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Original Investigation |

Maternal Smoking During Pregnancy and Offspring Conduct Problems:  Evidence From 3 Independent Genetically Sensitive Research Designs FREE

Darya Gaysina, PhD1; David M. Fergusson, PhD2; Leslie D. Leve, PhD3; John Horwood, MSc2; David Reiss, MD4; Daniel S. Shaw, PhD5; Kit K. Elam, PhD1; Misaki N. Natsuaki, PhD6; Jenae M. Neiderhiser, PhD7; Gordon T. Harold, PhD1
[+] Author Affiliations
1School of Psychology, College of Medicine, Biological Sciences and Psychology, University of Leicester, Leicester, England
2Christchurch Health and Development Study, Department of Psychological Medicine, University of Otago, Christchurch, New Zealand
3Oregon Social Learning Center, Eugene
4Yale Child Study Center, New Haven, Connecticut
5Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania
6Department of Psychology, University of California, Riverside
7Department of Psychology, The Pennsylvania State University, University Park
JAMA Psychiatry. 2013;70(9):956-963. doi:10.1001/jamapsychiatry.2013.127.
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Importance  Several studies report an association between maternal smoking during pregnancy and offspring conduct disorder. However, past research evidences difficulty in disaggregating prenatal environmental influences from genetic and postnatal environmental influences.

Objective  To examine the relationship between maternal smoking during pregnancy and offspring conduct problems among children reared by genetically related mothers and genetically unrelated mothers.

Design, Setting, and Participants  The following 3 studies using distinct but complementary research designs were used: The Christchurch Health and Development Study (a longitudinal cohort study that includes biological and adopted children), the Early Growth and Development Study (a longitudinal adoption-at-birth study), and the Cardiff IVF (In Vitro Fertilization) Study (an adoption-at-conception study among genetically related families and genetically unrelated families). Maternal smoking during pregnancy was measured as the mean number of cigarettes per day (0, 1-9, or ≥10) smoked during pregnancy. Possible covariates were controlled for in the analyses, including child sex, birth weight, race/ethnicity, placement age, and breastfeeding, as well as maternal education and maternal age at birth and family breakdown, parenting practices, and family socioeconomic status.

Main Outcomes and Measure  Offspring conduct problems (age range, 4-10 years) reported by parents or teachers using the behavior rating scales by Rutter and Conners, the Child Behavior Checklist and the Children’s Behavior Questionnaire Short Form, and the Strengths and Difficulties Questionnaire.

Results  A significant association between maternal smoking during pregnancy and offspring conduct problems was observed among children reared by genetically related mothers and genetically unrelated mothers. Results from a meta-analysis affirmed this pattern of findings across pooled study samples.

Conclusions and Relevance  Findings across 3 studies using a complement of genetically sensitive research designs suggest that smoking during pregnancy is a prenatal risk factor for offspring conduct problems when controlling for specific perinatal and postnatal confounding factors.

Conduct disorder represents an issue of significant social, clinical, and practice concern, with evidence highlighting increasing rates of child conduct problems internationally.1,2 Identifying risk factors and understanding mechanisms by which these risk factors influence conduct problems have important implications for future intervention and prevention efforts.

Maternal smoking during pregnancy is known to be a risk factor for offspring psychological problems, including attention deficits and conduct problems.3,4 Plausible biological mechanisms have been proposed to explain the prenatal effect of nicotine exposure on neurodevelopmental processes in animals57; however, the underlying mechanisms specific to smoking in humans are not well understood.3,8 It has been suggested that anorexigenic, hypoxic, vascular, and placental effects of nicotine may have direct teratogenic influences on the fetus and result in adverse physiological and psychological development.9

Longitudinal epidemiological studies have reported statistical associations between the extent of maternal smoking during pregnancy and subsequent offspring conduct disorder,1014 attention-deficit/hyperactivity disorder,15,16 and criminal behavior.17,18 Some investigations have provided evidence of a dose-response relationship between the number of cigarettes smoked during pregnancy and the rate of subsequent conduct problems in offspring.19

However, the effect of maternal pregnancy smoking on offspring conduct problems can be confounded by several background factors, including race/ethnicity, early age at pregnancy, low socioeconomic status, child-rearing environment, and history of maternal psychopathologic conditions.11,13,2023 For example, mothers who smoke during pregnancy are more likely to provide a child-rearing environment that promotes or at least condones externalizing behavior.21 Therefore, the postnatal environment (independent of pregnancy smoking) may influence the development of conduct problems. Investigations have found that the association between maternal smoking during pregnancy and offspring conduct problems persists after accounting for these possible confounders, while others have failed to demonstrate the association when confounders were considered.21,24

Another problem with correlational family-based studies is the possibility of genetic risk factors and unmeasured environmental factors confounding the relationship between maternal smoking during pregnancy and offspring conduct problems.25 Both maternal smoking during pregnancy26 and conduct problems27,28 are influenced by genetic factors that have been shown to overlap.29 Maternal smoking during pregnancy is associated with externalizing problems and forming partnerships with antisocial males.21,30,31 Moreover, adults with a history of externalizing behavior tend to provide postnatal environments that foster the transmission of this behavior across generations.32 Indeed, passive genotype-environment correlation may be a factor in this association whereby genetic factors common to both the rearing environment (eg, harsh parenting) and the specific phenotype considered (eg, child conduct problems) underlie any observed association.33 Thus, maternal smoking during pregnancy could be a marker of a genetic liability rather than a direct cause of children’s later conduct problems. Therefore, the association between maternal smoking during pregnancy and offspring conduct problems may be genetically rather than environmentally mediated.

Recent studies using genetically sensitive designs have attempted to overcome this limitation of prior studies. Findings of studies3437 using sibling designs suggest that environmental variables influencing both pregnancy smoking and offspring conduct problems account for the observed associations. Previous results using an in vitro fertilization (IVF) study design, in which children are either genetically related or genetically unrelated to the mother undergoing the pregnancy,38 and a children of twins39 study design also suggest that unmeasured confounders indexed by inherited influences contribute to the link.

Much of the existing evidence has been obtained from studying biological parents rearing their biological children, which does not allow the effects of genetics from prenatal and postnatal environmental factors to be clearly disentangled. Nor does it allow for the role of passive genotype-environment correlation to be disentangled from genetic and postnatal environmental (eg, parenting behavior) associations.

The present study focuses on examining the links between prenatal smoking and offspring conduct problems and the contribution of psychosocial and inherited factors using data from the following 3 independent studies: the Christchurch Health and Development Study (CHDS) in New Zealand, the Early Growth and Development Study (EGDS) in the United States, and the Cardiff IVF (C-IVF) Study in the United Kingdom. In these 3 studies, data about pregnancy smoking and the behavioral outcomes have been gathered from the following: (1) in the CHDS, 1088 children reared by genetically related mothers and 36 children reared by genetically unrelated adoptive mothers; (2) in the EGDS, 310 children reared by genetically unrelated adoptive mothers; and (3) in the C-IVF Study, 636 children reared by genetically related mothers and 206 children reared by genetically unrelated mothers.

