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1.  Prenatal Stress and Risk of Febrile Seizures in Children: A Nationwide Longitudinal Study in Denmark 
We aimed to examine whether exposure to prenatal stress following maternal bereavement is associated with an increased risk of febrile seizures. In a longitudinal population-based cohort study, we followed 1,431,175 children born in Denmark. A total of 34,777 children were born to women who lost a close relative during pregnancy or within 1 year before the pregnancy and they were included in the exposed group. The exposed children had a risk of febrile seizures similar to that of the unexposed children (hazard ratio (HR) 1.00, 95% CI 0.94–1.06). The HRs did not differ according to the nature or timing of bereavement. Our data do not suggest any causal link between exposure to prenatal stress and febrile seizures in childhood.
doi:10.1007/s10803-009-0717-4
PMCID: PMC2694316  PMID: 19291382
Prenatal stress; Bereavement; Febrile seizures; Fetal programming; Longitudinal study
2.  Antenatal maternal bereavement and childhood cancer in the offspring: a population-based cohort study in 6 million children 
British Journal of Cancer  2012;107(3):544-548.
Background:
Prenatal stress may increase the susceptibility to childhood cancer by affecting immune responses and hormonal balance. We examined whether antenatal stress following maternal bereavement increased the risk of childhood cancer.
Methods:
All children born in Denmark from 1968 to 2007 (N=2 743 560) and in Sweden from 1973 to 2006 (N=3 400 212) were included in this study. We compared cancer risks in children born to women who lost a first-degree relative (a child, spouse, a parent, or a sibling) the year before pregnancy or during pregnancy with cancer risks in children of women who did not experience such bereavement.
Results:
A total of 9795 childhood cancer cases were observed during follow-up of 68 360 707 person years. Children born to women who lost a child or a spouse, but not those who lost other relatives, had an average 30% increased risk of any cancer (hazard ratio (HR) 1.30, 95% confidence interval (CI) 0.96–1.77). The HRs were the highest for non-Hodgkin disease (512 cases in total, HR 3.40, 95% CI 1.51–7.65), hepatic cancer (125 cases in total, HR 5.51, 95% CI 1.34–22.64), and testicular cancer (86 cases in total, HR 8.52, 95% CI 2.03–37.73).
Conclusion:
Our data suggest that severe antenatal stress following maternal bereavement, especially due to loss of a child or a spouse, is associated with an increased risk of certain childhood cancers in the offspring, such as hepatic cancer and non-Hodgkin disease, but not with childhood cancer in general.
doi:10.1038/bjc.2012.288
PMCID: PMC3405225  PMID: 22759879
childhood cancer; bereavement; prenatal stress; mother; association
3.  Prenatal Exposure to Bereavement and Type-2 Diabetes: A Danish Longitudinal Population Based Study 
PLoS ONE  2012;7(8):e43508.
Background
The etiology of type-2 diabetes is only partly known, and a possible role of prenatal stress in programming offspring for insulin resistance has been suggested by animal models. Previously, we found an association between prenatal stress and type-1 diabetes. Here we examine the association between prenatal exposure to maternal bereavement during preconception and pregnancy and development of type-2 diabetes in the off-spring.
Methods
We utilized data from the Danish Civil Registration System to identify singleton births in Denmark born January 1st 1979 through December 31st 2008 (N = 1,878,246), and linked them to their parents, grandparents, and siblings. We categorized children as exposed to bereavement during prenatal life if their mothers lost an elder child, husband or parent during the period from one year before conception to the child’s birth. We identified 45,302 children exposed to maternal bereavement; the remaining children were included in the unexposed cohort. The outcome of interest was diagnosis of type-2 diabetes. We estimated incidence rate ratios (IRRs) from birth using log-linear poisson regression models and used person-years as the offset variable. All models were adjusted for maternal residence, income, education, marital status, sibling order, calendar year, sex, and parents’ history of diabetes at the time of pregnancy.
Results
We found children exposed to bereavement during their prenatal life were more likely to have a type-2 diabetes diagnosis later in life (aIRR: 1.31, 1.01–1.69). These findings were most pronounced when bereavement was caused by death of an elder child (aIRR: 1.51, 0.94–2.44). Results also indicated the second trimester of pregnancy to be the most sensitive period of bereavement exposure (aIRR:2.08, 1.15–3.76).
Conclusions
Our data suggests that fetal exposure to maternal bereavement during preconception and the prenatal period may increase the risk for developing type-2 diabetes in childhood and young adulthood.
doi:10.1371/journal.pone.0043508
PMCID: PMC3429491  PMID: 22952698
4.  Early Life Disease Programming during the Preconception and Prenatal Period: Making the Link between Stressful Life Events and Type-1 Diabetes 
PLoS ONE  2010;5(7):e11523.
Background
To assess the risk of developing Type-1 diabetes among children who were exposed to maternal bereavement during the prenatal or 1-year preconception period.
Methods
We identified N = 1,548,746 singleton births born in Denmark between January 1st 1979 through December 31st 2004, and their next of kin. Altogether, 39,857 children were exposed to bereavement during their prenatal life. The main outcome of interest was hospitalization for type-1 diabetes (ICD 8: 249; ICD 10: E10).
Results
We found the strongest association for type-1 diabetes among children exposed to traumatic father or sibling deaths (aIRR: 2.03, 1.22–3.38); the association was mainly seen for girls (aIRR: 2.91, 1.61–5.26).
