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Prenatal Risk Factors and the Etiology of ADHD—Review of Existing Evidence

Abstract

While it is well accepted that attention-deficit/hyperactivity disorder (ADHD) is a highly heritable disorder, not all of the risk is genetic. It is estimated that between 10 and 40% of the variance associated with ADHD is likely to be accounted for by environmental factors. There is considerable interest in the role that the prenatal environment might play in the development of ADHD with previous reviews concluding that despite demonstration of associations between prenatal risk factors (e.g. prematurity, maternal smoking during pregnancy) and ADHD, there remains insufficient evidence to support a definite causal relationship. This article provides an update of research investigating the relationship between prenatal risk factors and ADHD published over the past 3 years. Recently, several epidemiological and data linkage studies have made substantial contributions to our understanding of this relationship. In particular, these studies have started to account for some of the genetic and familial confounds that, when taken into account, throw several established findings into doubt. None of the proposed prenatal risk factors can be confirmed as causal for ADHD, and the stronger the study design, the less likely it is to support an association. We need a new benchmark for studies investigating the etiology of ADHD whereby there is an expectation not only that data will be collected prospectively but also that the design allows the broad range of genetic and familial factors to be accounted for.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Biederman J, Faraon SV. Attention-deficit hyperactivity disorder. Lancet. 2005;366(9481):237–48. doi:10.1016/S0140-6736(05)66915-2.

    Article  PubMed  Google Scholar 

  2. Akutagava-Martins GC, Salatino-Oliveira A, Kieling CC, Rohde LA, Hutz MH. Genetics of attention-deficit/hyperactivity disorder: current findings and future directions. Expert Rev Neurother. 2013;13(4):435–45. doi:10.1586/ern.13.30.

    CAS  Article  PubMed  Google Scholar 

  3. Thapar A, Cooper M, Eyre O, Langley K. Practitioner review: what have we learnt about the causes of ADHD? J Child Psychol Psychiatry. 2013;54(1):3–16.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Banerjee TD, Middleton F, Faraone SV. Environmental risk factors for attention‐deficit hyperactivity disorder. Acta Paediatr. 2007;96(9):1269–74.

    Article  PubMed  Google Scholar 

  5. Coghill D, Bazian L, Faraon SV, Nigg J, Sonuga-Barke E, Rohde LA. A systematic review of the causes of attention deficit hyperactivity disorder (ADHD): an evidence report. London: Department of Health; 2011.

    Google Scholar 

  6. Thapar A, Rice F, Hay D, Boivin J, Langley K, van den Bree M, et al. Prenatal smoking might not cause attention-deficit/hyperactivity disorder: evidence from a novel design. Biol Psychiatry. 2009;66(8):722–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Obel C, Olsen J, Henriksen TB, Rodriguez A, Järvelin M-R, Moilanen I, et al. Is maternal smoking during pregnancy a risk factor for hyperkinetic disorder?—findings from a sibling design. Int J Epidemiol. 2010:dyq185.

  8. • Henriksen L, Wu CS, Secher NJ, Obel C, Juhl M. Medical augmentation of labor and the risk of ADHD in offspring: a population-based study. Pediatrics. 2015;135(3):e672–7. A large registry-based study with sufficient statistical power to allow adjustment for multiple potentially confounding variables and the detection of small effects.

    Article  PubMed  Google Scholar 

  9. • Silva D, Colvin L, Hagemann E, Bower C. Environmental risk factors by gender associated with attention-deficit/hyperactivity disorder. Pediatrics. 2014;133(1):e14–22. A large high-quality population-based study with sufficient statistical power to allow adjustment for multiple potentially confounding variables and the detection of small effects.

    Article  PubMed  Google Scholar 

  10. Halmøy A, Klungsøyr K, Skjærven R, Haavik J. Pre- and perinatal risk factors in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2012;71(5):474–81.

    Article  PubMed  Google Scholar 

  11. Zhu JL, Olsen J, Liew Z, Li J, Niclasen J, Obel C. Parental smoking during pregnancy and ADHD in children: the Danish national birth cohort. Pediatrics. 2014;134(2):e382–8.

    Article  PubMed  Google Scholar 

  12. Harris MN, Voigt RG, Barbaresi WJ, Voge GA, Killian JM, Weaver AL, et al. ADHD and learning disabilities in former late preterm infants: a population-based birth cohort. Pediatrics. 2013;132(3):e630–6.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Clements CC, Castro VM, Blumenthal SR, Rosenfield HR, Murphy SN, Fava M, et al. Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Mol Psychiatry. 2015;20(6):727–34. doi:10.1038/mp.2014.90.

