Grand multiparity and reproductive cancer in the Jerusalem Perinatal Study Cohort.

OBJECTIVES: Grand multiparity is associated with reduced mortality from reproductive cancers. We aimed to separate the components of mortality, by measuring incidence of and survival after reproductive cancer onset in grand multiparous compared to other parous women. STUDY DESIGN: We linked data from the population-based Jerusalem Perinatal Study Cohort, which included women aged 13-55 who delivered 1964-1976, with Israel's National Cancer Registry. We compared breast and gynecologic cancer risk and all-cause survival following a cancer diagnosis, among grand multiparae (GMPs = parity 5+, n = 8,246) versus women with parity 1-4 (n = 19,703), adjusting for reproductive and demographic variables. RESULTS: Grand multiparae were at significantly lower risk of breast cancer than others (adjusted hazard ratio (HRadj) = 0.62, 95 % confidence interval (CI) 0.54-0.71), after controlling for age at first birth, education, and other covariates. This reduction was greater among GMPs whose first birth occurred after age 30 (p-interaction = 0.0001) and for cancer occurring before age 50 years (p = 0.002). In contrast, GMPs were at greater risk of death than women with parity <5, following a breast cancer diagnosis (HRadj = 1.69, CI 1.39-2.1). Ovarian, uterine, and cervical cancer incidence did not differ between the groups, but survival was reduced for GMPs with uterine cancer (HRadj = 2.48, CI 1.22-5.03). CONCLUSION: Reduced reproductive cancer mortality reported among GMPs masks two opposing phenomena: decreased breast cancer risk and poorer survival after breast and uterine cancers. The latter unfavorable outcome suggests that tumors in GMPs may be particularly aggressive, having perhaps escaped protective mechanisms conferred by parity. This finding calls for heightened clinical attention in this group.

Socioeconomic disparities in breast cancer incidence and survival among parous women: findings from a population-based cohort, 1964-2008.

BACKGROUND: Socioeconomic position (SEP) has been associated with breast cancer incidence and survival. We examined the associations between two socioeconomic indicators and long-term breast cancer incidence and survival in a population-based cohort of parous women. METHODS: Residents of Jerusalem who gave birth between 1964-1976 (n = 40,586) were linked to the Israel Cancer Registry and Israel Population Registry to determine breast cancer incidence and vital status through mid-2008. SEP was assessed by husband's occupation and the woman's education. We used log ranks tests to compare incidence and survival curves by SEP, and Cox proportional hazard models to adjust for demographic, reproductive and diagnostic factors and assess effect modification by ethnic origin. RESULTS: In multivariable models, women of high SEP had a greater risk of breast cancer compared to women of low SEP (Occupation: HR 1.18, 95 % CI 1.03-1.35; Education: HR 1.39, 95 % CI 1.21-1.60) and women of low SEP had a greater risk of mortality after a breast cancer diagnosis (Occupation: HR 1.33, 95 % CI 1.04-1.70; Education: HR 1.37, 95 % CI 1.06-1.76). The association between education and survival was modified by ethnic origin, with a gradient effect observed only among women of European origin. Women of Asian, North African and Israeli origin showed no such trend. CONCLUSIONS: SEP was associated with long-term breast cancer incidence and survival among Israeli Jews. Education had a stronger effect on breast cancer outcomes than occupation, suggesting that a behavioral mechanism may underlie disparities. More research is needed to explain the difference in the effect of education on survival among European women compared to women of other ethnicities.

Prenatal stress and affective disorders in a population birth cohort.

