Maternal Cigarette Smoking and Congenital Heart Defects

Abstract

See related article, p 978Congenital heart defects (CHDs) are of public health concern because they affect approximately 1% of newborns,1Reller M.D. Strickland M.J. Riehle-Colarusso T. Mahle W.T. Correa A. Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005.J Pediatr. 2008; 153: 807-813Abstract Full Text Full Text PDF PubMed Scopus (648) Google Scholar, 2Hoffman J.I. Kaplan S. The incidence of congenital heart disease.J Am Coll Cardiol. 2002; 39: 1890-1900Abstract Full Text Full Text PDF PubMed Scopus (3664) Google Scholar, 3van der Linde D. Konings E.E. Slager M.A. Witsenburg M. Helbing W.A. Takkenberg J.J. et al.Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis.J Am Coll Cardiol. 2011; 58: 2241-2247Abstract Full Text Full Text PDF PubMed Scopus (1691) Google Scholar are a leading cause of infant mortality,4Go A.S. Mozaffarian D. Roger V.L. Benjamin E.J. Berry J.D. Blaha M.J. et al.Heart disease and stroke statistics–2014 update: a report from the American Heart Association.Circulation. 2014; 129: 399-410Crossref PubMed Scopus (1227) Google Scholar and often result in increased use and costs of health services among affected children, adolescents, and adults.5Boulet S.L. Riehle-Colarusso T. Correa-Villasenor A. Health care costs of congenital heart defects.in: Wyszynski D.F. Graham T.P. Congenital heart defects: from origin to treatment. Oxford University Press, New York2010: 493-501Google Scholar In recent decades, epidemiologic research has made notable progress in the identification of modifiable risk factors for some CHDs (eg, congenital rubella infection, use of certain medications, and pregestational diabetes).6Jenkins K.J. Correa A. Feinstein J.A. Botto L. Britt A.E. Daniels S.R. 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: 2995-3014Crossref PubMed Scopus (562) Google Scholar For most CHDs, however, the causes remain unknown. In this issue of The Journal, Sullivan et al7Sullivan P.M. Dervan L.A. Reiger S. Buddhe S. Schwartz S.M. Risk of congenital heart defects in the offspring of smoking mothers: a population-based study.J Pediatr. 2015; 166: 978-984PubMed Google Scholar describe results of a population-based study in which they assessed the possible association of maternal periconceptional cigarette smoking and the occurrence of CHDs among live births by linking self-reports of cigarette smoking on birth certificates with records of children with CHD (ie, cases) identified from birth certificates and a statewide hospital discharge registry. The authors examined 19 specific CHD phenotypes and observed associations between maternal cigarette smoking during the first trimester of pregnancy and 3 phenotypes: pulmonary valve anomalies, pulmonary artery anomalies, and isolated secundum type of atrial septal defects. They also observed a suggestion of a dose-response relationship between maternal cigarette smoking and the risk of CHDs examined as a group. These findings are of interest because they highlight: (1) methodologic issues common to studies of associations of maternal cigarette smoking, a prevalent and modifiable exposure, with specific CHD phenotypes in the offspring; (2) challenges in interpreting the nature of observed associations between maternal cigarette smoking and CHDs; and (3) opportunities for prevention and smoking cessation efforts among women of childbearing age. See related article, p 978 There are a number of methodologic issues in epidemiologic studies of cigarette smoking and CHDs that careful design and execution can help address. CHDs encompass a wide range of phenotypes with varying severity and potentially different etiologies. These can involve a single cardiac lesion or multiple cooccurring cardiac lesions. Additional defects also may be present in other organ systems. These additional defects may or may not be part of known genetic disorders. The different phenotypes of CHDs also can vary in risk factors and in the proportion that result in spontaneous fetal death or elective termination of pregnancy after prenatal diagnosis. The