Conclusions
We found evidence to suggest that female fetuses exposed to severe prenatal stress are at increased risk for developing type-1 diabetes.
doi:10.1371/journal.pone.0011523
PMCID: PMC2901388  PMID: 20634978
5.  Risks of Overweight and Abdominal Obesity at Age 16 Years Associated With Prenatal Exposures to Maternal Prepregnancy Overweight and Gestational Diabetes Mellitus 
Diabetes Care  2010;33(5):1115-1121.
OBJECTIVE
The associations of prenatal exposures to maternal prepregnancy overweight and gestational diabetes mellitus (GDM) with offspring overweight are controversial. Research estimating risk for offspring overweight due to these exposures, separately and concomitantly, is limited.
RESEARCH DESIGN AND METHODS
Prevalence of overweight and abdominal obesity at age 16 years and odds ratios (ORs) for prenatal exposures to maternal prepregnancy overweight and GDM were estimated in participants of the prospective longitudinal Northern Finland Birth Cohort of 1986 (N = 4,168).
RESULTS
The prevalence and estimates of risk for overweight and abdominal obesity were highest in those exposed to both maternal prepregnancy overweight and GDM (overweight prevalence 40% [OR 4.05], abdominal obesity prevalence 25.7% [3.82]). Even in offspring of mothers with a normal oral glucose tolerance test during pregnancy, maternal prepregnancy overweight is associated with increased risk for these outcomes (overweight prevalence 27.9% [2.56], abdominal obesity prevalence 19.5% [2.60]). In offspring of women with prepregnancy normal weight, the prevalence or risks of the outcomes were not increased by prenatal exposure to GDM. These estimates of risk were adjusted for parental prepregnancy smoking, paternal overweight, and offspring sex and size at birth.
CONCLUSIONS
Maternal prepregnancy overweight is an independent risk factor for offspring overweight and abdominal obesity at age 16 years. The risks are highest in offspring with concomitant prenatal exposure to maternal prepregnancy overweight and GDM, whereas the risks associated with GDM are only small.
doi:10.2337/dc09-1871
PMCID: PMC2858187  PMID: 20427685
6.  Severe bereavement stress during the prenatal and childhood periods and risk of psychosis in later life: population based cohort study 
Objective To examine the risk of psychosis associated with severe bereavement stress during the antenatal and postnatal period, between conception to adolescence, and with different causes of death.
Design Population based cohort study.
Setting Swedish national registers including births between 1973 and 1985 and followed-up to 2006.
Participants In a cohort of 1 045 336 Swedish births (1973-85), offspring born to mothers exposed to severe maternal bereavement stress six months before conception or during pregnancy, or exposed to loss of a close family member subsequently from birth to 13 years of age were followed until 2006. Admissions were identified by linkage to national patient registers.
Main outcome measures Crude and adjusted odds ratios for all psychosis, non-affective psychosis, and affective psychosis.
Results Maternal bereavement stress occurring preconception or during the prenatal period was not associated with a significant excess risk of psychosis in offspring (adjusted odds ratio, preconception 1.24, 95% confidence interval 0.96 to 1.62; first trimester 0.95, 0.58 to1.56; second trimester 0.79, 0.46 to 1.33; third trimester 1.14, 0.78 to 1.66). Risks increased modestly after exposure to the loss of a close family member from birth to adolescence for all psychoses (adjusted odds ratio 1.17, 1.04 to 1.32). The pattern of risk was generally similar for non-affective and affective psychosis. Thus estimates were higher after death in the nuclear compared with extended family but remained non-significant for prenatal exposure; the earlier the exposure to death in the nuclear family occurred in childhood (all psychoses: adjusted odds ratio, birth to 2.9 years 1.84, 1.41 to 2.41; 3-6.9 years 1.47, 1.16 to 1.85; 7-12.9 years 1.32, 1.10 to 1.58) and after suicide. Following suicide, risks were especially higher for affective psychosis (birth to 2.9 years 3.33, 2.00 to 5.56; 6.9 years 1.84, 1.04 to 3.25; 7-12.9 years 2.68, 1.84 to 3.92). Adjustment for key confounders attenuated but did not explain associations with risk.
Conclusions Postnatal but not prenatal bereavement stress in mothers is associated with an increased risk of psychosis in offspring. Risks are especially high for affective psychosis after suicide in the nuclear family, an effect that is not explained by family psychiatric history. Future studies are needed to understand possible sources of risk and resilience so that structures can be put in place to support vulnerable children and their families.
doi:10.1136/bmj.f7679
PMCID: PMC3898661  PMID: 24449616
7.  Maternal Bereavement and Childhood Asthma—Analyses in Two Large Samples of Swedish Children 
PLoS ONE  2011;6(11):e27202.
Background
Prenatal factors such as prenatal psychological stress might influence the development of childhood asthma.