OBJECTIVES: Pregnant women exposed to an acute traumatic event are thought to produce offspring with an increased incidence of affective disorders. It is not known whether there are specific times in pregnancy which confer increased vulnerability, or if psychosocial stress alone can increase the incidence of affective disorders in offspring. We examined the relationship of the timing of an acute psychosocial threat during pregnancy to the incidence of affective disorders in offspring using data from a large birth cohort. METHODS: Using data on 90079 offspring born in Jerusalem in 1964-1976 and linked to Israel's psychiatric registry, we constructed proportional hazards models to evaluate the link between gestational age during the Arab-Israeli war of June 1967 and incidence of mood disorders. RESULTS: Those in their first trimester of fetal development during the war were more likely to be admitted to hospitals for any mood disorders [relative risk (RR) = 3.01, 95% confidence interval (CI): 1.68-5.39, p = 0.0002]; for bipolar disorder the risk was doubled (RR = 2.44, 95% CI: 0.996-5.99, p = 0.054) and for all 'other' mood disorders the risk was tripled (RR = 3.61, 95% CI: 1.68-7.80, p = 0.001). Mood disorders were also increased in offspring whose mothers had been in the third month of pregnancy in June of 1967 (RR = 5.54, 95% CI: 2.73-11.24, p < 0.0001). CONCLUSIONS: A time-limited exposure to a severe threat during early gestation may be associated with an increased incidence of affective disorders in offspring. The third month of fetal development was a moment of special vulnerability.

Olfaction and cognition in schizophrenia: sex matters.

Cognitive and olfactory deficits occur in schizophrenia, but little is known whether sex modifies these deficits. We examined the relationship between olfaction and cognition in 55 schizophrenia patients and 32 healthy controls. Patients and controls demonstrated significant differences performing cognitive tasks. In patients, sex modified all relationships of odor identification to cognition. Female patients showed significantly stronger trends than male patients correlating better smell identification with higher scores on intelligence, memory, and attention, whereas their correlations of odor identification with executive functioning contradicted those of male patients. Odor acuity significantly correlated with several cognitive measures, especially in male patients, in whom better acuity was generally associated with better cognition. Female patients again differed significantly from males; odor acuity correlations with cognitive measures were weaker, or contradicted, those of male patients. These findings indicate significant sex differences in olfactory processing in schizophrenia. Combining the sexes in research analyses may obscure important differences.

Older paternal age strongly increases the morbidity for schizophrenia in sisters of affected females.

The effect of a family history of schizophrenia on the risk for this disorder in the offspring has rarely been examined in a prospective population cohort accounting for the sex of the proband and the first-degree relatives, and certainly not with respect to later paternal age. The influence of affected relatives on offspring risk of schizophrenia was estimated using Cox proportional hazards regression in models that accounted for sex, relation of affected first degree relatives and paternal age in the prospective population-based cohort of the Jerusalem Perinatal Schizophrenia Study. Of all first-degree relatives, an affected mother conferred the highest risk to male and female offspring among the cases with paternal age <35 years, however, female offspring of fathers ≥35 years with an affected sister had the highest risk (RR = 8.8; 95% CI = 3.9-19.8). The risk seen between sisters of older fathers was fourfold greater than the risk to sisters of affected females of younger fathers (RR = 2.2, 95% CI 0.7-6.7). The test for interaction was significant (P = 0.03). By contrast, the risk of schizophrenia to brothers of affected males was only doubled between older (RR = 3.3, 95% 1.6-6.6) and younger fathers (RR = 1.6, 95% CI 0.7-3.5). The most striking finding from this study was the very large increase in risk of schizophrenia to sisters of affected females born to older fathers. The authors speculate that the hypothesized paternally expressed genes on the X chromosome might play some role in these observations.

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. Cox's 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.

Incidence of schizophrenia among second-generation immigrants in the jerusalem perinatal cohort.