This complement of genetically sensitive research designs offers several advantages that allow advances in this important research question relative to past studies (Table 1). First, it allows examination of associations between maternal smoking and conduct problems in children who are reared by genetically related or genetically unrelated mothers. Second, all the studies provide information on multiple covariates, including child sex, birth weight, race/ethnicity, placement age, and breastfeeding, as well as maternal education and maternal age at birth and family breakdown, parenting practices, and family socioeconomic status. Third, results obtained from individual studies can be pooled using a meta-analytic approach to allow examination of the magnitude of common effects generated across studies. Fourth, 2 of the studies allow examination of the contribution of prenatal and possible postnatal passive genotype-environment correlation influences on the derived associations.

Table Graphic Jump LocationTable 1.  Summary of Genetically Sensitive Designs of 3 Longitudinal Studies
Sample
Study 1: CHDS

The CHDS is a longitudinal study of a birth cohort of 1265 children born in the Christchurch, New Zealand, urban region in 1977. Of this cohort 1124 (88.9%) were assessed on maternal smoking during pregnancy and child behavior to age 7 years. This group comprised 1088 children reared by biological mothers and 36 children reared by nonrelative adoptive mothers. The median child age at placement for adoption was 3 weeks (age range, 2-12 weeks). A detailed description of the study40 is available elsewhere.

Study 2: EGDS

The EGDS is an ongoing, longitudinal, multisite study of linked sets of adopted children, adoptive parents, and birth parents.41 This study drew its sample from adoption agencies from the following 4 regions in the United States: the Northwest, Southwest, Midwest, and Mid-Atlantic. The EGDS has 2 cohorts, but only data from cohort 1 were used in this study because cohort 2 does not have data at these ages yet. Cohort 1 included children who were born between 2003 and 2006 (n = 361) and were placed in nonrelative adoptive homes within 90 days of birth (median age at placement, 2 days). Birth parent data were used to assess maternal smoking, and adoptive family data were considered to evaluate the child-rearing environment (n = 311). A detailed description of the study41 is available elsewhere.

Study 3: C-IVF Study

Children conceived via assisted reproductive technologies42 may be genetically related to both parents (homologous IVF), the mother only (sperm donation), the father only (egg donation), or neither parent (embryo donation). Families who had a live birth between 1994 and 2002 following successful artificial reproductive treatment from any of 4 conception groups were recruited from 18 clinics in the United Kingdom and 1 US clinic.43,44 The study design required that all donors were unrelated to either rearing parent. The numbers of families in each conception group in the full sample are 444 homologous IVF, 210 IVF with sperm donation, 175 IVF with egg donation, and 36 IVF with embryo donation. Results of comparisons among the present sample, United Kingdom national norms, and an age-matched twin sample suggest minimal differences in the mean levels of behavior.45 Furthermore, no appreciable differences were noted among the IVF subgroups for mother-rated or father-rated adjustment problems. For the purpose of the present study, we focused on comparing mothers and children who were genetically related (homologous IVF and sperm donation) (n = 636) and those who were genetically unrelated (egg and embryo donation) (n = 206) who provided information on smoking status during pregnancy and child behavior outcomes.

Measures
Offspring Conduct Problems

In study 1 (CHDS), mothers and teachers reported on children’s conduct problems at ages 6 and 7 years using selected items from the behavior rating scales by Rutter and Conners.46 Standardized mother- and teacher-derived scores were summed for each year and then averaged over the 2 assessments to derive an overall measure of childhood conduct problems. The internal consistency of the measure was α = .76.

In study 2 (EGDS), adoptive mothers and fathers reported on children’s conduct problems at ages 4½ and 6 years using the externalizing subscale of the Child Behavior Checklist47 and the impulsivity subscale of the Children’s Behavior Questionnaire Short Form.48 Similar to the CHDS, the 2 scales were standardized and averaged at each age and then were averaged over the 2 assessments to derive an overall measure of childhood conduct problems. The internal consistency of the measure was α = .69.

In study 3 (C-IVF Study), mothers and fathers reported on children’s conduct problems at ages 4 to 10 years (mean [SD] age, 5.50 [0.37] years) using the Strengths and Difficulties Questionnaire.49 Internal consistency was acceptable (α = .67 for mothers and α = .66 for fathers).

In each study, the behavior reports have been scaled to a mean (SD) of 100 (10) within each cohort. This is to facilitate comparisons across studies.

Maternal Smoking During Pregnancy

Pregnancy smoking was reported retrospectively by mothers in all 3 studies, within 1 to 3 days of giving birth in the CHDS, at 4 months’ postpartum using a life history calendar method to facilitate recall in the EGDS, and using maternal retrospective recall and antenatal records in the C-IVF Study, with reports provided by mothers during the initial assessment (children aged ≥4 years). In study 1 (CHDS) and study 2 (EGDS), birth mothers reported on the mean number of cigarettes smoked per day in each trimester of pregnancy. In study 3 (C-IVF Study), mothers answered questions about whether they smoked 0, 1 to 9, or 10 or more cigarettes per day during pregnancy. Because the number of cigarettes smoked per day across the trimesters was highly correlated (r = 0.89 to r = 0.95 in the EGDS and r = 0.86 to r = 0.94 in the CHDS) and to make the measures comparable across the 3 studies, the maternal reports on smoking during pregnancy in studies 1 and 2 were first averaged across the trimesters and then classified into 3 levels (0, 1-9, or ≥10 cigarettes per day), thereby matching the measurement of smoking in study 3.

Covariates

To control for perinatal factors and specific characteristics of the postnatal child-rearing environment, several covariates were included in the models. These were child sex, birth weight, race/ethnicity, placement age, and breastfeeding, as well as maternal education and maternal age at birth and family breakdown, parenting practices, and family socioeconomic status (eTable in the Supplement).

Parenting Practices

In study 1 (CHDS), the maternal emotional responsiveness and avoidance of restriction and punishment subscales of the Home Observation for Measurement of the Environment Inventory50 assessed at ages 3 to 5 years were used to measure parenting practices. The reliability of each of these scales was α = .68. In study 2 (EGDS) and study 3 (C-IVF Study), the hostility subscale of the Iowa Family Interaction Rating Scales51 assessed parents’ negative behaviors expressed toward their child. In study 2, the 5-item hostility subscale was completed by adoptive mothers and fathers when children were 27 months old and 4½ years old, and a mean score was used across both parents at both time points. In study 3, the 4-item hostility subscale was administered when children were 4 to 10 years old. Sample items include “Shout or yell at him/her because you were mad at him/her,” “Criticize him/her or his/her ideas,” and “Hit, push, shove, or grab him/her.” Internal consistency estimates were acceptable for study 2 (α = .74) and study 3 (α = .81).