effect of inclusion or exclusion of these birth outcomes on the estimated prevalence may vary for different CHD phenotypes. Therefore, population-based studies of CHDs generally should aim to include all CHD cases among live births, stillbirths, and pregnancy terminations, whenever possible, to minimize the potential for selection bias and use a system of classification of CHD phenotypes into relatively homogeneous subgroups with respect to the presence of known underlying etiologies and the potential risk factors under study to maximize the potential for meaningful analysis.8Riehle-Colarusso T. Strickland M.J. Reller M.D. Mahle W.T. Botto L.D. Siffel C. et al.Improving the quality of surveillance data on congenital heart defects in the metropolitan Atlanta congenital defects program.Birth Defects Res A Clin Mol Teratol. 2007; 79: 743-753Crossref PubMed Scopus (48) Google Scholar Classification of CHDs, however, into specific phenotypes requires expertise that often is not readily available, and, when available, can pose a dilemma for analysis. Although classification of specific CHD phenotypes may offer a better potential for identifying risk factors specific for such phenotypes, individual CHD phenotypes tend to be rare. The sample size obtained for a given phenotype in a given study may be inadequate for reliable analysis. A case-control study design often is used to examine multiple risk factors for various specific CHD phenotypes because this type of design generally is less costly and more efficient than cohort studies designed to examine one specific exposure in relation to the risk for various specific CHD phenotypes. However, case-control studies of prenatal exposures often rely on maternal self-reports (ie, subject to recall errors) that may result in misclassification of exposure status and possible biases in the relative risk estimates. Because of these and other methodologic issues (eg, accuracy of CHD phenotype classification based on International Classification of Diseases, 9th Revision, Clinical Modification codes, multiple comparisons of exposures and phenotypes), epidemiologic studies of cigarette smoking and CHDs clearly are challenging to conduct. Nonetheless, such studies are needed and valuable because they help to add to the body of literature on a possible risk factor for CHDs that is prevalent and potentially modifiable.6Jenkins K.J. Correa A. Feinstein J.A. Botto L. Britt A.E. Daniels S.R. 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: 2995-3014Crossref PubMed Scopus (562) Google Scholar, 9The health consequences of smoking—50 years of progress: a report of the Surgeon General. – Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014. http://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf. Accessed January 7, 2015.Google Scholar, 10Committee opinion no. 503: tobacco use and women's health.Obstet Gynecol. 2011; 118: 746-750Crossref PubMed Scopus (34) Google Scholar, 11Lee L.J. Lupo P.J. Maternal smoking during pregnancy and the risk of congenital heart defects in offspring: a systematic review and metaanalysis.Pediatr Cardiol. 2013; 34: 398-407Crossref PubMed Scopus (68) Google Scholar Interpreting associations between maternal cigarette smoking and CHDs is further complicated by the fact that different CHD phenotypes are multifactorial in origin, involving complex interplays between genetic and environmental factors, so that infants with the same CHD phenotype (eg, hypoplastic left heart syndrome) may exhibit different risk factor profiles. Therefore, in interpreting whether observed associations between one type of exposure such as cigarette smoking and specific CHDs are likely to be causal, it is useful to consider the quality of the evidence with respect to guidelines for establishing causality for a given exposure (ie, temporality, strength of association, biological or dose-response gradient, consistency across studies, plausibility/coherence, experimental evidence, and specificity).12Hill A.B. The environment and disease: association or causation?.Proc R Soc Med. 1965; 56: 295-300Google Scholar Maternal cigarette smoking can be considered causally related to oral clefts because there is moderate-to-strong evidence for 5 of the 7 guidelines for causality.9The health consequences of smoking—50 years of progress: a report of the Surgeon General. – Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014. http://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf. Accessed January 7, 2015.Google Scholar, 13Little J. Cardy A. Munger R.G. Tobacco smoking and oral clefts: a meta-analysis.Bull World Health Organ. 