[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Figure 1.
Risk for Nonaffective Psychosis and Schizophrenia in Association With Maternal Baseline Body Mass Index (BMI)
Risk for Nonaffective Psychosis and Schizophrenia in Association With Maternal Baseline Body Mass Index (BMI)

Histograms illustrate the distribution of maternal BMI (calculated as weight in kilograms divided by height in meters squared) for those included in each analysis. Basic and adjusted estimates are shown for nonaffective psychosis and schizophrenia. Sibling comparison is shown for only nonaffective psychosis. The curved solid black line represents the hazard ratio (HR) calculated through restricted cubic splines models with 5 knots, with BMI of 21.0 as the reference category. The blue bands represent the 95% CI. The black dotted line represents HR estimates from the categorical model of maternal BMI (see Table 2) and is shown here for comparison. A reference line is included for an HR of 1.00.

aAdjusted for birth year and sex.

bAdjusted for birth year, sex, family income, parent older than 35 years, parent born outside Sweden, and parental history of psychosis.

cAdjusted for birth order and sex.

Figure 2.
Risk for Nonaffective Psychosis and Schizophrenia With Respect to Gestational Weight Gain (GWG) During Pregnancy
Risk for Nonaffective Psychosis and Schizophrenia With Respect to Gestational Weight Gain (GWG) During Pregnancy

The distribution of GWG for each cohort and subcohort is provided in histograms. Results for nonaffective psychosis are presented for the full cohort and stratified by maternal body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) category and the sibling comparison. Results for narrowly defined schizophrenia are presented for the full cohort and restricted to mothers in the normal BMI category. The curved black line represents hazard ratios (HRs) calculated by restricted cubic spline analysis with 5 knots, with GWG of 11 kg as the reference category. The blue bands represent the 95% CIs. A reference line is included for HR of 1.00.

aAdjusted for birth year and sex.

bAdjusted for birth order and sex.