Methodology and Principal Findings
We assessed the association between maternal bereavement shortly before and during pregnancy, as a proxy for prenatal stress, and the risk of childhood asthma in the offspring, based on two samples of children 1–4 (n = 426 334) and 7–12 (n = 493 813) years assembled from the Swedish Medical Birth Register. Exposure was maternal bereavement of a close relative from one year before pregnancy to child birth. Asthma event was defined by a hospital contact for asthma or at least two dispenses of inhaled corticosteroids or montelukast. In the younger sample we calculated hazards ratios (HRs) of a first-ever asthma event using Cox models and in the older sample odds ratio (ORs) of an asthma attack during 12 months using logistic regression. Compared to unexposed boys, exposed boys seemed to have a weakly higher risk of first-ever asthma event at 1–4 years (HR: 1.09; 95% confidence interval [CI]: 0.98, 1.22) as well as an asthma attack during 12 months at 7–12 years (OR: 1.10; 95% CI: 0.96, 1.24). No association was suggested for girls. Boys exposed during the second trimester had a significantly higher risk of asthma event at 1–4 years (HR: 1.55; 95% CI: 1.19, 2.02) and asthma attack at 7–12 years if the bereavement was an older child (OR: 1.58; 95% CI: 1.11, 2.25). The associations tended to be stronger if the bereavement was due to a traumatic death compared to natural death, but the difference was not statistically significant.
Conclusions/Significance
Our results showed some evidence for a positive association between prenatal stress and childhood asthma among boys but not girls.
doi:10.1371/journal.pone.0027202
PMCID: PMC3210147  PMID: 22087265
8.  Maternal Distress during Pregnancy and Offspring Childhood Overweight 
Journal of Obesity  2012;2012:462845.
Background. Maternal distress during pregnancy increases the intrauterine level of glucocorticoids, which may have long-term health consequences for the child. Objective. To examine if distress as a combined measure of anxiety, depression, and stress of the mother during pregnancy was associated with offspring childhood overweight at age 7. Methods. We performed a cohort study using prospective data from 37,764 women and child dyads from the Danish National Birth Cohort (1996–2002). At a telephone interview at approximately 30 weeks gestation, the women reported whether they felt anxious, depressed, or stressed. The 95 percentile for body mass index in an international reference defined childhood overweight at any given age. Logistic regression was used for the analyses. Results. The prevalence of overweight children at 7 years of age was 9.9%. Prenatal exposure to maternal distress during pregnancy was not associated with childhood overweight at 7 years of age (adjusted OR 1.06 (95% CI 0.96; 1.18)). In analyses stratified on sex, a small tendency of overweight was seen in boys (OR 1.15 (0.99; 1.33)), but not in girls (OR 0.98 (0.85; 1.13)). Conclusions. Maternal distress during pregnancy appeared to have limited, if any, influence on the risk of overweight in offspring at 7 years of age.
doi:10.1155/2012/462845
PMCID: PMC3364588  PMID: 22685634
9.  Timing of prenatal maternal exposure to severe life events and adverse pregnancy outcomes: A population study of 2.6 million pregnancies 
Psychosomatic medicine  2011;73(3):234-241.
Objective
To identify the impact of timing of prenatal stress exposure on offspring risk for shortened gestational age (GA), preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA) using a population-based sample.
Methods
Swedish longitudinal population registries were linked to study all individuals born in Sweden 1973–2004. Prenatal maternal stress exposure was defined as death of the father of the child or first degree relative of the mother. Using linear and logistic regression, timing of stress exposure was examined across pregnancy, by month, and by novel periods created based on month of stress exposure findings.
Results
A total of 2,618,777 live-born, singleton infants without congenital anomalies were included; 32,286 exposed to prenatal maternal stress. Examining associations between stress exposure and outcome by the month revealed that risk increases mid-gestation, particularly following months 5 and 6. Combining months 1–4, 5 and 6, and 7–9 as potential periods of differing vulnerability, it was found that stress during period 2 (months 5 and 6) was associated with the greatest risk for shortened GA (−0.52 days, SE=0.15, p=0.0006), PTB (OR=1.24, 99% CI=1.08–1.42), LBW (OR=1.38, 99% CI=1.19–1.61), and SGA (OR=1.25, 99% CI=1.05–1.49).
Conclusions
Risk for shortened GA, PTB, LBW, and SGA are greater following stress exposure during the 5th and/or 6th month of pregnancy. It may be beneficial to refine future analyses to these months. Possible mechanisms include alterations in the hypothalamic-pituitary-adrenal axis and associated stress-responsive molecular regulators.
doi:10.1097/PSY.0b013e31820a62ce
PMCID: PMC3070756  PMID: 21321257
Stress; pregnancy; timing; preterm birth; low birth weight; small for gestational age
10.  In-Utero Exposure to Bereavement and Offspring IQ: A Danish National Cohort Study 
PLoS ONE  2014;9(2):e88477.
Background
Intelligence is a life-long trait that has strong influences on lifestyle, adult morbidity and life expectancy. Hence, lower cognitive abilities are therefore of public health interest. Our primary aim was to examine if prenatal bereavement measured as exposure to death of a close family member is associated with the intelligence quotient (IQ) scores at 18-years of age of adult Danish males completing a military cognitive screening examination.
Methods
We extracted records for the Danish military screening test and found kinship links with biological parents, siblings, and maternal grandparents using the Danish Civil Registration System (N = 167,900). The prenatal exposure period was defined as 12 months before conception until birth of the child. We categorized children as exposed in utero to severe stress (bereavement) during prenatal life if their mothers lost an elder child, husband, parent or sibling during the prenatal period; the remaining children were included in the unexposed cohort. Mean score estimates were adjusted for maternal and paternal age at birth, residence, income, maternal education, gestational age at birth and birth weight.
Results
When exposure was due to death of a father the offsprings' mean IQ scores were lower among men completing the military recruitment exam compared to their unexposed counterparts, adjusted difference of 6.5 standard IQ points (p-value = 0.01). We did not observe a clinically significant association between exposure to prenatal maternal bereavement caused by death of a sibling, maternal uncle/aunt or maternal grandparent even after stratifying deaths only due to traumatic events.