2004; 82: 213-218PubMed Google Scholar In contrast, the evidence for causality for the association between maternal cigarette smoking and right-sided obstructive heart lesions and secundum type of atrial septal defects is more limited: there is moderate-to-strong evidence for only 3 of the guidelines (temporality, strength of association, and specificity) and weak-to-moderate evidence for a fourth and fifth (consistency across studies and dose-response).9The health consequences of smoking—50 years of progress: a report of the Surgeon General. – Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014. http://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf. Accessed January 7, 2015.Google Scholar, 11Lee L.J. Lupo P.J. Maternal smoking during pregnancy and the risk of congenital heart defects in offspring: a systematic review and metaanalysis.Pediatr Cardiol. 2013; 34: 398-407Crossref PubMed Scopus (68) Google Scholar However, there is little to no evidence for coherence/biologic plausibility and no experimental evidence in support of the associations between maternal cigarette smoking early in pregnancy and CHDs. Thus, at present, the level of evidence regarding a causal relationship between maternal cigarette smoking and right obstructive heart defects and secundum atrial septal defects probably could be considered suggestive at best. Worth noting is that because most studies of CHDs and maternal cigarette smoking have involved multiple comparisons of various groupings of CHDs, there is always the concern that some of the observed associations in analyses of multiple exposures and/or phenotypes could reflect chance (ie, type I error). Further studies are needed to rule out chance and bias inherent to observational studies as possible explanations for the observed associations between maternal cigarette smoking and CHDs.9The health consequences of smoking—50 years of progress: a report of the Surgeon General. – Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014. http://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf. Accessed January 7, 2015.Google Scholar, 11Lee L.J. Lupo P.J. Maternal smoking during pregnancy and the risk of congenital heart defects in offspring: a systematic review and metaanalysis.Pediatr Cardiol. 2013; 34: 398-407Crossref PubMed Scopus (68) Google Scholar, 14Alverson C.J. Strickland M.J. Gilboa S.M. Correa A. Maternal smoking and congenital heart defects in the Baltimore-Washington Infant Study.Pediatrics. 2011; 127: e647-e653Crossref PubMed Scopus (93) Google Scholar, 15Malik S. Cleves M.A. Honein M.A. Romitti P.A. Botto L.D. Yang S. et al.Maternal smoking and congenital heart defects.Pediatrics. 2008; 121: e810-e816Crossref PubMed Scopus (158) Google Scholar In this issue of The Journal, Sullivan et al7Sullivan P.M. Dervan L.A. Reiger S. Buddhe S. Schwartz S.M. Risk of congenital heart defects in the offspring of smoking mothers: a population-based study.J Pediatr. 2015; 166: 978-984PubMed Google Scholar report on a population-based, case-control study in which they examined possible associations of CHDs with maternal cigarette smoking. They found frequencies of CHDs and of maternal cigarette smoking comparable with those reported in other recent population-based studies.14Alverson C.J. Strickland M.J. Gilboa S.M. Correa A. Maternal smoking and congenital heart defects in the Baltimore-Washington Infant Study.Pediatrics. 2011; 127: e647-e653Crossref PubMed Scopus (93) Google Scholar, 15Malik S. Cleves M.A. Honein M.A. Romitti P.A. Botto L.D. Yang S. et al.Maternal smoking and congenital heart defects.Pediatrics. 