Hostname: page-component-5d59c44645-ndqjc Total loading time: 0 Render date: 2024-02-23T12:14:41.948Z Has data issue: false hasContentIssue false

Maternal smoking during pregnancy, offspring smoking, adverse childhood events, and risk of major depression: a sibling design study

Published online by Cambridge University Press:  26 April 2021

Edmond D. Shenassa*
Maternal & Child Health Program, Department of Family Science and Department of Epidemiology and Biostatistics, School of Public Health, University of Maryland, College Park, MD, USA Department of Epidemiology, School of Public Health, Brown University, Providence, RI, USA Department of Epidemiology & Biostatistics, School of Medicine, University of Maryland, Baltimore, MD, USA
Michelle L. Rogers
Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, RI, USA
Stephen L. Buka
Department of Epidemiology, School of Public Health, Brown University, Providence, RI, USA
Author for correspondence: Edmond D. Shenassa, E-mail:



Evidence of a biologically plausible association between maternal smoking during pregnancy (MSP) and the risk of depression is discounted by null findings from two sibling studies. However, valid causal inference from sibling studies is subject to challenges inherent to human studies of MSP and biases particular to this design. We addressed these challenges in the first sibling study of MSP and depression conducted among adults past the peak age for the onset of depression, utilizing a prospectively collected and biologically validated measure of MSP and accounting for non-shared as well as mediating factors.


We fit GEE binomial regression models to correct for dependence in the risk of depression across pregnancies of the same mother. We also fit marginal structural models (MSM) to estimate the controlled direct effect of MSP on depression that is not mediated by the offspring's smoking status. Both models allow the estimation of within- and between-sibling risk ratios.


The adjusted within-sibling risk ratios (RRW) from both models (GEE: RRW = 1.97, CI 1.16–3.32; MSM: RRW = 2.08, CI 1.04–4.17) evinced an independent association between MSP and risk of depression. The overall effects from a standard model evinced lower associations (GEE: RRT = 1.12, CI 0.98–1.28; MSM: RRT = 1.18, CI 1.01–1.37).


Based on within-sibling information free of unmeasured shared confounders and accounting for a range of unshared factors, we found an effect of MSP on the offspring's risk of depression. Our findings, should they be replicated in future studies, highlight the importance of considering challenges inherent to human studies of MSP and affective disorders.

