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Just DO(HaD) It! Testing the clinical potential of the DOHaD hypothesis to prevent mental disorders using experimental study designs

  • R. J. Van Lieshout (a1) and J. E. Krzeczkowski (a2)

Optimal early cognitive and emotional development are vital to reaching one’s full potential and represent our best chance to improve the mental health of the population. The developmental origins of health and disease (DOHaD) hypothesis posits that adverse perinatal exposures can alter physiology and increase disease risk. As physiological plasticity decreases with age, interventions applied during gestation may hold the most promise for reducing the impact of mental disorders across the lifespan. However, this vast clinical potential remains largely unrealized as the majority of human DOHaD research is observational in nature. The application of more rigorous experimental designs [e.g. Randomized Controlled Trials (RCTs)] not only represents a major step toward unlocking this potential, but are required to fully test the scientific validity of the DOHaD hypothesis as it pertains to mental illness. Here, we argue that the optimization of maternal diet and exercise during pregnancy represents our best chance to improve offspring neurodevelopment and reduce the burden of mental disorders. Follow-up studies of the offspring of pregnant women enrolled in new and existing RCTs of maternal gestational nutrition+exercise interventions are required to determine if acting during pregnancy can prevent and/or meaningfully reduce the prevalence and severity of mental disorders in the population.

Corresponding author
*Address for correspondence: J. E. Krzeczkowski, Department of Health Sciences, 1280 Main Street West, McMaster University, Hamilton, ON, L8S 4K1, Canada. (Email
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1. Kessler, RC, Berglund, P, Demler, O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the national comorbidity survey replication. Arch Gen Psychiatry. 2005; 62, 593602.
2. Costello, EJ, Foley, DL, Angold, A. 10-year research update review: the epidemiology of child and adolescent psychiatric disorders: II. developmental epidemiology. J Am Acad Child Adolesc Psychiatry. 2005; 45, 825.
3. Offord, DR, Boyle, MH, Szatmari, P, et al. Ontario child health study. Arch Gen Psychiatry. 1987; 44, 832836.
4. Kim-Cohen, J, Caspi, A, Moffitt, TE, et al. Prior juvenile diagnoses in adults with mental disorder. Arch Gen Psychiatry. 2003; 60, 709717.
5. WHO. The world health report 2001: Mental Health: New understanding new hope, 2001. World Health Organization: Geneva.
6. Gandhi, S, Chiu, M, Lam, K, et al. Mental health service use among children and youth in Ontario: population-based trends over time. Can J Psychiatry. 2016; 61, 510.
7. Wang, PS, Lane, M, Olfson, M, et al. Twelve-month use of mental health services in the United States. Arch Gen Psychiatry. 2005; 62, 629640.
8. Gluckman, PD, Hanson, MA, Cooper, C, Thornburg, KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2014; 359, 6173.
9. Van Den Bergh BRH. Developmental programming of early brain and behaviour development and mental health: a conceptual framework. Dev Med Child Neurol. 2011; 53, 1923.
10. Heckman, JJ, Masterov, DV. The productivity argument for investing in young children. App Econ Perspect and Policy. 2007; 29, 446493.
11. Mervis, J. Past successes shape effort to expand early intervention. Science. 2011; 333, 952956.
12. Muennig, P, Robertson, D, Johnson, G, et al. The effect of an early education program on adult health: The Carolina abecedarian project randomized controlled trial. Am J Public Health. 2011; 101, 512516.
13. Rolnick, A, Grunewald, R. Early childhood development: economic development with a high public return. The Region. 2003; 17, 612.
14. Levitt, P. Structural and functional maturation of the developing primate brain. J Pediatr. 2003; 143(Suppl. 4), S35S45.
15. Robling, M, Bekkers, MJ, Bell, K, et al. Effectiveness of a nurse-led intensive home-visitation programme for first-time teenage mothers (building blocks): a pragmatic randomised controlled trial. Lancet. 2016; 387, 146155.
16. Mendelson, T, Tandon, SD. Prevention of depression in childhood and adolescence. Child Adolesc Psychiatr Clin N Am. 2016; 25, 201218.
17. Burger, K. How does early childhood care and education affect cognitive development? An international review of the effects of early interventions for children from different social backgrounds. Early Child Res Q. 2010; 25, 140165.
18. Cina, A, Röösli, M, Schmid, H, et al. Enhancing positive development of children: effects of a multilevel randomized controlled intervention on parenting and child problem behavior. Fam Sci. 2011; 2, 4357.
19. Anderson, LM, Shinn, C, Fullilove, MT, et al. The effectiveness of early childhood development programs: a systematic review. Am J Prev Med. 2003; 24(Suppl. 3), 3246.