Table 1.  
Characteristics of Psychiatry Sweden Cohort and Each Subcohort
Characteristics of Psychiatry Sweden Cohort and Each Subcohort
Table 2.  
Associations Between Nonaffective Psychosis and Maternal BMI in Full and Matched-Sibling Cohorts
Associations Between Nonaffective Psychosis and Maternal BMI in Full and Matched-Sibling Cohorts
Table 3.  
Associations Between Nonaffective Psychosis and GWG
Associations Between Nonaffective Psychosis and GWG
1.
Murray  RM, Lewis  SW.  Is schizophrenia a neurodevelopmental disorder?  BMJ (Clin Res Ed). 1987;295(6600):681-682.PubMedGoogle ScholarCrossref
2.
Weinberger  DR.  Implications of normal brain development for the pathogenesis of schizophrenia.  Arch Gen Psychiatry. 1987;44(7):660-669. PubMedGoogle ScholarCrossref
3.
Piper  M, Beneyto  M, Burne  THJ, Eyles  DW, Lewis  DA, McGrath  JJ.  The neurodevelopmental hypothesis of schizophrenia: convergent clues from epidemiology and neuropathology.  Psychiatr Clin North Am. 2012;35(3):571-584. PubMedGoogle ScholarCrossref
4.
Insel  BJ, Schaefer  CA, McKeague  IW, Susser  ES, Brown  AS.  Maternal iron deficiency and the risk of schizophrenia in offspring.  Arch Gen Psychiatry. 2008;65(10):1136-1144. PubMedGoogle ScholarCrossref
5.
Debnath  M, Venkatasubramanian  G, Berk  M.  Fetal programming of schizophrenia: select mechanisms.  Neurosci Biobehav Rev. 2015;49:90-104. PubMedGoogle ScholarCrossref
6.
Susser  E, Neugebauer  R, Hoek  HW,  et al.  Schizophrenia after prenatal famine: further evidence.  Arch Gen Psychiatry. 1996;53(1):25-31.PubMedGoogle ScholarCrossref
7.
Hoek  HW, Brown  AS, Susser  E.  The Dutch famine and schizophrenia spectrum disorders.  Soc Psychiatry Psychiatr Epidemiol. 1998;33(8):373-379.PubMedGoogle ScholarCrossref
8.
Susser  ES, Lin  SP.  Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944-1945.  Arch Gen Psychiatry. 1992;49(12):983-988.PubMedGoogle ScholarCrossref
9.
St Clair  D, Xu  M, Wang  P,  et al.  Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961.  JAMA. 2005;294(5):557-562.PubMedGoogle ScholarCrossref
10.
Xu  MQ, Sun  WS, Liu  BX,  et al.  Prenatal malnutrition and adult schizophrenia: further evidence from the 1959-1961 Chinese famine.  Schizophr Bull. 2009;35(3):568-576. PubMedGoogle ScholarCrossref
11.
Brown  AS, Susser  ES.  Prenatal nutritional deficiency and risk of adult schizophrenia.  Schizophr Bull. 2008;34(6):1054-1063.PubMedGoogle ScholarCrossref
12.
Susser  E, St Clair  D.  Prenatal famine and adult mental illness: interpreting concordant and discordant results from the Dutch and Chinese Famines.  Soc Sci Med. 2013;97:325-330.PubMedGoogle ScholarCrossref
13.
Black  RE, Victora  CG, Walker  SP,  et al; Maternal and Child Nutrition Study Group.  Maternal and child undernutrition and overweight in low-income and middle-income countries.  Lancet. 2013;382(9890):427-451. PubMedGoogle ScholarCrossref
14.
Tomedi  LE, Chang  C-CH, Newby  PK,  et al.  Pre-pregnancy obesity and maternal nutritional biomarker status during pregnancy: a factor analysis.  Public Health Nutr. 2013;16(8):1414-1418.PubMedGoogle ScholarCrossref
15.
van der Burg  JW, Sen  S, Chomitz  VR, Seidell  JC, Leviton  A, Dammann  O.  The role of systemic inflammation linking maternal BMI to neurodevelopment in children.  Pediatr Res. 2016;79(1-1):3-12.PubMedGoogle ScholarCrossref
16.
Rasmussen  SA, Chu  SY, Kim  SY, Schmid  CH, Lau  J.  Maternal obesity and risk of neural tube defects: a metaanalysis.  Am J Obstet Gynecol. 2008;198(6):611-619. PubMedGoogle ScholarCrossref
17.
Khandaker  GM, Dibben  CRM, Jones  PB.  Does maternal body mass index during pregnancy influence risk of schizophrenia in the adult offspring?  Obes Rev. 2012;13(6):518-527.PubMedGoogle ScholarCrossref
18.
Lawlor  DA.  The Society for Social Medicine John Pemberton Lecture 2011: developmental overnutrition—an old hypothesis with new importance?  Int J Epidemiol. 2013;42(1):7-29.PubMedGoogle ScholarCrossref
19.
Lipsitch  M, Tchetgen Tchetgen  E, Cohen  T.  Negative controls: a tool for detecting confounding and bias in observational studies.  Epidemiology. 2010;21(3):383-388. PubMedGoogle ScholarCrossref
20.
Richmond  RC, Al-Amin  A, Smith  GD, Relton  CL.  Approaches for drawing causal inferences from epidemiological birth cohorts: a review.  Early Hum Dev. 2014;90(11):769-780.PubMedGoogle ScholarCrossref
21.
Blomström  Å, Karlsson  H, Gardner  R, Jörgensen  L, Magnusson  C, Dalman  C.  Associations between maternal infection during pregnancy, childhood infections and the risk of subsequent psychotic disorder: a Swedish cohort study of nearly 2 million individuals.  Schizophr Bull. 2016;42(1):125-133.PubMedGoogle Scholar
22.
Gardner  RM, Lee  BK, Magnusson  C,  et al.  Maternal body mass index during early pregnancy, gestational weight gain, and risk of autism spectrum disorders: results from a Swedish total population and discordant sibling study.  Int J Epidemiol. 2015;44(3):870-883.PubMedGoogle ScholarCrossref
23.
Johansson  K, Hutcheon  JA, Stephansson  O, Cnattingius  S.  Pregnancy weight gain by gestational age and BMI in Sweden: a population-based cohort study.  Am J Clin Nutr. 2016;103(5):1278-1284.PubMedGoogle ScholarCrossref
24.
Status  P.  The Use and Interpretation of Anthropometry. Report of a WHO Expert Committee. WHO Technical Report Series No. 854. Geneva, Switzerland: World Health Organization; 1995, http://apps.who.int/iris/bitstream/10665/37003/1/WHO_TRS_854.pdf. Accessed January 8, 2017.
25.
Rasmussen  KM, Yaktine  AL.  Weight Gain During Pregnancy: Reexamining the Guidelines Consequences of Gestational Weight Gain for the Mother. Washington, DC: National Academies Press; 2009.
26.
Wicks  S, Hjern  A, Dalman  C.  Social risk or genetic liability for psychosis? a study of children born in Sweden and reared by adoptive parents.  Am J Psychiatry. 2010;167(10):1240-1246.PubMedGoogle ScholarCrossref