Original Article
Copyright © The Author(s), 2021. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Albers, A. B., & Biener, L. (2002). The role of smoking and rebelliousness in the development of depressive symptoms among a cohort of Massachusetts adolescents. Preventive Medicine, 34(6), 625631. ScholarPubMed
American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders: DSM-IV-TR (4th ed.). Washington, DC: American Psychiatric Association.Google Scholar
Ashford, J., Van Lier, P. A. C., Timmermans, M., Cuijpers, P., & Koot, H. M. (2008). Prenatal smoking and internalizing and externalizing problems in children studied from childhood to late adolescence. Journal of the American Academy of Child & Adolescent Psychiatry, 47(7), 779787. ScholarPubMed
Bakhshaie, J., Zvolensky, M. J., & Goodwin, R. D. (2015). Cigarette smoking and the onset and persistence of depression among adults in the United States: 1994–2005. Comprehensive Psychiatry, 60(July), 142148. ScholarPubMed
Baler, R. D., Volkow, N. D., Fowler, J. S., & Benveniste, H. (2008). Is fetal brain monoamine oxidase inhibition the missing link between maternal smoking and conduct disorders? Journal of Psychiatry & Neuroscience: JPN, 33(3), 187195. ScholarPubMed
Balfour, D. J., & Ridley, D. (2000). The effects of nicotine on neural pathways implicated in depression. Pharmacology Biochemistry and Behavior, 66(1), 7985. ScholarPubMed
Batstra, L., Hadders-Algra, M., & Neeleman, J. (2003). Effect of antenatal exposure to maternal smoking on behavioural problems and academic achievement in childhood: Prospective evidence from a Dutch birth cohort. Early Human Development, 75(1–2), 2133. ScholarPubMed
Brion, M.-J., Victora, C., Matijasevich, A., Horta, B., Anselmi, L., Steer, C., … Davey Smith, G. (2010). Maternal smoking and child psychological problems: Disentangling causal and noncausal effects. Pediatrics, 126(1), e57e65. ScholarPubMed
Buka, S. L., Shenassa, E. D., & Niaura, R. (2003). Elevated risk of tobacco dependence among offspring of mothers who smoked during pregnancy: A 30-year prospective study. American Journal of Psychiatry, 160(11), 19781984. ScholarPubMed
Colby, S. M., Clark, M. A., Rogers, M. L., Ramsey, S., Graham, A. L., Boergers, J., … Abrams, D. B. (2012). Development and reliability of the lifetime interview on smoking trajectories. Nicotine & Tobacco Research, 14(3), 290298. ScholarPubMed
D'Onofrio, B. M., Lahey, B. B., Turkheimer, E., & Lichtenstein, P. (2013). Critical need for family-based, quasi-experimental designs in integrating genetic and social science research. American Journal of Public Health, 103(S1), S46S55. ScholarPubMed
Ekblad, M., Gissler, M., Lehtonen, L., & Korkeila, J. (2010). Prenatal smoking exposure and the risk of psychiatric morbidity into young adulthood. Archives of General Psychiatry, 67(8), 841849. ScholarPubMed
Fergusson, D. M., Woodward, L. J., & Horwood, L. J. (1998). Maternal smoking during pregnancy and psychiatric adjustment in late adolescence. Archives of General Psychiatry, 55(8), 721727. ScholarPubMed
Frisell, T., Öberg, S., Kuja-Halkola, R., & Sjölander, A. (2012). Sibling comparison designs: Bias from non-shared confounders and measurement error. Epidemiology (Cambridge, Mass.), 23(5), 713720. ScholarPubMed
Gilman, S. E., Kawachi, I., Fitzmaurice, G. M., & Buka, S. L. (2003). Socio-economic status, family disruption and residential stability in childhood: Relation to onset, recurrence and remission of major depression. Psychological Medicine, 33(8), 13411355. ScholarPubMed
Haro, J. M., Arbabzadeh-Bouchez, S., Brugha, T. S., de Girolamo, G., Guyer, M. E., Jin, R., … Kessler, R. C. (2006). Concordance of the Composite International Diagnostic Interview Version 3.0 (CIDI 3.0) with standardized clinical assessments in the WHO World Mental Health surveys. International Journal of Methods in Psychiatric Research, 15(4), 167180. ScholarPubMed
