Karine Kleinhaus

Acute maternal stress in pregnancy and schizophrenia in offspring: A cohort prospective study

Schizophrenia has been linked with intrauterine exposure to maternal stress due to bereavement, famine and major disasters. Recent evidence suggests that human vulnerability may be greatest in the first trimester of gestation and rodent experiments suggest sex specificity. We aimed to describe the consequence of an acute maternal stress, through a follow-up of offspring whose mothers were pregnant during the Arab-Israeli war of 1967. A priori, we focused on gestational month and offsprings sex.MethodIn a pilot study linking birth records to Israels Psychiatric Registry, we analyzed data from a cohort of 88,829 born in Jerusalem in 1964–76. Proportional hazards models were used to estimate the relative risk (RR) of schizophrenia, according to month of birth, gender and other variables, while controlling for fathers age and other potential confounders. Other causes of hospitalized psychiatric morbidity (grouped together) were analyzed for comparison.ResultsThere was a raised incidence of schizophrenia for those who were in the second month of fetal life in June 1967 (RR = 2.3, 1.1–4.7), seen more in females (4.3, 1.7–10.7) than in males (1.2, 0.4–3.8). Results were not explained by secular or seasonal variations, altered birth weight or gestational age. For other conditions, RRs were increased in offspring who had been in the third month of fetal life in June 1967 (2.5, 1.2–5.2), also seen more in females (3.6, 1.3–9.7) than males (1.8, 0.6–5.2).ConclusionThese findings add to a growing literature, in experimental animals and humans, attributing long term consequences for offspring of maternal gestational stress. They suggest both a sex-specificity and a relatively short gestational time-window for gestational effects on vulnerability to schizophrenia.

Cancer Risk After Exposure to Treatments for Ovulation Induction

Uncertainty continues as to whether treatments for ovulation induction are associated with increased risk of cancer. The authors conducted a long-term population-based historical cohort study of parous women. A total of 15,030 women in the Jerusalem Perinatal Study who gave birth in 1974-1976 participated in a postpartum survey. Cancer incidence through 2004 was analyzed using Coxs proportional hazards models, controlling for age and other covariates. Women who used drugs to induce ovulation (n = 567) had increased risks of cancer at any site (multivariate hazard ratio (HR) = 1.36, 95% confidence interval (CI): 1.06, 1.74). An increased risk of uterine cancer was found among women treated with ovulation-inducing agents (HR = 3.39, 95% CI: 1.28, 8.97), specifically clomiphene (HR = 4.56, 95% CI: 1.56, 13.34). No association was noted between use of ovulation-inducing agents and ovarian cancer (age-adjusted HR = 0.61, 95% CI: 0.08, 4.42). Ovulation induction was associated with a borderline-significant increased risk of breast cancer (multivariate HR = 1.42, 95% CI: 0.99, 2.05). Increased risks were also observed for malignant melanoma and non-Hodgkin lymphoma. These associations appeared stronger among women who waited more than 1 year to conceive. Additional follow-up studies assessing these associations by drug type, dosage, and duration are needed.

Prenatal stress, gestational age and secondary sex ratio: the sex-specific effects of exposure to a natural disaster in early pregnancy

BACKGROUND Previous research suggests that maternal exposure to acute stress has a negative impact on the duration of pregnancy, and that this effect may vary by the time of exposure. It has also been proposed that stress exposure reduces the ratio of male-to-female births. To date, no study has jointly examined both outcomes, although they may be strongly related. Using population-level data with no selectivity, we jointly study the sex-specific effect of stress on the duration of pregnancy and the observed sex ratio among pregnant women exposed to a major earthquake in Chile. METHODS In a quasi-experimental design, women exposed to the earthquake in different months of gestation were compared with women pregnant 1 year earlier. Estimates from a comparison group of pregnant women living in areas not affected by the earthquake were also examined to rule out confounding trends. Regression models were used to measure the impact of earthquake exposure on gestational age and preterm birth by sex across month of gestation. A counterfactual simulation was implemented to assess the effect of the earthquake on the secondary sex ratio accounting for the differential impact of stress on gestational age by sex. RESULTS Earthquake exposure in Months 2 and 3 of gestation resulted in a significant decline in gestational age and increase in preterm delivery. Effects varied by sex, and were much larger for female than male pregnancies. Among females, the probability of preterm birth increased by 0.038 [95% confidence interval (CI): 0.005, 0.072] in Month 2 and by 0.039 (95% CI: 0.002, 0.075) in Month 3. Comparable increases for males were insignificant at the conventional P < 0.05 level. After accounting for the sex-specific impact on gestational age, a decline in the male-to-female ratio in Month 3 of exposure was detected [-0.058 (95% CI: -0.113, -0.003)]. CONCLUSIONS Maternal exposure to an exogenous stressor early but not late in the pregnancy affects gestational age and the probability of preterm birth. This effect is much stronger in females than males. Stress exposure in early pregnancy may also contribute to a decline in the ratio of male-to-female live births in exposed cohorts.