Conclusion
We found maternal bereavement to be adversely associated with IQ in male offspring, which could be related to prenatal stress exposure though more likely is due to changes in family conditions after death of the father. This finding supports other literature on maternal adversity during fetal life and cognitive development in the offspring.
doi:10.1371/journal.pone.0088477
PMCID: PMC3928249  PMID: 24558394
11.  Health Risk Behaviors in Parentally Bereaved Youth 
Objective
To investigate whether parentally bereaved offspring are more likely to engage in health risk behaviors than nonbereaved control offspring.
Design
Controlled population-based study.
Setting
Bereaved families were recruited from coroner records and by advertisement. Control families were recruited using random-digit dialing and by advertisement.
Participants
At 9.0 months after the death, 186 offspring aged 7 to 25 years of parents who died of suicide, accident, or sudden natural death were compared with 167 nonbereaved control offspring.
Main Outcome Measures
The association of bereavement with health risk behaviors was examined. The prevalences of health risk behaviors on the Youth Risk Behavior Questionnaire were compared between bereaved and nonbereaved offspring. Risk behaviors surveyed were related to unintentional injury, violence, sexual behavior, cigarette smoking, and alcohol or other drug use.
Results
No statistically significant difference was noted in the examined health risk behaviors between bereaved and nonbereaved offspring.
Conclusions
Bereaved offspring did not engage in more health risk behaviors compared with nonbereaved offspring. Primary care physicians counseling youth should inquire about health risk behaviors in general.
doi:10.1001/archpediatrics.2010.101
PMCID: PMC3006435  PMID: 20603461
12.  Maternal Use of Antibiotics, Hospitalisation for Infection during Pregnancy, and Risk of Childhood Epilepsy: A Population-Based Cohort Study 
PLoS ONE  2012;7(1):e30850.
Background
Maternal infection during pregnancy may be a risk factor for epilepsy in offspring. Use of antibiotics is a valid marker of infection.
Methodology/Principal Findings
To examine the relationship between maternal infection during pregnancy and risk of childhood epilepsy we conducted a historical cohort study of singletons born in northern Denmark from 1998 through 2008 who survived ≥29 days. We used population-based medical databases to ascertain maternal use of antibiotics or hospital contacts with infection during pregnancy, as well as first-time hospital contacts with a diagnosis of epilepsy among offspring. We compared incidence rates (IR) of epilepsy among children of mothers with and without infection during pregnancy. We examined the outcome according to trimester of exposure, type of antibiotic, and total number of prescriptions, using Poisson regression to estimate incidence rate ratios (IRRs) while adjusting for covariates. Among 191 383 children in the cohort, 948 (0.5%) were hospitalised or had an outpatient visit for epilepsy during follow-up, yielding an IR of 91 per 100 000 person-years (PY). The five-year cumulative incidence of epilepsy was 4.5 per 1000 children. Among children exposed prenatally to maternal infection, the IR was 117 per 100 000 PY, with an adjusted IRR of 1.40 (95% confidence interval (CI): 1.22–1.61), compared with unexposed children. The association was unaffected by trimester of exposure, antibiotic type, or prescription count.
Conclusions/Significance
Prenatal exposure to maternal infection is associated with an increased risk of epilepsy in childhood. The similarity of estimates across types of antibiotics suggests that processes common to all infections underlie this outcome, rather than specific pathogens or drugs.
doi:10.1371/journal.pone.0030850
PMCID: PMC3266299  PMID: 22295115
13.  Offspring from families at high risk for alcohol dependence: Increased body mass index in association with prenatal exposure to cigarettes but not alcohol 
Psychiatry Research  2005;135(3):203-216.
The prevalence of overweight and obese children is increasing, a tendency that can be expected to increase the risk of adverse outcomes in adulthood. The aim of this study was to determine if prenatal exposure to alcohol, cigarettes, and street drugs would be associated with differences in body mass index (BMI) in childhood and adolescence in offspring from families at high and low genetic risk for developing alcohol dependence. Annual follow-up of offspring (N =288) provided 1200 height and weight assessments for analysis. Maternal substance use data were available for 235 offspring from families stratified for familial/genetic risk for alcohol dependence (high or low risk), providing the opportunity to assess prenatal exposure and familial/genetic risk in relation to BMI in the offspring. When data were grouped by the presence or absence of any prenatal cigarette exposure, a significant difference in offspring BMI was seen for 8- to 11-year-olds. Significant group differences were also seen at ages 12–15 and 16–18 years. A dose–response relationship between cigarette use by the mother and offspring BMI was also seen. With the strong tendency for individuals who are overweight in childhood and adolescence to become overweight adults, prenatal exposure to nicotine may be a harbinger of increased risk for numerous adult-onset, weight-related health problems.
doi:10.1016/j.psychres.2005.04.003
PMCID: PMC3286006  PMID: 16000226
Risk for obesity; Childhood obesity; Prenatal smoking; Prenatal use of substances; Body mass index; Genetic susceptibility; Familial risk for alcohol dependence
14.  The Effect of Parenting Stress on Child Behavior Problems in High-Risk Children with Prenatal Drug Exposure 
Objective
To examine the relationship between early parenting stress and later child behavior in a high risk sample and measure the effect of drug exposure on the relationship between parenting stress and child behavior.