    CAS  Article  PubMed  Google Scholar 

  14. Getahun D, Rhoads GG, Demissie K, Lu SE, Quinn VP, Fassett MJ, et al. In utero exposure to ischemic-hypoxic conditions and attention-deficit/hyperactivity disorder. Pediatrics. 2013;131(1):e53–61.

    Article  PubMed  Google Scholar 

  15. Langley K, Heron J, Smith GD, Thapar A. Maternal and paternal smoking during pregnancy and risk of ADHD symptoms in offspring: testing for intrauterine effects. Am J Epidemiol. 2012;176(3):261–8.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Sundquist J, Sundquist K, Ji J. Autism and attention-deficit/hyperactivity disorder among individuals with a family history of alcohol use disorders. eLife. 2014;3, e02917.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Biederman J, Petty CR, Bhide PG, Woodworth KY, Faraone S. Does exposure to maternal smoking during pregnancy affect the clinical features of ADHD? Results from a controlled study. World J Biol Psychiatry. 2012;13(1):60–4. doi:10.3109/15622975.2011.562243.

    Article  PubMed  Google Scholar 

  18. Wakschlag LS, Lahey BB, Loeber R, Green SM, Gordon RA, Leventhal BL. Maternal smoking during pregnancy and the risk of conduct disorder in boys. Arch Gen Psychiatry. 1997;54(7):670–6.

    CAS  Article  PubMed  Google Scholar 

  19. •• Skoglund C, Chen Q, D’Onofrio BM, Lichtenstein P, Larsson H. Familial confounding of the association between maternal smoking during pregnancy and ADHD in offspring. J Child Psychol Psychiatry. 2014;55(1):61–8. doi:10.1111/jcpp.12124. A high quality study that suggests that the association between maternal smoking during pregnancy and ADHD in the child are due to unmeasured familial confounding rather than the smoking per se.

    Article  PubMed  Google Scholar 

  20. Thakur GA, Sengupta SM, Grizenko N, Schmitz N, Pagé V, Joober R. Maternal smoking during pregnancy and ADHD: a comprehensive clinical and neurocognitive characterization. NicotineTob Res. 2013;15(1):149–57. doi:10.1093/ntr/nts102.

    Article  Google Scholar 

  21. Sengupta SM, Fortier MÈ, Thakur GA, Bhat V, Grizenko N, Joober R. Parental psychopathology in families of children with attention‐deficit/hyperactivity disorder and exposed to maternal smoking during pregnancy. J Child Psychol Psychiatry. 2015;56(2):122–9. doi:10.1111/jcpp.12286.

    Article  PubMed  Google Scholar 

  22. 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):21–33.

    CAS  Article  PubMed  Google Scholar 

  23. 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):352–8.

    CAS  Article  PubMed  Google Scholar 

  24. Cornelius MD, Ryan CM, Day NL, Goldschmidt L, Willford JA. Prenatal tobacco effects on neuropsychological outcomes among preadolescents. J Dev Behav Pediatr. 2001;22(4):217–25.

    CAS  Article  PubMed  Google Scholar 

  25. • Laugesen K, Olsen MS, Andersen ABT, Frøslev T, Sørensen HT. In utero exposure to antidepressant drugs and risk of attention deficit hyperactivity disorder: a nationwide Danish cohort study. BMJ Open. 2013;3(9). A large registry study using a sibling control design demonstrated that when controlling for familial factors, previously demonstrated associations between maternal antidepressant use and ADHD were no longer significant.

  26. Liew Z, Ritz B, Rebordosa C, Lee P-C, Olsen J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr. 2014;168(4):313–20. doi:10.1001/jamapediatrics.2013.4914.

    Article  PubMed  Google Scholar 

  27. Thompson JM, Waldie KE, Wall CR, Murphy R, Mitchell EA, Group AS. Associations between acetaminophen use during pregnancy and ADHD symptoms measured at ages 7 and 11 years. PLoS ONE. 2014;9(9), e108210. doi:10.1371/journal.pone.0108210.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Flory K, Molina BS, Pelham Jr WE, Gnagy E, Smith B. ADHD and risky sexual behavior. ADHD Rep. 2007;15(3):1–4.

