Yehiel Friedlander

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 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.

Cancer after pre-eclampsia: follow up of the Jerusalem perinatal study cohort

>Objective To compare the incidence of cancer among women with and without a history of pre-eclampsia. Design Cohort study. Setting Jerusalem perinatal study of women who delivered in three large hospitals in West Jerusalem during 1964-76. Participants 37 033 women. Main outcome measures Age adjusted and multivariable adjusted hazard ratios for cancer incidence for the entire cohort and for women who were primiparous at study entry. Results Cancer developed in 91 women who had pre-eclampsia and 2204 who did not (hazard ratio 1.27, 95% confidence interval 1.03 to 1.57). The risk of site specific cancers was increased, particularly of the stomach, ovary epithelium, breast, and lung or larynx. The incidence of cancer of the stomach, breast, ovary, kidney, and lung or larynx was increased in primiparous women at study entry who had a history pre-eclampsia. Conclusions A history of pre-eclampsia is associated with increases in overall risk of cancer and incidence at several sites. This may be explained by environmental and genetic factors common to the development of pre-eclampsia and cancer in this population.

Ethnic ancestry and increased paternal age are risk factors for breast cancer before the age of 40 years.

To study the risk factors associated with breast cancer in women younger than 40 years, a cohort study (The Jerusalem Perinatal Study) of 42 822 female offspring born in hospitals in West Jerusalem during 1964–1976 was carried out. Hazard ratios of potential parental and perinatal risk factors for early breast cancer were measured. The overall incidence of breast cancer was 5.2/100 000 person–years. The highest incidence was found among Jewish women of West Asian ancestry (8.6/100 000 person–years), specifically those whose maternal grandfathers were born in Iraq, Iran or Afghanistan (9.5/100 000 person–years). Using Cox models we found independent risk factors for early breast cancer to be paternal age (relative risk/year=1.06, 95% confidence interval=1.02–1.10, P=0.005), and ancestry from Iraq/Iran/Afghanistan (relative risk=3.1, 95% confidence interval=1.50–6.52, P=0.002). The study confirms a previously observed effect of advanced paternal age on the occurrence of early breast cancer and identifies a novel population group at increased risk for the disease. The excess risk of early breast cancer associated with ancestry from Iraq, Iran and Afghanistan suggests involvement of genetic determinants, environmental exposures and/or lifestyle factors and mandates further investigation.

The Risk of Cancer following Hospitalization for Infection in Infancy: A Population-Based Cohort Study

Background: The relation between infections in infancy and subsequent cancer risk in children and young adults is controversial. Our aim was to examine this association in the Jerusalem Perinatal Study, a population-based cohort comprising all offspring from western Jerusalem and surroundings born from 1964 to 1976. Methods: Identity numbers of nonmalformed singletons with recorded data about hospital admission in the 1st year of life (n = 24,554) were linked to the Population and Cancer Registries. Person-year incidence rates were calculated for the exposed (admitted for infection) and nonexposed (not admitted for infection) groups from birth to date of cancer diagnosis, death, or December 31, 2004. We used Cox proportional hazards models to adjust for covariates associated with hospitalization. Results: The median follow-up was 36 years. Cancer developed in 283 individuals. Hospitalization for infection was not associated with overall cancer risk [risk ratio (RR), 0.88; 95% confidence interval (95% CI), 0.56-1.37]. The incidence rate for non–Hodgkins lymphoma was higher in the exposed compared with the nonexposed group (RR, 3.46; 95% CI, 1.38-8.68), remaining unchanged after controlling for birth weight, gender, and maternal education. Leukemia risk was not significantly associated (RR, 0.44; 95% CI, 0.06-3.24) with hospitalization for infection. Conclusions: Hospital admission in the 1st year of life due to infection is associated with an increased risk of non–Hodgkins lymphoma. This is consistent with observations that mild immunodeficiencies predispose to lymphoma. Survival of infants with subtle immune defects, who may have previously succumbed to their infection, may contribute to the increased incidence of non–Hodgkins lymphoma observed over the last 50 years. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1964–8)

Twin pregnancy and the risk of schizophrenia

BACKGROUND Twins are exposed to intrauterine environments that differ significantly from those of singletons. These diverse environments might alter the risk for schizophrenia in twins and make it difficult to generalize from findings in twins when studying the risk of schizophrenia in the general population. Previous studies report contradictory findings on the risk for schizophrenia in twins. METHODS We studied the incidence of schizophrenia spectrum disorders, ascertained from Israels National Psychiatric Registry, in a cohort of 2124 twins and 87,955 singletons. These offspring were followed from their birth in 1964-76 in the Jerusalem Perinatal study. Cox proportional hazards methods were used to compare outcomes over 28-41 years, adjusting for ages of parents. RESULTS Twins showed a relative risk [RR] of .84 relative to singletons, with a 95% confidence interval [CI] of (.51-1.4). RRs and CIs for males and females were .68 [.34-1.4] and 1.1 [.55-2.2] respectively. Twins in male-male, female-female or opposite-sex sets showed no significant variation in RRs; furthermore, first- or second-born twins did not differ significantly from each other. Siblings of twins had the same risk of schizophrenia as siblings of singletons. CONCLUSION Twins have the same risk for schizophrenia as the general population.

Paternal age and twinning in the Jerusalem Perinatal Study

OBJECTIVE To investigate whether incidence of twin deliveries is related to fathers age, independently of mothers age, and whether it differs for same-sex or opposite-sex twin sets. STUDY DESIGN In a program of research on effects of paternal age, this study used data from a prospective cohort of 92,408 offspring born in Jerusalem from 1964 to 1976. Of the 91,253 deliveries in the Jerusalem Perinatal Study, 1115 were twin deliveries. The data were analyzed with General Estimate Equations to inform unconditional logistic regression. RESULTS After controlling for maternal age, odds ratios (ORs) and 95% confidence intervals (95% CI) associated with fathers ages 25-34 and 35+ were 1.3 (1.1, 1.7) and 1.5 (1.2, 2.1) respectively, compared with fathers <25 years old. The effect of maternal age was partly explained by paternal age. The ORs for opposite-sex twin sets and male-male twin sets increased slightly with paternal age, while the OR for same-sex and female-female twin decreased. CONCLUSION Studies of twins are used to estimate effects of genes and environment in a variety of diseases. Our findings highlight the need to consider paternal as well as maternal age when analyzing data on twins to explore etiology of diseases.

Very high birth weight of offspring is associated with an increased risk of leukemia in their mothers: Results of a population-based cohort study

Although the association between birth weight and childhood leukemia is well described, the relation between a childs birth weight and parental risk of leukemia is unknown. We linked data from the Jerusalem Perinatal Study to the Israel Cancer Registry to ascertain the incidence of leukemia in mothers and fathers in relation to their offsprings birth weight. Birth weight >or=4500 g in any of the offspring was associated with a >3-fold risk of leukemia in mothers, but not fathers. Potential mechanisms include shared exposures of high birth weight infants and their mothers, possibly to radiation or growth factors, or genetic pathways leading to both high birth weight and leukemia.