OBJECTIVE: Increased incidence of schizophrenia is observed among some immigrant groups in Europe, with the offspring of immigrants, ie "second-generation" immigrants particularly vulnerable. Few contemporary studies have evaluated the risk of schizophrenia among second-generation immigrants in other parts of the world. METHODS: We studied the incidence of schizophrenia in relation to parental immigrant status in a population-based cohort of 88 829 offspring born in Jerusalem in 1964-1976. Parental countries of birth were obtained from birth certificates and grouped together as (1) Israel, (2) Other West Asia, (3) North Africa, and (4) Europe and industrialized countries. Cox proportional hazards methods were used in adjusting for sex, parents' ages, maternal education, social class, and birth order. RESULTS: Linkage with Israel's Psychiatric Registry identified 637 people admitted to psychiatric care facilities with schizophrenia-related diagnoses, before 1998. Incidence of schizophrenia was not increased among second-generation immigrants in this birth cohort, neither overall nor by specific group. CONCLUSIONS: The difference in risk of schizophrenia among second-generation immigrants in Europe and in this Israeli birth cohort suggests that the nature of the immigration experience may be relevant to risk, including reasons for migration, the nature of entry, and subsequent position in the host country for immigrants and their offspring. Minority status may be of importance as, in later studies, immigrants to Israel from Ethiopia had increased risk of schizophrenia.

Effect of socioeconomic status and parents' education at birth on risk of schizophrenia in offspring.

Although it is known that schizophrenia is associated with social class, controversy exists as to the nature of this association. The authors studied the incidence of schizophrenia in relation to social class at birth in a population-based cohort of 88,829 offspring born in Jerusalem in 1964-1976. They constructed a six-point scale to index social class, based on paternal occupation at the time of birth, with each of 108 occupations being ranked by mean education. Cox proportional hazards methods were used in adjusting for sex, parents' ages, duration of marriage and birth order. Linkage with Israel's Psychiatric Registry identified 637 people admitted to psychiatric care facilities with schizophrenia-related diagnoses, before 1998. There was no gradient of risk for schizophrenia associated with social class at birth; however, offspring of fathers in the lowest social class showed a modest increase in risk (adjusted Relative Risk = 1.4; 95% Confidence interval = 1.1-1.8, P = 0.002). These data suggest that in contrast to many other health outcomes, there is not a continuous gradient for increasing schizophrenia with decreasing social class of origin. Instead, a modest increase in risk for schizophrenia was observed only for those born at the bottom of the social ladder.

Short duration of marriage at conception as an independent risk factor for schizophrenia.

Short duration of marriage (DoM) is a risk factor for preeclampsia that is also related to the risk for schizophrenia. This analysis examined the risk for schizophrenia associated with DoM and its independence from parental psychiatric disorders, parental ages and fathers' age at marriage. METHOD: Relative Risks (RR) for schizophrenia were estimated using continuous and stratified Cox proportional hazards models in the 90,079 offspring from the prospective population-based Jerusalem birth cohort study (1964-1976). Schizophrenia diagnos in offspring and parental diagnoses of schizophrenia or other psychiatric conditions were identified by cross-linkage to Israel's psychiatric case registry. DoM and paternal age at marriage were abstracted from birth certificates. RESULTS: In the full model, RR for schizophrenia decreased for each 5 years DoM: 0.83 (0.75-0.95), ptrend = 0.0015. Stratified analyses showed the greatest RR risk for DoM <2 years: 1.53 (1.11-1.66) with lesser risk for 2-4 years DoM: 1.38 (1.05-1.81) compared to more DOM of 10+ years. DoM effects were independent from parental psychiatric diagnoses (RRs = 2-6, p~0.00001), paternal age (1.34: p = 0.0001 /5 years- including fathers of 25-34 years). The apparent risk related to later fathers' age at marriage (1.27: p < 0.0001) was eliminated in after accounting for DoM and later paternal age. CONCLUSIONS: Offspring born to couples married for less than 3 years, across all paternal ages, harbored a small increased risk for schizophrenia, which was independent of parental psychiatric disorders and paternal age. Fathers who married late had particularly short DoM, which, along with paternal age, completely explained the risks related to later paternal age at marriage. Further studies are needed to replicate these results and examine if pathogenic pathways include prenatal immune activation.