Hook, B., Cederblad, M., & Berg, R. (2006). Prenatal and postnatal maternal smoking as risk factors for preschool children's mental health. Acta Paediatrica, 95(6), 671677. ScholarPubMed
Indredavik, M. S., Brubakk, A.-M., Romundstad, P., & Vik, T. (2007). Prenatal smoking exposure and psychiatric symptoms in adolescence. Acta Paediatrica, 96(3), 377382. ScholarPubMed
Jaspers, M., de Meer, G., Verhulst, F. C., Ormel, J., & Reijneveld, S. A. (2010). Limited validity of parental recall on pregnancy, birth, and early childhood at child age 10 years. Journal of Clinical Epidemiology, 63(2), 185191. ScholarPubMed
Kessler, R. C., Berglund, P., Demler, O., Jin, R., Marikangas, K. R., & Walters, E. E. (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey replication. Archives of General Psychiatry, 62(6), 593602.CrossRefGoogle ScholarPubMed
Klebanoff, M. A., Levine, R. J., Clemens, J. D., DerSimonian, R., & Wilkins, D. G. (1998). Serum cotinine concentration and self-reported smoking during pregnancy. American Journal of Epidemiology, 148(3), 259262.CrossRefGoogle ScholarPubMed
Klungsoyr, O., Nygard, J. F., Sorensen, T., & Sandanger, I. (2006). Cigarette smoking and incidence of first depressive episode: An 11-year, population-based follow-up study. American Journal of Epidemiology, 163(5), 421432. ScholarPubMed
Knopik, V. S. (2009). Maternal smoking during pregnancy and child outcomes: Real or spurious effect? Developmental Neuropsychology, 34(1), 136. ScholarPubMed
Lavigne, J. V., Hopkins, J., Gouze, K. R., Bryant, F. B., LeBailly, S. A., Binns, H. J., & Lavigne, P. M. (2011). Is smoking during pregnancy a risk factor for psychopathology in young children? A methodological caveat and report on preschoolers. Journal of Pediatric Psychology, 36(1), 1024. ScholarPubMed
McEwen, B. S., & Akil, H. (2020) Revisiting the stress concept: Implications for affective disorders. Journal of Neuroscience, 40, 1221.CrossRefGoogle ScholarPubMed
Meier, S. M., Plessen, K. J., Verhulst, F., Mors, O., Mortensen, P. B., Pedersen, C. B., & Agerbo, E. (2017). Familial confounding of the association between maternal smoking during pregnancy and internalizing disorders in offspring. Psychological Medicine, 47(08), 14171426. ScholarPubMed
Menezes, A. M. B., Murray, J., László, M., Wehrmeister, F. C., Hallal, P. C., Gonçalves, H., … Barros, F. C. (2013). Happiness and depression in adolescence after maternal smoking during pregnancy: Birth cohort study. PLoS ONE, 8(11), e80370. ScholarPubMed
Merrick, M. T., Ford, D. C., Ports, K. A., Guinn, A. S., Chen, J., Klevens, J., … Mercy, J. A. (2019). Vital signs: Estimated proportion of adult health problems attributable to adverse childhood experiences and implications for prevention – 25 states, 2015–2017. MMWR. Morbidity and Mortality Weekly Report, 68(44), 9991005. Scholar
Mojtabai, R., & Crum, R. M. (2013). Cigarette smoking and onset of mood and anxiety disorders. American Journal of Public Health, 103, 16561665. ScholarPubMed
Monshouwer, K., Huizink, A. C., Harakeh, Z., Raaijmakers, Q. A. W., Reijneveld, S. A., Oldehinkel, A. J., … Vollebergh, W. A. M. (2011). Prenatal smoking exposure and the risk of behavioral problems and substance use in adolescence: The TRAILS study. European Addiction Research, 17(6), 342350. ScholarPubMed
Moylan, S., Gustavson, K., Øverland, S., Karevold, E. B., Jacka, F. N., Pasco, J. A., & Berk, M. (2015). The impact of maternal smoking during pregnancy on depressive and anxiety behaviors in children: The Norwegian Mother and Child Cohort Study. BMC Medicine, 13(1), 24. ScholarPubMed
Myrianthopoulos, N. C., & French, K. S. (1968). An application of the U.S. Bureau of the Census socioeconomic index to a large, diversified patient population. Social Science & Medicine, 2(3), 283299.CrossRefGoogle ScholarPubMed
Nandi, A., Glymour, M. M., Kawachi, I., & VanderWeele, T. J. (2012). Using marginal structural models to estimate the direct effect of adverse childhood social conditions on onset of heart disease, diabetes, and stroke. Epidemiology (Cambridge, Mass.), 23(2), 223.CrossRefGoogle ScholarPubMed