2008; 121: e810-e816Crossref PubMed Scopus (158) Google Scholar, 16Osterman M.J. Martin J.A. Curtin S.C. Matthews T.J. Wilson E.C. Kirmeyer S. Newly released data from the revised U.S. birth certificate, 2011.Natl Vital Stat Rep. 2013; 62: 1-22Google Scholar In addition, they reported aORs for maternal cigarette smoking that were weakly to modestly associated with pulmonary valve anomalies (aOR 1.48, 95% CI 1.15-1.90); pulmonary artery anomalies (aOR 1.71, 95% CI 1.40-2.09); and isolated secundum type of atrial septal defects (aOR 1.22, 95% CI 1.08-1.38). These findings are consistent with findings from 2 population-based case-control studies that also examined maternal cigarette smoking and CHDs (Table).14Alverson C.J. Strickland M.J. Gilboa S.M. Correa A. Maternal smoking and congenital heart defects in the Baltimore-Washington Infant Study.Pediatrics. 2011; 127: e647-e653Crossref PubMed Scopus (93) Google Scholar, 15Malik S. Cleves M.A. Honein M.A. Romitti P.A. Botto L.D. Yang S. et al.Maternal smoking and congenital heart defects.Pediatrics. 2008; 121: e810-e816Crossref PubMed Scopus (158) Google Scholar Furthermore, Sullivan et al7Sullivan P.M. Dervan L.A. Reiger S. Buddhe S. Schwartz S.M. Risk of congenital heart defects in the offspring of smoking mothers: a population-based study.J Pediatr. 2015; 166: 978-984PubMed Google Scholar reported a dose-response relationship between maternal cigarette smoking and the risk for all CHDs as a group, particularly among offspring of mothers 35 years of age and older. Because these dose-response data were presented only for all CHDs combined, and different studies differ in inclusion and exclusion criteria and classification systems for specific CHD phenotypes, direct comparison with previous studies is not possible.TableORs from published studies of associations between maternal cigarette smoking, atrial septal defects, and right ventricular outflow tract obstruction defectsStudy, locationTypes of CHDsLight smoking∗The study by Malik et al15 included maternal smoking from 1 month before conception through the end of the first trimester; smoking levels were defined as light, 1-14 cigarettes per day; medium, 15-24 cigarettes per day; heavy, ≥25 cigarettes per day.,†The study by Alverson et al14 included maternal smoking during the first trimester; smoking levels were defined as light, 1-10 cigarettes per day; medium, 11-20 cigarettes per day; heavy, ≥21 cigarettes per day.Moderate smoking∗The study by Malik et al15 included maternal smoking from 1 month before conception through the end of the first trimester; smoking levels were defined as light, 1-14 cigarettes per day; medium, 15-24 cigarettes per day; heavy, ≥25 cigarettes per day.,†The study by Alverson et al14 included maternal smoking during the first trimester; smoking levels were defined as light, 1-10 cigarettes per day; medium, 11-20 cigarettes per day; heavy, ≥21 cigarettes per day.Heavy smoking∗The study by Malik et al15 included maternal smoking from 1 month before conception through the end of the first trimester; smoking levels were defined as light, 1-14 cigarettes per day; medium, 15-24 cigarettes per day; heavy, ≥25 cigarettes per day.,†The study by Alverson et al14 included maternal smoking during the first trimester; smoking levels were defined as light, 1-10 cigarettes per day; medium, 11-20 cigarettes per day; heavy, ≥21 cigarettes per day.No. of case/control infantsOR (95% CI)No. of case/control infantsOR (95% CI)No. of case/control infantsOR (95% CI)Malik, et al,15Malik S. Cleves M.A. Honein M.A. Romitti P.A. Botto L.D. Yang S. et al.Maternal smoking and congenital heart defects.Pediatrics. 2008; 121: e810-e816Crossref PubMed Scopus (158) Google Scholar USAtrial septal defects‡This category refers to secundum type of atrial septal defects.69/4582.02 (1.47-2.77)22/1901.78 (1.05-3.01)6/452.35 (0.92-6.00)Right ventricular outflow tract obstruction defects79/5221.25 (0.95-1.65)23/2040.93 (0.59-1.49)13/472.35 (1.21-4.53)Pulmonary valve stenosis58/4581.24 (0.90-1.70)17/1900.91 (0.53-1.55)10/452.31 (1.11-4.83)Alverson, et al,14Alverson C.J. Strickland M.J. Gilboa S.M. Correa A. Maternal smoking and congenital heart defects in the Baltimore-Washington Infant Study.Pediatrics. 