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 child's 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 offspring's 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.

Birthweight of offspring and mortality of parents: the Jerusalem perinatal study cohort.

PURPOSE: We sought to examine the association between birthweight in offspring and mortality in their parents. Distinguishing between risks of outcomes in mothers from fathers potentially provides clues as to the relative roles of genetic versus nongenetic mechanisms underlying these associations. METHODS: We studied total and cause-specific mortality in a population-based cohort of 37,718 mothers and 38,002 fathers whose offspring were delivered in West Jerusalem during 1964-1976, after an average follow-up of 34.12 years. RESULTS: Hazard models controlling for sociodemographic and lifestyle characteristics indicated a U-shaped relationship between offspring's birthweight and overall mortality, deaths from coronary heart disease, circulatory and other non-neoplastic causes in their mothers. Greater rates of mortality from coronary heart disease were observed among mothers who gave birth to babies with low (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.40-3.25) and high birthweight (HR, 1.98; 95% CI, 1.36-2.88), as compared with mothers whose offspring weighed 2500-3999 g at birth. Adjustment for maternal pre-eclampsia slightly attenuated these results. Multivariate models indicated a negative linear relationship (HR, 0.95; 95% CI, 0.91-0.99) between offspring's birthweight and overall mortality in their fathers. Unlike the association in mothers, the relation was noted primarily with deaths from "other causes." CONCLUSIONS: Birthweight of offspring is associated with parental mortality although the relation differs for fathers and mothers. These findings broaden previous observations that intra-uterine events have long-term consequences for adult health and support the need to explore genetic and/or environmental mechanisms underlying these associations.

The interval between cancer diagnosis among mothers and offspring in a population-based cohort.

BACKGROUND: Familial cancers may be due to shared genes or environment, or chance aggregation. We explored the possibility that ascertainment bias influences cancer detection in families, bearing upon the time interval between diagnosis of affected mothers and offspring. METHODS: The Jerusalem Perinatal Study (JPS) comprises all mothers (n = 39,734) from Western Jerusalem who gave birth 1964 -1976 and their offspring (n = 88,829). After linking identification numbers with Israel's Cancer Registry we measured the absolute time interval between initial cancer diagnoses in affected mother-offspring pairs. We tested the probability of obtaining intervals as short as those observed by chance alone, using a permutation test on the median interval. RESULTS: By June 2003 cancer had developed in 105 mother-offspring pairs within the cohort. Common sites among mothers were breast (47%), colorectal (9%), non-Hodgkin lymphoma (NHL) (8%) and cervix (7%), while for offspring in affected pairs common cancers were leukemia (12.4%), thyroid (13.3%), NHL (10.5%), breast (10.5%) and melanoma (7.6%). The median interval between diagnoses was 5.9 years, but for 33% of affected pairs the interval was < or =3 years. The probability of this occurring by chance alone was 0.03. This held true whether the offspring's or mother's diagnosis was first (P < 0.01). CONCLUSIONS: In a population-based cohort followed for three decades, the absolute interval between the diagnosis of cancer in mothers and their offspring is shorter than expected by chance. Explanations include shared environmental exposures or the possibility that cancer ascertainment in one pair member affects health behaviors in the other resulting in early diagnosis. The latter may bias the estimation of anticipation and survival in familial cancers.

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.

Late stillbirths and long-term mortality of mothers.