20. Wachs, TD, Georgieff, M, Cusick, S, Mcewen, BS. Issues in the timing of integrated early interventions: contributions from nutrition, neuroscience, and psychological research. Ann N Y Acad Sci. 2014; 1308, 89106.
21. Campbell, FA, Ramey, CT, Pubgello, E, Sparling, J, Miller-Johnson, S. Early childhood education: young adult outcomes from the abecedarian project. Appl Dev Sci. 2002; 6, 4257.
22. Olson, CM. Tracking of food choices across the transition to motherhood. J Nutr Educ Behav. 2005; 37, 129136.
23. Erickson, MF, Aird, EG. The motherhood study: fresh insights on mothers’ attitudes and concerns. Children, Youth and Family Consortium, University of Minnesota, Minneapolis, MN. 2005.
24. Schlotz, W, Phillips, DIW. Fetal origins of mental health: evidence and mechanisms. Brain Behav Immun. 2009; 23, 905916.
25. Räikkönen, K, Pesonen, AK, Roseboom, TJ, Eriksson, JG. Early determinants of mental health. Best Pract Res Clin Endocrinol Metab. 2012; 26, 599611.
26. Van Lieshout, RJ, Boyle, MH. Is bigger better? Macrosomia and psychopathology later in life. Obes Rev. 2011; 12, 405411.
27. Kim, DR, Bale, TL, Epperson, CN. Prenatal programming of mental illness: current understanding of relationship and mechanisms. Curr Psychiatry Rep. 2015; 17, 19.
28. Colman, I, Ataullahjan, A, Naicker, K, Van Lieshout, RJ. Birth weight, stress, and symptoms of depression in adolescence: evidence of fetal programming in a National Canadian Cohort. Can J Psychiatry. 2012; 57, 422428.
29. Colman, I, Ploubidis, GB, Wadsworth, MEJ, Jones, PB, Croudace, TJ. A longitudinal typology of symptoms of depression and anxiety over the life course. Biol Psychiatry. 2007; 62, 12651271.
30. Bale, TL, Baram, TZ, Brown, AS, et al. Early life programming and neurodevelopmental disorders. Biol Psychiatry. 2010; 68, 314319.
31. Rivera, HM, Christiansen, KJ, Sullivan, EL. The role of maternal obesity in the risk of neuropsychiatric disorders. Front Neurosci. 2015; 9, 116.
32. Jacka, FN, Ystrom, E, Brantsaeter, AL, et al. Maternal and early postnatal nutrition and mental health of offspring by age 5 years: a prospective cohort study. J Am Acad Child Adolesc Psychiatry. 2013; 52, 10381047.
33. Keyes, KM, Davey Smith, G, Susser, E. Associations of prenatal maternal smoking with offspring hyperactivity: causal or confounded? Psychol Med. 2013; 44, 857867.
34. Golan, HM, Lev, V, Hallak, M, Sorokin, Y, Huleihel, M. Specific neurodevelopmental damage in mice offspring following maternal inflammation during pregnancy. Neuropharmacology. 2005; 48, 903917.
35. Ramsay, JE, Ferrell, WR, Crawford, L, et al. Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways. J Clin Endocrinol Metab. 2002; 87, 42314237.
36. Vucetic, Z, Kimmel, J, Totoki, K, Hollenbeck, E, Reyes, TM. Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. Endocrinology. 2010; 151, 47564764.
37. Sullivan, EL, Grayson, B, Takahashi, D, et al. Chronic consumption of a high-fat diet during pregnancy causes perturbations in the serotonergic system and increased anxiety-like behavior in nonhuman primate offspring. J Neurosci. 2010; 30, 38263830.
38. Gage, SH, Munafò, MR, Davey Smith, G. Causal inference in developmental origins of health and disease (DOHaD) research. Annu Rev Psychol. 2016; 67, 567585.
39. D’Onofrio, BM, Class, QA, Lahey, BB, Larsson, H. Testing the developmental origins of health and disease hypothesis for psychopathology using family-based quasi- experimental designs. Child Dev Perspect. 2014; 8, 151157.
40. Antoniou, EE, Fowler, T, Reed, K, et al. Maternal pre-pregnancy weight and externalising behaviour problems in preschool children: a UK-based twin study. BMJ Open. 2014; 4, e005974.
41. Chen, Q, Sjolander, A, Langstrom, N, 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, 8390.
42. Class, QA, Rickert, ME, Larsson, H, Lichtenstein, P, D’Onofrio, BM. Fetal growth and psychiatric and socioeconomic problems: Population-based sibling comparison. Br J Psychiatry. 2014; 205, 355361.
43. Smith, GD. Assessing intrauterine influences on offspring health outcomes: can epidemiological studies yield robust findings? Basic Clin Pharmacol Toxicol. 2008; 102, 245256.