27.
Harrison  G, Fouskakis  D, Rasmussen  F, Tynelius  P, Sipos  A, Gunnell  D.  Association between psychotic disorder and urban place of birth is not mediated by obstetric complications or childhood socio-economic position: a cohort study.  Psychol Med. 2003;33(4):723-731. PubMedGoogle ScholarCrossref
28.
Cantor-Graae  E, Selten  JP.  Schizophrenia and migration: a meta-analysis and review.  Am J Psychiatry. 2005;162(1):12-24.PubMedGoogle ScholarCrossref
29.
Byrne  M, Agerbo  E, Ewald  H, Eaton  WW, Mortensen  PB.  Parental age and risk of schizophrenia: a case-control study.  Arch Gen Psychiatry. 2003;60(7):673-678.PubMedGoogle ScholarCrossref
30.
Dean  K, Stevens  H, Mortensen  PB, Murray  RM, Walsh  E, Pedersen  CB.  Full spectrum of psychiatric outcomes among offspring with parental history of mental disorder.  Arch Gen Psychiatry. 2010;67(8):822-829.PubMedGoogle ScholarCrossref
31.
Orsini  N, Greenland  S.  A procedure to tabulate and plot results after flexible modeling of a quantitative covariate.  Stata J. 2011;11(1):1-29.Google Scholar
32.
Wahlbeck  K, Forsén  T, Osmond  C, Barker  DJ, Eriksson  JG.  Association of schizophrenia with low maternal body mass index, small size at birth, and thinness during childhood.  Arch Gen Psychiatry. 2001;58(1):48-52. PubMedGoogle ScholarCrossref
33.
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(3):355-364. PubMedGoogle ScholarCrossref
34.
Schaefer  CA, Brown  AS, Wyatt  RJ,  et al.  Maternal prepregnant body mass and risk of schizophrenia in adult offspring.  Schizophr Bull. 2000;26(2):275-286.PubMedGoogle ScholarCrossref
35.
Kawai  M, Minabe  Y, Takagai  S,  et al.  Poor maternal care and high maternal body mass index in pregnancy as a risk factor for schizophrenia in offspring.  Acta Psychiatr Scand. 2004;110(4):257-263.PubMedGoogle ScholarCrossref
36.
Bulik-Sullivan  B, Finucane  HK, Anttila  V,  et al; ReproGen Consortium; Psychiatric Genomics Consortium; Genetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3.  An atlas of genetic correlations across human diseases and traits.  Nat Genet. 2015;47(11):1236-1241PubMedGoogle ScholarCrossref
37.
Abel  KM, Drake  R, Goldstein  JM.  Sex differences in schizophrenia.  Int Rev Psychiatry. 2010;22(5):417-428. PubMedGoogle ScholarCrossref
38.
Bao  Y, Ibram  G, Blaner  WS,  et al.  Low maternal retinol as a risk factor for schizophrenia in adult offspring.  Schizophr Res. 2012;137(1-3):159-165. PubMedGoogle ScholarCrossref
39.
Tamimi  RM, Lagiou  P, Mucci  LA, Hsieh  C-C, Adami  H-O, Trichopoulos  D.  Average energy intake among pregnant women carrying a boy compared with a girl.  BMJ. 2003;326(7401):1245-1246.PubMedGoogle ScholarCrossref
40.
Cagnacci  A, Renzi  A, Arangino  S, Alessandrini  C, Volpe  A.  Influences of maternal weight on the secondary sex ratio of human offspring.  Hum Reprod. 2004;19(2):442-444. PubMedGoogle ScholarCrossref
41.
Abel  KM, Wicks  S, Susser  ES,  et al.  Birth weight, schizophrenia, and adult mental disorder: is risk confined to the smallest babies?  Arch Gen Psychiatry. 2010;67(9):923-930.PubMedGoogle ScholarCrossref
42.
Nielsen  PR, Mortensen  PB, Dalman  C,  et al.  Fetal growth and schizophrenia: a nested case-control and case-sibling study.  Schizophr Bull. 2013;39(6):1337-1342. PubMedGoogle ScholarCrossref
43.
Murray  CL, Conroy  SA.  Experiences of low gestational weight gain: a phenomenological study with pregnant women.  Health. 2014;19(6):2611-2623.Google ScholarCrossref
44.
Frisell  T, Öberg  S, Kuja-Halkola  R, Sjölander  A.  Sibling comparison designs: bias from non-shared confounders and measurement error.  Epidemiology. 2012;23(5):713-720. PubMedGoogle ScholarCrossref
45.
Ekholm  B, Ekholm  A, Adolfsson  R,  et al.  Evaluation of diagnostic procedures in Swedish patients with schizophrenia and related psychoses.  Nord J Psychiatry. 2005;59(6):457-464.PubMedGoogle ScholarCrossref
46.
Hutcheon  JA, Bodnar  LM, Joseph  KS, Abrams  B, Simhan  HN, Platt  RW.  The bias in current measures of gestational weight gain.  Paediatr Perinat Epidemiol. 2012;26(2):109-116.PubMedGoogle ScholarCrossref
47.
Lichtenstein  P, Yip  BH, Björk  C,  et al.  Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study.  Lancet. 2009;373(9659):234-239.PubMedGoogle ScholarCrossref
48.
Sullivan  PF, Kendler  KS, Neale  MC.  Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies.  Arch Gen Psychiatry. 2003;60(12):1187-1192. PubMedGoogle ScholarCrossref
49.
Miyamoto  S, Duncan  GE, Marx  CE, Lieberman  JA.  Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs.  Mol Psychiatry. 2005;10(1):79-104. PubMedGoogle ScholarCrossref
50.
Kessler  RC, Amminger  GP, Aguilar-Gaxiola  S, Alonso  J, Lee  S, Ustün  TB.  Age of onset of mental disorders: a review of recent literature.  Curr Opin Psychiatry. 2007;20(4):359-364.PubMedGoogle ScholarCrossref
51.
Holowko  N, Chaparro  MP, Nilsson  K,  et al.  Social inequality in pre-pregnancy BMI and gestational weight gain in the first and second pregnancy among women in Sweden.  J Epidemiol Community Health. 2015;69(12):1154-1161.PubMedGoogle ScholarCrossref
52.
Kiel  DW, Dodson  EA, Artal  R, Boehmer  TK, Leet  TL.  Gestational weight gain and pregnancy outcomes in obese women: how much is enough?  Obstet Gynecol. 2007;110(4):752-758.PubMedGoogle ScholarCrossref
53.
Sridhar  SB, Darbinian  J, Ehrlich  SF,  et al.  Maternal gestational weight gain and offspring risk for childhood overweight or obesity.  Am J Obstet Gynecol. 2014;211(3):259.e1-259.e8.PubMedGoogle ScholarCrossref
54.
Ota  E, Haruna  M, Suzuki  M,  et al.  Maternal body mass index and gestational weight gain and their association with perinatal outcomes in Viet Nam.  Bull World Health Organ. 2011;89(2):127-136.PubMedGoogle ScholarCrossref
Original Investigation
April 2017

Association of Gestational Weight Gain and Maternal Body Mass Index in Early Pregnancy With Risk for Nonaffective Psychosis in Offspring

Author Affiliations
  • 1Epidemiology of Mental Health Division, Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden
  • 2Centre for Epidemiology and Community Medicine, Stockholm County Council, Stockholm, Sweden
  • 3Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
 

Copyright 2017 American Medical Association. All Rights Reserved.

JAMA Psychiatry. 2017;74(4):339-349. doi:10.1001/jamapsychiatry.2016.4257
Key Points

Question  Are gestational weight gain during pregnancy and maternal body mass index in early pregnancy associated with a risk for nonaffective psychosis in offspring?

Findings  In this population-based cohort study of 526 042 individuals born in Sweden from 1982 through 1989, extremely inadequate gestational weight gain was associated with a significantly increased risk for nonaffective psychosis in offspring in adjusted and sibling comparison models. A weak, U-shaped association was found between maternal body mass index at the beginning of pregnancy and risk for nonaffective psychosis in offspring in adjusted models.

Meaning  Insufficient weight gain during pregnancy may increase the risk for nonaffective disorders in offspring, even in an affluent and well-nourished population.

Abstract

Importance  Prenatal exposure to famine is associated with a 2-fold risk for nonaffective psychoses. Less is known about whether maternal nutrition states during pregnancy modify offspring risk for nonaffective psychoses in offspring in well-fed populations.

Objective  To determine whether gestational weight gain (GWG) during pregnancy and maternal body mass index (BMI) in early pregnancy are associated with risk for nonaffective psychoses in offspring.

Design, Setting and Participants  This population-based cohort study used data from Swedish health and population registers to follow up 526 042 individuals born from January 1, 1982, through December 31, 1989, from 13 years of age until December 31, 2011. Cox proportional hazards regression models adjusted for socioeconomic status and potential risk factors were used to examine the risk for developing nonaffective psychoses. Family-based study designs were used to further test causality. Data were analyzed from February 1 to May 14, 2016.

Exposures  Gestational weight gain during pregnancy, maternal body mass index at the first antenatal visit, and paternal body mass index at the time of conscription into the Swedish military (at 18 years of age).

Main Outcomes and Measures  Hazard ratios (HRs) for the diagnosis of nonaffective psychoses (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes F20 to F29 and International Classification of Diseases, Ninth Revision [ICD-9] codes 295, 297 and 298, except 298A and 298B) and narrowly defined schizophrenia (ICD-9 code 295 and ICD-10 code F20).

Results  The 526 042 individuals in the cohort (48.52% female and 51.47% male; mean [SD] age, 26 [2.3] years) included 2910 persons with nonaffective psychoses at the end of follow-up, of whom 704 had narrowly defined schizophrenia. Among the persons with nonaffective psychosis, 184 (6.32%) had mothers with extremely inadequate GWG (<8 kg for mothers with normal baseline BMI), compared with 23 627 (4.52%) of unaffected individuals. Extremely inadequate GWG was associated with an increased risk for nonaffective psychoses among offspring in adjusted models (HR, 1.32; 95% CI, 1.13-1.54) and in matched-sibling analysis (HR, 1.61; 95% CI, 1.02-2.56). Similar patterns were observed when considering narrowly defined schizophrenia as the outcome. Maternal mild thinness in early pregnancy was weakly associated with an increased risk for nonaffective psychosis in offspring (HR for BMI≥17.0 and <18.5, 1.21; 95% CI, 1.01-1.45), as was paternal severe thinness (HR for BMI<16.0, 2.53; 95% CI, 1.26-5.07) in mutually adjusted models. In matched-sibling analysis, no association was observed between maternal underweight (HR, 1.46; 95% CI, 0.90-2.35), overweight (HR, 1.11; 95% CI, 0.73-1.68), or obesity (HR, 0.56; 95% CI, 0.23-1.38) and risk for nonaffective psychosis in offspring.

Conclusions and Relevance  Inadequate GWG was associated with an increased risk for nonaffective psychosis in offspring, consistent with historical studies on maternal starvation. These findings support the role of maternal undernutrition in nonaffective psychosis pathogenesis.

Introduction

Nonaffective psychoses, or schizophrenia spectrum disorders, are increasingly considered neurodevelopmental disorders.1-5 Prenatal exposure to famine during the Dutch Hunger Winter (1944-1945) was associated with a 2-fold increase in the risk for nonaffective psychosis in offspring.6-8 Similarly, exposure to prenatal famine during the Chinese Great Leap Forward (1959-1961) led to a 2-fold increased relative risk for schizophrenia.9,10 Results from such disparate settings demonstrate that maternal malnutrition during pregnancy may increase the risk for psychosis among offspring.11,12

Deficits in maternal nutrition during pregnancy, including micronutrient deficiencies (eg, folate, vitamin D, iron) and protein-caloric malnutrition, have been associated with abnormalities in offspring neurodevelopment.11,13 Obesity, paradoxically, has been associated with deficiencies in nutrients vital to neurodevelopment, such as vitamin A, folate, vitamin D, and essential fatty acids,14,15 and offspring risk for neural tube defects.16 A range of maternal nutritional states during pregnancy may contribute to the risk for psychoses in offspring. Khandaker et al17 reviewed several studies that used maternal body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) as a proxy for maternal nutrition, but these produced conflicting results hampered by low numbers of cases.

This study’s aim was to investigate the association among maternal baseline BMI, gestational weight gain (GWG), and offspring risk for nonaffective psychosis in the largest cohort studied to date. We hypothesize that extremes in baseline maternal BMI or GWG, signifying suboptimal prenatal nutrition, would contribute to an increased risk for nonaffective psychosis in offspring. We posit that extremely low GWG is analogous to early gestational exposure to starvation seen in the famine studies. We used 2 family-based study designs—paternal-offspring comparisons and matched-sibling comparisons18-20—to evaluate the weight of evidence for any observed associations.

Methods
Study Design

This national, population-based cohort study used data from Psychiatry Sweden, a linkage of Swedish health and population registers.21 Ethical approval was granted by the Regional Ethical Committee of Stockholm. No informed consent was required for the analysis of anonymized register data.

Study Population

The study population included all nonadopted individuals born in Sweden from January 1, 1982, through December 31, 1989 (n = 798 934), who were followed up from 13 years of age until December 31, 2011, for diagnoses of nonaffective psychoses.21 Children were excluded who died or emigrated before their 13th birthday (2.7%), had incomplete Medical Birth Register data (0.4%), were missing information on their biological father (0.5%), or were part of multiple births (1.9%) (eFigure 1 in the Supplement). In addition, 30.2% of eligible mother-child pairs lacked maternal BMI or GWG data. Those individuals excluded from the final study population were demographically similar to those included (eTable 1 in the Supplement).

Variables
Diagnoses of Nonaffective Psychoses

Data on psychiatric history were taken from the National Patient Register, which has been collecting diagnoses for inpatient care since 1973 and psychiatric outpatient care since 2001. Nonaffective psychosis status was defined as receipt of 1 of the following diagnoses from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), or International Classification of Diseases, Ninth Revision (ICD-9): ICD-10 codes F20 to F29 and ICD-9 codes 295, 297, and 298 (except 298A and 298B) (eTable 2 in the Supplement) before December 31, 2011.21 Narrowly defined schizophrenia (ICD-9 code 295 and ICD-10 code F20) was also considered as an outcome.

Exposure: Maternal BMI and GWG

Maternal weight and height at the first antenatal visit were used to approximate baseline maternal BMI. Such data were recorded by midwives in the Medical Birth Register beginning in 1982. The timing of the first antenatal visit was unavailable. However, first trimester weight gain was on average low, and 90% of initial antenatal visits in Sweden occurred before 12 weeks’ gestation.22,23 Weights of less than 40 kg or greater than 140 kg were censored as unrealistic or indicating an existing medical condition, as were heights of less than 140 cm or greater than 210 cm. Maternal baseline BMI values were categorized according to World Health Organization guidelines24 into standard and extended BMI classifications.

Maternal weight was also recorded before delivery. Gestational weight gain was calculated as the difference in maternal weight between the first antenatal visit and delivery. Based on Institute of Medicine guidelines,25 GWG was categorized as ideal, inadequate, or excessive according to the maternal baseline BMI categories of underweight (12.5-18.0 kg), normal weight (11.5-16.0 kg), overweight (7.0-11.5 kg), and obese (5.0-9.0 kg). The GWG categories of inadequate and excessive were divided at their respective medians (by BMI category) to create the following 5 extended GWG categories (eTable 3 in the Supplement): ideal, extremely inadequate, inadequate, excessive, and extremely excessive.

Exposure: Paternal BMI

Paternal BMI was calculated from Swedish conscription register data, collected since 1969. Weight and height were measured objectively at the time of conscription into the Swedish military (at 18 years of age). Measurements were censored and categorized as with maternal BMI. Of the offspring with maternal BMI data, 64.74% also had paternal BMI data and are considered as the paternal BMI subcohort (eFigure 1 in the Supplement).

Covariates

Covariates were considered as potential confounders based on current literature. The following covariates were included in the study and classified as in Blomström et al21: birth year, offspring sex,3 household income at birth (in quintiles, with highest quintile as the reference category),26 highest level of parental education achieved, single-parent household status,26 urban birth (child born in a municipality with ≥200 000 inhabitants in 1980),27 parental immigration status (categorized as 0-2 parents born outside Sweden),28 parent older than 35 years at the time of birth (0-2 parents),29 parental nonaffective psychosis diagnosis (0-2 parents), and parental history of psychiatric care (0-2 parents).30

Statistical Analysis
BMI and Nonaffective Psychoses

Data were analyzed from February 1 to May 14, 2016. Statistical analyses were performed using STATA/IC software (version 14.1; StataCorp). We analyzed BMI as a categorical variable, then a continuous variable, using Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% CIs for nonaffective psychosis (or schizophrenia) in offspring with robust SEs to account for clustering of observations with mothers. Offspring were followed up from 13 years of age until the diagnosis of nonaffective psychosis, emigration, death, or December 31, 2011, whichever came first. Basic HRs were adjusted for birth year and sex of offspring. The final model for BMI was adjusted for birth year, offspring sex, family income quintile, parent older than 35 years, parental history of nonaffective psychosis, and parent born outside Sweden. Parental educational level was not included in the model owing to colinearity with income quintile. Normal BMI was the reference category in categorical analyses. Categorical analyses were repeated with extended BMI categories.

For continuous analyses, we fit Cox proportional hazards regression models using restricted cubic splines with 5 knots. Restricted cubic spline models allow for the flexible fitting of nonmonotonic associations between variables.31 Postestimation xbrcspline31 was used, with the reference category set as BMI of 21.0, denoting minimal risk.22

GWG and Nonaffective Psychoses

Similar to BMI, GWG was also analyzed as a categorical (reference category, ideal GWG) and continuous (reference category, 11 kg) variable. Models were adjusted as described above for BMI. Additional models considered maternal baseline BMI and gestational age as covariates. Continuous analysis was repeated with stratification by maternal BMI category.

Sibling Analyses

Matched-sibling analyses comparing affected individuals with their unaffected full siblings were performed to investigate whether observed associations among maternal BMI and GWG and offspring nonaffective psychosis could be the result of confounding by shared familial factors. Narrowly defined schizophrenia was not considered as an outcome in sibling analyses owing to lack of power. Cox proportional hazards regression, stratified by family identity, was performed for matched full siblings, discordant on outcome, adjusted for birth order and sex. We considered BMI and GWG as categorical and continuous exposures as above.

Sensitivity Analyses

Analyses of maternal and paternal BMI were repeated among those individuals with a paternal BMI observation (paternal BMI subcohort) and were analyzed individually as above and in a mutually adjusted model. Finally, the main analyses were repeated stratified by sex.

Results
Study Cohorts

The 526 042 individuals in the study cohort (48.52% female and 51.47% male; mean [SD] age, 26 [2.3] years) included 2910 cases of nonaffective psychoses at the end of follow-up. As expected, offspring who developed nonaffective psychosis or narrowly defined schizophrenia were more likely to be male and to be born in an urban center or to a single parent, an immigrant, or a parent with a history of psychiatric care compared with unaffected offspring (Table 1 and eTable 4 in the Supplement). In the paternal BMI subcohort, offspring were less likely to have a foreign-born parent compared with the full cohort and were less likely to have a parent 35 years or older, because the conscription register began in 1969 (eTable 1 in the Supplement). Covariates by maternal BMI and GWG categories are presented in eTables 5 and 6 in the Supplement.

Maternal BMI and Nonaffective Psychosis Risk

In the categorical analysis (Table 2), offspring of underweight mothers displayed a somewhat increased risk for nonaffective psychosis (adjusted HR, 1.14; 95% CI, 1.00-1.30). In the analysis of extended BMI categories, offspring of mothers with mild thinness (BMI≥17.0 and <18.5) had an increased risk for nonaffective psychosis (adjusted HR, 1.21; 95% CI, 1.06-1.39), as did offspring of mothers with class 2 obesity (BMI≥35.0 and <40.0; adjusted HR, 1.93; 95% CI, 1.00-3.71).

Similarly, in continuous analysis of maternal BMI (Figure 1), we observed a U-shaped association between maternal BMI and nonaffective psychosis among offspring in crude or adjusted models, although with wide CIs. Maternal underweight was usually associated with schizophrenia; no association was apparent between elevated maternal BMI and schizophrenia risk (Figure 1). In matched-sibling analyses, we found little apparent association between maternal BMI and offspring nonaffective psychosis in categorical (Table 2) or continuous analysis (Figure 1).

GWG and Nonaffective Psychosis Risk

Normal-weight and underweight mothers were more likely to gain weight within their recommended ranges (44.59% and 56.52%, respectively), compared with overweight (26.91%) and obese (34.20%) mothers (eTable 7 in the Supplement). Broad GWG categories were not associated with offspring nonaffective psychosis (Table 3). For extended GWG categories, the offspring of mothers with extremely inadequate weight gain had an increased risk for nonaffective psychosis (adjusted HR, 1.36; 95% CI, 1.16-1.58), even after accounting for gestational age and maternal BMI (Table 3).

In continuous analysis, nonaffective psychosis risk in offspring was associated with a low GWG (<11 kg) in unadjusted (Figure 2) and adjusted (eFigure 2 in the Supplement) models. Similar patterns were observed for narrowly defined schizophrenia (Figure 2 and eFigure 3 in the Supplement). When stratified by baseline maternal BMI category, the association of low GWG and the risk for nonaffective psychosis remained for the normal-weight and overweight or obese groups (BMI≥25.0), but not for the underweight group.

In the matched-sibling analysis, the risk for nonaffected psychosis increased for offspring born to mothers with extremely inadequate GWG (HR, 1.61; 95% CI, 1.02-2.56) (Table 3). In continuous analysis, a similar finding was observed, although the CIs were wide and included 1 (Figure 2).

Sensitivity Analyses

In the analysis of paternal BMI, we observed an increased risk for nonaffective psychosis among the offspring of severely thin fathers (BMI<16.0; adjusted HR, 2.52; 95% CI, 1.26-5.04) (eTable 8 in the Supplement) and a weak, U-shaped association between paternal BMI and nonaffective psychosis in offspring in continuous analysis, a pattern comparable with that of maternal BMI (eFigure 4 in the Supplement). The association between maternal obesity and the risk for nonaffective psychosis in offspring was strengthened by adjusting for paternal BMI, although the CIs remained wide (eFigure 4 and eTable 8 in the Supplement). In mutually adjusted models, maternal mild thinness in early pregnancy was weakly associated with an increased risk for nonaffective psychosis in offspring (HR for BMI≥17.0 and <18.5, 1.21; 95% CI, 1.01-1.45), as was paternal severe thinness (HR for BMI<16.0, 2.53; 95% CI, 1.26-5.07).

After stratification by sex (eTables 9 and 10 in the Supplement), maternal mild thinness was associated with nonaffective psychosis in male (HR, 1.30; 95% CI, 1.10-1.55) but not female (HR, 1.14; 95% CI, 0.91-1.43) offspring. Extremely inadequate GWG was associated with risk for psychosis in male (HR, 1.32; 95% CI, 1.07-1.63) and female (HR, 1.60; 95% CI, 1.27-2.01) offspring but was more pronounced in the latter.

Discussion
Key Results

Extremely inadequate GWG was associated with an increased risk for nonaffective psychosis in offspring in categorical and continuous analyses, even after adjustment for potential confounders. The sibling analysis suggests that this result is unlikely to be attributable to unmeasured familial confounding. Together these results indicate, similarly to the Dutch Hunger Winter and Great Leap Forward studies,7-9 that inadequate maternal nutrition during pregnancy increases the risk for nonaffective psychosis in offspring, even in the context of an affluent and well-nourished population.

This study also demonstrated a weak U-shaped association between maternal BMI at the beginning of pregnancy and the increased risk for nonaffective psychosis in offspring. However, the results of the paternal comparison indicate that the associations between the risk for nonaffective psychosis in offspring and parental BMI may be partly attributable to genetic or other shared familial factors.

Comparison With Previous Studies

Previous studies have reported contradictory associations between maternal BMI and risk for psychosis in offspring.17 Low late-pregnancy maternal BMI (≤24.0) was associated with a 3-fold risk for schizophrenia in offspring (reference BMI>30.0).32 However, late-pregnancy maternal BMI was used as a combined proxy for prepregnancy BMI and GWG, obscuring the contribution of each.

High maternal prepregnancy33,34 and late pregnancy35 BMI have also been linked to psychosis in offspring. We observed a 2-fold increased risk associated with maternal obesity (class 2) and an elevated risk for obesity and its subclasses. The results of our family comparison studies indicate that the associations between maternal BMI and the risk for nonaffective psychosis in offspring are at least partly confounded by genetic or other shared familial factors. The only study to date considering a potential correlation between genetic determinants of BMI and the risk for schizophrenia reported an inverse association: evidence of genetic correlation between low BMI and risk for schizophrenia.36

We observed a greater effect for female offspring of mothers with extremely inadequate GWG compared with male offspring, but effect estimates overlapped between the sexes. The initial Dutch famine study reported a similar sex effect,8 but this difference was not apparent in a later, more rigorous analysis.6 Our result merits cautious interpretation owing to the relative youth of our cohort and the differential age at onset for male and female offspring.37

Mechanisms

Although other mechanisms cannot be ruled out based on these observational studies, the association of inadequate GWG with nonaffective psychosis in concert with the findings of the Dutch and Chinese famine studies implicates malnutrition as the effector. Multiple nutrient deficiencies have been demonstrated to affect neurodevelopment and risk for schizophrenia in offspring.4,11,38 Low GWG during pregnancy may therefore represent an inability to meet the nutrient demands of the placental-fetal unit. Suboptimal nutrient status of mothers with extremely inadequate GWG in our study is evidenced by their lower rates of male births (eTable 10 in the Supplement). Male fetuses place a higher energy demand on mothers during pregnancy,39 such that states of maternal deprivation lead to fewer male births.40 Fetal growth restriction, indicated by infants who are small for gestational age, can result from inadequate GWG, although other factors also contribute. Small size for gestational age has also been linked to an increased risk for nonaffective psychosis.41,42

Severely inadequate GWG may otherwise be indicative of an existing maternal medical condition, such as endrocrinologic disorders, malabsorption, anorexia nervosa, bulimia nervosa, or hyperemesis gravidarum. Further research is necessary to understand the association between conditions that lead to insufficient maternal weight gain and the risk for nonaffective psychosis in offspring. Insufficient weight gain can also occur in otherwise healthy individuals owing to insufficient medical guidance or by a drive to conform to societal (but not medical) standards of appropriate weight gain.43

Strengths

This study is, to our knowledge, the largest to date to examine the association of maternal BMI and the risk for psychosis in offspring and the first to examine the role of GWG. The large sample size facilitated the use of family-based study designs for more rigorous inference of causation.20,44 We calculated BMI and GWG from objectively measured, prospectively recorded register data. Swedish registry data on nonaffective diagnoses have high validity.45

We were able to adjust GWG for gestational age. Gestational weight gain and gestational age are highly correlated, with inadequate GWG associated with preterm births and low birth weights.23,46 Accounting for parental psychosis likewise strengthened our results. Nonaffective psychoses are highly heritable,47,48 and traditional antipsychotics can lead to pronounced weight gain.49

Limitations

One issue is the limited follow-up time: ages of offspring at the end of follow-up varied from 22 to 29 years. Nonaffective psychoses manifest typically from the third decade of life onward.50 As such, our sample is considerably right censored. Although we statistically accounted for this, we may have captured more early-onset, possibly phenotypically distinct cases, which limits generalizability.17 Future studies will allow for reanalysis as the cohort continues to age. Another limitation is the rate of missing BMI and GWG in the eligible study population, although these data seem to be missing at random from the Medical Birth Register.22

Paternal BMI at conscription was used to examine the independence of any observable effect of maternal BMI on nonaffective psychosis among offspring.18-20 Paternal BMI was unavailable for any later time points. Using paternal BMI at 18 years of age allowed for exploration of the contribution of paternal factors to nonaffective psychosis in offspring while removing the effects of the shared parental environment at the time of pregnancy. Increasing paternal age is related to increased BMI and increased risk for nonaffective psychosis in offspring. By capturing BMI at the same age for all fathers, we avoided potential confounding owing to these associations.22

Sibling comparisons were used to test for unmeasured familial confounding. Using sibling analysis in extended categories for a rare outcome reduced power, possibly obscuring true associations. Also, in discordant sibling design, only mothers who varied in BMI or GWG between their 2 index pregnancies contribute to effect estimates; such designs are susceptible to confounding by nonshared factors that might lead to such changes in the same mother.44

We improve on the Dutch and Chinese famine studies by using individual measures of parental BMI and GWG as proxies for nutrition in place of population-level measures of starvation. However, BMI and GWG are incomplete representations of metabolic health and nutritional intake and cannot discount other mechanisms of action. We were also limited by the small number of mothers at the extremes of BMI categories.

Last, we recognize the dissonance of applying Institute of Medicine 2009 GWG guidelines to mothers in the 1980s. Using the rationale of Holowko et al,51 we believe the guidelines represent optimal maternal and child health outcomes, regardless of advice at the time. Our study seemingly validates the 2009 guidelines for mothers with BMI in the normal range, because ideal GWG conferred the lowest risk. However, offspring of overweight and obese women showed an elevated risk for nonaffective psychosis, even at the lower end of the Institute of Medicine ideal GWG range, potentially raising the question of the adequacy of weight gain guidelines for populations outside the normal BMI range, specifically for nonobstetric outcomes.46,52-54

Conclusions

Our results corroborate evidence from previous research and indicate that inadequate weight gain during pregnancy contributes to the risk for nonaffective psychosis in offspring. Weight gain outside Institute of Medicine guidelines may have deleterious effects on offspring neurodevelopment.

Back to top
Article Information

Corresponding Author: Renee M. Gardner, PhD, EoiOMH, Department of Public Health Sciences, Karolinska Institutet, Tomtebodavägen 18A, Stockholm, Sweden (renee.gardner@ki.se).

Accepted for Publication: December 16, 2016.

Published Online: February 22, 2017. doi:10.1001/jamapsychiatry.2016.4257

Author Contributions: Dr Gardner had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Dalman, Gardner.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Mackay, Dalman.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Mackay, Gardner.

Obtained funding: Dalman, Karlsson.