OBJECTIVE: To assess whether women who experienced stillbirths have an excess risk of long-term mortality. METHODS: We conducted a cohort study in the setting of the Jerusalem Perinatal Study, a population-based database of all births to West Jerusalem residents. Through data linkage with the Israeli Population Registry, we followed mothers who gave birth at least twice between 1964 and 1976 and compared the survival of women who had at least one stillbirth (n=595) with that of women who had only live births (n=24,523), using Cox proportional hazards models. RESULTS: During the study period, 78 (13.1%) mothers with stillbirths died, compared with 1,518 (6.2%) women without stillbirth (crude hazard ratio 2.08, 95% confidence interval [CI] 1.65-2.61). The mortality risk remained significantly increased after adjustments for sociodemographic variables, maternal diseases at pregnancy, placental abruption, and preeclampsia (hazard ratio 1.40, 95% CI 1.11-1.77). Stillbirth was associated with an increased risk of death from coronary heart disease (adjusted hazard ratio 2.00, 95% CI 1.02-3.93), all circulatory (adjusted hazard ratio 1.70, 95% CI 1.02-2.84) and renal (adjusted hazard ratio 4.70, 95% CI 1.47-15.0) causes. Stratifying by country of origin, an increased risk was evident particularly among women of North African origin (all-cause mortality, adjusted hazard ratio 2.47, 95% CI 1.69-3.63). CONCLUSION: Stillbirth may be a risk marker for premature mortality among parous women.

Prepregnancy body mass index, hypertensive disorders of pregnancy, and long-term maternal mortality.

OBJECTIVE: Recent studies have shown increased maternal mortality rates after hypertensive disorders of pregnancy (HDP), but the reasons for this increase remain unclear. This study examines the relationship between elevated prepregnancy body mass index (BMI), HDP, and postpregnancy mortality. STUDY DESIGN: Data came from a 1975-1976 subset (n = 13,722 women) of a population-based cohort. Multiple logistic regression was used to examine the risk of HDP by BMI; age-adjusted Cox proportional hazards models were used to examine survival rates. RESULTS: Overweight (BMI, 25-29.9 kg/m2) and obesity (BMI, > or = 30 kg/m2) were associated with increased HDP (odds ratio [OR], 2.82; 95% confidence interval [CI], 2.40-3.31 and OR, 5.51; 95% CI, 4.15-7.31]) and decreased survival (hazard ratio [HR], 1.42; 95% CI, 1.10-1.83 and HR, 2.43; 95% CI, 1.61-3.68), compared with normal weight (BMI, 18.5-24.9 kg/m2). HDP was significantly associated with increased mortality rates for women who survived > 15 years (HR, 1.94; 95% CI, 1.42-2.67]; HR adjusted for BMI, 1.65; 95% CI, 1.19-2.79]). A greater increase in risk of death after HDP was seen in the overweight women (HR, 1.86; 95% CI, 1.07-3.20) and obese women (HR, 2.90; 95% CI, 1.28-6.58), compared with normal weight women (HR, 1.26; 95% CI, 0.74-2.14). CONCLUSION: Elevated prepregnancy BMI is associated with increased risk of HDP, which are in turn is associated with increased long-term maternal mortality rates. This association between HDP and mortality rates increases with elevated prepregnancy BMI.

Advancing paternal age and autism.

CONTEXT: Maternal and paternal ages are associated with neurodevelopmental disorders. OBJECTIVE: To examine the relationship between advancing paternal age at birth of offspring and their risk of autism spectrum disorder (ASD). DESIGN: Historical population-based cohort study. SETTING: Identification of ASD cases from the Israeli draft board medical registry. PARTICIPANTS: We conducted a study of Jewish persons born in Israel during 6 consecutive years. Virtually all men and about three quarters of women in this cohort underwent draft board assessment at age 17 years. Paternal age at birth was obtained for most of the cohort; maternal age was obtained for a smaller subset. We used the smaller subset (n = 132 271) with data on both paternal and maternal age for the primary analysis and the larger subset (n = 318 506) with data on paternal but not maternal age for sensitivity analyses. MAIN OUTCOME MEASURES: Information on persons coded as having International Classification of Diseases, 10th Revision ASD was obtained from the registry. The registry identified 110 cases of ASD (incidence, 8.3 cases per 10 000 persons), mainly autism, in the smaller subset with complete parental age data. RESULTS: There was a significant monotonic association between advancing paternal age and risk of ASD. Offspring of men 40 years or older were 5.75 times (95% confidence interval, 2.65-12.46; P<.001) more likely to have ASD compared with offspring of men younger than 30 years, after controlling for year of birth, socioeconomic status, and maternal age. Advancing maternal age showed no association with ASD after adjusting for paternal age. Sensitivity analyses indicated that these findings were not the result of bias due to missing data on maternal age. CONCLUSIONS: Advanced paternal age was associated with increased risk of ASD. Possible biological mechanisms include de novo mutations associated with advancing age or alterations in genetic imprinting.