44. Christian, P, Mullany, LC, Hurley, KM, Katz, J, Black, RE. Nutrition and maternal, neonatal, and child health. Semin Perinatol. 2015; 39, 361372.
45. Macleod, J, Tang, L, Hobbs, FDR, et al. Effects of nutritional supplementation during pregnancy on early adult disease risk : follow up of offspring of participants in a randomised controlled trial investigating effects of supplementation on infant birth weight. PloS one. 2013; 8, 115.
46. Horan, MK, McGowan, CA, Gibney, ER, Donnelly, JM, McAuliffe, FM. Maternal low glycaemic index diet, fat intake and postprandial glucose influences neonatal adiposity – secondary analysis from the ROLO study. Nutr J. 2014; 13, 1.
47. Higgins, ST, Bernstein, IM, Washio, Y, et al. Effects of smoking cessation with voucher-based contingency management on birth outcomes. Addiction. 2010; 105, 20232030.
48. Escamilla-Nuñez, MC, Barraza-Villarreal, A, Hernández-Cadena, L, et al. Omega-3 fatty acid supplementation during pregnancy and respiratory symptoms in children. Chest. 2014; 146, 373382.
49. Karamoozian, M, Askarizadeh, G. Impact of prenatal cognitive-behavioral stress management intervention on maternal anxiety and depression and newborns’ Apgar scores. Iran J Neonatol. 2015; 6, 1423.
50. Tanvig, M, Vinter, CA, Jørgensen, JS, et al. Effects of lifestyle intervention in pregnancy and anthropometrics at birth on offspring metabolic profile at 2.8 years: results from the Lifestyle in Pregnancy and Offspring (LiPO) study. J Clin Endocrinol Metab. 2015; 100, 175183.
51. Sagedal, L, Øverby, N, Bere, E, et al. Lifestyle intervention to limit gestational weight gain: the Norwegian Fit for Delivery randomised controlled trial. BJOG. 2016; doi:10.1111/1471-0528.13862.
52. Thangaratinam, S, Rogozinska, E, Jolly, K, et al. Effects of interventions in pregnancy on maternal weight and obstetric outcomes: meta-analysis of randomised evidence. BMJ. 2012; 344, e2088e2088.
53. Van Lieshout, RJ. Role of maternal adiposity prior to and during pregnancy in cognitive and psychiatric problems in offspring. Nutr Rev. 2013; 71(Suppl. 1), 95101.
54. Van Lieshout, RJ, Taylor, VH, Boyle, MH. Pre-pregnancy and pregnancy obesity and neurodevelopmental outcomes in offspring: a systematic review. Obes Rev. 2011; 12, 548559.
55. Monk, C, Georgieff, MK, Osterholm, EA. Research review: maternal prenatal distress and poor nutrition – Mutually influencing risk factors affecting infant neurocognitive development. J Child Psychol Psychiatry Allied Discip. 2013; 54, 115130.
56. Nyaradi, A, Li, J, Hickling, S, Foster, J, Oddy, WH. The role of nutrition in children’s neurocognitive development, from pregnancy through childhood. Front Hum Neurosci. 2013; 7, 97.
57. Georgieff, MK. Nutrition and the developing brain. Am J Clin Nutr. 2007; 85(Suppl), 614S619S.
58. Steenweg-de Graaff, J, Tiemeier, H, Steegers-Theunissen, RPM, et al. Maternal dietary patterns during pregnancy and child internalising and externalising problems. the Generation R study. Clin Nutr. 2014; 33, 115121.
59. Pina-Camacho, L, Jensen, SK, Gaysina, D, Barker, ED. Maternal depression symptoms, unhealthy diet and child emotional – behavioural dysregulation. Psychol Med. 2015; 45, 18511860.
60. Bartholomew, S. What mothers say: The Canadian Maternity Experiences Survey. Public Health Agency of Canada, Winnipeg, Manitoba. 2009.
61. Grantham-McGregor, S, Baker-Henningham, H. Review of the evidence linking protein and energy to mental development. Public Health Nutr. 2005; 8, 11911201.
62. Tamura, T, Goldenberg, RL, Hou, J, et al. Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age. J Pediatr. 2002; 140, 165170.
63. Hamadani, JD, Fuchs, GJ, Osendarp, SJM, Huda, SN, Grantham-McGregor, SM. Zinc supplementation during pregnancy and effects on mental development and behaviour of infants: a follow-up study. Lancet. 2002; 360, 290294.
64. Murcia, M, Rebagliato, M, Iinguez, C, et al. Effect of iodine supplementation during pregnancy on infant neurodevelopment at 1 year of age. Am J Epidemiol. 2011; 173, 804812.
