Skip to main content
    • Aa
    • Aa

Degree of fetal growth restriction associated with schizophrenia risk in a national cohort

  • M. G. Eide (a1) (a2), D. Moster (a3) (a4), L. M. Irgens (a3) (a5), T. Reichborn-Kjennerud (a6) (a7), C. Stoltenberg (a1), R. Skjærven (a3) (a5), E. Susser (a8) and K. Abel (a9)...

Accumulating evidence suggests that fetal growth restriction may increase risk of later schizophrenia but this issue has not been addressed directly in previous studies. We examined whether the degree of fetal growth restriction was linearly related to risk of schizophrenia, and also whether maternal pre-eclampsia, associated with both placental dysfunction and poor fetal growth, was related to risk of schizophrenia.


A population-based cohort of single live births in the Medical Birth Registry of Norway (MBRN) between 1967 and 1982 was followed to adulthood (n = 873 612). The outcome was schizophrenia (n=2207) registered in the National Insurance Scheme (NIS). The degree of growth restriction was assessed by computing sex-specific z scores (standard deviation units) of ‘birth weight for gestational age’ and ‘birth length for gestational age’. Analyses were adjusted for potential confounders. Maternal pre-eclampsia was recorded in the Medical Birth Registry by midwives or obstetricians using strictly defined criteria.


The odds ratio (OR) for schizophrenia increased linearly with decreasing birth weight for gestational age z scores (p value for trend = 0.005). Compared with the reference group (z scores 0.01–1.00), the adjusted OR [95% confidence interval (CI)] for the lowest z-score category (< − 3.00) was 2.0 (95% CI 1.2–3.5). A similar pattern was observed for birth length for gestational age z scores. Forty-nine individuals with schizophrenia were identified among 15 622 births with pre-eclampsia. The adjusted OR for schizophrenia following maternal pre-eclampsia was 1.3 (95% CI 1.0–1.8).


Associations of schizophrenia risk with degree of fetal growth restriction and pre-eclampsia suggest future research into schizophrenia etiology focusing on mechanisms that influence fetal growth, including placental function.

