Skip to main content Accessibility help

Familial confounding of the association between maternal smoking during pregnancy and internalizing disorders in offspring

  • S. M. Meier (a1) (a2) (a3), K. J. Plessen (a2) (a3) (a4), F. Verhulst (a5) (a4), O. Mors (a6), P. B. Mortensen (a1) (a2) (a7), C. B. Pedersen (a1) (a2) (a7) and E. Agerbo (a1) (a2) (a7)...



Maternal smoking has consistently been associated with multiple adverse childhood outcomes including externalizing disorders. In contrast the association between maternal smoking during pregnancy (MSDP) and internalizing (anxiety and depressive) disorders in offspring has received less investigation.


We conducted a nationwide cohort study including 957635 individuals born in Denmark between 1991 and 2007. Data on MSDP and diagnoses of depression or anxiety disorders were derived from national registers and patients were followed up from the age of 5 years to the end of 2012. Hazard rate ratios (HRRs) were estimated using stratified Cox regression models. Sibling data were used to disentangle individual- and familial-level effects of MSDP and to control for unmeasured familial confounding.


At the population level, offspring exposed to MSDP were at increased risk for both severe depression [HRR 1.29, 95% confidence interval (CI) 1.22–1.36] and severe anxiety disorders (HRR 1.26, 95% CI 1.20–1.32) even when controlling for maternal and paternal traits. However, there was no association between MSDP and internalizing disorders when controlling for the mother's propensity for MSDP (depression: HRR 1.11, 95% CI 0.94–1.30; anxiety disorders: HRR 0.94, 95% CI 0.80–1.11) or comparing differentially exposed siblings (depression: HRR 1.18, 95% CI 0.75–1.89; anxiety disorders: HRR 0.87, 95% CI 0.55–1.36).


The results suggest that familial background factors account for the association between MSDP and severe internalizing disorders not the specific exposure to MSDP.


Corresponding author

*Address for correspondence: Dr S. M. Meier, National Centre for Register-Based Research, Aarhus University, Fuglesangs Allé 4, 8210 Aarhus V, Denmark. (Email:


Hide All
Agerbo, E, Mortensen, PB, Munk-Olsen, T (2013). Childlessness parental mortality and psychiatric illness: a natural experiment based on in vitro fertility treatment and adoption. Journal of Epidemiology and Community Health 67, 374376.
Agrawal, A, Knopik, VS, Pergadia, ML, Waldron, M, Bucholz, KK, Martin, NG, Heath, AC, Madden, PA (2008). Correlates of cigarette smoking during pregnancy and its genetic and environmental overlap with nicotine dependence. Nicotine and Tobacco Research 10, 567578.
Andersen, TF, Madsen, M, Jorgensen, J, Mellemkjoer, L, Olsen, JH (1999). The Danish National Hospital Register. A valuable source of data for modern health sciences. Danish Medical Bulletin 46, 263268.
Ashford, J, van Lier, PA, Timmermans, M, Cuijpers, P, Koot, HM (2008). Prenatal smoking and internalizing and externalizing problems in children studied from childhood to late adolescence. Journal of the American Academy of Child and Adolescent Psychiatry 47, 779787.
Baadsgaard, M, Quitzau, J (2011). Danish registers on personal income and transfer payments. Scandinavian Journal of Public Health 39, 103105.
Begg, MD, Parides, MK (2003). Separation of individual-level and cluster-level covariate effects in regression analysis of correlated data. Statistics in Medicine 22, 25912602.
Brion, MJ, Victora, C, Matijasevich, A, Horta, B, Anselmi, L, Steer, C, Menezes, AM, Lawlor, DA, Davey Smith, G (2010). Maternal smoking and child psychological problems: disentangling causal and noncausal effects. Pediatrics 126, e57e65.
Carter, S, Paterson, J, Gao, W, Iusitini, L (2008). Maternal smoking during pregnancy and behaviour problems in a birth cohort of 2-year-old Pacific children in New Zealand. Early Human Development 84, 5966.
Chang, Z, Lichtenstein, P, Larsson, H (2012). The effects of childhood ADHD symptoms on early-onset substance use: a Swedish twin study. Journal of Abnormal Child Psychology 40, 425435.
Charlson, ME, Pompei, P, Ales, KL, Mackenzie, CR (1987). A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. Journal of Chronic Disorders 40, 373383.
Cnattingius, S (2004). The epidemiology of smoking during pregnancy: smoking prevalence maternal characteristics and pregnancy outcomes. Nicotine and Tobacco Research 6 (Suppl. 2) S125S140.
Dolan, CV, Geels, L, Vink, JM, van Beijsterveldt, CE, Neale, MC, Bartels, M, Boomsma, DI (2016). Testing causal effects of maternal smoking during pregnancy on offspring's externalizing and internalizing behavior. Behavior Genetics 46, 378388.
D'Onofrio, BM, Lahey, BB, 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 (Suppl. 1), S46S55.
D'Onofrio, BM, Singh, AL, Iliadou, A, Lambe, M, Hultman, CM, Grann, M, Neiderhiser, JM, Langstrom, N, Lichtenstein, P (2010 a). Familial confounding of the association between maternal smoking during pregnancy and offspring criminality: a population-based study in Sweden. Archives of General Psychiatry 67, 529538.
D'Onofrio, BM, Singh, AL, Iliadou, A, Lambe, M, Hultman, CM, Neiderhiser, JM, Langstrom, N, Lichtenstein, P (2010 b). A quasi-experimental study of maternal smoking during pregnancy and offspring academic achievement. Child Development 81, 80100.
Ellingson, JM, Rickert, ME, Lichtenstein, P, Langstrom, N, D'Onofrio, BM (2012). Disentangling the relationships between maternal smoking during pregnancy and co-occurring risk factors. Psychological Medicine 42, 15471557.