Methods
A subset of child-caregiver dyads (n = 607) were selected from the Maternal Lifestyle Study, which is a large sample of children (n = 1388) with prenatal cocaine exposure and a comparison sample unexposed to cocaine. Of the 607 dyads, 221 were prenatally exposed to cocaine and 386 were unexposed to cocaine. Selection was based on the presence of a stable caregiver at 4 and 36 months with no evidence of change in caregiver between those time points.
Results
Parenting stress at 4 months significantly predicted child externalizing behavior at 36 months. These relations were unaffected by cocaine exposure suggesting the relationship between parenting stress and behavioral outcome exists for high-risk children regardless of drug exposure history.
Conclusions
These results extend the findings of the relationship between parenting stress and child behavior to a sample of high-risk children with prenatal drug exposure. Implications for outcome and treatment are discussed.
doi:10.1007/s10578-008-0109-6
PMCID: PMC2861499  PMID: 18626768
disruptive behavior; parenting stress; high-risk children; prenatal drug exposure; cocaine
15.  Combined effect of maternal serotonin transporter genotype and prenatal stress in modulating offspring social interaction 
Several studies suggest that prenatal stress is a possible risk factor in the development of autism spectrum disorders. However, many children exposed to stress prenatally are born healthy and develop typically, suggesting that other factors must contribute to autism. Genes that contribute to stress reactivity may, therefore, exacerbate prenatal stress-mediated behavioral changes in the adult offspring. One candidate gene linked to increased stress reactivity encodes the serotonin transporter. Specifically, an insertion/deletion (long/short allele) polymorphism upstream of the serotonin transporter gene correlates with differential expression and function of the serotonin transporter and a heightened response to stressors. Heterozygous serotonin transporter knockout mice show reductions in serotonin transporter expression similar to the human short polymorphism. In this study, the role of prenatal stress and maternal serotonin transporter genotype were assessed in mice to determine whether their combined effect produces reductions in social behavior in the adult offspring. Pregnant serotonin transporter heterozygous knockout and wild-type dams were placed in either a control condition or subjected to chronic variable stress. The adult offspring were subsequently assessed for social interaction and anxiety using a 3-chamber social approach task, ultrasonic vocalization detection, elevated-plus maze and an open field task. Results indicated that prenatal stress and reduced serotonin transporter expression of the dam may have the combined effect of producing changes in social interaction and social interest in the offspring consistent with those observed in autism spectrum disorder. This data indicates a possible combined effect of maternal serotonin transporter genotype and prenatal stress contributing to the production of autistic-like behaviors in offspring.
doi:10.1016/j.ijdevneu.2010.05.002
PMCID: PMC2918686  PMID: 20470877
animal model; autism; knockout mouse; stress; prenatal stress; serotonin transporter
16.  Understanding putative risk factors for schizophrenia: retrospective and prospective studies 
This paper describes a research program intended to provide a better understanding of the influence of several putative risk factors for schizophrenia on child development and psychosis. Two related components of the overall program are described: the retrospective EnviroGen projects, which use a variety of putative risk factors to explain variance in several dimensions of schizophrenia and in psychotic symptoms in community controls, and Project Ice Storm, which prospectively examines the effects of prenatal maternal stress in the children of women who were exposed to the 1998 Quebec ice storm during their pregnancies. The EnviroGen projects have been successful in explaining variance in several dimensions of illness, including premorbid adjustment and severity of dissociative symptoms. Project Ice Storm has demonstrated the noxious effects of prenatal stress on cognitive and language development in children. We have also found that “ice storm children” exposed in specific weeks of gestation show greater dermatoglyphic asymmetry, as has been reported for samples of patients with schizophrenia. In both studies, prenatal maternal stress has been associated with more severe childhood behaviour problems. The combination of retrospective and prospective studies is a rich source of triangulated results providing information about developmental psychopathology.
PMCID: PMC1197279  PMID: 16151539
schizophrenia; stress, psychological; child development; prenatal development; risk factors
17.  Cortisol Response to Social Stress in Parentally Bereaved Youth 
Biological psychiatry  2012;73(4):379-387.
Background
Parental bereavement is associated with increased risk for psychiatric illness and functional impairment in youth. Dysregulated hypothalamic-pituitary-adrenal (HPA) axis functioning may be one pathway through which bereaved children experience increased risk for poor outcomes. However, few studies have prospectively examined the association between parental bereavement and cortisol response while accounting for psychiatric disorders in both youth and their caregivers.
Methods
One-hundred and eighty-one bereaved and nonbereaved offspring and their caregivers were assessed at multiple time points over a 5-year period after parental death. Offspring participated in an adaptation of the Trier Social Stress Task (TSST), and salivary cortisol samples were collected before and after exposure to social stressors. Mixed models for repeated measures were used to analyze the effects of bereavement status, psychiatric disorder in both offspring and caregiver, and demographic indices on trajectories of cortisol response.
Results
After controlling for demographic variables and offspring depression, bereaved offspring demonstrated significantly different trajectories of cortisol response compared with nonbereaved offspring, characterized by higher total cortisol output and an absence of cortisol reactivity to acute social stress. Within the bereaved group, offspring of parents who died by sudden natural death demonstrated significant cortisol reactivity to social stress compared with offspring whose parents died by suicide, who demonstrated more blunted trajectory of cortisol response.