Data Analysis

The following steps were used to test whether the association between maternal smoking during pregnancy and child conduct problems was evident and still present after considering all theoretical covariates in both genetically related and genetically unrelated mother-child dyads. First, we compared the mean scores of conduct problems in children with mothers who did not smoke during pregnancy, who smoked 1 to 9 cigarettes per day, or who smoked 10 or more cigarettes per day (step 1). Second, we used ordinary least squares regression analysis to test for a significant dose-response association between maternal smoking during pregnancy and child conduct problems in each of the 3 studies. We first fitted a model containing only the maternal smoking variable as a predictor (step 2) and then assessed the potential confounding effects of child covariates, including sex, birth weight, race/ethnicity, placement age, and breastfeeding (step 3), as well as the confounding effect of maternal characteristics and postnatal environment (maternal education and maternal age at birth and family breakdown, parenting practices, and family socioeconomic status) (step 4). Steps 1 and 2 test the extent to which the associations between maternal smoking during pregnancy and child conduct problems are related for cohorts of children reared by genetically related and genetically unrelated mothers. Steps 3 and 4 control for potentially important confounders that may underlie associations across studies.

Finally, to increase the statistical power of our analyses, the regression coefficients for the genetically related samples and the genetically unrelated samples (adoption at birth) were pooled across studies using standard meta-analytic methods and assuming a random-effects model for the calculation of the pooled SE.52 A statistical metan command (STATA, version 11.0; StataCorp LP) was applied to estimate the between-studies component of variance in the pooled regression analyses.

Maternal Smoking During Pregnancy in the 3 Studies

The prevalence of maternal smoking during pregnancy varied across the 3 studies. In the CHDS, the prevalences of pregnancy smoking were 50.0% among children who were reared by genetically unrelated mothers and 32.7% among children who were reared by genetically related mothers. This prevalence was similar to that among the EGDS sample, with 40.8% of children having a biological mother who smoked during pregnancy. The lowest prevalences of pregnancy smoking were observed among the C-IVF Study (5.7% of children who were reared by genetically related mothers and 3.9% of children who were reared by genetically unrelated mothers).

Offspring Conduct Problems and Maternal Smoking During Pregnancy

Table 2 gives the mean scores of conduct problems in the groups of children with different rates of maternal smoking during pregnancy (0, 1-9, or ≥10 cigarettes per day) across the 3 studies. The mean scores of conduct problems were significantly different across the rates of maternal smoking among children reared by genetically related mothers (P < .001 in the CHDS and P = .005 in the C-IVF) and among children reared by genetically unrelated mothers (adoption at birth) (P = .007 in the EGDS and P = .04 in the CHDS) but not among children reared by genetically unrelated mothers (adoption at conception) (P = .98 in the C-IVF Study).

Table Graphic Jump LocationTable 2.  Combined Reports of Offspring Conduct Problem Scores by Rates of Pregnancy Smoking Among Children Reared by Genetically Related Mothers and Genetically Unrelated Mothers

Across all the studies, for children reared by genetically related mothers and children reared by genetically unrelated mothers (adoption at birth), higher mean scores of conduct problems were observed for those whose mother smoked during pregnancy compared with those whose mother did not smoke during pregnancy. Furthermore, children whose mothers smoked 10 or more cigarettes per day had the highest mean scores of conduct problems. Because the sample size of the genetically unrelated mothers who smoked during pregnancy in the C-IVF Study was small (n = 8), we did not include this subgroup in further analyses because of limitations pertinent to statistical power. The correlation between the amount of smoking during pregnancy and child conduct problems varied between the C-IVF Study genetically related sample (r = 0.11, P = .005) and the CHDS genetically unrelated sample (r = 0.34, P = .04).

Association Between Maternal Smoking During Pregnancy and Child Conduct Problems

Table 3 summarizes results derived from the analysis of maternal smoking during pregnancy and child conduct problems using linear regression models (models 1-3). The unadjusted model (model 1), with maternal smoking during pregnancy as a predictor and child conduct problems score as an outcome, showed a significant association between pregnancy smoking and child conduct problems in the genetically related mother-child pairs (P < .001 in the CHDS and P = .005 in the C-IVF Study), as well as in the genetically unrelated rearing mother–child pairs (adoption at birth) (P = .007 in the EGDS and P = .04 in the CHDS).

Table Graphic Jump LocationTable 3.  Combined Reports of Estimated Effects of Pregnancy Smoking on Offspring Conduct Problems for Genetically Related Rearing Mothers and Adoption-at-Birth Genetically Unrelated Rearing Mothers Before and After Adjustment for Covariates

Results of the analysis using an unadjusted model with the maximum sample size were similar to those in the samples with complete information on covariates (data are available from the corresponding author on request). The comparisons between the maximum samples and those with the full information on all covariates showed that they were not different for the frequency of pregnancy smoking or the means of child conduct problems.

In the model adjusted for child sex, birth weight, and race/ethnicity (model 2), the associations remained similar to those in the unadjusted model. The final model was adjusted for all child covariates and maternal characteristics and postnatal environment (placement age and breastfeeding, maternal education and maternal age at birth, family breakdown, parenting practices, and family socioeconomic status) (model 3). In this fully adjusted model, the association between maternal smoking during pregnancy and child conduct problems was attenuated but remained statistically significant in the genetically related mother-child pairs (P = .03 in the CHDS and P = .04 in the C-IVF Study). In the genetically unrelated rearing mother–child pairs, the association remained statistically significant in the EGDS (P = .01) but was attenuated in the CHDS (P = .12).

Results of the meta-analysis using the effect estimate (SE) from each study are also given in Table 3. These results provide further evidence for a statistical dose-specific relationship between maternal smoking during pregnancy and offspring conduct problems in both the genetically related mother-child pairs (β = 2.66, SE = 0.35, P < .001 for the unadjusted model and β = 1.13, SE = 0.56, P = .04 for the fully adjusted model) and the genetically unrelated rearing mother–child pairs (β = 2.48, SE = 0.90, P = .006 for the unadjusted model and β = 2.17, SE = 0.74, P = .003 for the fully adjusted model).

Results derived from the present study showed that maternal smoking during pregnancy was associated with offspring conduct problems. This association was observed for children reared by both genetically related and genetically unrelated mothers. In the genetically unrelated (adoption at birth) mother-child pairs, the characteristics of an adoptive mother and the child-rearing environment are distinct from the presence or absence of pregnancy smoking. Therefore, our results suggest that the association between maternal smoking during pregnancy and offspring conduct problems was not confounded by maternal characteristics or the child-rearing environment, specifically parenting practices. Moreover, this association was observed when a possible passive genotype-environment correlation was removed using the attributes of the adoption-at-birth design (EGDS and CHDS adoptees).