Flenady, V, Koopmans, L, Middleton, P, Froen, JF, Smith, GC, Gibbons, K, Coory, M, Gordon, A, Ellwood, D, McIntyre, HD, Fretts, R, Ezzati, M (2011). Major risk factors for stillbirth in high-income countries: a systematic review and meta-analysis. Lancet 377, 13311340.
Frisell, T, Oberg, S, Kuja-Halkola, R, Sjolander, A (2012). Sibling comparison designs: bias from non-shared confounders and measurement error. Epidemiology 23, 713720.
Gilman, SE, Gardener, H, Buka, SL (2008). Maternal smoking during pregnancy and children's cognitive and physical development: a causal risk factor? American Journal of Epidemiology 168, 522531.
Gorog, K, Pattenden, S, Antova, T, Niciu, E, Rudnai, P, Scholtens, S, Splichalova, A, Slotova, K, Voko, Z, Zlotkowska, R, Houthuijs, D (2011). Maternal smoking during pregnancy and childhood obesity: results from the CESAR Study. Maternal and Child Health Jorunal 15, 985992.
Jaddoe, VW, Troe, EJ, Hofman, A, Mackenbach, JP, Moll, HA, Steegers, EA, Witteman, JC (2008). Active and passive maternal smoking during pregnancy and the risks of low birthweight and preterm birth: the generation R study. Paediatric and Perinatal Epidemiology 22, 162171.
Jensen, VM, Rasmussen, AW (2011). Danish education registers. Scandinavian Journal of Public Health 39, 9194.
Knopik, VS (2009). Maternal smoking during pregnancy and child outcomes: real or spurious effect? Developmental Neuropsychology 34, 136.
Knopik, VS, Sparrow, EP, Madden, PA, Bucholz, KK, Hudziak, JJ, Reich, W, Slutske, WS, Grant, JD, McLaughlin, TL, Todorov, A, Todd, RD, Heath, AC (2005). Contributions of parental alcoholism prenatal substance exposure and genetic transmission to child ADHD risk: a female twin study. Psychological Medicine 35, 625635.
Knudsen, LB, Olsen, J (1998). The danish medical birth registry. Danish Medical Bulletin 45, 320323.
Kuja-Halkola, R, D'Onofrio, BM, Larsson, H, Lichtenstein, P (2014). Maternal smoking during pregnancy and adverse outcomes in offspring: genetic and environmental sources of covariance. Behavior Genetics 44, 456467.
Lambe, M, Hultman, C, Torrang, A, Maccabe, J, Cnattingius, S (2006). Maternal smoking during pregnancy and school performance at age 15. Epidemiology 17, 524530.
Langley, K, Heron, J, Smith, GD, Thapar, A (2012). Maternal and paternal smoking during pregnancy and risk of ADHD symptoms in offspring: testing for intrauterine effects. American Journal of Epidemiology 176, 261268.
Lindqvist, R, Lendahls, L, Tollbom, O, Aberg, H, Hakansson, A (2002). Smoking during pregnancy: comparison of self-reports and cotinine levels in 496 women. Acta Obstetricia et Gynecologica Scandinavica 81, 240244.
Lundberg, F, Cnattingius, S, D'Onofrio, B, Altman, D, Lambe, M, Hultman, C, Iliadou, A (2010). Maternal smoking during pregnancy and intellectual performance in young adult Swedish male offspring. Paediatric and Perinatal Epidemiology 24, 7987.
Lynge, E, Sandegaard, JL, Rebolj, M (2011). The Danish National Patient Register. Scandinavian Journal of Public Health 39, 3033.
Meier, SM, Mors, O, Parner, ET (in press). Familial confounding of the association between maternal smoking during pregnancy and schizophrenia. American Journal of Psychiatry.
Mors, O, Perto, GP, Mortensen, PB (2011). The Danish Psychiatric Central Research Register. Scandinavian Journal of Public Health 39, 5457.