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 non-malformed 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-Hodgkin's 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-Hodgkin's 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-Hodgkin's lymphoma observed over the last 50 years.

Maternal household crowding during pregnancy and the offspring's risk of schizophrenia.

BACKGROUND: Animal models of schizophrenia suggest a link between maternal crowding during pregnancy and increased risk of the offspring to develop physiological, developmental, and behavioral abnormalities that are comparable to those observed in schizophrenia. We tested the hypothesis that a similar link is present in humans. METHOD: We investigated whether prenatal exposure to household crowding was associated with the risk of schizophrenia in a sub-cohort of the Jerusalem Perinatal Study (JPS) consisting 11,015 individuals born between 1964 and 1976. During these years mothers participated in face to face interviews in early pregnancy. The prenatal and birth data, including the number of rooms and individuals living in the mothers' household, was cross-linked with the Israel Psychiatric Registry by ministry personnel. RESULTS: 104 schizophrenia cases were identified in the cohort. Offspring who, while in utero, their mother resided in a household with five or more individuals had RR of 1.47 (95% CI: 0.99-2.16, p=0.05) to develop schizophrenia, compared to those whose mother resided with four or fewer individuals. However, when adjusted for paternal age, the RR was reduced to 1.18 (95% CI: 0.76-1.84, p=0.46). The number of rooms in the household and the household crowding during pregnancy did not significantly impact the offspring's risk to develop schizophrenia. CONCLUSION: The link between maternal household crowding during pregnancy and the offspring's risk of schizophrenia was explained primarily by the impact of paternal age. The authors discuss the results in view of findings from animal and human studies.

Paternal age and intelligence: implications for age-related genomic changes in male germ cells.

BACKGROUND: A robust association between advancing paternal age and schizophrenia risk is reported, and genetic changes in the germ cells of older men are presumed to underlie the effect. If that is so, then the pathway may include effects on cognition, as those with premorbid schizophrenia are reported to have lower intelligence. There are also substantial genetic influences on intelligence, so de novo genetic events in male germ cells, which accompany advancing paternal age, may plausibly influence offspring intelligence. OBJECTIVE: An association of paternal age with IQ in healthy adolescents may illuminate the mechanisms that link it to schizophrenia. METHOD: We examined the association of paternal age and IQ scores using the Israeli Army Board data on 44 175 individuals from a richly described birth cohort, along with maternal age and other potential modifiers. RESULTS: A significant inverted U-shaped relationship was observed between paternal age and IQ scores, which was independent from a similar association of IQ scores with maternal age. These relationships were not significantly attenuated by controlling for multiple possible confounding factors, including the other parent's age, parental education, social class, sex and birth order, birth weight and birth complications. Overall, parental age accounted for approximately 2% of the total variance in IQ scores, with later paternal age lowering non-verbal IQ scores more than verbal IQ scores. CONCLUSION: We found independent effects of maternal and paternal age on offspring IQ scores. The paternal age effect may be explained by de novo mutations or abnormal methylation of paternally imprinted genes, whereas maternal age may affect fetal neurodevelopment through age-related alterations in the in-utero environment. The influence of late paternal age to modify non-verbal IQ may be related to the pathways that increase the risk for schizophrenia in the offspring of older fathers.