2011; 127: e647-e653Crossref PubMed Scopus (93) Google Scholar Maryland, Washington, DC, northern VirginiaAtrial septal defects‡This category refers to secundum type of atrial septal defects.37/5391.41 (0.95-2.11)22/3141.59 (0.98-2.58)7/1071.64 (0.74-3.62)Right ventricular outflow tract obstruction defects49/5391.20 (0.88-1.69)27/3141.25 (0.81-1.91)12/1071.71 (0.92-3.18)Pulmonary valve stenosis45/5391.53 (1.06-2.19)18/3141.15 (0.69-1.92)9/1071.79 (0.88-3.54)Pulmonary atresia with intact ventricular septum4/5390.73 (0.25-2.14)8/3142.43 (1.06-5.53)1/1070.88 (0.12-6.62)∗ The study by Malik et al15Malik S. Cleves M.A. Honein M.A. Romitti P.A. Botto L.D. Yang S. et al.Maternal smoking and congenital heart defects.Pediatrics. 2008; 121: e810-e816Crossref PubMed Scopus (158) Google Scholar included maternal smoking from 1 month before conception through the end of the first trimester; smoking levels were defined as light, 1-14 cigarettes per day; medium, 15-24 cigarettes per day; heavy, ≥25 cigarettes per day.† The study by Alverson et al14Alverson C.J. Strickland M.J. Gilboa S.M. Correa A. Maternal smoking and congenital heart defects in the Baltimore-Washington Infant Study.Pediatrics. 2011; 127: e647-e653Crossref PubMed Scopus (93) Google Scholar included maternal smoking during the first trimester; smoking levels were defined as light, 1-10 cigarettes per day; medium, 11-20 cigarettes per day; heavy, ≥21 cigarettes per day.‡ This category refers to secundum type of atrial septal defects. Open table in a new tab Although the evidence for a causal relationship between cigarette smoking and CHDs is still open to question, the other known adverse effects of smoking for pregnancy outcomes9The health consequences of smoking—50 years of progress: a report of the Surgeon General. – Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014. http://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf. Accessed January 7, 2015.Google Scholar and the current 10%-15% prevalence of smoking among women of childbearing age16Osterman M.J. Martin J.A. Curtin S.C. Matthews T.J. Wilson E.C. Kirmeyer S. Newly released data from the revised U.S. birth certificate, 2011.Natl Vital Stat Rep. 2013; 62: 1-22Google Scholar make it imperative to continue to support smoking prevention and cessation efforts in this population. A variety of measures could be adopted to prevent women from initiating smoking and to encourage those who currently smoke to quit. These include increasing the price of tobacco products, implementing and enforcing comprehensive smoke-free laws, and increasing access to help quitting.17Sanchez-Rodriguez J.E. Bartolome M. Canas A.I. Huetos O. Navarro C. Rodriguez A.C. et al.Anti-smoking legislation and its effects on urinary cotinine and cadmium levels.Environ Res. 2015; 136: 227-233Crossref PubMed Scopus (21) Google Scholar, 18Hawkins S.S. Baum C.F. Oken E. Gillman M.W. Associations of tobacco control policies with birth outcomes.JAMA Pediatr. 2014; 168: e142365Crossref PubMed Scopus (34) Google Scholar, 19Centers for Disease Control and Prevention Best Practices for Comprehensive Tobacco Control Programs—2014.http://www.cdc.gov/tobacco/stateandcommunity/best_practices/index.htmGoogle Scholar Increasing awareness of the consequences of smoking during pregnancy among women is also important. A recent study conducted among a sample of US women who smoke found that they were aware there were general health risks of smoking during pregnancy, such as an increase in premature delivery or having an infant with low birth weight; however, many were not aware of other specific consequences, such as birth defects.20Levis D.M. Stone-Wiggins B. O'Hegarty M. Tong V.T. Polen K.N. Cassell C.H. et al.Women's perspectives on smoking and pregnancy and graphic warning labels.Am J Health Behav. 