Moylan, S, Gustavson, K, Overland, S, Karevold, EB, Jacka, FN, Pasco, JA, 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, 24.
Murray, CJ, Vos, T, Lozano, R, Naghavi, M, Flaxman, AD, Michaud, C, Ezzati, M, Shibuya, K, Salomon, JA, Abdalla, S, Aboyans, V, Abraham, J, Ackerman, I, Aggarwal, R, Ahn, SY, Ali, MK, Alvarado, M, Anderson, HR, Anderson, LM, Andrews, KG, Atkinson, C, Baddour, LM, Bahalim, AN, Barker-Collo, S, Barrero, LH, Bartels, DH, Basanez, MG, Baxter, A, Bell, ML, Benjamin, EJ, Bennett, D, Bernabe, E, Bhalla, K, Bhandari, B, Bikbov, B, Bin Abdulhak, A, Birbeck, G, Black, JA, Blencowe, H, Blore, JD, Blyth, F, Bolliger, I, Bonaventure, A, Boufous, S, Bourne, R, Boussinesq, M, Braithwaite, T, Brayne, C, Bridgett, L, Brooker, S, Brooks, P, Brugha, TS, Bryan-Hancock, C, Bucello, C, Buchbinder, R, Buckle, G, Budke, CM, Burch, M, Burney, P, Burstein, R, Calabria, B, Campbell, B, Canter, CE, Carabin, H, Carapetis, J, Carmona, L, Cella, C, Charlson, F, Chen, H, Cheng, AT, Chou, D, Chugh, SS, Coffeng, LE, Colan, SD, Colquhoun, S, Colson, KE, Condon, J, Connor, MD, Cooper, LT, Corriere, M, Cortinovis, M, de Vaccaro, KC, Couser, W, Cowie, BC, Criqui, MH, Cross, M, Dabhadkar, KC, Dahiya, M, Dahodwala, N, Damsere-Derry, J, Danaei, G, Davis, A, De Leo, D, Degenhardt, L, Dellavalle, R, Delossantos, A, Denenberg, J, Derrett, S, Des Jarlais, DC, Dharmaratne, SD, Dherani, M, Diaz-Torne, C, Dolk, H, Dorsey, ER, Driscoll, T, Duber, H, Ebel, B, Edmond, K, Elbaz, A, Ali, SE, Erskine, H, Erwin, PJ, Espindola, P, Ewoigbokhan, SE, Farzadfar, F, Feigin, V, Felson, DT, Ferrari, A, Ferri, CP, Fevre, EM, Finucane, MM, Flaxman, S, Flood, L, Foreman, K, Forouzanfar, MH, Fowkes, FG, Fransen, M, Freeman, MK, Gabbe, BJ, Gabriel, SE, Gakidou, E, Ganatra, HA, Garcia, B, Gaspari, F, Gillum, RF, Gmel, G, Gonzalez-Medina, D, Gosselin, R, Grainger, R, Grant, B, Groeger, J, Guillemin, F, Gunnell, D, Gupta, R, Haagsma, J, Hagan, H, Halasa, YA, Hall, W, Haring, D, Haro, JM, Harrison, JE, Havmoeller, R, Hay, RJ, Higashi, H, Hill, C, Hoen, B, Hoffman, H, Hotez, PJ, Hoy, D, Huang, JJ, Ibeanusi, SE, Jacobsen, KH, James, SL, Jarvis, D, Jasrasaria, R, Jayaraman, S, Johns, N, Jonas, JB, Karthikeyan, G, Kassebaum, N, Kawakami, N, Keren, A, Khoo, JP, King, CH, Knowlton, LM, Kobusingye, O, Koranteng, A, Krishnamurthi, R, Laden, F, Lalloo, R, Laslett, LL, Lathlean, T, Leasher, JL, Lee, YY, Leigh, J, Levinson, D, Lim, SS, Limb, E, Lin, JK, Lipnick, M, Lipshultz, SE, Liu, W, Loane, M, Ohno, SL, Lyons, R, Mabweijano, J, MacIntyre, MF, Malekzadeh, R, Mallinger, L, Manivannan, S, Marcenes, W, March, L, Margolis, DJ, Marks, GB, Marks, R, Matsumori, A, Matzopoulos, R, Mayosi, BM, McAnulty, JH, McDermott, MM, McGill, N, McGrath, J, Medina-Mora, ME, Meltzer, M, Mensah, GA, Merriman, TR, Meyer, AC, Miglioli, V, Miller, M, Miller, TR, Mitchell, PB, Mock, C, Mocumbi, AO, Moffitt, TE, Mokdad, AA, Monasta, L, Montico, M, Moradi-Lakeh, M, Moran, A, Morawska, L, Mori, R, Murdoch, ME, Mwaniki, MK, Naidoo, K, Nair, MN, Naldi, L, Narayan, KM, Nelson, PK, Nelson, RG, Nevitt, MC, Newton, CR, Nolte, S, Norman, P, Norman, R, O'Donnell, M, O'Hanlon, S, Olives, C, Omer, SB, Ortblad, K, Osborne, R, Ozgediz, D, Page, A, Pahari, B, Pandian, JD, Rivero, AP, Patten, SB, Pearce, N, Padilla, RP, Perez-Ruiz, F, Perico, N, Pesudovs, K, Phillips, D, Phillips, MR, Pierce, K, Pion, S, Polanczyk, GV, Polinder, S, Pope, CA 