65. Leung, BMY, Wiens, KP, Kaplan, BJ. Does prenatal micronutrient supplementation improve children’s mental development? A systematic review. BMC Pregnancy Childbirth. 2011; 11, 1.
66. Smithers, LG, Golley, RK, Mittinty, MN, et al. Dietary patterns at 6, 15 and 24 months of age are associated with IQ at 8 years of age. Eur J Epidemiol. 2012; 27, 525535.
67. Theodore, RF, Thompson, JMD, Waldie, KE, et al. Dietary patterns and intelligence in early and middle childhood. Intelligence. 2009; 37, 506513.
68. Ong, ZY, Muhlhausler, BS. Maternal ‘junk-food’ feeding of rat dams alters food choices and development of the mesolimbic reward pathway in the offspring. FASEB J. 2011; 25, 21672179.
69. Oades, RD. Dopamine-serotonin interactions in attention-deficit hyperactivity disorder (ADHD). Prog Brain Res. 2008; 172, 543565.
70. Davies, GA, Wolfe, LA, Mottola, MF, C. M. Joint SOGC/CSEP clinical practice guideline: exercise in pregnancy and the postpartum period. Canadain J Appl Physiol. 2003; 28, 330441.
71. American College of Obstetricians and Gynecologists. Committee opinion: physical activity and exercise during pregnancy and the postpartum period. Obstet Gynecol. 2015; 26, 135142.
72. Clapp, JF, Simonian, S, Lopez, B, Appleby-Wineberg, S, Harcar-Sevcik, R. The one-year morphometric and neurodevelopmental outcome of the offspring of women who continued to exercise regularly throughout pregnancy. Am J Obstet Gynecol. 1998; 178, 594599.
73. Clapp, JF. Morphometric and neurodevelopmental outcome at age five years of the offspring of women who continued to exercise regularly throughout pregnancy. J Pediatr. 1996; 129, 856863.
74. Clapp, JF, Lopez, B, Harcar-Sevcik, R. Neonatal behavioral profile of the offspring of women who continued to exercise regularly throughout pregnancy. Am J Obstet Gynecol. 1999; 180, 9194.
75. May, LE, Scholtz, SA, Suminski, R, Gustafson, KM. Aerobic exercise during pregnancy influences infant heart rate variability at one month of age. Early Hum Dev. 2014; 90, 3338.
76. Labonte-Lemoyne, E, Curnier, D, Ellemberg, D. Foetal brain development is influenced by maternal exercise during pregnancy (poster). Presented at Neuroscience 2013, San Diego, CA, November 10, 2013.
77. Trull, TJ, Ebner-Priemer, UW. Ambulatory assessment. Eur Psychol. 2009; 14, 9597.
78. Dunton, GF, Liao, Y, Dzubur, E, et al. Investigating within-day and longitudinal effects of maternal stress on children’s physical activity, dietary intake, and body composition: protocol for the MATCH study. Contemp Clin Trials. 2015; 43, 142154.
79. Flynn, AC, Dalrymple, K, Barr, S, et al. Dietary interventions in overweight and obese pregnant women: a systematic review of the content, delivery, and outcomes of randomized controlled trials. Nutr Rev. 2016; 74, 312328.
80. Martin, JC, Zhou, SJ, Flynn, AC, et al. The assessment of diet quality and its effects on health outcomes pre-pregnancy and during pregnancy. Semin Reprod Med. 2016; 34, 8392.
81. Kuhlmann, AKS, Dietz, PM, Galavotti, C, England, LJ. Weight-management interventions for pregnant or postpartum women. Am J Prev Med. 2008; 34, 523528.
82. Adamo, KB, Ferraro, ZM, Goldfield, G, et al. The Maternal Obesity Management (MOM) Trial Protocol: a lifestyle intervention during pregnancy to minimize downstream obesity. Contemp Clin Trials. 2013; 35, 8796.
83. Sagedal, LR, Øverby, NC, Lohne-Seiler, H, et al. Study protocol: fit for delivery – can a lifestyle intervention in pregnancy result in measurable health benefits for mothers and newborns? A randomized controlled trial. BMC Public Health. 2013; 13, 132.
84. Poston, L, Briley, AL, Barr, S, et al. Developing a complex intervention for diet and activity behaviour change in obese pregnant women (the UPBEAT trial); assessment of behavioural change and process evaluation in a pilot randomised controlled trial. BMC Pregnancy Childbirth. 2013; 13, 116.
85. Whiteford, HA, Degenhardt, L, Rehm, J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013; 382, 15751586.
86. Bloom, DE, Cafiero, E, Jané-Llopis, E, et al. The Global Economic Burden of Noncommunicable Diseases. World Economic Forum: Geneva, 2011; pp. 1–46.
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