Nurius, P. S., Logan-Greene, P., & Green, S. (2012). Adverse childhood experiences (ACE) within a social disadvantage framework: Distinguishing unique, cumulative, and moderated contributions to adult mental health. Journal of Prevention & Intervention in the Community, 40(4), 278290. ScholarPubMed
Robbins, A. S., Chao, S. Y., & Fonseca, V. P. (2002). What's the relative risk? A method to directly estimate risk ratios in cohort studies of common outcomes. Annals of Epidemiology, 12(7), 452454. ScholarPubMed
Shenassa, E. D. (2017). Maternal smoking during pregnancy and offspring weight gain: A consideration of competing explanations. Paediatric and Perinatal Epidemiology, 31(5), 409411. ScholarPubMed
Shenassa, E. D., Papandonatos, G. D., Rogers, M. L., & Buka, S. L. (2015). Elevated risk of nicotine dependence among sib-pairs discordant for maternal smoking during pregnancy: Evidence from a 40-year longitudinal study. Epidemiology (Cambridge, Mass.), 26(3), 441447. ScholarPubMed
Shenassa, E. D., Paradis, A. D., Dolan, S. L., Wilhelm, C. S., & Buka, S. L. (2012). Childhood impulsive behavior and problem gambling by adulthood: A 30-year prospective community-based study. Addiction, 107(1), 160168. ScholarPubMed
Shenassa, E. D., Wen, X., & Braid, S. (2016). Exposure to tobacco metabolites via breast milk and infant weight gain: A population-based study. Journal of Human Lactation, 32(3), 462471. doi: 10.1177/0890334415619154.CrossRefGoogle ScholarPubMed
Simard, J. F., Rosner, B. A., & Michels, K. B. (2008). Exposure to cigarette smoke in utero: Comparison of reports from mother and daughter. Epidemiology (Cambridge, Mass.), 19, 628633. ScholarPubMed
Slotkin, T. A., Pinkerton, K. E., Tate, C. A., & Seidler, F. J. (2006). Alterations of serotonin synaptic proteins in brain regions of neonatal Rhesus monkeys exposed to perinatal environmental tobacco smoke. Brain Research, 1111(1), 3035. ScholarPubMed
Slotkin, T. A., Skavicus, S., Levin, E. D., & Seidler, F. J. (2015). Prenatal nicotine changes the response to postnatal chlorpyrifos: Interactions targeting serotonergic synaptic function and cognition. Brain Research Bulletin, 111, 8496. ScholarPubMed
Stroud, L. R., Paster, R. L., Goodwin, M. S., Shenassa, E., Buka, S., Niaura, R., … Lipsitt, L. P. (2009). Maternal smoking during pregnancy and neonatal behavior: A large-scale community study. Pediatrics, 123(5), e842e848. ScholarPubMed
Taylor, A. E., Carslake, D., de Mola, C. L., Rydell, M., Nilsen, T. I. L., Bjørngaard, J. H., … Munafò, M. R. (2017). Maternal smoking in pregnancy and offspring depression: A cross cohort and negative control study. Scientific Reports, 7(1), 12579. ScholarPubMed
Tiesler, C. M. T., & Heinrich, J. (2014). Prenatal nicotine exposure and child behavioural problems. European Child & Adolescent Psychiatry, 23(10), 913929. ScholarPubMed
VanderWeele, T. J., & Ding, P. (2017). Sensitivity analysis in observational research: Introducing the E-value. Annals of Internal Medicine, 167(4), 268. ScholarPubMed
Wen, X., Shenassa, E. D., & Paradis, A. D. (2013). Maternal smoking, breastfeeding, and risk of childhood overweight: Findings from a national cohort. Maternal and Child Health Journal, 17(4), 746755. ScholarPubMed
Zetterqvist, J., Vansteelandt, S., Pawitan, Y., & Sjolander, A. (2016). Doubly robust methods for handling confounding by cluster. Biostatistics (Oxford, England), 17(2), 264276.CrossRefGoogle ScholarPubMed
Zhou, Q., Yin, Z., Wu, W., & Li, N. (2020). Childhood familial environment and adulthood depression: Evidence from a Chinese population-based study. International Health, 12(4), 299316. ScholarPubMed
Supplementary material: File

Shenassa et al. supplementary material

Shenassa et al. supplementary material

Download Shenassa et al. supplementary material(File)
File 18 KB