Infant Bonding and Attachment to the Caregiver: Insights from Basic and Clinical Science

Early life infant-caregiver attachment is a dynamic, bidirectional process that involving both the infant and caregiver. Infant attachment appears to have a dual function. First, it ensures the infant remains close to the caregiver in order to receive necessary care for survival. Second, the quality of attachment and its associated sensory stimuli organize the brain to define the infants cognitive and emotional development. Here we present attachment within an historical view and highlight the importance of integrating human and animal research in understanding infant care.

Advanced Parental Age at Birth Is Associated With Poorer Social Functioning in Adolescent Males: Shedding Light on a Core Symptom of Schizophrenia and Autism

BACKGROUND Evidence indicates an association between older parents at birth and increased risk for schizophrenia and autism. Patients with schizophrenia and autism and their first-degree relatives have impaired social functioning; hence, impaired social functioning is probably an intermediate phenotype of the illness. This study tested the hypothesis that advanced fathers age at birth would be associated with poorer social functioning in the general population. To test this hypothesis, we examined the association between parental age at birth and the social functioning of their adolescent male offspring in a population-based study. METHODS Subjects were 403486, 16- to 17-year-old Israeli-born male adolescents assessed by the Israeli Draft Board. The effect of parental age on social functioning was assessed in analyses controlling for cognitive functioning, the other parents age, parental socioeconomic status, birth order, and year of draft board assessment. RESULTS Compared with offspring of parents aged 25-29 years, the prevalence of poor social functioning was increased both in offspring of fathers younger than 20 years (odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.08-1.49) and in offspring of fathers 45 years old (OR = 1.52, 95% CI = 1.43-1.61). Male adolescent children of mothers aged 40 years and above were 1.15 (95% CI = 1.07-1.24) times more likely to have poor social functioning. CONCLUSIONS These modest associations between parental age and poor social functioning in the general population parallel the associations between parental age and risk for schizophrenia and autism and suggest that the risk pathways between advanced parental age and schizophrenia and autism might, at least partially, include mildly deleterious effects on social functioning.

Preeclampsia and subsequent risk of cancer: update from the Jerusalem Perinatal Study

OBJECTIVE The purpose of this study was to examine the association between preeclampsia and cancer incidence. STUDY DESIGN The Jerusalem Perinatal Study is a population-based cohort of all births to 41,206 residents of Western Jerusalem from 1964-76. Cancer incidence to 2004 was assessed by linkage of the cohort with the Israel Cancer Registry. Coxs proportional hazards models were constructed to estimate the hazard ratio for cancer among women who had had preeclampsia. RESULTS Preeclampsia was associated with a 1.23-fold increased risk of cancer at all sites, a 37% increased risk of breast cancer, and more than a doubling of ovarian cancer risk. Analysis by morphologic condition yielded significantly increased risks for malignancies that were classed as cystic mucinous and serous (relative risk, 1.96; 95% CI, 1.00-3.83) and for ductal, lobular, and medullary carcinomas (relative risk, 1.40; 95% CI, 1.07-1.83). No differential association was observed by sex of offspring. CONCLUSION Our study suggests that the previously described protective effect of preeclampsia on cancer is not universal.