3rd, Popova, S, Porrini, E, Pourmalek, F, Prince, M, Pullan, RL, Ramaiah, KD, Ranganathan, D, Razavi, H, Regan, M, Rehm, JT, Rein, DB, Remuzzi, G, Richardson, K, Rivara, FP, Roberts, T, Robinson, C, De Leon, FR, Ronfani, L, Room, R, Rosenfeld, LC, Rushton, L, Sacco, RL, Saha, S, Sampson, U, Sanchez-Riera, L, Sanman, E, Schwebel, DC, Scott, JG, Segui-Gomez, M, Shahraz, S, Shepard, DS, Shin, H, Shivakoti, R, Singh, D, Singh, GM, Singh, JA, Singleton, J, Sleet, DA, Sliwa, K, Smith, E, Smith, JL, Stapelberg, NJ, Steer, A, Steiner, T, Stolk, WA, Stovner, LJ, Sudfeld, C, Syed, S, Tamburlini, G, Tavakkoli, M, Taylor, HR, Taylor, JA, Taylor, WJ, Thomas, B, Thomson, WM, Thurston, GD, Tleyjeh, IM, Tonelli, M, Towbin, JA, Truelsen, T, Tsilimbaris, MK, Ubeda, C, Undurraga, EA, van der Werf, MJ, van Os, J, Vavilala, MS, Venketasubramanian, N, Wang, M, Wang, W, Watt, K, Weatherall, DJ, Weinstock, MA, Weintraub, R, Weisskopf, MG, Weissman, MM, White, RA, Whiteford, H, Wiebe, N, Wiersma, ST, Wilkinson, JD, Williams, HC, Williams, SR, Witt, E, Wolfe, F, Woolf, AD, Wulf, S, Yeh, PH, Zaidi, AK, Zheng, ZJ, Zonies, D, Lopez, AD, AlMazroa, MA, Memish, ZA (2012). Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 21972223.
Obel, C, Linnet, KM, Henriksen, TB, Rodriguez, A, Jarvelin, MR, Kotimaa, A, Moilanen, I, Ebeling, H, Bilenberg, N, Taanila, A, Ye, G, Olsen, J (2009). Smoking during pregnancy and hyperactivity-inattention in the offspring–comparing results from three Nordic cohorts. International Journal of Epidemiology 38, 698705.
Obel, C, Olsen, J, Henriksen, TB, Rodriguez, A, Jarvelin, MR, Moilanen, I, Parner, E, Linnet, KM, Taanila, A, Ebeling, H, Heiervang, E, Gissler, M (2011). Is maternal smoking during pregnancy a risk factor for hyperkinetic disorder?–Findings from a sibling design. International Journal of Epidemiology 40, 338345.
Obel, C, Zhu, JL, Olsen, J, Breining, S, Li, J, Gronborg, TK, Gissler, M, Rutter, M (2015). The risk of attention deficit hyperactivity disorder in children exposed to maternal smoking during pregnancy – a reexamination using a sibling design. Journal of Child Psychology and Psychiatry and Allied Disciplines 54, 532537.
Pedersen, CB (2011). The Danish Civil Registration System. Scandinavian Journal of Public Health 39, 2225.
Robinson, M, McLean, NJ, Oddy, WH, Mattes, E, Bulsara, M, Li, J, Zubrick, SR, Stanley, FJ, Newnham, JP (2010). Smoking cessation in pregnancy and the risk of child behavioural problems: a longitudinal prospective cohort study. Journal of Epidemiology and Community Health 64, 622629.
Roza, SJ, Verhulst, FC, Jaddoe, VW, Steegers, EA, Mackenbach, JP, Hofman, A, Tiemeier, H (2009). Maternal smoking during pregnancy and child behaviour problems: the generation R study. International Journal of Epidemiology 38, 680689.
Skoglund, C, Chen, Q, D'Onofrio, BM, Lichtenstein, P, Larsson, H (2014). Familial confounding of the association between maternal smoking during pregnancy and ADHD in offspring. Journal of Child Psychology and Psychiatry and Allied Disciplines 55, 6168.
Thapar, A, Fowler, T, Rice, F, Scourfield, J, van den Bree, M, Thomas, H, Harold, G, Hay, D (2003). Maternal smoking during pregnancy and attention deficit hyperactivity disorder symptoms in offspring. American Journal of Psychiatry 160, 19851989.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed