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. Author manuscript; available in PMC: 2020 Mar 16.
Published in final edited form as: Schizophr Res. 2019 Jul 22;213:15–22. doi: 10.1016/j.schres.2019.07.002

Maternal cortisol during pregnancy and offspring schizophrenia: Influence of fetal sex and timing of exposure

Lauren M Ellman a,*, Shannon K Murphy a, Seth D Maxwell a, Evan M Calvo a, Thomas Cooper b,e,f, Catherine A Schaefer c, Michaeline A Bresnahan d,e, Ezra S Susser d,e, Alan S Brown d,e,f
PMCID: PMC7074891  NIHMSID: NIHMS1558224  PMID: 31345704

Abstract

Introduction:

Maternal stress during pregnancy has been repeatedly linked to increased risk for schizophrenia; however, no study has examined maternal cortisol during pregnancy and risk for the disorder. Study aims were to determine whether prenatal cortisol was associated with risk for schizophrenia and risk for an intermediate phenotype—decreased fetal growth—previously linked to prenatal cortisol and schizophrenia. Timing of exposure and fetal sex also were examined given previous findings.

Methods:

Participants were 64 cases diagnosed with schizophrenia spectrum disorders (SSD) and 117 controls from a prospective birth cohort study. Maternal cortisol was determined from stored sera from each trimester and psychiatric diagnoses were assessed from offspring using semi-structured interviews and medical records review.

Results:

Maternal cortisol during pregnancy was not associated with risk for offspring schizophrenia. There was a significant interaction between 3rd trimester cortisol and case status on fetal growth. Specifically, cases exposed to higher 3rd trimester maternal cortisol had significantly decreased fetal growth compared to controls. In addition, these findings were restricted to male offspring.

Conclusions:

Our results indicate that higher prenatal cortisol is associated with an intermediate phenotype linked to schizophrenia, fetal growth, but only among male offspring who developed schizophrenia. Findings were consistent with evidence that schizophrenia genes may disrupt placental functioning specifically for male fetuses, as well as findings that males are more vulnerable to maternal cortisol during pregnancy. Finally, results suggest that examining fetal sex and intermediate phenotypes may be important in understanding the mechanisms involved in prenatal contributors to schizophrenia.

Keywords: Stress, Cortisol, Obstetric complications, Fetal growth, Birth weight, Schizophrenia

1. Introduction

Maternal stress during pregnancy has been repeatedly linked with increased risk of offspring schizophrenia and other spectrum disorders, herein referred to as schizophrenia (Fineberg et al., 2016). In particular, exposure to a number of severe life events during pregnancy, such as war (Malaspina et al., 2008; Van Os and Selten, 1998), natural disaster (Selten et al., 1999; Watson et al., 1999), famine (Susser and St Clair, 2013), and death of a spouse or close relative (Huttunen and Niskanen, 1978; Khashan et al., 2008), has been associated with schizophrenia in offspring. Several of these findings have been complicated by use of population-level exposure data (Selten et al., 1999; St Clair et al., 2005; Susser and Lin, 1992; Van Os and Selten, 1998) and measures of extreme and uncommon environmental stressors that likely involve other processes beyond stress (e.g., malnutrition; Susser and Lin, 1992; St Clair et al., 2005). Additionally, the findings relating bereavement during pregnancy to increased schizophrenia risk (Huttunen and Niskanen, 1978; Khashan et al., 2008) have been somewhat mixed (Abel et al., 2014; Class et al., 2014). Nevertheless, studies using more common stressful life events during pregnancy, as well improved methodologies (e.g., prospective measures of maternal psychological stress), have found similar associations between prenatal stress and offspring schizophrenia. For example, studies examining maternal reports of unwantedness of pregnancy have found associations between maternal report and later development of offspring schizophrenia (Herman et al., 2006; McNeil et al., 2009; Myhrman et al., 1996). Furthermore, prospectively collected maternal reports of daily life stress during pregnancy (e.g., financial stress, marriage difficulties) have been associated with significantly increased odds of schizophrenia in male offspring (Fineberg et al., 2016).

Several mechanisms have been investigated to explain the adverse effects of maternal stress on fetal neurodevelopment (Corcoran et al., 2003; Rakers et al., 2017; Walker et al., 2008). Higher levels during pregnancy of the stress hormone cortisol have been identified as a possible mediator of the maternal stress effects on fetal development (Cottrell and Seckl, 2009; Moisiadis and Matthews, 2014). For instance, higher maternal cortisol during pregnancy has been consistently associated with obstetric complications (OCs) and premorbid difficulties found in the histories of schizophrenia patients. Specifically, higher maternal cortisol (particularly in the 2nd trimester) has been associated with decreased gestational age and decreased birth weight/fetal growth restriction, OCs that have been associated with schizophrenia (Abel et al., 2010; Bloom et al., 2001; Cannon et al., 2002; Eide et al., 2013; Ellman et al., 2008; Fineberg et al., 2013; French et al., 1999; Ichiki et al., 2000; Lane and Albee, 1966; Murphy et al., 2006; Reinisch et al., 1978; Trainer, 2002). In addition, we have previously found that both fetal hypoxia and exposure to maternal influenza during pregnancy are associated with decreased fetal growth, but only for infants that later go on to develop schizophrenia and not controls, indicating that vulnerability associated with schizophrenia may interact with these prenatal events to impair fetal growth (Fineberg et al., 2013). Also, in both human and preclinical studies (Glover et al., 2010; Kapoor et al., 2008; Lemaire et al., 2000; McArthur et al., 2005; Sandman et al., 2018), higher maternal prenatal cortisol has been associated with a variety of offspring brain abnormalities that have been linked to schizophrenia, such as hippocampal alterations (e.g., inhibited neurogenesis) and dopaminergic abnormalities. Cumulatively, these findings suggest that fetal exposure to maternal cortisol is associated with birth outcomes and long-lasting neuronal and cognitive alterations similar to those found among schizophrenia patients.

In addition, accumulating evidence suggests that males and females differ in their vulnerability to adverse influences of prenatal stress (Chan et al., 2018; Mueller and Bale, 2008; Sandman et al., 2013). A number of studies show increased risk of schizophrenia among male, but not female, offspring whose mothers experienced psychological stress during pregnancy (Chan et al., 2018; Fineberg et al., 2016; Khashan et al., 2008; Van Os and Selten, 1998). Similarly, as compared to females, males appear to display greater vulnerability for early mortality and morbidity, including developmental delays in important markers of neonatal maturity (such as decreased fetal growth), following prenatal exposure to elevated levels of stress hormones and maternal psychosocial stress (Ellman et al., 2008; Sandman et al., 2013). Second, there is some evidence, albeit mixed, to suggest that males with schizophrenia are more susceptible to adverse pre- and perinatal events and obstetrical complications compared to females (Cannon et al., 2002; Foerster et al., 1991; Goldstein and Walder, 2006; Matsumoto et al., 2001), possibly contributing to a form of schizophrenia that has stronger “neurodevelopmental” origins (Castle and Murray, 1991; Walker et al., 2002). Third, males may be more vulnerable to prenatal gonadal hormone disruptions than females, contributing to sexual dimorphisms in behavioral sequelae and risk for psychopathology (Walder et al., 2006).

Hence, the present study sought to determine whether fetal exposure to higher maternal cortisol was associated with increased odds of offspring schizophrenia. In addition, this study investigated whether timing of exposure to cortisol and fetal sex contributed to the findings. Although there has been some variability in previous results, most studies have linked 2nd trimester maternal stress with offspring schizophrenia and outcomes associated with schizophrenia (Bloom et al., 2001; Cannon et al., 2002; Ellman et al., 2008; Fineberg et al., 2013; French et al., 1999; Ichicki et al., 2000; Lane and Albee, 1966; Murphy et al., 2006; Reinisch et al., 1978; Trainer, 2002). Finally, the present study aimed to investigate whether higher maternal cortisol during pregnancy was associated with decreased fetal growth and whether this association was influenced by fetal sex and case status, as has previously been suggested (Chan et al., 2018; Ellman et al., 2008; Fineberg et al., 2016; Khashan et al., 2008; Mueller and Bale, 2008; Sandman et al., 2013; Van Os and Selten, 1998). This latter aim was explored given the strong possibility that higher maternal cortisol during pregnancy is associated with an intermediate phenotype associated with both schizophrenia and prenatal cortisol, instead of the full diagnostic criteria for the disorder (Abel et al., 2010; Bloom et al., 2001; Cannon et al., 2002; Eide et al., 2013; Ellman et al., 2008; Fineberg et al., 2013; French et al., 1999; Ichicki et al., 2000; Lane and Albee, 1966; Murphy et al., 2006; Reinisch et al., 1978; Trainer, 2002). We hypothesized that higher levels of 2nd trimester maternal cortisol would be associated with increased odds of schizophrenia and decreased fetal growth among cases. We also hypothesized that these associations would be restricted to males, given repeated associations suggesting that male fetuses are preferentially sensitive to the effects of prenatal cortisol (Ellman et al., 2008; Sandman et al., 2013). We hypothesized that maternal cortisol during pregnancy would not be significantly associated with schizophrenia risk and/or fetal growth among female cases, based on previous findings (Ellman et al., 2008; Fineberg et al., 2016).

2. Materials and methods

The study was approved by the Institutional Review Boards of the New York State Psychiatric Institute, the Kaiser Foundation Research Institute, and Temple University.

2.1. Description of the cohort

Participants were derived from the Prenatal Determinants of Schizophrenia (PDS) study, which ascertained cases of schizophrenia and other spectrum disorders from a large birth cohort described in detail previously (Susser et al., 2000). Briefly, the PDS study included pregnant women (n = 12,094 live births) receiving obstetric care from the Kaiser Permanente Medical Care Plan (KPMCP) in Alameda County, California, as part of the Child Health and Development Studies (CHDS). Maternal serum samples were collected throughout the pregnancies and were frozen and stored at −20 ° C.

2.2. Ascertainment and diagnosis

Case ascertainment and screening were accomplished following computerized record linkage between the CHDS and KPMCP identifiers from inpatient, outpatient, and pharmacy registries of CHDS participants who belonged to KPMCP from 1981 to 1997 (corresponding to the initiation of KPMCP computerized psychiatric registries and to the end of follow-up). Potential cases were diagnosed using DSM-IV criteria following assessment with the Diagnostic Interview for Genetic Studies (DIGS; Nurnberger et al., 1994), chart review, and consensus of 3 experienced research psychiatrists. A “case” was defined as an individual diagnosed with a schizophrenia spectrum disorder (SSD; schizophrenia, schizoaffective disorder, schizotypal personality disorder, other non-affective psychoses), as described elsewhere (Susser et al., 2000). The PDS study included 71 cases of SSD. PDS control matching has been described elsewhere, but briefly up to 8 controls were matched to cases based on length of membership in KFHP, gender, number and gestational timing of prenatal blood draws, and date of birth, while randomly selecting one sibling for each family (Susser et al., 2000). The present study included 64 cases, each of whom were matched to 1 or 2 controls who had available sera, except for one case who had no matched controls. Among cases with trimester 2 cortisol data, 6 had matched controls without trimester 2 cortisol data; among cases with trimester 3 cortisol data, 5 were matched to controls without trimester 3 cortisol data. Therefore, controls for the unmatched case cortisol samples in trimesters 2 and 3 were matched to 1 of the control samples from the remaining controls with available cortisol data; for each case sample, the control sample with gestational age at blood draw closest to that of the case was selected, given known increases in cortisol throughout gestation (Trainer, 2002). For cases who had more than one blood draw in a given trimester, the blood draw was selected that minimized the difference in gestational age at the time of blood draw for the matched set (i.e., closest in weeks gestation at the time of blood draw between the case and control). The process yielded 57 first trimester samples (SSD = 20), 113 second trimester samples (SSD = 45), and 165 third trimester samples (SSD = 59). Of the cases, 38 were diagnosed with schizophrenia, 15 schizoaffective disorder, 5 schizotypal personality disorder, 1 delusional disorder, 5 other nonaffective psychosis.

2.3. Cortisol analyses

Although diurnal variations of cortisol remain intact during pregnancy, they are substantially blunted due to rising levels of cortisol throughout gestation, with the main variation consisting of a spike during the first 30 min following awakening (de Weerth and Buitelaar, 2005). Although times of the blood draws are not known, blood was collected primarily in the morning while fasting at the study site, which reduces the possibility that blood samples were obtained directly following awakening. Further, data from the CHDS cohort and another similar birth cohort study (NCPP cohort) during the same period as the CHDS study (also with unknown collection times) found that maternal cortisol values were consistent with values from published studies of fresh samples collected at similar points in gestation, indicating minimal degradation of cortisol over time (Stroud et al., 2007).

Serum cortisol was measured in the Analytical Psychopharmacology Laboratory at Nathan Kline Institute. Cortisol was measured by radioimmunoassay after denaturation of the binding proteins by heat. Primary antibodies (raised in rabbit against cortisol-3-carboxymethyl oxime-bovine serum albumin) and 125I-labeled cortisol were purchased from MP Biomedicals (Santa Ana, CA). The cortisol standard was purchased from Sigma Chemical Company (Saint-Louis, MO). Anti-rabbit globulin serum in conjunction with polyethylene glycol was used for separation of the bound and free fractions. Samples were assayed in duplicate. The intra- and interassay critical values were: 2.95% and 6.0% at 3.1 μg/dL level, 2.53% and 3.93% at 19.3 μg/dL level, and 2.00% and 2.91% at 32.7 μg/dL level.

2.4. Statistical analyses

All statistical analyses were performed using SAS software version 9.4 (Cary, NC). Cortisol distributions by trimester were inspected for the overall analytic sample and when stratifying by presence/absence of SSD by examining kurtosis and skewness values, as well as visually inspecting the distributions. Potential covariates were determined by conducting correlations between the main study variables (i.e., cortisol variables and SSD) and birthweight, gestational age (measured in weeks from last menstrual period to birth), maternal race (African-American versus not African-American), maternal age, and maternal education (HS degree or below vs. above HS). If these variables were associated with both the main IVs and DVs, then they were included in subsequent models. In addition, bivariate correlations in each trimester were tested for significance among cortisol and SSD.

Separate logistic regressions were conducted for the second and third trimesters to determine whether cortisol and/or the interaction between cortisol and infant sex were associated with increased odds of SSD. Cortisol, infant sex, and an interaction between cortisol and sex were included as independent variables in each model, conducted separately by trimester. If interaction variables were significant, logistic regressions were conducted stratifying by sex, in order to descriptively probe the significant interaction. Due to small sample sizes in the first trimester, a logistic regression was conducted with cortisol as the independent variable without a cortisol by sex interaction term, as the interaction would not be interpretable with such small cell numbers (i.e., when breaking down case status by sex). Separate regressions were conducted by trimester to determine if SSD, cortisol, and the interaction between SSD and cortisol were associated with birth weight. All regression analyses controlled for gestational age, to assess fetal growth accounting for variations in the length of the pregnancy and significant findings were probed by conducting regressions stratifying by case status. Additionally, any significant stratified case/control results were probed for sex differences by adding infant sex interaction terms (excluding the first trimester due to small sample sizes). For all other analyses, significance was based on two-tailed p-values<0.05.

3. Results

No major deviations from normality were found for cortisol levels, so analyses were performed using raw values. Demographic characteristics are listed in Table 1 (and Supplementary Table 1 for characteristics broken down by infant sex). Bivariate correlations indicated that one of the potential covariates, maternal education, was significantly associated with both cortisol and SSD (see Table 2). As such, maternal education was included as a covariate in logistic regression analyses of trimester 2 cortisol predicting schizophrenia. No additional covariates were included in analyses, as they were not significantly associated with both the predictor and outcome variables (see Table 2).

Table 1.

Demographics characteristics.

Overall sample
(n = 181)		 Cases
(n = 64)		 Controls
(n = 117)		 p-Value
(t or χ2)
Cortisol (μg/dL): M (SD)
 Trimester 1 14.77 (5.12) 14.40 (5.44) 14.97 (5.00) 0.688
 Trimester 2 23.23 (9.45) 21.79 (7.75) 24.19 (10.36) 0.163
 Trimester 3 38.44 (12.17) 36.77 (11.44) 39.37 (12.51) 0.190
Gestational age at blood draw (weeks): M (SD)
 Trimester 1 10.92 (1.92) 11.19 (1.86) 10.77 (1.96) 0.443
 Trimester 2 20.27 (3.61) 20.04 (3.69) 20.42 (3.58) 0.589
 Trimester 3 34.57 (2.85) 34.68 (3.02) 34.51 (2.77) 0.708
Potential covariates
 Birth weight (grams): M (SD) 3322.43 (521.57) 3379.85 (552.52) 3291.02 (503.50) 0.275
 Gestational age (weeks): M (SD) 40.16 (2.37) 40.48 (2.02) 39.99 (2.53) 0.183
 Maternal age at childbirth: M (SD) 27.84 (6.27) 28.30 (6.24) 27.59 (6.30) 0.474
 Maternal race: N (%)
  Caucasian 96 (53.93) 32 (50.79) 64 (55.65) 0.534
  African American 69 (38.76) 27 (42.86) 42 (36.52) 0.407
  Asian 9 (5.06) 1 (1.59) 8 (6.96) 0.118
 Maternal education: N (%)
  High school or less 89 (54.94) 38 (66.67) 51 (48.57) 0.027*
  More than high school 73 (45.06) 19 (33.33) 54 (51.43)
 Infant sex: %M (%F) 67.40 (32.60) 65.63 (34.38) 68.38 (31.62) 0.706
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The following variables had missing data: For cases: maternal race (n = 4), maternal education (n = 7). For controls: gestational age (n = 1), maternal age at childbirth (n = 1), maternal race (n = 3), maternal education (n = 12). p-Values correspond to tests of differences between cases and controls (t-tests for continuous variables and chi-square tests for categorical variables).

*

p < 0.05.

Table 2.

Bivariate correlations between case status, cortisol by trimester, gestational age at blood draw, and potential covariates.

Case
status		 Cortisol
(T1)		 GA at blood
draw (T1)		 Cortisol
(T2)		 GA at blood
draw (T2)		 Cortisol
(T3)		 GA at blood
draw (T3)		 Birth
weight		 Gestational
age		 Maternal age at
childbirth		 African-
American		 Maternal
education
Cortisol (T1) −0.05 –
GA at blood draw (T1) 0.10 0.13 –
Cortisol (T2) −0.12 0.30 −0.31 –
GA at blood draw (T2) −0.05 −0.13 0.28 0.32*** –
Cortisol (T3) −0.10 0.44** −0.08 0.53*** 0.09 –
GA at blood draw (T3) 0.03 0.06 −0.09 −0.09 0.11 −0.07 –
Birth weight 0.08 0.14 0.08 −0.10 −0.05 −0.05 −0.02 –
Gestational age 0.10 −0.22 0.15 −0.08 −0.07 −0.05 0.001 0.37*** –
Maternal age at childbirth 0.05 −0.13 −0.01 −0.02 −0.11 −0.25** 0.05 −0.09 −0.02 –
Race (African American) 0.06 0.11 −0.26* −0.22* −0.01 −0.02 0.01 −0.21** −0.14 −0.13 –
Maternal education −0.17* −0.12 0.10 0.22* 0.09 −0.01 0.15 0.06 0.01 0.20* −0.22** –
Male sex −0.03 0.07 0.27* −0.09 −0.12 −0.18* 0.07 0.10 −0.07 0.09 0.04 −0.08
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a

Abbreviations: GA: gestational age; T1: Trimester1; T2: Trimester 2; T3; Trimester3.

*

p < 0.05.

**

p < 0.01.

***

p < 0.001.

Logistic regression analyses indicated that cortisol did not significantly increase the odds of SSD in any trimester, and there were no significant sex by cortisol interactions (see Table 3). As Table 4 indicates, linear regression analyses indicated that SSD status significantly interacted with trimester 3 cortisol levels to predict birthweight while controlling for gestational age, such that higher third trimester cortisol levels were associated with lower birthweight in cases, but not in controls (p = 0.011). When stratifying by SSD status, for each unit increase in cortisol, there was a 12.83 g decrease in birthweight (p = 0.029) among those who later developed SSD, but not control infants, controlling for gestational age (see Table 5). Similarly, when stratifying by sex, the interaction between SSD status and trimester 3 cortisol was significantly associated with decreased fetal growth among males, but not females. In males, for each unit increase in cortisol, there was a 29.00 g decrease in birthweight (p = 0.001) among those who later developed SSD, but not control infants.

Table 3.

Logistic regression results for cortisol (μg/dL) by trimester predicting case status, with and without cortisol by sex interaction.

Cortisol by trimester Without interaction
 Cortisol by sex interaction
OR 95% CI p-Value p-value
Trimester 1a 0.977 0.874–1.091 0.679 Underpowered
Trimester 2b 0.971 0.927–1.018 0.223 0.792
Trimester 3a 0.980 0.953–1.008 0.158 0.153
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Table 3 includes logistic regression results for models that included a cortisol by sex interaction term, as well as models that did not include this interaction term to predict case status.

a

Controlling for infant sex.

b

Controlling for infant sex and maternal education.

Table 4.

Linear regression results with cortisol, case status, and a cortisol by case status interaction predicting birth weight (in grams), with and without controlling for gestational age.

Cortisol
 Case status
 Cortisol x Case Status
Unstandardized coefficient p > ∣t∣ Unstandardized coefficient p > ∣t∣ Unstandardized coefficient p > ∣t∣
Without controlling for gestational age
Trimester 1 3.71 0.818 −339.77 0.402 23.27 0.374
Trimester 2 −0.76 0.907 437.76 0.147 −16.31 0.194
Trimester 3 3.92 0.316 745.03 0.007** −18.10 0.0099**
Controlling for gestational age
Trimester 1 10.50 0.503 −378.79 0.328 10.50 0.503
Trimester 2 −0.04 0.995 298.50 0.269 −0.04 0.995
Trimester 3 4.47 0.228 691.50 0.0097** −17.28 0.011 *
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*

p < 0.05.

**

p < 0.01.

Table 5.

Linear regression results for trimester 3 cortisol predicting birth weight (in grams).

Without controlling for gestational age
Overall sample
Case status Unstandardized coefficient 95% CI t (SE) p > ∣t∣
Cases −14.18 (−25.76, −2.60) −2.45 (5.78) 0.017*
Controls 3.92 (−3.78, 11.62) 1.01 (3.89) 0.315
Stratified by sex
Case status Sex Unstandardized coefficient 95% CI t (SE) p > ∣t∣
Cases Males −32.18 (−46.45, −17.91) −4.57 (7.04) <0.0001***
Females 14.14 (−4.07, 32.35) 1.62 (8.70) 0.121
Controls Males 1.99 (−7.91, 11.89) 0.40 (4.96) 0.689
Females 8.63 (−4.01, 21.25) 1.39 (6.20) 0.174
Controlling for gestational age
Overall sample
Case status Unstandardized coefficient 95% CI t (SE) p > ∣t∣
Cases −12.83 (−24.30, −1.37) −2.24 (5.72) 0.029*
Controls 4.49 (−2.78, 11.76) 1.22 (3.67) 0.224
Stratified by sex
Case status Sex Unstandardized coefficient 95% CI t (SE) p > ∣t∣
Cases Males −29.00 (−45.34, −12.66) −3.61 (8.04) 0.001**
Females 13.84 (−9.35, 37.03) 1.25 (11.04) 0.226
Controls Males 2.37 (−7.07, 11.80) 0.50 (4.73) 0.618
Females 10.50 (−1.05, 22.06) 1.85 (5.66) 0.073
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The table above includes linear regression analyses (with and without controlling for gestational age) stratifying by case status, as well as stratifying by cases status and sex. Only 3rd trimester results are included, given that the significant interactions were only found in trimester 3 analyses.

*

p < 0.05

**

p < 0.01

***

p < 0.001.

4. Discussion

This is the first study to determine that higher third trimester maternal cortisol is associated with decreased fetal growth among infants who later develop schizophrenia, but not control infants. Specifically, our findings suggest that liability associated with schizophrenia appears to render the fetus vulnerable to the influences of maternal cortisol with observable decrements in fetal growth. Contrary to our hypotheses, maternal cortisol during pregnancy was not associated with increased risk of offspring schizophrenia, but rather was associated with a phenotype, decreased fetal growth, that has been linked to schizophrenia and prenatal cortisol in previous studies. Our results highlight the importance of examining phenotypes that may be more proximal to risk factors for disorders, such as fetal growth, and may have more biological relevance than DSM criteria (Ellman et al., 2018).

Our findings also suggest that fetal sex and timing of exposure to maternal cortisol during pregnancy matter in terms of fetal growth. Specifically, maternal cortisol during the third trimester of pregnancy was associated with decreased fetal growth for male infants who later developed schizophrenia, but not for control infants or females. These findings are consistent with our previous results suggesting that maternal influenza during pregnancy and fetal hypoxia are associated with decreased fetal growth only for cases who develop schizophrenia and not control infants, indicating that vulnerability associated with schizophrenia renders the fetus more susceptible to these obstetric complications and leads to observable decreases in fetal growth (Fineberg et al., 2013). These findings are also consistent with a variety of studies that have found sex differences in fetal responses to maternal cortisol, with males more likely to exhibit decreases in fetal growth and maturation when exposed to higher maternal cortisol (Ellman et al., 2008; Sandman et al., 2013). Although we hypothesized that the 2nd trimester would be particularly important based on previous studies linking second trimester cortisol (including early and later second trimester) to reduced fetal growth and maturation (Ellman et al., 2008; Sandman et al., 2013), the present study was limited by including serum samples throughout the extent of the second and third trimesters; therefore, it remains possible that our significant findings were driven by early third trimester cortisol, a possibility that we were underpowered to examine. While cortisol is critical for fetal maturation during later parts of gestation (Murphy et al., 2006; Trainer, 2002; Welberg and Seckl, 2001), it has been repeatedly demonstrated that women receiving synthetic corticosteroids (with administration typically in late second and third trimesters) were more likely to deliver infants with fetal growth restriction and low birth weight, even when controlling for length of gestation, suggesting that high levels of glucocorticoids may be detrimental to fetal growth even in the third trimester (Bloom et al., 2001; Davis et al., 2011; French et al., 1999; Reinisch et al., 1978). Finally, decreased fetal growth has been associated with schizophrenia (Cannon et al., 2002), supporting the plausibility of our findings, and suggesting that higher maternal cortisol during pregnancy may be an additional factor contributing to this association.

As predicted, our findings were restricted to male offspring. Our findings are consistent with a variety of studies that have found increased vulnerability of male fetuses following maternal experiences of traumatic life events (e.g., 9/11) and stress during pregnancy, with a number of studies suggesting that male fetuses are less likely to survive, more likely to suffer from motor and cognitive difficulties, and more likely to have poor birth outcomes (e.g., preterm delivery/fetal growth restriction; Bruckner and Nobles, 2013; Sandman et al., 2013). Our findings also are consistent with studies that have linked higher levels of cortisol during pregnancy to adverse birth outcomes and premorbid difficulties commonly found among schizophrenia samples (Ellman et al., 2008). Nevertheless, our findings are inconsistent with our previous results linking maternal stress during pregnancy to male offspring with schizophrenia (Fineberg et al., 2016). We were unable to compare the current results to our previous findings, given that collection of maternal prenatal interviews that reported stress occurred before most of our blood draws (mean gestational age at time of interview = 15.85). However, some studies suggest that maternal reports of stress decrease as gestation progresses, even as cortisol levels become increasingly elevated (maternal cortisol increases throughout gestation partially as a function of a feedback loop between the mother’s adrenal cortex and the placenta that releases corticotropin-releasing hormone [CRH]); therefore, elevations in cortisol may not fully reflect stress processes in pregnant samples (Glynn et al., 2004; Glynn et al., 2001; Trainer, 2002). In addition, although the variability in levels of cortisol in our study were consistent with previous studies (Ellman et al., 2008; Stroud et al., 2007), we combined samples throughout an entire trimester, potentially obscuring relevant findings. It is possible that higher maternal cortisol during specific periods within trimesters portends increased risk for schizophrenia, particularly among male offspring; however, to address this question would require a very large sample with multiple blood draws throughout pregnancy.

The mechanisms by which elevated maternal cortisol during the third trimester impact fetal growth are unclear; however, the third trimester is a period of rapid fetal growth (in length, weight, and most organ systems), so our findings fit with what is occurring developmentally (Pardi and Cetin, 2006; Prayer and Brugger, 2007). The preponderance of studies in community samples suggest that elevated cortisol in the 2nd trimester primes the placenta to release more CRH in the third trimester (particularly for males; Sandman et al., 2006), which is further associated with earlier parturition and reduced fetal growth, implicating placental functioning as one potential mediator of this association (Ellman et al., 2008; Sandman et al., 2013). In addition, there is evidence that human fetal testosterone (which is higher in male fetuses) increases fetal cortisol; therefore, maternal cortisol could alter fetal exposure to glucocorticoids in multiple ways (Gitau et al., 2005). Although there is an enzyme in the placenta that converts cortisol to its inactive form cortisone, (11 β hydroxysteroid dehydrogenase 2, 11β-HSD2), expression of this enzyme decreases over the course of gestation (with the highest levels of cortisol getting to the fetus in the third trimester) and there is evidence of less activity in this enzyme in male placentas (Stark et al., 2009). Our findings also are consistent with recent reports that schizophrenia genes (using polygenic risk scores, PRS) are highly expressed in male placental tissue (primarily for genes involving cellular stress responses), and these genes are more expressed in placentas of fetuses with intrauterine growth restriction, indicating that genetic vulnerability associated with schizophrenia may render male fetuses particularly sensitive to a range of obstetric events, thus increasing the likelihood of decreased fetal growth (Ursini et al., 2018).

Our findings also may have been influenced by health-risk behaviors (e.g., substance use) during pregnancy that have been associated with stress and decreased fetal growth (Auerbach et al., 2014; Lobel et al., 2008; Pereira et al., 2017) In addition, although no other study (to our knowledge) using the current cohort has examined fetal growth among SSD cases and controls, a variety of other OCs (e.g., infections, inflammation, etc.) have been linked to SSD in this cohort (Brown et al., 2004b; Brown et al., 2004a). While many of the OCs that have been examined in this cohort have not been associated with decreased fetal growth, studies have linked prenatal cortisol and stress to higher incidences of infection and higher levels of inflammation (Coussons-Read et al., 2007; Coussons-Read et al., 2005). In addition, other parental factors that have been linked to decreased fetal growth and SSD (e.g., psychiatric disorders and paternal age) would be important to examine in future studies (Wallwiener et al., 2019). Therefore, future studies with larger samples should consider the possible additive and/or interactive effects of other pre- and postnatal influences in contributing to decreased fetal growth among cases and SSD risk.

There were several limitations of the present study that should be noted. Specifically, no information pertaining to time of day of blood collection was available; therefore, it is possible the diurnal variations in cortisol may have influenced our findings (Allolio et al., 1990). Nevertheless, any differences in blood collection times were minimized by the majority of samples being collected in the morning and that diurnal variations in cortisol are blunted during pregnancy (de Weerth and Buitelaar, 2005). In addition, it is unlikely that diurnal variations in cortisol would preferentially affect cases or controls. It also is possible that degradation of cortisol over time influenced findings; however, cortisol has a fairly long half-life, and we and others in a similar birth cohort have found cortisol levels consistent with fresh samples (Stroud et al., 2007). It also is unlikely that degradation of sera would influence one comparison group more than another. The small sample sizes in the first trimester also may have obscured findings that could be addressed in future studies; however, most human and animal studies linking prenatal cortisol to decreased fetal growth have focused on mid-to-late gestation which bolster our findings (Braithwaite et al., 2017; Fameli et al., 1994; Graham et al., 2018; Osterholm et al., 2012).

This study also had a number of strengths, including being the first study to examine the timing of exposure to maternal cortisol during pregnancy and risk for offspring schizophrenia and decreased fetal growth in a longitudinal, prospective, representative birth cohort. In addition, this study was unique in its continuous follow-up of offspring and well-validated diagnoses of SSD in a cohort with prospectively collected prenatal information.

The current study has the potential to further our understanding of prenatal contributors to schizophrenia, particularly those involving stress, trauma, and cortisol levels during pregnancy. As we have written previously (Ellman and Susser, 2009; Ellman et al., 2018), findings indicate that examining phenotypes that are more proximal to prenatal events, such as decreased fetal growth, have the potential to shed light on how obstetric events influence the course of schizophrenia. The present study also adds to our previous findings by suggesting that higher prenatal cortisol is one of multiple obstetric complications that results in decreased fetal growth in male infants who later develop schizophrenia, but not in male controls or females. However, it is important to note that there were no case/control differences in maternal cortisol levels; therefore, our findings suggest that variations in normal levels of cortisol may be influencing fetal growth only for male cases who develop schizophrenia. These findings are consistent with our previous findings and recent reports that suggest that liability for schizophrenia may render fetuses particularly sensitive to a range of obstetric events (Fineberg et al., 2013; Ursini et al., 2018). Nevertheless, our findings highlight that high maternal cortisol during pregnancy and genetic risk for schizophrenia may only increase risk for a phenotype associated with the disorder. Accordingly, we should view these risk factors within the context of an evolving developmental framework, in which exposure to high maternal cortisol levels in utero may increase vulnerability to schizophrenia, but only in conjunction with other developmental risk factors, such as genetic vulnerability for psychosis and exposure to other environmental risk factors (Ellman et al., 2018; Fineberg and Ellman, 2013). Our findings may facilitate the development of more precise prediction models that include a range of developmental risk factors, which is a first step towards identifying who is at the greatest risk for both psychosis and reduced fetal growth, a necessary step before developing early intervention and prevention strategies.

Supplementary Material

Supplemental Table 1. Demographics of the sample, by offspring sex.

Acknowledgements

We thank all of the women in the Child Health and Development Studies who participated in the study during their pregnancies and all of their children who participated in follow-up assessments. We also thank Justin Penner, David Kern, Aundrea Cook Emery, and Nashid Chaudhury who helped create the original cortisol database, as well as select serum samples for cortisol analyses.

Role of the funding source

This study was supported by funding to LME (NIMH R01 MH096478, NIMH R01 MH118545, Temple University start-up award, schizophrenia research fellowship, T32 MH018870-20), CAS (NIMH R01 MH069819), ESS (NIMH R01MH-53147), ASB (NIMH R01MH-63264)) and grants N01HD13334 and N01HD63258 from The Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Footnotes

Supplementary data to this article can be found online at https://doi.org/10.1016/j.schres.2019.07.002.

Declaration of Competing Interest

All authors declare that they have no conflicts of interest to report.

References

  1. Abel KM, Wicks S, Susser ES, Dalman C, Pedersen MG, Mortensen PB, Webb RT, 2010. Birth weight, schizophrenia, and adult mental disorder: is risk confined to the smallest babies? Arch. Gen. Psychiatr 67 (9), 923–930. [DOI] [PubMed] [Google Scholar]
  2. Abel KM, Heuvelman HP, Jorgensen L, Magnusson C, Wicks S, Susser E, Hallkvist J, Dalman C, 2014. Severe bereavement stress during the prenatal and childhood periods and risk of psychosis in later life: population based cohort study. BMJ 348, f7679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Allolio B, Hoffmann J, Linton EA, Winkelmann W, Kusche M, Schulte HM, 1990. Diurnal salivary cortisol patterns during pregnancy and after delivery: relationship to plasma corticotrophin-releasing-hormone. Clin. Endocrinol 33 (2), 279–289. [DOI] [PubMed] [Google Scholar]
  4. Auerbach MV, Lobel M, Cannella DT, 2014. Psychosocial correlates of health-promoting and health-impairing behaviors in pregnancy. J. Psychosom. Obstet. Gynaecol 35, 76–83. [DOI] [PubMed] [Google Scholar]
  5. Bloom SL, Sheffield JS, Mcintire DD, Leveno KJ, 2001. Antenatal dexamethasone and decreased birth weight. Obstet. Gynecol 97 (4), 485–490. [DOI] [PubMed] [Google Scholar]
  6. Braithwaite EC, Pickles A, Sharp H, Glover V, O'Donnell KJ, Tibu F, Hill J, 2017. Maternal prenatal cortisol predicts infant negative emotionality in a sex-dependent manner. Physiol. Behav 175, 31–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ, Bresnahan M, Susser ES, 2004. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch. Gen. Psychiatry 61 (8), 774–780. [DOI] [PubMed] [Google Scholar]
  8. Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, Susser ES, 2004. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am. Journal. Psychiatry 161 (5), 889–895. [DOI] [PubMed] [Google Scholar]
  9. Bruckner TA, Nobles J, 2013. Intrauterine stress and male cohort quality: the case of September 11, 2001. Soc. Sci. Med 76, 107–114. [DOI] [PubMed] [Google Scholar]
  10. Cannon M, Jones PB, Murray RM, 2002. Obstetric complications and schizophrenia: historical and meta-analytic review. Am. J. Psychiatr 159, 1080–1092. [DOI] [PubMed] [Google Scholar]
  11. Castle DJ, Murray RM, 1991. The neurodevelopmental basis of sex differences in schizophrenia. Psychol. Med 21, 565–575. [DOI] [PubMed] [Google Scholar]
  12. Chan JC, Nugent BM, Bale TL, 2018. Parental advisory: maternal and paternal stress can impact offspring neurodevelopment. Biol. Psychiatry 83 (10), 886–894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Class QA, Abel KM, Khashan AS, Rickert ME, Dalman C, Larsson H, Hultman CM, Långström N, Lichtenstein P, D'Onofrio BM, 2014. Offspring psychopathology following preconception, prenatal and postnatal maternal bereavement stress. Psychol. Med 44, 71–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Corcoran C, Walker E, Huot R, Mittal V, Tessner K, Kestler L, Malaspina D, 2003. The stress cascade and schizophrenia: etiology and onset. Schizophr. Bull 29 (4), 671–692. [DOI] [PubMed] [Google Scholar]
  15. Cottrell EC, Seckl J, 2009. Prenatal stress, glucocorticoids and the programming of adult disease. Frontiers Behav. Neurosci 3, 19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Coussons-Read ME, Okun ML, Schmitt MP, Giese S, 2005. Prenatal stress alters cytokine levels in a manner that may endanger human pregnancy. Psychosom. Med 67 (4), 625–631. [DOI] [PubMed] [Google Scholar]
  17. Coussons-Read ME, Okun ML, Nettles CD, 2007. Psychosocial stress increases inflammatory markers and alters cytokine production across pregnancy. Brain Behav. Immun 21 (3), 343–350. [DOI] [PubMed] [Google Scholar]
  18. Davis EP, Waffarn F, Sandman CA, 2011. Prenatal treatment with glucocorticoids sensitizes the HPA axis response to stress among full-term infants. Dev. Psychobiol 53 (2), 175–183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. de Weerth C, Buitelaar JK, 2005. Cortisol awakening response in pregnant women. Psychoneuroendocr 30 (9), 902–907. [DOI] [PubMed] [Google Scholar]
  20. Eide MG, Moster D, Irgens LM, Reichborn-Kjennerud T, Stoltenberg C, Skjaerven R, Susser E, Abel K, 2013. Degree of fetal growth restriction associated with schizophrenia risk in a national cohort. Psychol. Med 43 (10), 2057–2066. [DOI] [PubMed] [Google Scholar]
  21. Ellman LM, Susser ES, 2009. The promise of epidemiologic studies: neuro-immune mechanisms in the etiologies of brain disorders. Neuron 64(1), 25–27. [DOI] [PubMed] [Google Scholar]
  22. Ellman LM, Schetter CD, Hobel CJ, Chicz-DeMet A, Glynn LM, Sandman CA, 2008. Timing of fetal exposure to stress hormones: effects on newborn physical and neuromuscular maturation. Dev. Psychobiol 50 (3), 232–241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ellman LM, Murphy SK, Maxwell SD, 2018. Pre- and perinatal risk factors for serious mental illness: ethical considerations in prevention and prediction efforts. J. Ethics Ment. Health. Open 10 (IV), 1–14. June 15, Special Theme. [PMC free article] [PubMed] [Google Scholar]
  24. Fameli M, Kitraki E, Stylianopoulou F, 1994. Effects of hyperactivity of the maternal hypothalamic-pituitary-adrenal (HPA) axis during pregnancy on the development of the HPA axis and brain monoamines of the offspring. Int. J. Dev. Neurosci 12 (7), 651–659. [DOI] [PubMed] [Google Scholar]
  25. Fineberg AM, Ellman LM, 2013. Inflammatory cytokines and neurological and neurocognitive alterations in the course of schizophrenia. Biol. Psychiatry 73 (10), 951–966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Fineberg AM, Ellman LM, Buka S, Yolken R, Cannon TD, 2013. Decreased birth weight in psychosis: influence of prenatal exposure to serologically determined influenza and hypoxia. Schizophr. Bull 39 (5), 1037–1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Fineberg AM, Ellman LM, Schaefer CA, Maxwell SD, Shen L, Chaudhury NH, Cook AL, Bresnahan MA, Susser ES, Brown AS, 2016. Fetal exposure to maternal stress and risk for schizophrenia spectrum disorders among offspring: differential influences of fetal sex. Psychiatry Res. 236, 91–97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Foerster A, Lewis SW, Owen MJ, Murray RM, 1991. Low birth weight and a family history of schizophrenia predict poor premorbid functioning in psychosis. Schizophr. Res 5 (1), 13–20. [DOI] [PubMed] [Google Scholar]
  29. French NP, Hagan R, Evans SF, Godfrey M, Newnham JP, 1999. Repeated antenatal corticosteroids: size at birth and subsequent development. Am. J. Obstet. Gynecol 180 (1), 114–121. [DOI] [PubMed] [Google Scholar]
  30. Gitau R, Adams D, Fisk NM, Glover V, 2005. Fetal plasma testosterone correlates positively with cortisol. Arch. Dis. Child-Fetal 90 (2), F166–F169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Glover V, O'Connor TG, O'Donnell K, 2010. Prenatal stress and the programming of the HPA axis. Neurosci. Biobehav. Rev 35 (1), 17–22. [DOI] [PubMed] [Google Scholar]
  32. Glynn LM, Wadhwa PD, Dunkel-Schetter C, Chicz-DeMet A, Sandman CA, 2001. When stress happens matters: effects of earthquake timing on stress responsivity in pregnancy. Am. J. Obstet. Gynecol 184 (4), 637–642. [DOI] [PubMed] [Google Scholar]
  33. Glynn LM, Schetter CD, Wadhwa PD, Sandman CA, 2004. Pregnancy affects appraisal of negative life events. J. Psychosom. Res 56 (1), 47–52. [DOI] [PubMed] [Google Scholar]
  34. Goldstein JM, Walder DJ, 2006. Sex differences in schizophrenia: the case for developmental origins and etiological implications In: Sharma T, Harvey PD (Eds.), The Early Course of Schizophrenia. Oxford University Press, New York, pp. 147–173. [Google Scholar]
  35. Graham AM, Rasmussen JM, Entringer S, Ward EB, Rudolph MD, Gilmore JH, Styner M, Wadhwa PD, Fair DA, Buss C, 2018. Maternal cortisol concentrations during pregnancy and sex-specific associations with neonatal amygdala connectivity and emerging internalizing behaviors. Biol. Psychiatry 85 (2), 172–181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Herman DB, Brown AS, Opler MG, Desai M, Malaspina D, Bresnahan M, Susser ES, 2006. Does unwantedness of pregnancy predict schizophrenia in the offspring? Soc. Psychiatr. Psychiatr. Epidemiol 41 (8), 605–610. [DOI] [PubMed] [Google Scholar]
  37. Huttunen MO, Niskanen P, 1978. Prenatal loss of father and psychiatric disorders. Arch. Gen. Psychiatr 35, 429–431. [DOI] [PubMed] [Google Scholar]
  38. Ichiki M, Kunugi H, Takei N, Murray RM, Baba H, Arai H, …, Nanko S, 2000. Intra-uterine physical growth in schizophrenia: evidence confirming excess of premature birth. Psychol. Med 30 (3), 597–604. [DOI] [PubMed] [Google Scholar]
  39. Kapoor A, Petropoulos S, Matthews SG, 2008. Fetal programming of hypothalamic-pituitary-adrenal (HPA) axis function and behavior by synthetic glucocorticoids. Brain Res. Rev 57 (2), 586–595. [DOI] [PubMed] [Google Scholar]
  40. 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. Arch. Gen. Psychiatr 65, 146–152. [DOI] [PubMed] [Google Scholar]
  41. Lane EA, Albee GW, 1966. Comparative birth weights of schizophrenics and their siblings. J. Psychol 64 (2), 227–231. [Google Scholar]
  42. Lemaire V, Koehl M, Le Moal M, Abrous DN, 2000. Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc. Natl. Acad. Sci 97 (20), 11032–11037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Lobel M, Cannella DL, Graham JE, DeVincent C, Schneider J, Meyer BA, 2008. Pregnancy-specific stress, prenatal health behaviors, and birth outcomes. Health Psychol. 27, 604–615. [DOI] [PubMed] [Google Scholar]
  44. Malaspina D, Corcoran C, Kleinhaus KR, Perrin MC, Fennig S, Nahon D, Friedlander Y, Harlap S, 2008. Acute maternal stress in pregnancy and schizophrenia in offspring: a cohort prospective study. BMC Psychiatry 8, 71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Matsumoto H, Takei N, Saito F, Kachi K, Mori N, 2001. The association between obstetric complications and childhood-onset schizophrenia: a replication study. Psychol. Med 31 (5), 907–914. [DOI] [PubMed] [Google Scholar]
  46. McArthur S, McHale E, Dalley JW, Buckingham JC, Gillies GE, 2005. Altered mesencephalic dopaminergic populations in adulthood as a consequence of brief perinatal glucocorticoid exposure. J. Neuroendocrinol 17 (8), 475–482. [DOI] [PubMed] [Google Scholar]
  47. McNeil TF, Schubert EW, Cantor-Graae E, Brossner M, Schubert P, Henriksson KM, 2009. Unwanted pregnancy as a risk factor for offspring schizophrenia-spectrum and affective disorders in adulthood: a prospective high-risk study. Psychol. Med 39 (6), 957–965. [DOI] [PubMed] [Google Scholar]
  48. Moisiadis VG, Matthews SG, 2014. Glucocorticoids and fetal programming part 1: outcomes. Nat. Rev. Endocrinol 10 (7), 391. [DOI] [PubMed] [Google Scholar]
  49. Mueller BR, Bale TL, 2008. Sex-specific programming of offspring emotionality after stress early in pregnancy. Journal Neurosci 28, 9055–9065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Murphy VE, Smith R, Giles WB, Clifton VL, 2006. Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus. Endocr. Rev 27 (2), 141–169. [DOI] [PubMed] [Google Scholar]
  51. Myhrman A, Rantakallio P, Isohanni M, Jones P, Partanen U, 1996. Unwantedness of a pregnancy and schizophrenia in the child. Brit. J. Psychiatr 169 (5), 637–640. [DOI] [PubMed] [Google Scholar]
  52. Nurnberger JI, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, …, Reich T, 1994. Diagnostic interview for genetic studies: rationale, unique features, and training. Arch. Gen. Psychiat 51 (11), 849–859. [DOI] [PubMed] [Google Scholar]
  53. Osterholm EA, Hostinar CE, Gunnar MR, 2012. Alterations in stress responses of the hypothalamic-pituitary-adrenal axis in small for gestational age infants. Psychoneuroendocr 37 (10), 1719–1725. [DOI] [PubMed] [Google Scholar]
  54. Pardi G, Cetin I, 2006. Human fetal growth and organ development: 50 years of discoveries. Am. J. Obstet. Gynecol 194 (4), 1088–1099. [DOI] [PubMed] [Google Scholar]
  55. Pereira PP da S, Da Mata FAF, Figueiredo ACG, de Andrade KRC, Pereira MG, 2017. Maternal active smoking during pregnancy and low birth weight in the Americas: a systematic review and meta-analysis. Nicotine Tob. Res. 19, 497–505. [DOI] [PubMed] [Google Scholar]
  56. Prayer D, Brugger PC, 2007. Investigation of normal organ development with fetal MRI. Eur. Radiol 17 (10), 2458–2471. [DOI] [PubMed] [Google Scholar]
  57. Rakers F, Rupprecht S, Dreiling M, Bergmeier C, Witte OW, Schwab M, 2017. Transfer of maternal psychosocial stress to the fetus. Neurosci. Biobehav. Rev 10.1016/j.neubiorev.2017.02.019 [Epub ahead of print]. [DOI] [PubMed] [Google Scholar]
  58. Reinisch JM, Simon NG, Karow WG, Gandelman R, 1978. Prenatal exposure to prednisone in humans and animals retards intrauterine growth. Sci 202 (4366), 436–438. [DOI] [PubMed] [Google Scholar]
  59. Sandman CA, Glynn L, Schetter CD, Wadhwa P, Garite T, Chicz-DeMet A, Hobel C, 2006. Elevated maternal cortisol early in pregnancy predicts third trimester levels of placental corticotropin releasing hormone (CRH): priming the placental clock. peptides 27 (6), 1457–1463. [DOI] [PubMed] [Google Scholar]
  60. Sandman CA, Glynn LM, Davis EP, 2013. Is there a viability-vulnerability tradeoff? Sex differences in fetal programming. J. Psychosom. Res 75, 327–335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Sandman CA, Curran MM, Davis EP, Glynn LM, Head K, Baram TZ, 2018. Cortical thinning and neuropsychiatric outcomes in children exposed to prenatal adversity: a role for placental CRH? Am. J. Psychiatr 175 (5), 471–479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Selten JP, van der Graaf Y, van Duursen R, Gispen-de Wied CC, Kahn RS, 1999. Psychotic illness after prenatal exposure to the 1953 Dutch Flood Disaster. Schizophr. Res 35, 243–245. [DOI] [PubMed] [Google Scholar]
  63. St Clair D, Xu M, Wang P, Yu Y, Fang Y, Zhang F, Zheng X, Gu N, Feng G, Sham P, He L, 2005. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961. JAMA 294 (5), 557–562. [DOI] [PubMed] [Google Scholar]
  64. Stark MJ, Wright IM, Clifton VL, 2009. Sex-specific alterations in placental 11β-hydroxysteroid dehydrogenase 2 activity and early postnatal clinical course following antenatal betamethasone. Am. J. Physiol. Regul. Integr. Comp. Physiol 297 (2), R510–R514. [DOI] [PubMed] [Google Scholar]
  65. Stroud LR, Solomon C, Shenassa E, Papandonatos G, Niaura R, Lipsitt LP, Lewinn K, Buka SL, 2007. Long-term stability of maternal prenatal steroid hormones from the National Collaborative Perinatal Project: still valid after all these years. Psychoneuroendocr 32 (2), 140–150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Susser ES, Lin SP, 1992. Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944-1945. Arch. Gen. Psychiatr 49 (12), 983–988. [DOI] [PubMed] [Google Scholar]
  67. Susser E, St Clair D, 2013. Prenatal famine and adult mental illness: interpreting concordant and discordant results from the Dutch and Chinese Famines. Soc. Sci. Med 97, 325. [DOI] [PubMed] [Google Scholar]
  68. Susser ES, Schaefer CA, Brown AS, Begg MD, Wyatt RJ, 2000. The design of the prenatal determinants of schizophrenia study. Schizophr. Bull 26 (2), 257–273. [DOI] [PubMed] [Google Scholar]
  69. Trainer PJ, 2002. Corticosteroids and pregnancy. Semin. Reproductive Med 20 (04), 375–380. [DOI] [PubMed] [Google Scholar]
  70. Ursini G, Punzi G, Chen Q, Marenco S, Robinson JF, Porcelli A, Seidel J, 2018. Convergence of placenta biology and genetic risk for schizophrenia. Nat. Med 24 (6), 792. [DOI] [PubMed] [Google Scholar]
  71. Van Os J, Selten JP, 1998. Prenatal exposure to maternal stress and subsequent schizophrenia. The May 1940 invasion of The Netherlands. Brit. J. Psychiatr 172, 324–326. [DOI] [PubMed] [Google Scholar]
  72. Walder DJ, Andersson TL, McMillan AL, Breedlove SM, Walker EF, 2006. Sex differences in digit ratio (2D:4D) are disrupted in adolescents with schizotypal personality disorder: altered prenatal gonadal hormone levels as a risk factor. Schizophr. Res 86 (1–3), 118–122. [DOI] [PubMed] [Google Scholar]
  73. Walker EF, Walder DJ, Lewine R, Loewy R, 2002. Sex differences in the origins and premorbid development of schizophrenia In: Lewis-Hall F, Williams TS, Panetta JA, Herrera JM (Eds.), Psychiatric Illness in Women: Emerging Treatments and Research. American Psychiatric Publishing, Inc., Arlington, VA, pp. 193–214. [Google Scholar]
  74. Walker E, Mittal V, Tessner K, 2008. Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia. Annu. Rev. Clin. Psychol 4, 189–216. [DOI] [PubMed] [Google Scholar]
  75. Wallwiener S, Goetz M, Lanfer A, Gillessen A, Suling M, Feisst M, Wallwiener M, 2019. Epidemiology of mental disorders during pregnancy and link to birth outcome: a large-scale retrospective observational database study including 38,000 pregnancies. Arch. Gynecol. Obstet 299 (3), 755–763. [DOI] [PubMed] [Google Scholar]
  76. Watson JB, Mednick SA, Huttunen M, Wang X, 1999. Prenatal teratogens and the development of adult mental illness. Dev. Psychopathol 11, 457–466. [DOI] [PubMed] [Google Scholar]
  77. Welberg LA, Seckl JR, 2001. Prenatal stress, glucocorticoids and the programming of the brain. J. Endocrinol 13 (2), 113–128. [DOI] [PubMed] [Google Scholar]

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Supplementary Materials

Supplemental Table 1. Demographics of the sample, by offspring sex.
NIHMS1558224-supplement-Supplemental_Table_1__Demographics_of_the_sample__by_offspring_sex_.docx (15.1KB, docx)

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