CHD and its subtypes was determined, and logistic regression analysis performed to establish associations between maternal conditions and CHD in offspring to estimate relative risk. This was expressed as adjusted ORs (aORs).

Findings The authors identified a total of 23 200 infants with CHD after excluding 3228 preterm infants with isolated patent ductus arteriosus (PDA). The overall prevalence of CHD was 101.8/10 000 live-births and 22.3/10 000 live-births for severe CHD. A declining trend in the incidence of CHD

from 2002 to 2010 was observed. Within CHD subsets, the highest prevalent were isolated septal defects (32/10 000 live-births) and PDA (23.7/ 10 000 term live-births) while conotruncal defects were the most common severe CHD (10.4/10 000 live-births). Among maternal conditions, mothers with CHD had the highest risk for having an offspring with CHD consistent with genetic contributors. Maternal diabetes and systemic connective tissue disorders were found to be strongly associated with CHD. Multifetal pregnancy and maternal age above 40 years also increased risk. In CHD subtype analysis, type 2 diabetes and connective tissue disorders were associated with heterotaxy and left ventricular outflow tract obstruction, while type 1 diabetes increased risk for conotruncal and atrioventricular septal defects. Maternal smoking and alcohol or substance use did not increase risk for tested CHD subtypes and only alcohol or substance use was associated with an increased overall CHD risk. An estimated 14% of CHD could be prevented if maternal risk factors were eliminated.

Commentary Although numerous studies have demonstrated associations between specific maternal conditions and CHD risk in offspring, this study represents one of the largest and most comprehensive studies. The majority of the findings confirm those of other reports.5 6 The novelty of this work, due to the large study population, is its power to examine risk factors for specific CHD subtypes, as well as its ability to estimate the proportion of children with preventable cardiac malformations. An inherent limitation arises from the difficulty in conducting accurate, quantitative assessment of maternal exposures and conditions from hospital records. Another significant limitation is that some maternal characteristics are not independent risk factors, such as obesity, type 2 diabetes, multifetal pregnancy and advanced maternal age (fertility drug usage is reported to increase CHD risk).4 The lack of investigation into medication use during pregnancy, a known CHD risk factor, also limits the study’s impact.3 4 This study suggests a significant reduction in CHD prevalence could be achieved by improved preconception counselling to reduce modifiable risk factors such as alcohol use and obesity, or by encouraging better managed maternal diabetes and hypertension, potentially in a targeted fashion in combination with genetic risk factors. Implementation of these measures requires coordinated efforts to both improve education and assist with maternal disease management. Competing interests None. References 1. Go AS, Mozaffarian D, Roger VL. Executive summary: heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 2013;127:143–52. 2. Richards AA, Garg V. Genetics of congenital heart disease. Curr Cardiol Rev 2010;6:91–7. 3. Jenkins KJ, Correa A, Feinstein JA, et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007;115:2995–3014. 4. Patel SS, Burns TL. Nongenetic risk factors and congenital heart defects. Pediatr Cardiol 2013;34:1535–55. 5. Khoshnood B, Loane M, Garne E, et al. Recent decrease in the prevalence of congenital heart defects in Europe. J Pediatr 2013;162:108–13.e2. 6. Oyen N, Poulsen G, Boyd HA, et al. National time trends in congenital heart defects, Denmark, 1977–2005. Am Heart J 2009;157:467–73.e1.

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Beyond genetics: focusing on maternal environment for congenital heart disease prevention.

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