Corresponding author
*Address for correspondence: Dr M. G. Eide, Department of Obstetrics and Gynecology, Haukeland University Hospital, N-5021 Bergen, Norway. (Email:
Hide All
Abel KM (2004). Foetal origins of schizophrenia: testable hypotheses of genetic and environmental influences. British Journal of Psychiatry 184, 383385.
Abel KM, Allin M (2006). Placental programming leading to mental ill health: fetal growth and schizophrenia. Clinics in Developmental Medicine 169, 118136.
Abel KM, Wicks S, Susser E, Dalman C, Pedersen MG, Mortensen PB, Webb RT (2010). Birth weight, schizophrenia, and adult mental disorder: is risk confined to the smallest babies? Archives of General Psychiatry 67, 923930.
Boden R, Lundgren M, Brandt L, Reutfors J, Kieler H (2012). Antipsychotics during pregnancy: relation to fetal and maternal metabolic effects. Archives of General Psychiatry 69, 715721.
Byrne M, Agerbo E, Bennedsen B, Eaton WW, Mortensen PB (2007). Obstetric conditions and risk of first admission with schizophrenia: a Danish national register based study. Schizophrenia Research 97, 5159.
Dalman C, Allebeck P, Cullberg J, Grunewald C, Koster M (1999). Obstetric complications and the risk of schizophrenia: a longitudinal study of a national birth cohort. Archives of General Psychiatry 56, 234240.
Donovan SJ, Susser E (2011). Commentary: Advent of sibling designs. International Journal of Epidemiology 40, 345349.
Dunger DB, Ong KK (2005). Endocrine and metabolic consequences of intrauterine growth retardation. Endocrinology and Metabolism Clinics of North America 34, 597615, ix.
Ellison PT (2010). Fetal programming and fetal psychology. Infant and Child Development 19, 620.
Eriksen W, Sundet JM, Tambs K (2010). Birth weight standardized to gestational age and intelligence in young adulthood: a register-based birth cohort study of male siblings. American Journal of Epidemiology 172, 530536.
Gluckman PD, Hanson MA, Cooper C, Thornburg KL (2008) Effect of in utero and early-life conditions on adult health and disease. New England Journal of Medicine 359, 6173.
Gunnell D, Harrison G, Whitley E, Lewis G, Tynelius P, Rasmussen F (2005). The association of fetal and childhood growth with risk of schizophrenia. Cohort study of 720,000 Swedish men and women. Schizophrenia Research 79, 315322.
Hultman CM, Sparen P, Takei N, Murray RM, Cnattingius S (1999). Prenatal and perinatal risk factors for schizophrenia, affective psychosis, and reactive psychosis of early onset: case-control study. British Medical Journal 318, 421426.
Irgens LM (2000). The Medical Birth Registry of Norway. Epidemiological research and surveillance throughout 30 years. Acta Obstetricia et Gynecologica Scandinavica 79, 435439.
Jacobsson B, Ahlin K, Francis A, Hagberg G, Hagberg H, Gardosi J (2008). Cerebral palsy and restricted growth status at birth: population-based case-control study. British Journal of Obstetrics and Gynecology 115, 12501255.
Jansson T, Powell TL (2007). Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches. Clinical Science 113, 113.
Jarvis S, Glinianaia SV, Torrioli MG, Platt MJ, Miceli M, Jouk PS, Johnson A, Hutton J, Hemming K, Hagberg G, Dolk H, Chalmers J; Surveillance of Cerebral Palsy in Europe (SCPE) collaboration of European Cerebral Palsy Registers (2003). Cerebral palsy and intrauterine growth in single births: European collaborative study. Lancet 362, 11061111.
Jones P (1999). Longitudinal approaches to the search for the causes of schizophrenia: past, present and future. In Searches for the Causes of Schizophrenia. Vol. IV. Balance of the Century (ed. Gattaz W. F. and Hafner H.), pp. 91119. Steinkopf: Darmstadt Berlin.
Jones PB, Rantakallio P, Hartikainen AL, Isohanni M, Sipila P (1998). 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. American Journal of Psychiatry 155, 355364.
Khashan AS, Abel KM, McNamee R, Pedersen MG, Webb RT, Baker PN, Kenny LC, Mortensen PB (2008). Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Archives of General Psychiatry 65, 146152.
Kuh D, Ben-Shlomo Y (2004). A Life Course Approach to Chronic Disease Epidemiology. Oxford University Press: Oxford.
Lucas A (1991). Programming by early nutrition in man. Ciba Foundation Symposium 156, 3850.
Ludwig DS, Currie J (2010). The association between pregnancy weight gain and birthweight: a within-family comparison. Lancet 376, 984990.
McClellan JM, Susser E, King MC (2006). Maternal famine, de novo mutations, and schizophrenia. Journal of the American Medical Association 296, 582584.
McNeil TF, Cantor-Graae E, Ismail B (2000). Obstetric complications and congenital malformation in schizophrenia. Brain Research. Brain Reearch Reviews 31, 166178.
Moster D, Lie RT, Irgens LM, Bjerkedal T, Markestad T (2001). The association of Apgar score with subsequent death and cerebral palsy: a population-based study in term infants. Journal of Pediatrics 138, 798803.
Moster D, Lie RT, Markestad T (2008). Long-term medical and social consequences of preterm birth. New England Journal of Medicine 359, 262273.
Murray RM, Lewis SW (1987). Is schizophrenia a neurodevelopmental disorder? British Medical Journal (Clinical Research Edition) 295, 681682.
Nilsson E, Stalberg G, Lichtenstein P, Cnattingius S, Olausson PO, Hultman CM (2005). Fetal growth restriction and schizophrenia: a Swedish twin study. Twin Research and Human Genetics 8, 402408.
Rifkin L, Lewis S, Jones P, Toone B, Murray R (1994). Low birth weight and schizophrenia. British Journal of Psychiatry 165, 357362.
Roberts JM, Cooper DW (2001). Pathogenesis and genetics of pre-eclampsia. Lancet 357, 5356.
Roberts JM, Lain KY (2002). Recent insights into the pathogenesis of pre-eclampsia. Placenta 23, 359372.
Sacker A, Done DJ, Crow TJ, Golding J (1995). Antecedents of schizophrenia and affective illness. Obstetric complications. British Journal of Psychiatry 166, 734741.
Schaefer CA, Brown AS, Wyatt RJ, Kline J, Begg MD, Bresnahan A, Susser E (2000). Maternal prepregnant body mass and risk of schizophrenia in adult offspring. Schizophrenia Bulletin 26, 275286.
Skjaerven R, Gjessing HK, Bakketeig LS (2000). Birthweight by gestational age in Norway. Acta Obstetricia et Gynecologica Scandinavica 79, 440449.
Skjaerven R, Wilcox AJ, Lie RT (2002). The interval between pregnancies and the risk of preeclampsia. New England Journal of Medicine 346, 3338.
Smith GN, Flynn SW, McCarthy N, Meistrich B, Ehmann TS, MacEwan GW, Altman S, Kopala LC, Honer WG (2001). Low birthweight in schizophrenia: prematurity or poor fetal growth? Schizophrenia Research 47, 177184.
Susser E, Hoek HW, Brown A (1998). Neurodevelopmental disorders after prenatal famine: the story of the Dutch Famine Study. American Journal of Epidemiology 147, 213216.
Tsuang MT, Stone WS, Faraone SV (2001). Genes, environment and schizophrenia. British Journal of Psychiatry (Suppl.) 40, s18s24.
Vestrheim LC, Austgulen R, Melve KK, Roten LT, Tappert C, Araya E (2010). Classification of pre-eclamptic pregnancies in health registries. Pregnancy Hypertension 1, 54.
Wahlbeck K, Forsen T, Osmond C, Barker DJ, Eriksson JG (2001). Association of schizophrenia with low maternal body mass index, small size at birth, and thinness during childhood. Archives of General Psychiatry 58, 4852.
Zondervan KT, Cardon LR (2007). Designing candidate gene and genome-wide case-control association studies. Nature Protocols 2, 24922501.
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: 2
Total number of PDF views: 18 *
Loading metrics...

Abstract views

Total abstract views: 163 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 24th October 2017. This data will be updated every 24 hours.