Conclusions
Parentally bereaved youth demonstrate higher cortisol output than nonbereaved youth but are less able to mount an acute response in the face of social stressors.
doi:10.1016/j.biopsych.2012.08.016
PMCID: PMC3789373  PMID: 23021533
Adolescent; bereavement; cortisol; depression; HPA axis; TSST
18.  Serious psychiatric outcome of subjects prenatally exposed to diethylstilboestrol in the E3N cohort study 
Psychological Medicine  2007;37(9):1315-1322.
Background
Prenatal exposure to diethylstilboestrol (DES) may induce neurodevelopmental disturbances potentially mediating an increased risk of psychiatric disorders in exposed subjects. Most findings of an increased prevalence of psychiatric disorders in men and women prenatally exposed to DES are not easy to interpret because of selection biases.
Method
Information on hormonal treatment during pregnancy and on offspring’s medical outcome was collected from women participating in the Etude Epidemiologique de Femmes de la Mutuelle Générale de l’Education Nationale (E3N) prospective cohort who completed consecutive postal questionnaires on a range of medical events since 1990. Information on hormonal treatment during pregnancy was collected in 1992 and on offspring’s medical outcome in 2004. The psychiatric outcome of subjects prenatally exposed to DES was compared to that of their unexposed siblings.
Results
A total of 1352 mothers with DES treatment for at least one pregnancy provided information on 1680 exposed children and 1447 unexposed siblings. After adjustment for duration of follow-up, educational level, history of obstetric complication, prenatal exposure to progestagen drugs or other hormones and parental history of psychiatric hospitalization, no association was found between prenatal exposure to DES and occurrence of strictly defined serious psychiatric outcome (suicide or psychiatric hospitalization) [adjusted odds ratio (OR) 0.8, 95% confidence interval (CI) 0.5–1.2], or of broadly defined serious psychiatric outcome (same events plus psychiatric or psychological consultation) (adjusted OR 1.0, 95% CI 0.8–1.2).
Conclusions
These findings suggest that the impact of prenatal DES exposure on foetal brain development, if any, is unlikely to increase the risk of serious psychiatric disorders.
doi:10.1017/S0033291707000438
PMCID: PMC1976181  PMID: 17407619
19.  The Association between Prenatal Psychosocial Stress and Blood Pressure in the Child at Age 5–7 Years 
PLoS ONE  2012;7(8):e43548.
Objective
Prenatal maternal stress could have permanent effects on the offspring’s tissue structure and function, which may predispose to cardiovascular diseases. We investigated whether maternal psychosocial stress is a prenatal factor affecting the blood pressure (BP) of offspring.
Study Design
In the Amsterdam Born Children and their Development (ABCD) study, around gestational week 16, depressive symptoms, state-anxiety, pregnancy-related anxiety, parenting daily hassles and job strain were recorded by questionnaire. A cumulative stress score was also calculated (based on 80th percentiles). Systolic and diastolic BP and mean arterial pressure (MAP) were measured in the offspring at age 5–7 years. Inclusion criteria were: no use of antihypertensive medication during pregnancy; singleton birth; no reported cardiovascular problems in the child (N = 2968 included).
Results
After adjustment for confounders, the single stress scales were not associated with systolic and diastolic BP, MAP and hypertension (p>0.05). The presence of 3–4 psychosocial stressors prenatally (4%) was associated with 1.5 mmHg higher systolic and diastolic BP (p = 0.046; p = 0.04) and 1.5 mmHg higher MAP in the offspring (p = 0.02) compared to no stressors (46%). The presence of 3–4 stressors did not significantly increase the risk for hypertension (OR 1.8; 95% CI 0.93.4). Associations did not differ between sexes. Bonferroni correction for multiple testing rendered all associations non-significant.
Conclusions
The presence of multiple psychosocial stressors during pregnancy was associated with higher systolic and diastolic BP and MAP in the child at age 5–7. Further investigation of maternal prenatal stress may be valuable for later life cardiovascular health.
doi:10.1371/journal.pone.0043548
PMCID: PMC3424234  PMID: 22927987
20.  Long-Term Health Outcomes in Children Born to Mothers with Diabetes: A Population-Based Cohort Study 
PLoS ONE  2012;7(5):e36727.
Background
To examine whether prenatal exposure to parental type 1 diabetes, type 2 diabetes, or gestational diabetes is associated with an increased risk of malignant neoplasm or diseases of the circulatory system in the offspring.
Methods/Principal Findings
We conducted a population-based cohort study of 1,781,576 singletons born in Denmark from 1977 to 2008. Children were followed for up to 30 years from the day of birth until the onset of the outcomes under study, death, emigration, or December 31, 2009, whichever came first. We used Cox proportional hazards model to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) for the outcomes under study while adjusting for potential confounders. An increased risk of malignant neoplasm was found in children prenatally exposed to maternal type 2 diabetes (HR = 2.2, 95%CI: 1.5–3.2). An increased risk of diseases of the circulatory system was found in children exposed to maternal type 1 diabetes (HR = 2.2, 95%CI: 1.6–3.0), type 2 diabetes (HR = 1.4, 95%CI: 1.1–1.7), and gestational diabetes (HR = 1.3, 95%CI: 1.1–1.6), but results were attenuated after excluding children with congenital malformations. An increased risk of diseases of the circulatory system was also found in children exposed to paternal type 2 diabetes (HR = 1.5, 95%CI: 1.1–2.2) and the elevated risk remained after excluding children with congenital malformations.
