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Maternal tobacco, cannabis and alcohol use during pregnancy and risk of adolescent psychotic symptoms in offspring

  • Stanley Zammit (a1), Kate Thomas (a2), Andrew Thompson (a3), Jeremy Horwood (a2), Paulo Menezes (a3), David Gunnell (a2), Chris Hollis (a4), Dieter Wolke (a5), Glyn Lewis (a6) and Glynn Harrison (a6)...



Adverse effects of maternal substance use during pregnancy on fetal development may increase risk of psychopathology.


To examine whether maternal use of tobacco, cannabis or alcohol during pregnancy increases risk of offspring psychotic symptoms.


A longitudinal study of 6356 adolescents, age 12, who completed a semi-structured interview for psychotic symptoms in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort.


Frequency of maternal tobacco use during pregnancy was associated with increased risk of suspected or definite psychotic symptoms (adjusted odds ratio 1.20, 95% CI 1.05–1.37, P = 0.007). Maternal alcohol use showed a non-linear association with psychotic symptoms, with this effect almost exclusively in the offspring of women drinking >21 units weekly. Maternal cannabis use was not associated with psychotic symptoms. Results for paternal smoking during pregnancy and maternal smoking post-pregnancy lend some support for a causal effect of tobacco exposure in utero on development of psychotic experiences.


These findings indicate that risk factors for development of non-clinical psychotic experiences may operate during early development. Future studies of how in utero exposure to tobacco affects cerebral development and function may lead to increased understanding of the pathogenesis of psychotic phenomena.

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Corresponding author

Stanley Zammit, Department of Psychological Medicine, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, Wales, UK. Email:


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This study was funded by the Wellcome Trust grant No. GR072043MA. S.Z. is funded through a Clinician Scientist Award funded by the National Assembly for Wales. The UK Medical Research Council, the Wellcome Trust and the University of Bristol provide core support for ALSPAC.