    Article  Google Scholar 

  29. Harpin VA. The effect of ADHD on the life of an individual, their family, and community from preschool to adult life. Arch Dis Child. 2005;90 suppl 1:i2–7.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chang Z, Lichtenstein P, D’Onofrio BM, Almqvist C, Kuja-halkola R, Sjölander A, et al. Maternal age at childbirth and risk for ADHD in offspring: a population-based cohort study. Int J Epidemiol. 2014;43(6):1815–24.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Park S, Cho S-C, Kim J-W, Shin M-S, Yoo H-J, Oh SM, et al. Differential perinatal risk factors in children with attention-deficit/hyperactivity disorder by subtype. Psychiatry Res. 2014;219(3):609–16. doi:10.1016/j.psychres.2014.05.036.

    Article  PubMed  Google Scholar 

  32. Chen Q, Sjölander A, Långström N, Rodriguez A, Serlachius E, D’Onofrio BM, et al. Maternal pre-pregnancy body mass index and offspring attention deficit hyperactivity disorder: a population-based cohort study using a sibling-comparison design. Int J Epidemiol. 2014;43(1):83–90.

    CAS  Article  PubMed  Google Scholar 

  33. Andersen SL, Laurberg P, Wu CS, Olsen J. Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study. BJOG. 2014;121(11):1365–74.

    CAS  Article  PubMed  Google Scholar 

  34. Liew Z, Ritz B, Bonefeld-Jørgensen EC, Henriksen TB, Nøhr EA, Bech BH, et al. Perfluorinated chemicals in maternal serum and the risk of autism, attention-deficit/hyperactivity disorder and cerebral palsy in children. Eur J Epidemiol. 2013;28(1):S174.

    Google Scholar 

  35. Hoffman K, Webster TF, Weinberg J, Vieira VM, Weisskopf MG. Exposure to polyfluoroalkyl chemicals and attention deficit/hyperactivity disorder in US children 12–15 years of age. Environ Health Perspect. 2010;118(12):1762–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Stein CR, Savitz DA. Serum perfluorinated compound concentration and attention deficit/hyperactivity disorder in children 5–18 years of age. Environmental Hazards and Neurodevelopment: Where Ecology and Well-Being Connect. 2015:265.

  37. Ode A, Källén K, Gustafsson P, Rylander L, Jönsson BAG, Olofsson P et al. Fetal exposure to perfluorinated compounds and attention deficit hyperactivity disorder in childhood. PLoS ONE. 2014;9(4).

  38. Ode A, Rylander L, Gustafsson P, Lundh T, Källén K, Olofsson P, et al. Manganese and selenium concentrations in umbilical cord serum and attention deficit hyperactivity disorder in childhood. Environ Res. 2015;137:373–81.

    CAS  Article  PubMed  Google Scholar 

  39. Yoshimasu K, Kiyohara C, Takemura S, Nakai K. A meta-analysis of the evidence on the impact of prenatal and early infancy exposures to mercury on autism and attention deficit/hyperactivity disorder in the childhood. NeuroToxicology. 2014;44:121–31.

    CAS  Article  PubMed  Google Scholar 

  40. Malin AJ, Till C. Exposure to fluoridated water and attention deficit hyperactivity disorder prevalence among children and adolescents in the United States: an ecological association children’s environmental health. Environmental Health: A Global Access Science Source. 2015;14(1).

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Acknowledgements

The authors would like to acknowledge Alicia White and the staff of Bazian Ltd for their work on the systematic reviews that this article builds upon. Dr Sciberras is funded by an NHMRC Early Career Fellowships in Population Health (No. 1037159). The Murdoch Childrens Research Institute is supported by the Victorian Government’s Operational Infrastructure Support Program.

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Correspondence to David Coghill.

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Emma Sciberras, Melissa Mulraney and Desiree Silva declare that they have no conflict of interest.

David Coghill reports grants and personal fees from Shire; personal fees from Eli Lilly, Novartis, Sandoz and Oxford University Press; and grants from Vifor Pharma, outside the submitted work.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Attention-Deficit Disorder

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Sciberras, E., Mulraney, M., Silva, D. et al. Prenatal Risk Factors and the Etiology of ADHD—Review of Existing Evidence. Curr Psychiatry Rep 19, 1 (2017). https://doi.org/10.1007/s11920-017-0753-2

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  • DOI: https://doi.org/10.1007/s11920-017-0753-2

Keywords

  • ADHD
  • Etiology
  • Prenatal
  • Environmental
  • Pregnancy