Conclusions
This study suggests that susceptibility to malignant neoplasm is modified partly by fetal programming. Diseases of the circulatory system may be modified by genetic factors, other time-stable family factors, or fetal programming.
doi:10.1371/journal.pone.0036727
PMCID: PMC3359312  PMID: 22649497
21.  Parental smoking during pregnancy and risk of overweight and obesity in the daughter 
Objective
Emerging evidence suggests that prenatal exposures may affect long-term health outcomes. In utero exposure to smoking is associated with an increased risk of overweight and obesity in children and adolescents. However, few studies have examined how prenatal exposure to parental smoking influences risk of obesity in adulthood and whether these associations are independent of childhood and adolescent adiposity. The aim of the current study was to investigate whether prenatal exposure to parental smoking influences body size in adulthood and whether any association may be mediated by childhood and adolescent body size.
Methods
We investigated the association between parental smoking during pregnancy and risk of overweight and obesity in adulthood and at age 18, and adiposity during childhood among 35,370 participants in the Nurses’ Health Study II. Data on smoking during pregnancy and socioeconomic variables were provided by the mothers, and anthropometric data and adult risk factors were reported by participants.
Results
After adjustment for socioeconomic and behavioral variables, maternal smoking during pregnancy was associated with adiposity at ages 5–10, age 18, and during adulthood. For age 18 overweight the ORs (95% CIs) for 1–14, 15–24, and 25+cigarettes/day were 1.13 (1.18–1.50), 1.40 (1.20–1.64), and 1.15 (0.79–1.69) and for obesity were 1.41 (1.14–1.75), 1.69 (1.31–2.18), and 2.36 (1.44–3.86). The corresponding ORs (95% CIs) for obesity in adulthood were 1.26 (1.16–1.37), 1.46 (1.30–1.63), and 1.43 (1.10–1.86). Risk of adiposity was not increased among daughters whose mothers stopped smoking during the first trimester (OR [95% CI] for overweight (1.03 [95% CI 0.90–1.17] and obesity (1.12 [95% CI 0.97–1.30]). Women whose fathers smoked during pregnancy were also at increased risk of overweight and obesity in adulthood with covariate-adjusted ORs (95% CIs) for obesity of 1.19 (1.11–1.29) for 1–14 cigarettes/day, 1.27 (1.18–1.37) for 15–24 cigarettes/day, and 1.40 (1.27–1.54) for 25+ cigarettes/day compared to fathers who did not smoke (ptrend<0.0001). Paternal smoking during pregnancy was also associated with an increased risk of obesity at age 18 among those whose fathers smoked 15 or more cigarettes/day but was not associated with childhood body size.
Conclusions
Maternal smoking during pregnancy was associated in a dose-response manner with overweight and obesity in the daughter through adolescence and adult life. Smoking cessation during the first trimester appears to mitigate this excess risk.
Paternal smoking was also associated with risk of overweight and obesity of the adult daughter and this association persisted after adjustment for maternal smoking.
doi:10.1038/ijo.2013.101
PMCID: PMC3795801  PMID: 23736356
pregnancy; prenatal programming; cigarette smoking; obesity
22.  Psychological Stress and Hospitalization for Childhood Asthma-a Nationwide Cohort Study in Two Nordic Countries 
PLoS ONE  2013;8(10):e78816.
Objective
Exposures to psychological stress in early life may contribute to the development or exacerbation of asthma. We undertook a cohort study based on data from several population-based registers in Denmark and Sweden to examine whether bereavement in childhood led to increased asthma hospitalization.
Methods
All singleton children born in Denmark during 1977-2008 and in Sweden during 1973-2006 were included in the study (N=5,202,576). The children were followed from birth to the date of first asthma hospitalization, emigration, death, their 18th birthday, or the end of study (31 December 2007 in Sweden and 31 December 2008 in Denmark), whichever came first. All the children were assigned to the non-bereaved group until they lost a close relative (mother, father or a sibling), from when they were included in the bereaved group. We evaluated the hazard ratio (HR) of first hospitalization for asthma in bereaved children using Cox proportional hazards regression models, compared to those who were in the non-bereaved group. We also did a sub-analysis on the association between bereavement and first asthma medication.
Results
A total of 147,829 children were hospitalized for asthma. The overall adjusted HR of asthma hospitalization in bereaved children was 1.10 (95% confidence interval (CI): 1.04-1.16), compared to non-bereaved children. The risk of asthma hospitalization was increased in those who lost a close relative at age of 14-17 years (HR=1.54, 95% CI: 1.23-1.92), but not in younger age groups. The association between bereavement and asthma hospitalization did not change over time since bereavement. In the sub-analysis in singleton live births during 1996-2008 recorded in the DMBR, bereavement was associated with a lower use of asthma medication (HR=0.87, 95% CI: 0.80-0.95).
Conclusions
Our data suggests that psychological stress following bereavement in late adolescence is associated with an increased risk of asthma hospitalization or lowers the threshold for asthma hospitalization.
doi:10.1371/journal.pone.0078816
PMCID: PMC3808299  PMID: 24205324
23.  Diabetes mellitus during pregnancy and increased risk of schizophrenia in offspring: a review of the evidence and putative mechanisms 
Objective
To identify converging themes from the neurodevelopmental hypothesis of schizophrenia and the pathophysiology of diabetic pregnancy and to examine mechanisms by which diabetes mellitus in a pregnant mother may increase the risk of schizophrenia in offspring.