Our findings add to evidence highlighting the adverse effects of smoking during pregnancy as a risk factor for offspring conduct problems. First, results of prior sibling design studies3436 suggest that siblings who differed in their exposure to pregnancy smoking did not differ for conduct problems across childhood and adolescence. However, these studies were not able to control for a passive genotype-environment correlation, whereas our study included an adoption-at-birth design and could demonstrate that having a postnatal environment free from genetic confounding did not explain the association between maternal smoking during pregnancy and offspring conduct problems. Second, prenatal exposure to smoking might represent an inherited rather than a true environmental risk factor underlying offspring conduct problems.38,39 It is possible that preexisting genetically based differences in the propensity to engage in externalizing behavior may confound the relationship between maternal smoking during pregnancy and offspring conduct problems.53 For example, a previous study by Rice et al38 using data from the C-IVF Study showed that the association between prenatal smoking and child antisocial behavior was observed in genetically related but not in genetically unrelated mother-child pairs, suggesting that the association represents an inherited rather than a truly causal effect.

Results from previous studies using the IVF design38 and a children-of-twins design39,54 suggest that a passive genotype-environment correlation may contribute to the link between maternal smoking during pregnancy and offspring conduct problems. Combined with existing research, findings from the present study demonstrate that the underlying mechanisms for the association between maternal pregnancy smoking and offspring conduct problems are present during the prenatal period. These may involve common genetic factors that may interact with pregnancy smoking. Results of recent molecular genetic studies5558 revealed that offspring with a particular genetic profile are more sensitive to the negative effect of maternal smoking during pregnancy than those without. For example, a gene × environment interaction between the COMT and MAOA genes and maternal smoking during pregnancy on offspring aggressive behavior has been reported.56,57 Most important, the interaction between COMT and pregnancy smoking might be explained at the epigenetic level because the association of nicotine exposure with methylation of the gene promoter has recently been demonstrated.59 To further our knowledge of the effects of maternal smoking during pregnancy on offspring conduct problems, genetically sensitive designs incorporating information on genetic and epigenetic markers are needed in future studies.

Our study has strengths and limitations. Findings provided in the present study were obtained by using comparable measures of maternal smoking during pregnancy across the 3 studies. There is a possibility that our results are affected by historical smoking trends, specifically in relation to the CHDS. However, any bias due to cohort effects is likely to be minimal because results are consistent across studies. Multi-informant reports (from a mother and a father or from a mother and a teacher) were used to measure child conduct problems. These measures are not identical, yet the pattern of findings is consistent across independent samples of mother-child pairs derived from distinct geographical and social backgrounds when controlling for a wide range of possible covariates. In addition, we confirmed the substantive findings in the pooled data sets using meta-analysis. Given that each design has its own set of strengths and weaknesses, different designs were used. Indeed, as Rutter60 outlines, greater confidence is achieved when there is convergence of findings across studies using a complement of research designs.

Strengths notwithstanding, several limitations of the study should be noted. First, the number of smokers in the genetically unrelated group in study 3 (C-IVF Study) was small (n = 8), thereby precluding incorporation of this group in the regression analysis and meta-analysis. Second, the prevalence of maternal smoking during pregnancy among the C-IVF Study genetically related sample was significantly lower than that among the CHDS (5.7% vs 32.7%). However, the magnitude of association between maternal smoking during pregnancy and conduct problems was similar in these 2 distinct sample groups before adjustment for potential confounders (β = 2.61 in the CHDS and β = 3.07 in the C-IVF). Third, exposure to other substances (drugs and alcohol) during pregnancy, as well as postnatal smoking exposure (passive smoking) following birth, may be important risk factors for child development and need to be considered in future studies. As an additional test, we examined the role of passive smoking or environmental tobacco smoke if this measure was available (CHDS). Results remained unchanged when we incorporated this measure into the analysis (data are available from the corresponding author on request). Fourth, our study (like most in the field) predominantly relied on maternal self-report of smoking. Although such methods have been shown to have excellent agreement with antenatal records,35,46 biological measures may provide more accurate quantitative data concerning the true levels of nicotine that the fetus was exposed to during pregnancy. Also, future studies may need to explore a time-specific effect of exposure to pregnancy smoking.

In conclusion, using a complement of genetically sensitive research designs, the present study examined the relationship between maternal smoking during pregnancy and offspring conduct problems among children reared by genetically related and genetically unrelated mothers when controlling for specific perinatal and postnatal factors. Our findings suggest an association between pregnancy smoking and child conduct problems that is unlikely to be fully explained by postnatal environmental factors (ie, parenting practices) even when the postnatal passive genotype-environment correlation has been removed. The causal explanation for the association between smoking in pregnancy and offspring conduct problems is not known but may include genetic factors and other prenatal environmental hazards, including smoking itself. Research designs that allow disaggregation of genetic and environmental pathways underlying intergenerational transmission of psychopathologic conditions are critical for understanding the role of maternal smoking during pregnancy and could have important implications for future intervention and prevention programs aimed at remediating child conduct problems.

Submitted for Publication: August 23, 2012; final revision received November 9, 2012; accepted December 27, 2012.

Corresponding Author: Gordon T. Harold, PhD, School of Psychology, College of Medicine, Biological Sciences and Psychology, University of Leicester, Lancaster Road, Leicester LE19HN, England (gth9@le.ac.uk).

Published Online: July 24, 2013. doi:10.1001/jamapsychiatry.2013.127.

Author Contributions: Dr Harold takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors had full access to all the data in the study. Drs Gaysina, Fergusson, and Harold contributed equally to the writing of the manuscript.

Study concept and design: Gaysina, Fergusson, Leve, Horwood, Reiss, Shaw, Neiderhiser, Harold.

Acquisition of data: Fergusson, Leve, Horwood, Reiss, Natsuaki, Neiderhiser, Harold.

Analysis and interpretation of data: Gaysina, Fergusson, Leve, Horwood, Shaw, Elam, Neiderhiser, Harold.

Drafting of the manuscript: Gaysina, Fergusson, Leve, Shaw, Elam, Harold.

Critical revision of the manuscript for important intellectual content: Fergusson, Leve, Horwood, Reiss, Shaw, Elam, Natsuaki, Neiderhiser, Harold.

Statistical analysis: Gaysina, Fergusson, Leve, Horwood, Elam, Harold.

Obtained funding: Fergusson, Leve, Horwood, Reiss, Shaw, Neiderhiser, Harold.

Administrative, technical, and material support: Leve, Reiss, Shaw, Elam, Natsuaki.

Study supervision: Leve, Neiderhiser, Harold.

Conflict of Interest Disclosures: None reported.

Funding/Support: The Christchurch Health and Development Study was supported by grants from the Health Research Council of New Zealand, the Canterbury Medical Research Foundation, the Child Health Research Foundation (Cure Kids), and the New Zealand Lottery Grants Board. The Early Growth and Development Study was supported by grant R01 HD042608 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Drug Abuse, and Office of Behavioral and Social Sciences Research, National Institutes of Health, US Public Health Service (Drs Leve and Reiss); by grant R01 DA020585 from the National Institute on Drug Abuse, National Institute of Mental Health, and Office of Behavioral and Social Sciences Research, National Institutes of Health, US Public Health Service (Dr Neiderhiser); and by grant R01 MH092118 from the National Institute of Mental Health, National Institutes of Health, US Public Health Service (Drs Leve and Neiderhiser). The Cardiff IVF Study was supported by a Wellcome Trust showcase award, a Wellcome Trust project grant, and a Nuffield Foundation project grant award.