Declaration of interest




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1 Office for National Statistics. Statistics on Smoking: England 2006. ONS, 2006.
2 NHS Information Centre. Statistics on Alcohol: England 2007. The Information Centre, 2007.
3 Fried, PA. Conceptual issues in behavioral teratology and their application in determining long-term sequelae of prenatal marihuana exposure. J Child Psychol Psychiatry 2002; 43: 81102.
4 Huizink, AC, Mulder, EJ. Maternal smoking, drinking or cannabis use during pregnancy and neurobehavioral and cognitive functioning in human offspring. Neurosci Biobehav Rev 2006; 30: 2441.
5 Andres, RL, Day, MC. Perinatal complications associated with maternal tobacco use. Semin Neonatol 2000; 5: 231–41.
6 Ernst, M, Moolchan, ET, Robinson, ML. Behavioral and neural consequences of prenatal exposure to nicotine. J Am Acad Child Adolesc Psychiatry 2001; 40: 630–41.
7 Winzer-Serhan, UH. Long-term consequences of maternal smoking and developmental chronic nicotine exposure. Front Biosci 2008; 13: 636–49.
8 Fried, PA, Watkinson, B, Gray, R. Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 2003; 25: 427–36.
9 Mortensen, EL, Michaelsen, KF, Sanders, SA, Reinisch, JM. A dose-response relationship between maternal smoking during late pregnancy and adult intelligence in male offspring. Paediatr Perinat Epidemiol 2005; 19: 411.
10 Fergusson, DM, Woodward, LJ, Horwood, LJ. Maternal smoking during pregnancy and psychiatric adjustment in late adolescence. Arch Gen Psychiatry 1998; 55: 721–7.
11 Linnet, KM, Dalsgaard, S, Obel, C, Wisborg, K, Henriksen, TB, Rodriguez, A, et al. Maternal lifestyle factors in pregnancy risk of attention deficit hyperactivity disorder and associated behaviors: review of the current evidence. Am J Psychiatry 2003; 160: 1028–40.
12 Thapar, A, Fowler, T, Rice, F, Scourfield, J, van den Bree, M, Thomas, H, et al. Maternal smoking during pregnancy and attention deficit hyperactivity disorder symptoms in offspring. Am J Psychiatry 2003; 160: 1985–9.
13 Smith, GD. Assessing intrauterine influences on offspring health outcomes: can epidemiological studies yield robust findings? Basic Clin Pharmacol Toxicol 2008; 102: 245–56.
14 Dwyer, JB, Broide, RS, Leslie, FM. Nicotine and brain development. Birth Defects Res C Embryo Today 2008; 84: 3044.
15 Slotkin, TA. Cholinergic systems in brain development and disruption by neurotoxicants: nicotine, environmental tobacco smoke, organophosphates. Toxicol Appl Pharmacol 2004; 198: 132–51.
16 Sundram, S. Cannabis and neurodevelopment: implications for psychiatric disorders. Hum Psychopharmacol 2006; 21: 245–54.
17 Cannon, M, Jones, PB, Murray, RM. Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry 2002; 159: 1080–92.
18 Jones, PB, Rantakallio, P, Hartikainen, AL, Isohanni, M, Sipila, P. Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications: a 28-year follow-up of the 1966 north Finland general population birth cohort. Am J Psychiatry 1998; 155: 355–64.
19 Sacker, A, Done, DJ, Crow, TJ, Golding, J. Antecedents of schizophrenia and affective illness. Obstetric complications. Br J Psychiatry 1995; 166: 734–41.
20 Spauwen, J, Krabbendam, L, Lieb, R, Wittchen, HU, van Os, J. Early maternal stress and health behaviours and offspring expression of psychosis in adolescence. Acta Psychiatr Scand 2004; 110: 356–64.
21 Horwood, J, Salvi, G, Thomas, K, Duffy, L, Gunnell, D, Hollis, C, et al. IQ and non-clinical psychotic symptoms in 12-year-olds: results from the ALSPAC birth cohort. Br J Psychiatry 2008; 193: 185–91.
22 Golding, J, Pembrey, M, Jones, R. ALSPAC – the Avon Longitudinal Study of Parents and Children. I. Study methodology. Paediatr Perinat Epidemiol 2001; 15: 7487.
23 Shaffer, D, Fisher, P, Lucas, CP, Dulcan, MK, Schwab-Stone, ME. NIMH Diagnostic Interview Schedule for Children Version IV (NIMH DISC-IV): description, differences from previous versions, and reliability of some common diagnoses. J Am Acad Child Adolesc Psychiatry 2000; 39: 2838.
24 World Health Organization. Schedules for Clinical Assessment in Neuropsychiatry. American Psychiatric Research, 1994.
25 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM–IV). APA, 1994.
26 World Health Organization. The ICD–10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. WHO, 1992.
27 Office for Population Censuses and Surveys. Standard Occupational Classification 1990. OPCS, 1990.
28 Cox, JL, Holden, JM, Sagovsky, R. Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry 1987; 150: 782–6.
29 Wechsler, D. Manual for the Wechsler Intelligence Scale for Children (3rd edn) (WISC–III). Psychological Corporation, 1991.
30 Raghunathan, TE, Lepkowski, JM, Van Hoewyk, J, Solenberger, P. A multivariate technique for multiply imputing missing values using a sequence of regression models. Surv Methodol 2001; 27: 8595.
31 Royston, P. Multiple imputation of missing values. The Stata Journal 2004; 3: 227–41.
32 Kirkwood, BR, Sterne, JAC. Regression modelling. In Essential Medical Statistics (eds Kirkwood, BR, Sterne, JAC): 337–9. Blackwell Science, 2003.
33 Spencer, N. Explaining the social gradient in smoking in pregnancy: early life course accumulation and cross-sectional clustering of social risk exposures in the 1958 British national cohort. Soc Sci Med 2006; 62: 1250–9.
34 Wicks, S, Hjern, A, Gunnell, D, Lewis, G, Dalman, C. Social adversity in childhood and the risk of developing psychosis: a national cohort study. Am J Psychiatry 2005; 162: 1652–7.
35 Day, NL, Cottreau, CM, Richardson, GA. The epidemiology of alcohol, marijuana, and cocaine use among women of childbearing age and pregnant women. Clin Obstet Gynecol 1993; 36: 232–45.
36 Callaway, LK, McIntyre, HD, O'Callaghan, M, Williams, GM, Najman, JM, Lawlor, DA. The association of hypertensive disorders of pregnancy with weight gain over the subsequent 21 years: findings from a prospective cohort study. Am J Epidemiol 2007; 166: 421–8.
37 Plewis, I, Calderwoof, L, Hawkes, D, Nathan, G. National Child Development Study and 1970 British Cohort Study Technical Report: Changes in the NCDS and BCS70 Populations and Samples Over Time. Centre for Longitudinal Studies, Institute of Education, 2004.
38 St Clair, D, Xu, M, Wang, P, Yu, Y, Fang, Y, Zhang, F, et al. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959–1961. JAMA 2005; 294: 557–62.
39 Susser, E, Neugebauer, R, Hoek, HW, Brown, AS, Lin, S, Labovitz, D, et al. Schizophrenia after prenatal famine. Further evidence. Arch Gen Psychiatry 1996; 53: 2531.
40 Brown, AS, Begg, MD, Gravenstein, S, Schaefer, CA, Wyatt, RJ, Bresnahan, M, et al. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 2004; 61: 774–80.
41 Byrne, M, Agerbo, E, Bennedsen, B, Eaton, WW, Mortensen, PB. Obstetric conditions and risk of first admission with schizophrenia: a Danish national register based study. Schizophr Res 2007; 97: 51–9.
42 Wang, X, Tager, IB, Van Vunakis, H, Speizer, FE, Hanrahan, JP. Maternal smoking during pregnancy, urine cotinine concentrations, and birth outcomes. A prospective cohort study. Int J Epidemiol 1997; 26: 978–88.
43 Jaddoe, VW, Verburg, BO, de Ridder, MA, Hofman, A, Mackenbach, JP, Moll, HA, et al. Maternal smoking and fetal growth characteristics in different periods of pregnancy: the generation R study. Am J Epidemiol 2007; 165: 1207–15.
44 Burd, L, Roberts, D, Olson, M, Odendaal, H. Ethanol and the placenta: a review. J Matern Fetal Neonatal Med 2007; 20: 361–75.
45 Henderson, J, Gray, R, Brocklehurst, P. Systematic review of effects of low-moderate prenatal alcohol exposure on pregnancy outcome. BJOG 2007; 114: 243–52.
46 Poulton, R, Caspi, A, Moffitt, TE, Cannon, M, Murray, R, Harrington, H. Children's self-reported psychotic symptoms and adult schizophreniform disorder: a 15-year longitudinal study. Arch Gen Psychiatry 2000; 57: 1053–8.
47 Hanssen, M, Bak, M, Bijl, R, Vollebergh, W, van Os, J. The incidence and outcome of subclinical psychotic experiences in the general population. Br J Clin Psychol 2005; 44: 181–91.
48 Eaton, WW, Romanoski, A, Anthony, JC, Nestadt, G. Screening for psychosis in the general population with a self-report interview. J Nerv Ment Dis 1991; 179: 689–93.
49 Johns, LC, Cannon, M, Singleton, N, Murray, RM, Farrell, M, Brugha, T, et al. Prevalence and correlates of self-reported psychotic symptoms in the British population. Br J Psychiatry 2004; 185: 298305.
50 van Os, J, Hanssen, M, Bijl, RV, Vollebergh, W. Prevalence of psychotic disorder and community level of psychotic symptoms: an urban-rural comparison. Arch Gen Psychiatry 2001; 58: 663–8.
51 Wiles, NJ, Zammit, S, Bebbington, P, Singleton, N, Meltzer, H, Lewis, G. Self-reported psychotic symptoms in the general population. Results from the longitudinal study of the British National Psychiatric Morbidity Survey. Br J Psychiatry 2006; 188: 519–26.
52 Rossler, W, Riecher-Rossler, A, Angst, J, Murray, R, Gamma, A, Eich, D, et al. Psychotic experiences in the general population: a twenty-year prospective community study. Schizophr Res 2007; 92: 114.


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Maternal tobacco, cannabis and alcohol use during pregnancy and risk of adolescent psychotic symptoms in offspring

  • Stanley Zammit (a1), Kate Thomas (a2), Andrew Thompson (a3), Jeremy Horwood (a2), Paulo Menezes (a3), David Gunnell (a2), Chris Hollis (a4), Dieter Wolke (a5), Glyn Lewis (a6) and Glynn Harrison (a6)...
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Antenatal tobacco exposure and risk for psychosis - a role for epigenetics?

Helge Frieling, MD
02 December 2009

Dear Sir,

Stanley Zammit and co-workers have reported that maternal tobacco consumption during pregnancy increases the risk for the development of non-clinical psychotic experiences and might be a risk factor for psychotic disorders like schizophrenia (1). The authors discuss some possible biological mechanisms, but we believe that the important aspect of epigenetic programming during pregnancy was omitted. Disturbances in epigenetic mechanisms like DNA methylation and histone modifications have been shown to be the biological substrate of long-term behavioural programming due to early events and aberrant DNA methylation of different genes has been described in schizophrenia (2-3). We have recently shown that tobacco consumption influences DNA methylation (4) and epigenetic disturbances are believed to be one important way of tobacco-associated carcinogenesis.

To us it seems plausible to assume that the reported effect of maternal tobacco consumption on psychosis-like symptoms in the offspring might be mediated by epigenetic means. This could also help understand whymaternal smoking during the third trimester of pregnancy was associated with the highest risk, as other ‘epigenetic’ risk factors like hyperhomocysteinemia are also most deleterious during this time period (5). Further studies should also address the effect of maternal tobacco consumption on epigenetic markers in the offspring, which might open a window to effective preventive measures even after exposure during pregnancy.

1Zammit S., Thomas K., Thompson A., Horwood J., Menezes P., Gunnell D., et al. Maternal tobacco, cannabis and alcohol use during pregnancy andrisk of adolescent psychotic symptoms in offspring. Br J Psychiatry 2009; 195: 294-300.

2Mill J., Tang T., Kaminsky Z., Khare T., Yazdanpanah S., Bouchard L., et al. Epigenomic Profiling Reveals DNA-Methylation Changes Associatedwith Major Psychosis. The American Journal of Human Genetics 2008; 82: 696-711.

3Krebs M. O., Bellon A., Mainguy G., Jay T. M.,Frieling H. One-carbon metabolism and schizophrenia: current challenges and future directions. Trends in Molecular Medicine In Press, Corrected Proof:

4Hillemacher T., Frieling H., Moskau S., Muschler M. A., Semmler A.,Kornhuber J., et al. Global DNA methylation is influenced by smoking behaviour. Eur Neuropsychopharmacol 2008; 18: 295-298.

5Brown A. S., Bottiglieri T., Schaefer C. A., Quesenberry C. P., Jr., Liu L., Bresnahan M., et al. Elevated Prenatal Homocysteine Levels asa Risk Factor for Schizophrenia. Arch Gen Psychiatry 2007; 64: 31-39.
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Conflict of interest: None Declared

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