Methods
We reviewed relevant publications on clinical, epidemiologic and animal studies of diabetic pregnancy and the neurodevelopmental aspects of schizophrenia.
Results
Epidemiologic studies have shown that the offspring of mothers who experienced diabetes mellitus during their pregnancies are 7 times more likely to develop schizophrenia, compared with those who were not exposed to diabetic pregnancy. Maternal hyperglycemia during pregnancy could predispose to schizophrenia in adult life through at least 3 prenatal mechanisms: hypoxia, oxidative stress and increased inflammation. Hyperglycemia increases oxidative stress, alters lipid metabolism, affects mitochondrial structure, causes derangements in neural cell processes and neuronal architecture and results in premature specialization before neural tube closure. The molecular mechanisms underlying these processes include the generation of excess oxyradicals and lipid peroxide intermediates as well as reductions in levels of polyunsaturated fatty acids that are known to cause increased dopaminergic and lowered γ-aminobutyric acidergic activity. The combination of hyperglycemia and hypoxia in pregnancy also leads to altered immune function including increased tumour necrosis factor-α, C-reactive protein and upregulation of other proinflammatory cytokines. Finally, maternal hyperglycemia could have a lasting impact on fetal cellular physiology, resulting in increased vulnerability to stress and predisposition to schizophrenia via a mechanism known as programming. These prenatal events can also result in obstetric complications such as fetal growth abnormalities and increased susceptibility to prenatal infection, all of which are associated with a spectrum of neurodevelopmental anomalies and an enhanced risk of schizophrenia.
Conclusion
On the basis of the evidence presented and taking into consideration the projected increases in the rates of diabetes mellitus among younger women of child-bearing potential, it is imperative that the neurodevelopmental sequelae of diabetic pregnancy in general, and the increased risk for schizophrenia in particular, receive further study.
PMCID: PMC2527714  PMID: 18787655
diabetes mellitus; schizophrenia; fetal hypoxia
24.  Children's Cognitive Ability from 4- to 9-Years as a Function of Prenatal Cocaine Exposure, Environmental Risk, and Maternal Verbal Intelligence 
Developmental psychology  2008;44(4):919-928.
This study examined the effects of prenatal cocaine exposure, environmental risk, and maternal verbal intelligence on children's cognitive ability. Gender and age were examined as moderators of potential cocaine exposure effects. The Stanford-Binet IV intelligence test was administered to 231 children (91 cocaine exposed, 140 unexposed) at 4, 6, and 9 years of age. Neonatal medical risk and other prenatal exposures (alcohol, cigarettes, and marijuana) were also examined for their unique effects on child IQ. Mixed models analysis indicated that prenatal cocaine exposure interacted with gender as cocaine exposed boys had lower composite IQ scores. Age of assessment did not moderate this relation, indicating that cocaine exposed boys had lower IQs across this age period. A stimulating home environment and high maternal verbal IQ also predicted higher composite IQ scores. Cocaine exposed boys had lower scores on the Abstract/Visual Reasoning subscale, with trends for lower scores on the Short-term Memory and Verbal Reasoning subscales, as exposure effects were observed across domains. The findings indicate that cocaine exposure continues to place children at risk for mild cognitive deficits into preadolescence. Possible mechanisms for the exposure by gender interaction are discussed.
doi:10.1037/0012-1649.44.4.919
PMCID: PMC2556289  PMID: 18605824
prenatal cocaine exposure; environmental risk; gender differences; intelligence
25.  Chronic Maternal Depression Is Associated with Reduced Weight Gain in Latino Infants from Birth to 2 Years of Age 
PLoS ONE  2011;6(2):e16737.
Background
Latino children are at increased risk for mirconutrient deficiencies and problems of overweight and obesity. Exposures in pregnancy and early postpartum may impact future growth trajectories.
Objectives
To evaluate the relationship between prenatal and postnatal maternal depressive symptoms experienced in pregnancy and infant growth from birth to 2 years of age in a cohort of Latino infants.
Methods
We recruited pregnant Latina mothers at two San Francisco hospitals and followed their healthy infants to 24 months of age. At 6, 12 and 24 months of age, infants were weighed and measured. Maternal depressive symptoms were assessed prenatally and at 4-6 weeks postpartum. Women who had high depressive symptoms at both time periods were defined as having chronic depression. Logistic mixed models were applied to compare growth curves and risk for overweight and underweight based on exposure to maternal depression.
Results
We followed 181 infants to 24 months. At 12 and 24 months, respectively, 27.4% and 40.5% were overweight, and 5.6% and 2.2% were underweight. Exposure to chronic maternal depression was associated with underweight (OR = 12.12, 95%CI 1.86-78.78) and with reduced weight gain in the first 2 years of life (Coef = -0.48, 95% CI -0.94—0.01) compared with unexposed infants or infants exposed to episodic depression (depression at one time point). Exposure to chronic depression was also associated with reduced risk for overweight in the first 2 years of life (OR 0.28, 95%CI 0.03-0.92).
Conclusions
Exposure to chronic maternal depression in the pre- and postnatal period was associated with reduced weight gain in the first two years of life and greater risk for failure to thrive, in comparison with unexposed infants or those exposed episodically. The infants of mothers with chronic depression may need additional nutritional monitoring and intervention.
doi:10.1371/journal.pone.0016737
PMCID: PMC3044151  PMID: 21373638

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