Role of the Sponsor: The funding bodies had no further role in the study design, the collection, analysis and interpretation of data, manuscript preparation, or in the decision to submit the paper for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health.

Additional Contributions: Xiaojia Ge, PhD, John Reid, PhD, Rand Conger, PhD, Laura Scaramella, PhD, Jody Ganiban, PhD, and Brandon Gibson, MS, provided scientific and data analytic contributions to the Early Growth and Development Study. Frances Rice, PhD, Dale Hay, PhD, Jacky Boivin, PhD, Marianne van den Bree, PhD, Allyson Lewis, BSc, Valerie Russell, and the late Xiaojia Ge, PhD, assisted with the Cardiff IVF Study. Anita Thapar, MD, PhD, gave helpful comments on early versions of the manuscript. We are grateful to all the families who participated in these studies.

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Day  NL, Richardson  GA, Goldschmidt  L, Cornelius  MD.  Effects of prenatal tobacco exposure on preschoolers’ behavior. J Dev Behav Pediatr. 2000;21(3):180-188.
PubMed
Fergusson  DM, Woodward  LJ, Horwood  LJ.  Maternal smoking during pregnancy and psychiatric adjustment in late adolescence. Arch Gen Psychiatry. 1998;55(8):721-727.
PubMed   |  Link to Article
Orlebeke  JF, Knol  DL, Verhulst  FC.  Increase in child behavior problems resulting from maternal smoking during pregnancy. Arch Environ Health. 1997;52(4):317-321.
PubMed   |  Link to Article
Milberger  S, Biederman  J, Faraone  SV, Jones  J.  Further evidence of an association between maternal smoking during pregnancy and attention deficit hyperactivity disorder: findings from a high-risk sample of siblings. J Clin Child Psychol. 1998;27(3):352-358.
PubMed   |  Link to Article
Knopik  VS, Sparrow  EP, Madden  PAF,  et al.  Contributions of parental alcoholism, prenatal substance exposure, and genetic transmission to child ADHD risk: a female twin study. Psychol Med. 2005;35(5):625-635.
PubMed   |  Link to Article
Brennan  PA, Grekin  ER, Mednick  SA.  Maternal smoking during pregnancy and adult male criminal outcomes. Arch Gen Psychiatry. 1999;56(3):215-219.
PubMed   |  Link to Article
Räsänen  P, Hakko  H, Isohanni  M, Hodgins  S, Järvelin  MR, Tiihonen  J.  Maternal smoking during pregnancy and risk of criminal behavior among adult male offspring in the Northern Finland 1966 Birth Cohort. Am J Psychiatry. 1999;156(6):857-862.
PubMed
Brennan  PA, Grekin  ER, Mortensen  EL, Mednick  SA.  Relationship of maternal smoking during pregnancy with criminal arrest and hospitalization for substance abuse in male and female adult offspring. Am J Psychiatry. 2002;159(1):48-54.
PubMed   |  Link to Article
Breslau  N, Kilbey  MM, Andreski  P.  Vulnerability to psychopathology in nicotine-dependent smokers: an epidemiologic study of young adults. Am J Psychiatry. 1993;150(6):941-946.
PubMed
Maughan  B, Taylor  A, Caspi  A, Moffitt  TE.  Prenatal smoking and early childhood conduct problems: testing genetic and environmental explanations of the association. Arch Gen Psychiatry. 2004;61(8):836-843.
PubMed   |  Link to Article
Zimmer  MH, Zimmer  M.  Socioeconomic determinants of smoking behavior during pregnancy. Soc Sci J. 1998;35(1):133-142.
Link to Article
Bowes  L, Chollet  A, Fombonne  E, Galéra  C, Melchior  M.  Lifecourse SEP and tobacco and cannabis use. Eur J Public Health. 2013;23(2):322-327.
PubMed   |  Link to Article
Silberg  JL, Parr  T, Neale  MC, Rutter  M, Angold  A, Eaves  LJ.  Maternal smoking during pregnancy and risk to boys’ conduct disturbance: an examination of the causal hypothesis. Biol Psychiatry. 2003;53(2):130-135.
PubMed   |  Link to Article
Thapar  A, Rutter  M.  Do prenatal risk factors cause psychiatric disorder? be wary of causal claims. Br J Psychiatry. 2009;195(2):100-101.
PubMed   |  Link to Article
Agrawal  A, Knopik  VS, Pergadia  ML,  et al.  Correlates of cigarette smoking during pregnancy and its genetic and environmental overlap with nicotine dependence. Nicotine Tob Res. 2008;10(4):567-578.
PubMed   |  Link to Article
Rhee  SH, Waldman  ID.  Genetic and environmental influences on antisocial behavior: a meta-analysis of twin and adoption studies. Psychol Bull. 2002;128(3):490-529.
PubMed   |  Link to Article
Tuvblad  C, Narusyte  J, Grann  M, Sarnecki  J, Lichtenstein  P.  The genetic and environmental etiology of antisocial behavior from childhood to emerging adulthood. Behav Genet. 2011;41(5):629-640.
PubMed   |  Link to Article
Stephens  SH, Hoft  NR, Schlaepfer  IR,  et al.  Externalizing behaviors are associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 gene cluster. Behav Genet. 2012;42(3):402-414.
PubMed   |  Link to Article
Kodl  MM, Wakschlag  LS.  Does a childhood history of externalizing problems predict smoking during pregnancy? Addict Behav. 2004;29(2):273-279.
PubMed   |  Link to Article
Roza  SJ, Verhulst  FC, Jaddoe  VW,  et al.  Maternal smoking during pregnancy and child behaviour problems: the Generation R Study. Int J Epidemiol. 2009;38(3):680-689.
PubMed   |  Link to Article
Jaffee  SR, Belsky  J, Harrington  H, Caspi  A, Moffitt  TE.  When parents have a history of conduct disorder: how is the caregiving environment affected? J Abnorm Psychol. 2006;115(2):309-319.
PubMed   |  Link to Article
Jaffee  SR, Price  TS.  Gene-environment correlations: a review of the evidence and implications for prevention of mental illness. Mol Psychiatry. 2007;12(5):432-442.
PubMed
Gilman  SE, Gardener  H, Buka  SL.  Maternal smoking during pregnancy and children’s cognitive and physical development: a causal risk factor? Am J Epidemiol. 2008;168(5):522-531.
PubMed   |  Link to Article
Hao  LX, Matsueda  RL.  Family dynamics through childhood: a sibling model of behavior problems. Soc Sci Res. 2006;35(2):500-524.
Link to Article
D’Onofrio  BM, Van Hulle  CA, Waldman  ID,  et al.  Smoking during pregnancy and offspring externalizing problems: an exploration of genetic and environmental confounds. Dev Psychopathol Win. 2008;20(1):139-164.
D’Onofrio  BM, Singh  AL, Iliadou  A,  et al.  Familial confounding of the association between maternal smoking during pregnancy and offspring criminality: a population-based study in Sweden. Arch Gen Psychiatry. 2010;67(5):529-538.
PubMed   |  Link to Article
Rice  F, Harold  GT, Boivin  J, Hay  DF, van den Bree  M, Thapar  A.  Disentangling prenatal and inherited influences in humans with an experimental design. Proc Natl Acad Sci U S A. 2009;106(7):2464-2467.
PubMed   |  Link to Article
D’Onofrio  BM, Turkheimer  EN, Eaves  LJ,  et al.  The role of the children of twins design in elucidating causal relations between parent characteristics and child outcomes. J Child Psychol Psychiatry. 2003;44(8):1130-1144.
PubMed   |  Link to Article
Fergusson  DM, Horwood  LJ.  The Christchurch Health and Development Study: review of findings on child and adolescent mental health. Aust N Z J Psychiatry. 2001;35(3):287-296.
PubMed   |  Link to Article
Leve  LD, Neiderhiser  JM, Shaw  DS, Ganiban  J, Natsuaki  MN, Reiss  D.  The Early Growth and Development Study: a prospective adoption study from birth through middle childhood. Twin Res Hum Genet. 2013;16(1):412-423.
Link to Article
Andersen  AN, Gianaroli  L, Felberbaum  R, de Mouzon  J, Nygren  KG; European IVF-Monitoring Programme (EIM), European Society of Human Reproduction and Embryology (ESHRE).  Assisted reproductive technology in Europe, 2001: results generated from European registers by ESHRE. Hum Reprod. 2005;20(5):1158-1176.
PubMed   |  Link to Article
Harold  GT, Rice  F, Hay  DF, Boivin  J, van den Bree  M, Thapar  A.  Familial transmission of depression and antisocial behavior symptoms: disentangling the contribution of inherited and environmental factors and testing the mediating role of parenting. Psychol Med. 2010;41(6):1175-1185.
PubMed   |  Link to Article
Thapar  A, Harold  G, Rice  F,  et al.  Do intrauterine or genetic influences explain the foetal origins of chronic disease? a novel experimental method for disentangling effects. BMC Med Res Methodol. 2007;7(1):25.
PubMed   |  Link to Article
Shelton  KH, Boivin  J, Hay  D,  et al.  Examining differences in psychological adjustment problems among children conceived by assisted reproductive technologies. Int J Behav Dev. 2009;33(5):385-392.
Link to Article
Fergusson  DM, Horwood  LJ.  The trait and method components of ratings of conduct disorder, part I: maternal and teacher evaluations of conduct disorder in young children. J Child Psychol Psychiatry. 1987;28(2):249-260.
PubMed   |  Link to Article
Achenbach  TM, Rescorla  LA. ASEBA School Age Forms and Profiles. Burlington, VT: ASEBA; 2001.
Putnam  SP, Rothbart  MK.  Development of short and very short forms of the Children’s Behavior Questionnaire. J Pers Assess. 2006;87(1):102-112.
PubMed   |  Link to Article
Goodman  R.  The Strengths and Difficulties Questionnaire: a research note. J Child Psychol Psychiatry. 1997;38(5):581-586.
PubMed   |  Link to Article
Bradley  RH, Caldwell  BM.  Home Observation for Measurement of the Environment: a validation study of screening efficiency. Am J Ment Defic. 1977;81(5):417-420.
Melby  JN, Conger  RD. The Iowa Family Interaction Rating Scales: instrument summary. In: Kerig  PK, Lindahl  KM, eds. Family Observational Coding Systems: Resources for Systemic Research. Mahwah, NJ: Lawrence A Erlbaum Associates; 2001:33-58.
DerSimonian  R, Kacker  R.  Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials. 2007;28(2):105-114.
PubMed   |  Link to Article
Jaffee  SR, Strait  LB, Odgers  CL.  From correlates to causes: can quasi-experimental studies and statistical innovations bring us closer to identifying the causes of antisocial behavior? Psychol Bull. 2012;138(2):272-295.
PubMed   |  Link to Article
Knopik  VS, Heath  AC, Jacob  T,  et al.  Maternal alcohol use disorder and offspring ADHD: disentangling genetic and environmental effects using a children-of-twins design. Psychol Med. 2006;36(10):1461-1471.
PubMed   |  Link to Article
Morales  E, Sunyer  J, Julvez  J,  et al.  GSTM1 polymorphisms modify the effect of maternal smoking during pregnancy on cognitive functioning in preschoolers. Int J Epidemiol. 2009;38(3):690-697.
PubMed   |  Link to Article
Wakschlag  LS, Kistner  EO, Pine  DS,  et al.  Interaction of prenatal exposure to cigarettes and MAOA genotype in pathways to youth antisocial behavior. Mol Psychiatry. 2010;15(9):928-937.
PubMed   |  Link to Article
Brennan  PA, Hammen  C, Sylvers  P,  et al.  Interactions between the COMT Val108/158Met polymorphism and maternal prenatal smoking predict aggressive behavior outcomes. Biol Psychol. 2011;87(1):99-105.
PubMed   |  Link to Article
Kahn  RS, Khoury  J, Nichols  WC, Lanphear  BP.  Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors. J Pediatr. 2003;143(1):104-110.
PubMed   |  Link to Article
Xu  Q, Ma  JZ, Payne  TJ, Li  MD.  Determination of methylated CpG sites in the promoter region of catechol-O-methyltransferase (COMT) and their involvement in the etiology of tobacco smoking. Front Psychiatry. 2010;1:16.
PubMed
Rutter  M.  Proceeding from observed correlation to causal inference: the use of natural experiments. Perspect Psychol Sci. 2007;2(4):377-395.
Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Summary of Genetically Sensitive Designs of 3 Longitudinal Studies
Table Graphic Jump LocationTable 2.  Combined Reports of Offspring Conduct Problem Scores by Rates of Pregnancy Smoking Among Children Reared by Genetically Related Mothers and Genetically Unrelated Mothers
Table Graphic Jump LocationTable 3.  Combined Reports of Estimated Effects of Pregnancy Smoking on Offspring Conduct Problems for Genetically Related Rearing Mothers and Adoption-at-Birth Genetically Unrelated Rearing Mothers Before and After Adjustment for Covariates