Study supervision: Dalman, Gardner.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by grant 523 2010 1052 from the Swedish Research Council for data linkage and staffing costs; by the Stanley Medical Research Institute for additional staff costs; and by grant 2007008 from the Stockholm County Council, grant 2007-2064 from the Swedish Council for Working Life and Social Research, grant 523-2010-1052 from the Swedish Research Council, and the Swedish Regional agreement on medical training and clinical research for data linkages and staff costs.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Murray  RM, Lewis  SW.  Is schizophrenia a neurodevelopmental disorder?  BMJ (Clin Res Ed). 1987;295(6600):681-682.PubMedGoogle ScholarCrossref
2.
Weinberger  DR.  Implications of normal brain development for the pathogenesis of schizophrenia.  Arch Gen Psychiatry. 1987;44(7):660-669. PubMedGoogle ScholarCrossref
3.
Piper  M, Beneyto  M, Burne  THJ, Eyles  DW, Lewis  DA, McGrath  JJ.  The neurodevelopmental hypothesis of schizophrenia: convergent clues from epidemiology and neuropathology.  Psychiatr Clin North Am. 2012;35(3):571-584. PubMedGoogle ScholarCrossref
4.
Insel  BJ, Schaefer  CA, McKeague  IW, Susser  ES, Brown  AS.  Maternal iron deficiency and the risk of schizophrenia in offspring.  Arch Gen Psychiatry. 2008;65(10):1136-1144. PubMedGoogle ScholarCrossref
5.
Debnath  M, Venkatasubramanian  G, Berk  M.  Fetal programming of schizophrenia: select mechanisms.  Neurosci Biobehav Rev. 2015;49:90-104. PubMedGoogle ScholarCrossref
6.
Susser  E, Neugebauer  R, Hoek  HW,  et al.  Schizophrenia after prenatal famine: further evidence.  Arch Gen Psychiatry. 1996;53(1):25-31.PubMedGoogle ScholarCrossref
7.
Hoek  HW, Brown  AS, Susser  E.  The Dutch famine and schizophrenia spectrum disorders.  Soc Psychiatry Psychiatr Epidemiol. 1998;33(8):373-379.PubMedGoogle ScholarCrossref
8.
Susser  ES, Lin  SP.  Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944-1945.  Arch Gen Psychiatry. 1992;49(12):983-988.PubMedGoogle ScholarCrossref
9.
St Clair  D, Xu  M, Wang  P,  et al.  Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961.  JAMA. 2005;294(5):557-562.PubMedGoogle ScholarCrossref
10.
Xu  MQ, Sun  WS, Liu  BX,  et al.  Prenatal malnutrition and adult schizophrenia: further evidence from the 1959-1961 Chinese famine.  Schizophr Bull. 2009;35(3):568-576. PubMedGoogle ScholarCrossref
11.
Brown  AS, Susser  ES.  Prenatal nutritional deficiency and risk of adult schizophrenia.  Schizophr Bull. 2008;34(6):1054-1063.PubMedGoogle ScholarCrossref
12.
Susser  E, St Clair  D.  Prenatal famine and adult mental illness: interpreting concordant and discordant results from the Dutch and Chinese Famines.  Soc Sci Med. 2013;97:325-330.PubMedGoogle ScholarCrossref
13.
Black  RE, Victora  CG, Walker  SP,  et al; Maternal and Child Nutrition Study Group.  Maternal and child undernutrition and overweight in low-income and middle-income countries.  Lancet. 2013;382(9890):427-451. PubMedGoogle ScholarCrossref
14.
Tomedi  LE, Chang  C-CH, Newby  PK,  et al.  Pre-pregnancy obesity and maternal nutritional biomarker status during pregnancy: a factor analysis.  Public Health Nutr. 2013;16(8):1414-1418.PubMedGoogle ScholarCrossref
15.
van der Burg  JW, Sen  S, Chomitz  VR, Seidell  JC, Leviton  A, Dammann  O.  The role of systemic inflammation linking maternal BMI to neurodevelopment in children.  Pediatr Res. 2016;79(1-1):3-12.PubMedGoogle ScholarCrossref
16.
Rasmussen  SA, Chu  SY, Kim  SY, Schmid  CH, Lau  J.  Maternal obesity and risk of neural tube defects: a metaanalysis.  Am J Obstet Gynecol. 2008;198(6):611-619. PubMedGoogle ScholarCrossref
17.
Khandaker  GM, Dibben  CRM, Jones  PB.  Does maternal body mass index during pregnancy influence risk of schizophrenia in the adult offspring?  Obes Rev. 2012;13(6):518-527.PubMedGoogle ScholarCrossref
18.
Lawlor  DA.  The Society for Social Medicine John Pemberton Lecture 2011: developmental overnutrition—an old hypothesis with new importance?  Int J Epidemiol. 2013;42(1):7-29.PubMedGoogle ScholarCrossref
19.
Lipsitch  M, Tchetgen Tchetgen  E, Cohen  T.  Negative controls: a tool for detecting confounding and bias in observational studies.  Epidemiology. 2010;21(3):383-388. PubMedGoogle ScholarCrossref
20.
Richmond  RC, Al-Amin  A, Smith  GD, Relton  CL.  Approaches for drawing causal inferences from epidemiological birth cohorts: a review.  Early Hum Dev. 2014;90(11):769-780.PubMedGoogle ScholarCrossref
21.
Blomström  Å, Karlsson  H, Gardner  R, Jörgensen  L, Magnusson  C, Dalman  C.  Associations between maternal infection during pregnancy, childhood infections and the risk of subsequent psychotic disorder: a Swedish cohort study of nearly 2 million individuals.  Schizophr Bull. 2016;42(1):125-133.PubMedGoogle Scholar
22.
Gardner  RM, Lee  BK, Magnusson  C,  et al.  Maternal body mass index during early pregnancy, gestational weight gain, and risk of autism spectrum disorders: results from a Swedish total population and discordant sibling study.  Int J Epidemiol. 2015;44(3):870-883.PubMedGoogle ScholarCrossref
23.
Johansson  K, Hutcheon  JA, Stephansson  O, Cnattingius  S.  Pregnancy weight gain by gestational age and BMI in Sweden: a population-based cohort study.  Am J Clin Nutr. 2016;103(5):1278-1284.PubMedGoogle ScholarCrossref
24.
Status  P.  The Use and Interpretation of Anthropometry. Report of a WHO Expert Committee. WHO Technical Report Series No. 854. Geneva, Switzerland: World Health Organization; 1995, http://apps.who.int/iris/bitstream/10665/37003/1/WHO_TRS_854.pdf. Accessed January 8, 2017.
25.
Rasmussen  KM, Yaktine  AL.  Weight Gain During Pregnancy: Reexamining the Guidelines Consequences of Gestational Weight Gain for the Mother. Washington, DC: National Academies Press; 2009.
26.
Wicks  S, Hjern  A, Dalman  C.  Social risk or genetic liability for psychosis? a study of children born in Sweden and reared by adoptive parents.  Am J Psychiatry. 2010;167(10):1240-1246.PubMedGoogle ScholarCrossref
27.
Harrison  G, Fouskakis  D, Rasmussen  F, Tynelius  P, Sipos  A, Gunnell  D.  Association between psychotic disorder and urban place of birth is not mediated by obstetric complications or childhood socio-economic position: a cohort study.  Psychol Med. 2003;33(4):723-731. PubMedGoogle ScholarCrossref
28.
Cantor-Graae  E, Selten  JP.  Schizophrenia and migration: a meta-analysis and review.  Am J Psychiatry. 2005;162(1):12-24.PubMedGoogle ScholarCrossref
29.
Byrne  M, Agerbo  E, Ewald  H, Eaton  WW, Mortensen  PB.  Parental age and risk of schizophrenia: a case-control study.  Arch Gen Psychiatry. 2003;60(7):673-678.PubMedGoogle ScholarCrossref
30.
Dean  K, Stevens  H, Mortensen  PB, Murray  RM, Walsh  E, Pedersen  CB.  Full spectrum of psychiatric outcomes among offspring with parental history of mental disorder.  Arch Gen Psychiatry. 2010;67(8):822-829.PubMedGoogle ScholarCrossref
31.
Orsini  N, Greenland  S.  A procedure to tabulate and plot results after flexible modeling of a quantitative covariate.  Stata J. 2011;11(1):1-29.Google Scholar
32.
Wahlbeck  K, Forsén  T, Osmond  C, Barker  DJ, Eriksson  JG.  Association of schizophrenia with low maternal body mass index, small size at birth, and thinness during childhood.  Arch Gen Psychiatry. 2001;58(1):48-52. PubMedGoogle ScholarCrossref
33.
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(3):355-364. PubMedGoogle ScholarCrossref
34.
Schaefer  CA, Brown  AS, Wyatt  RJ,  et al.  Maternal prepregnant body mass and risk of schizophrenia in adult offspring.  Schizophr Bull. 2000;26(2):275-286.PubMedGoogle ScholarCrossref
35.
Kawai  M, Minabe  Y, Takagai  S,  et al.  Poor maternal care and high maternal body mass index in pregnancy as a risk factor for schizophrenia in offspring.  Acta Psychiatr Scand. 2004;110(4):257-263.PubMedGoogle ScholarCrossref
36.
Bulik-Sullivan  B, Finucane  HK, Anttila  V,  et al; ReproGen Consortium; Psychiatric Genomics Consortium; Genetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3.  An atlas of genetic correlations across human diseases and traits.  Nat Genet. 2015;47(11):1236-1241PubMedGoogle ScholarCrossref
37.
Abel  KM, Drake  R, Goldstein  JM.  Sex differences in schizophrenia.  Int Rev Psychiatry. 2010;22(5):417-428. PubMedGoogle ScholarCrossref
38.
Bao  Y, Ibram  G, Blaner  WS,  et al.  Low maternal retinol as a risk factor for schizophrenia in adult offspring.  Schizophr Res. 2012;137(1-3):159-165. PubMedGoogle ScholarCrossref
39.
Tamimi  RM, Lagiou  P, Mucci  LA, Hsieh  C-C, Adami  H-O, Trichopoulos  D.  Average energy intake among pregnant women carrying a boy compared with a girl.  BMJ. 2003;326(7401):1245-1246.PubMedGoogle ScholarCrossref
40.
Cagnacci  A, Renzi  A, Arangino  S, Alessandrini  C, Volpe  A.  Influences of maternal weight on the secondary sex ratio of human offspring.  Hum Reprod. 2004;19(2):442-444. PubMedGoogle ScholarCrossref
41.
Abel  KM, Wicks  S, Susser  ES,  et al.  Birth weight, schizophrenia, and adult mental disorder: is risk confined to the smallest babies?  Arch Gen Psychiatry. 2010;67(9):923-930.PubMedGoogle ScholarCrossref
42.
Nielsen  PR, Mortensen  PB, Dalman  C,  et al.  Fetal growth and schizophrenia: a nested case-control and case-sibling study.  Schizophr Bull. 2013;39(6):1337-1342. PubMedGoogle ScholarCrossref
43.
Murray  CL, Conroy  SA.  Experiences of low gestational weight gain: a phenomenological study with pregnant women.  Health. 2014;19(6):2611-2623.Google ScholarCrossref
44.
Frisell  T, Öberg  S, Kuja-Halkola  R, Sjölander  A.  Sibling comparison designs: bias from non-shared confounders and measurement error.  Epidemiology. 2012;23(5):713-720. PubMedGoogle ScholarCrossref
45.
Ekholm  B, Ekholm  A, Adolfsson  R,  et al.  Evaluation of diagnostic procedures in Swedish patients with schizophrenia and related psychoses.  Nord J Psychiatry. 2005;59(6):457-464.PubMedGoogle ScholarCrossref
46.
Hutcheon  JA, Bodnar  LM, Joseph  KS, Abrams  B, Simhan  HN, Platt  RW.  The bias in current measures of gestational weight gain.  Paediatr Perinat Epidemiol. 2012;26(2):109-116.PubMedGoogle ScholarCrossref
47.
Lichtenstein  P, Yip  BH, Björk  C,  et al.  Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study.  Lancet. 2009;373(9659):234-239.PubMedGoogle ScholarCrossref
48.
Sullivan  PF, Kendler  KS, Neale  MC.  Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies.  Arch Gen Psychiatry. 2003;60(12):1187-1192. PubMedGoogle ScholarCrossref
49.
Miyamoto  S, Duncan  GE, Marx  CE, Lieberman  JA.  Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs.  Mol Psychiatry. 2005;10(1):79-104. PubMedGoogle ScholarCrossref
50.
Kessler  RC, Amminger  GP, Aguilar-Gaxiola  S, Alonso  J, Lee  S, Ustün  TB.  Age of onset of mental disorders: a review of recent literature.  Curr Opin Psychiatry. 2007;20(4):359-364.PubMedGoogle ScholarCrossref
51.
Holowko  N, Chaparro  MP, Nilsson  K,  et al.  Social inequality in pre-pregnancy BMI and gestational weight gain in the first and second pregnancy among women in Sweden.  J Epidemiol Community Health. 2015;69(12):1154-1161.PubMedGoogle ScholarCrossref
52.
Kiel  DW, Dodson  EA, Artal  R, Boehmer  TK, Leet  TL.  Gestational weight gain and pregnancy outcomes in obese women: how much is enough?  Obstet Gynecol. 2007;110(4):752-758.PubMedGoogle ScholarCrossref
53.
Sridhar  SB, Darbinian  J, Ehrlich  SF,  et al.  Maternal gestational weight gain and offspring risk for childhood overweight or obesity.  Am J Obstet Gynecol. 2014;211(3):259.e1-259.e8.PubMedGoogle ScholarCrossref
54.
Ota  E, Haruna  M, Suzuki  M,  et al.  Maternal body mass index and gestational weight gain and their association with perinatal outcomes in Viet Nam.  Bull World Health Organ. 2011;89(2):127-136.PubMedGoogle ScholarCrossref
×