2014; 38: 755-764Crossref PubMed Scopus (25) Google Scholar Providing more information to women about the risks of smoking during pregnancy could motivate many of them to quit. Studies suggest that pregnant women are often motivated to change or adopt new behaviors because they want their unborn babies to be healthy.21Prue C.E. Flores A.L. Panissidi P. Lira A. But I've already had a healthy baby: folic acid formative research with Latina mothers.J Womens Health (Larchmt). 2008; 17: 1257-1269Crossref PubMed Scopus (11) Google Scholar, 22Squiers L. Mitchell E.W. Levis D.M. Lynch M. Dolina S. Margolis M. et al.Consumers' perceptions of preconception health.Am J Health Promot. 2013; 27: S10-S19Crossref PubMed Scopus (25) Google Scholar Health education efforts also could include antismoking media campaigns such as Centers for Disease Control and Prevention Tips from Former Smokers campaign,23Centers for Disease Control and Prevention [homepage on the Internet]. Atlanta, GA [updated 2014 Oct 7; cited 2014 Dec 4]. Tips from former smokers; [about 9 screens]. http://www.cdc.gov/tobacco/campaign/tips/. Accessed January 7, 2015.Google Scholar which features a story about the dangers of smoking during pregnancy. Women who wish to quit smoking during pregnancy have options such as brief tobacco counseling (eg, the 5As: ask, advise, assess, assist, arrange24Agency for Healthcare Research and Quality [homepage on the Internet]. Rockville, MD. [updated 2012 Dec; cited 2014 Dec 4]. Five major steps to intervention (the “5 A’s”); [1 screen]. http://www.ahrq.gov/professionals/clinicians-providers/guidelines-recommendations/tobacco/5steps.html. Accessed January 7, 2015.Google Scholar) in settings in which women of child-bearing age encounter medical professionals and calling a quitline. The ideal time to reach women with prevention messages and cessation assistance, however, is during the preconception period. By the time a woman finds out about her pregnancy and begins prenatal care, it may be too late to prevent some adverse outcomes, such as oral clefts, CHDs, and other birth defects, that occur early in pregnancy.25Atrash H.K. Johnson K. Adams M. Cordero J.F. Howse J. Preconception care for improving perinatal outcomes: the time to act.Matern Child Health J. 2006; 10: S3-S11Crossref PubMed Scopus (157) Google Scholar Additionally, women who decide to quit smoking before pregnancy have more treatment options available for doing so. Cessation medication is not recommended as first-line treatment for pregnant women, and the safety and efficacy of nicotine-replacement therapy during pregnancy has not been established.10Committee opinion no. 503: tobacco use and women's health.Obstet Gynecol. 2011; 118: 746-750Crossref PubMed Scopus (34) Google Scholar, 262008 PHS Guideline Update Panel, Liaisons, and StaffTreating tobacco use and dependence: 2008 update U.S. Public Health Service Clinical Practice Guideline executive summary.Respir Care. 2008; 53: 1217-1222PubMed Google Scholar, 27Coleman T. Cooper S. Thornton J.G. Grainge M.J. Watts K. Britton J. et al.A randomized trial of nicotine-replacement therapy patches in pregnancy.N Engl J Med. 2012; 366: 808-818Crossref PubMed Scopus (148) Google Scholar The study by Sullivan et al7Sullivan P.M. Dervan L.A. Reiger S. Buddhe S. Schwartz S.M. Risk of congenital heart defects in the offspring of smoking mothers: a population-based study.J Pediatr. 2015; 166: 978-984PubMed Google Scholar adds to the body of literature on possible associations between maternal cigarette smoking early in pregnancy and 3 of 19 specific CHD phenotypes examined in the offspring. Although further studies are warranted to corroborate the observed associations, the current evidence on adverse effects of maternal cigarette smoking on pregnancy outcomes suggests that the wisest course of action is to continue to promote smoking prevention and cessation efforts among women of childbearing age. Risk of Congenital Heart Defects in the Offspring of Smoking Mothers: A Population-Based StudyThe Journal of PediatricsVol. 166Issue 4PreviewTo conduct a population-based study examining the occurrence of congenital heart defects (CHDs) in relation to maternal smoking during the first trimester of pregnancy. Full-Text PDF