References

Ford  T.  Practitioner review: how can epidemiology help us plan and deliver effective child and adolescent mental health services? J Child Psychol Psychiatry. 2008;49(9):900-914.
PubMed   |  Link to Article
Collishaw  S, Maughan  B, Goodman  R, Pickles  A.  Time trends in adolescent mental health. J Child Psychol Psychiatry. 2004;45(8):1350-1362.
PubMed   |  Link to Article
Knopik  VS.  Maternal smoking during pregnancy and child outcomes: real or spurious effect? Dev Neuropsychol. 2009;34(1):1-36.
PubMed   |  Link to Article
Abbott  LC, Winzer-Serhan  UH.  Smoking during pregnancy: lessons learned from epidemiological studies and experimental studies using animal models. Crit Rev Toxicol. 2012;42(4):279-303.
PubMed   |  Link to Article
Seidler  FJ, Levin  ED, Lappi  SE, Slotkin  TA.  Fetal nicotine exposure ablates the ability of postnatal nicotine challenge to release norepinephrine from rat brain regions. Brain Res Dev Brain Res. 1992;69(2):288-291.
PubMed   |  Link to Article
Liang  K, Poytress  BS, Chen  YL, Leslie  FM, Weinberger  NM, Metherate  R.  Neonatal nicotine exposure impairs nicotinic enhancement of central auditory processing and auditory learning in adult rats. Eur J Neurosci. 2006;24(3):857-866.
PubMed   |  Link to Article
Schneider  T, Ilott  N, Brolese  G, Bizarro  L, Asherson  PJ, Stolerman  IP.  Prenatal exposure to nicotine impairs performance of the 5-choice serial reaction time task in adult rats. Neuropsychopharmacology. 2011;36(5):1114-1125.
PubMed   |  Link to Article
Button  TMM, Maughan  B, McGuffin  P.  The relationship of maternal smoking to psychological problems in the offspring. Early Hum Dev. 2007;83(11):727-732.
PubMed   |  Link to Article
Ursini  G, Bollati  V, Fazio  L,  et al.  Stress-related methylation of the catechol-O-methyltransferase Val158 allele predicts human prefrontal cognition and activity. J Neurosci. 2011;31(18):6692-6698.
PubMed   |  Link to Article
Batstra  L, Hadders-Algra  M, Neeleman  J.  Effect of antenatal exposure to maternal smoking on behavioural problems and academic achievement in childhood: prospective evidence from a Dutch birth cohort. Early Hum Dev. 2003;75(1-2):21-33.
PubMed   |  Link to Article
Brook  DW, Zhang  C, Rosenberg  G, Brook  JS.  Maternal cigarette smoking during pregnancy and child aggressive behavior. Am J Addict. 2006;15(6):450-456.
PubMed   |  Link to Article
Day  NL, Richardson  GA, Goldschmidt  L, Cornelius  MD.  Effects of prenatal tobacco exposure on preschoolers’ behavior. J Dev Behav Pediatr. 2000;21(3):180-188.
PubMed
Fergusson  DM, Woodward  LJ, Horwood  LJ.  Maternal smoking during pregnancy and psychiatric adjustment in late adolescence. Arch Gen Psychiatry. 1998;55(8):721-727.
PubMed   |  Link to Article
Orlebeke  JF, Knol  DL, Verhulst  FC.  Increase in child behavior problems resulting from maternal smoking during pregnancy. Arch Environ Health. 1997;52(4):317-321.
PubMed   |  Link to Article
Milberger  S, Biederman  J, Faraone  SV, Jones  J.  Further evidence of an association between maternal smoking during pregnancy and attention deficit hyperactivity disorder: findings from a high-risk sample of siblings. J Clin Child Psychol. 1998;27(3):352-358.
PubMed   |  Link to Article
Knopik  VS, Sparrow  EP, Madden  PAF,  et al.  Contributions of parental alcoholism, prenatal substance exposure, and genetic transmission to child ADHD risk: a female twin study. Psychol Med. 2005;35(5):625-635.
PubMed   |  Link to Article
Brennan  PA, Grekin  ER, Mednick  SA.  Maternal smoking during pregnancy and adult male criminal outcomes. Arch Gen Psychiatry. 1999;56(3):215-219.
PubMed   |  Link to Article
Räsänen  P, Hakko  H, Isohanni  M, Hodgins  S, Järvelin  MR, Tiihonen  J.  Maternal smoking during pregnancy and risk of criminal behavior among adult male offspring in the Northern Finland 1966 Birth Cohort. Am J Psychiatry. 1999;156(6):857-862.
PubMed
Brennan  PA, Grekin  ER, Mortensen  EL, Mednick  SA.  Relationship of maternal smoking during pregnancy with criminal arrest and hospitalization for substance abuse in male and female adult offspring. Am J Psychiatry. 2002;159(1):48-54.
PubMed   |  Link to Article
Breslau  N, Kilbey  MM, Andreski  P.  Vulnerability to psychopathology in nicotine-dependent smokers: an epidemiologic study of young adults. Am J Psychiatry. 1993;150(6):941-946.
PubMed
Maughan  B, Taylor  A, Caspi  A, Moffitt  TE.  Prenatal smoking and early childhood conduct problems: testing genetic and environmental explanations of the association. Arch Gen Psychiatry. 2004;61(8):836-843.
PubMed   |  Link to Article
Zimmer  MH, Zimmer  M.  Socioeconomic determinants of smoking behavior during pregnancy. Soc Sci J. 1998;35(1):133-142.
Link to Article
Bowes  L, Chollet  A, Fombonne  E, Galéra  C, Melchior  M.  Lifecourse SEP and tobacco and cannabis use. Eur J Public Health. 2013;23(2):322-327.
PubMed   |  Link to Article
Silberg  JL, Parr  T, Neale  MC, Rutter  M, Angold  A, Eaves  LJ.  Maternal smoking during pregnancy and risk to boys’ conduct disturbance: an examination of the causal hypothesis. Biol Psychiatry. 2003;53(2):130-135.
PubMed   |  Link to Article
Thapar  A, Rutter  M.  Do prenatal risk factors cause psychiatric disorder? be wary of causal claims. Br J Psychiatry. 2009;195(2):100-101.
PubMed   |  Link to Article
Agrawal  A, Knopik  VS, Pergadia  ML,  et al.  Correlates of cigarette smoking during pregnancy and its genetic and environmental overlap with nicotine dependence. Nicotine Tob Res. 2008;10(4):567-578.
PubMed   |  Link to Article
Rhee  SH, Waldman  ID.  Genetic and environmental influences on antisocial behavior: a meta-analysis of twin and adoption studies. Psychol Bull. 2002;128(3):490-529.
PubMed   |  Link to Article
Tuvblad  C, Narusyte  J, Grann  M, Sarnecki  J, Lichtenstein  P.  The genetic and environmental etiology of antisocial behavior from childhood to emerging adulthood. Behav Genet. 2011;41(5):629-640.
PubMed   |  Link to Article
Stephens  SH, Hoft  NR, Schlaepfer  IR,  et al.  Externalizing behaviors are associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 gene cluster. Behav Genet. 2012;42(3):402-414.
PubMed   |  Link to Article
Kodl  MM, Wakschlag  LS.  Does a childhood history of externalizing problems predict smoking during pregnancy? Addict Behav. 2004;29(2):273-279.
PubMed   |  Link to Article
Roza  SJ, Verhulst  FC, Jaddoe  VW,  et al.  Maternal smoking during pregnancy and child behaviour problems: the Generation R Study. Int J Epidemiol. 2009;38(3):680-689.
PubMed   |  Link to Article
Jaffee  SR, Belsky  J, Harrington  H, Caspi  A, Moffitt  TE.  When parents have a history of conduct disorder: how is the caregiving environment affected? J Abnorm Psychol. 2006;115(2):309-319.
PubMed   |  Link to Article
Jaffee  SR, Price  TS.  Gene-environment correlations: a review of the evidence and implications for prevention of mental illness. Mol Psychiatry. 2007;12(5):432-442.
PubMed
Gilman  SE, Gardener  H, Buka  SL.  Maternal smoking during pregnancy and children’s cognitive and physical development: a causal risk factor? Am J Epidemiol. 2008;168(5):522-531.
PubMed   |  Link to Article
Hao  LX, Matsueda  RL.  Family dynamics through childhood: a sibling model of behavior problems. Soc Sci Res. 2006;35(2):500-524.
Link to Article
D’Onofrio  BM, Van Hulle  CA, Waldman  ID,  et al.  Smoking during pregnancy and offspring externalizing problems: an exploration of genetic and environmental confounds. Dev Psychopathol Win. 2008;20(1):139-164.
D’Onofrio  BM, Singh  AL, Iliadou  A,  et al.  Familial confounding of the association between maternal smoking during pregnancy and offspring criminality: a population-based study in Sweden. Arch Gen Psychiatry. 2010;67(5):529-538.
PubMed   |  Link to Article
Rice  F, Harold  GT, Boivin  J, Hay  DF, van den Bree  M, Thapar  A.  Disentangling prenatal and inherited influences in humans with an experimental design. Proc Natl Acad Sci U S A. 2009;106(7):2464-2467.
PubMed   |  Link to Article
D’Onofrio  BM, Turkheimer  EN, Eaves  LJ,  et al.  The role of the children of twins design in elucidating causal relations between parent characteristics and child outcomes. J Child Psychol Psychiatry. 2003;44(8):1130-1144.
PubMed   |  Link to Article
Fergusson  DM, Horwood  LJ.  The Christchurch Health and Development Study: review of findings on child and adolescent mental health. Aust N Z J Psychiatry. 2001;35(3):287-296.
PubMed   |  Link to Article
Leve  LD, Neiderhiser  JM, Shaw  DS, Ganiban  J, Natsuaki  MN, Reiss  D.  The Early Growth and Development Study: a prospective adoption study from birth through middle childhood. Twin Res Hum Genet. 2013;16(1):412-423.
Link to Article
Andersen  AN, Gianaroli  L, Felberbaum  R, de Mouzon  J, Nygren  KG; European IVF-Monitoring Programme (EIM), European Society of Human Reproduction and Embryology (ESHRE).  Assisted reproductive technology in Europe, 2001: results generated from European registers by ESHRE. Hum Reprod. 2005;20(5):1158-1176.
PubMed   |  Link to Article
Harold  GT, Rice  F, Hay  DF, Boivin  J, van den Bree  M, Thapar  A.  Familial transmission of depression and antisocial behavior symptoms: disentangling the contribution of inherited and environmental factors and testing the mediating role of parenting. Psychol Med. 2010;41(6):1175-1185.
PubMed   |  Link to Article
Thapar  A, Harold  G, Rice  F,  et al.  Do intrauterine or genetic influences explain the foetal origins of chronic disease? a novel experimental method for disentangling effects. BMC Med Res Methodol. 2007;7(1):25.
PubMed   |  Link to Article
Shelton  KH, Boivin  J, Hay  D,  et al.  Examining differences in psychological adjustment problems among children conceived by assisted reproductive technologies. Int J Behav Dev. 2009;33(5):385-392.
Link to Article
Fergusson  DM, Horwood  LJ.  The trait and method components of ratings of conduct disorder, part I: maternal and teacher evaluations of conduct disorder in young children. J Child Psychol Psychiatry. 1987;28(2):249-260.
PubMed   |  Link to Article
Achenbach  TM, Rescorla  LA. ASEBA School Age Forms and Profiles. Burlington, VT: ASEBA; 2001.
Putnam  SP, Rothbart  MK.  Development of short and very short forms of the Children’s Behavior Questionnaire. J Pers Assess. 2006;87(1):102-112.
PubMed   |  Link to Article
Goodman  R.  The Strengths and Difficulties Questionnaire: a research note. J Child Psychol Psychiatry. 1997;38(5):581-586.
PubMed   |  Link to Article
Bradley  RH, Caldwell  BM.  Home Observation for Measurement of the Environment: a validation study of screening efficiency. Am J Ment Defic. 1977;81(5):417-420.
Melby  JN, Conger  RD. The Iowa Family Interaction Rating Scales: instrument summary. In: Kerig  PK, Lindahl  KM, eds. Family Observational Coding Systems: Resources for Systemic Research. Mahwah, NJ: Lawrence A Erlbaum Associates; 2001:33-58.
DerSimonian  R, Kacker  R.  Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials. 2007;28(2):105-114.
PubMed   |  Link to Article
Jaffee  SR, Strait  LB, Odgers  CL.  From correlates to causes: can quasi-experimental studies and statistical innovations bring us closer to identifying the causes of antisocial behavior? Psychol Bull. 2012;138(2):272-295.
PubMed   |  Link to Article
Knopik  VS, Heath  AC, Jacob  T,  et al.  Maternal alcohol use disorder and offspring ADHD: disentangling genetic and environmental effects using a children-of-twins design. Psychol Med. 2006;36(10):1461-1471.
PubMed   |  Link to Article
Morales  E, Sunyer  J, Julvez  J,  et al.  GSTM1 polymorphisms modify the effect of maternal smoking during pregnancy on cognitive functioning in preschoolers. Int J Epidemiol. 2009;38(3):690-697.
PubMed   |  Link to Article
Wakschlag  LS, Kistner  EO, Pine  DS,  et al.  Interaction of prenatal exposure to cigarettes and MAOA genotype in pathways to youth antisocial behavior. Mol Psychiatry. 2010;15(9):928-937.
PubMed   |  Link to Article
Brennan  PA, Hammen  C, Sylvers  P,  et al.  Interactions between the COMT Val108/158Met polymorphism and maternal prenatal smoking predict aggressive behavior outcomes. Biol Psychol. 2011;87(1):99-105.
PubMed   |  Link to Article
Kahn  RS, Khoury  J, Nichols  WC, Lanphear  BP.  Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors. J Pediatr. 2003;143(1):104-110.
PubMed   |  Link to Article
Xu  Q, Ma  JZ, Payne  TJ, Li  MD.  Determination of methylated CpG sites in the promoter region of catechol-O-methyltransferase (COMT) and their involvement in the etiology of tobacco smoking. Front Psychiatry. 2010;1:16.
PubMed
Rutter  M.  Proceeding from observed correlation to causal inference: the use of natural experiments. Perspect Psychol Sci. 2007;2(4):377-395.
Link to Article

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
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