Tetrachloroethylene exposure and risk of schizophrenia: Offspring of dry cleaners in a population birth cohort, preliminary findings

Tetrachloroethylene is a solvent used in dry cleaning with reported neurotoxic effects. Using proportional hazard methods, we examined the relationship between parental occupation as a dry cleaner and risk for schizophrenia in a prospective population-based cohort of 88,829 offspring born in Jerusalem from 1964 through 1976, followed from birth to age 21-33 years. Of 144 offspring whose parents were dry cleaners, 4 developed schizophrenia. We observed an increased incidence of schizophrenia in offspring of parents who were dry cleaners (RR=3.4, 95% CI, 1.3-9.2, p=0.01). Tetrachloroethylene exposure warrants further investigation as a risk factor for schizophrenia.

Prenatal stress and affective disorders in a population birth cohort.

Kleinhaus K, Harlap S, Perrin M, Manor O, Margalit‐Calderon R, Opler M, Friedlander Y, Malaspina D. Prenatal stress and affective disorders in a population birth cohort. 
Bipolar Disord 2012: 00: 000–000.

Later paternal age and sex differences in schizophrenia symptoms

OBJECTIVE Advanced paternal age is consistently associated with an increased risk for schizophrenia, accounting for up to a quarter of cases in some populations. If paternal age-related schizophrenia (PARS) involves a distinct etiopathology, then PARS cases may show specific characteristics, vis-à-vis other schizophrenia cases. This study examined if PARS exhibits the symptom profile and sex differences that are consistently observed for schizophrenia in general, wherein males have an earlier onset age and more severe negative symptoms than females. METHOD Symptoms were assessed at baseline (admission) and during medication-free and treatment phases for 153 inpatients on a schizophrenia research unit, 38 of whom fulfilled operationally defined criteria for PARS (sporadic cases with paternal age > or = 35). RESULTS Males and females with PARS had the same age at onset and a similar preponderance of negative symptoms, whereas the other (non-PARS) cases showed the typical earlier onset age and more severe negative symptoms in males. When medications were withdrawn, PARS cases showed significantly worse symptoms than non-PARS cases (higher total PANSS scores and positive, activation, and autistic preoccupation scores). However these symptoms globally improved with antipsychotic treatment, such that the differences between the PARS and other schizophrenia cases receded. CONCLUSION The lack of sex differences in the age at onset and the greater severity of medication-free symptoms bolster the hypothesis that PARS has a distinct etiopathology. It also suggests that female sex does not exert a protective effect on the course of PARS, as it may in other forms of schizophrenia.

Olfactory acuity is associated with mood and function in a pilot study of stable bipolar disorder patients

OBJECTIVES Olfactory dysfunction is described in several neuropsychiatric disorders but there is little research on olfactory processing in bipolar disorder. METHODS We assessed odor detection threshold (sensitivity) and smell identification test scores, along with symptoms, cognition, and social function in 20 DSM-IV bipolar disorder patients and 44 control subjects. RESULTS The patient and control groups had similar demographic measures, intelligence, and mean olfaction scores, but significantly differed in social domains, including adjustment, function, and anxiety. Odor detection sensitivity showed significantly opposite correlations for the depressive and manic mood domains in bipolar disorder (r to z = 2.83, p = 0.005). Depressive symptoms were related to increased sensitivity (the ability to detect odors at a lower concentration) and mania symptoms were related to decreased sensitivity for odor detection. Increased sensitivity for odor detection also predicted significantly better employment (r = -0.642, p = 0.024), whereas less sensitivity was associated with social avoidance (r = 0.702, p =0.024) and social fear (r = 0.610, p = 0.046). CONCLUSIONS Diminished odor detection sensitivity predicted mania and social avoidance, whereas more sensitive odor detection predicted more depressive symptoms but better employment functioning in bipolar disorder patients. Odor acuity may be an illness state marker of mood syndromes in bipolar disorder. Alternatively, differences in odor acuity may identify heterogeneous subgroups within the bipolar spectrum. Longitudinal assessments in a large, sex-stratified sample are needed to understand the implications of odor sensitivity in patients with bipolar disorder.