Prenatal fever and autism risk.

Some studies suggest that prenatal infection increases risk of autism spectrum disorders (ASDs). This study was undertaken in a prospective cohort in Norway to examine whether we could find evidence to support an association of the prenatal occurrence of fever, a common manifestation of infection, with ASD risk. Prospective questionnaires provided maternal exposure data; case status was established from clinical assessments and registry linkages. In a large, prospectively ascertained cohort of pregnant mothers and their offspring, we examined infants born ⩾32 weeks for associations between fever exposure in each trimester and ASD risk using logistic regression. Maternal exposure to second-trimester fever was associated with increased ASD risk, adjusting for presence of fever in other trimesters and confounders (adjusted odds ratio (aOR), 1.40; 95% confidence interval, 1.09-1.79), with a similar, but nonsignificant, point estimate in the first trimester. Risk increased markedly with exposure to three or more fever episodes after 12 weeks' gestation (aOR, 3.12; 1.28-7.63). ASD risk appears to increase with maternal fever, particularly in the second trimester. Risk magnified dose dependently with exposure to multiple fevers after 12 weeks' gestation. Our findings support a role for gestational maternal infection and innate immune responses to infection in the pathogenesis of at least some cases of ASD.

ViPAR: a software platform for the Virtual Pooling and Analysis of Research Data.

BACKGROUND: Research studies exploring the determinants of disease require sufficient statistical power to detect meaningful effects. Sample size is often increased through centralized pooling of disparately located datasets, though ethical, privacy and data ownership issues can often hamper this process. Methods that facilitate the sharing of research data that are sympathetic with these issues and which allow flexible and detailed statistical analyses are therefore in critical need. We have created a software platform for the Virtual Pooling and Analysis of Research data (ViPAR), which employs free and open source methods to provide researchers with a web-based platform to analyse datasets housed in disparate locations. METHODS: Database federation permits controlled access to remotely located datasets from a central location. The Secure Shell protocol allows data to be securely exchanged between devices over an insecure network. ViPAR combines these free technologies into a solution that facilitates 'virtual pooling' where data can be temporarily pooled into computer memory and made available for analysis without the need for permanent central storage. RESULTS: Within the ViPAR infrastructure, remote sites manage their own harmonized research dataset in a database hosted at their site, while a central server hosts the data federation component and a secure analysis portal. When an analysis is initiated, requested data are retrieved from each remote site and virtually pooled at the central site. The data are then analysed by statistical software and, on completion, results of the analysis are returned to the user and the virtually pooled data are removed from memory. CONCLUSIONS: ViPAR is a secure, flexible and powerful analysis platform built on open source technology that is currently in use by large international consortia, and is made publicly available at [http://bioinformatics.childhealthresearch.org.au/software/vipar/].

Autism risk associated with parental age and with increasing difference in age between the parents.

Advancing paternal and maternal age have both been associated with risk for autism spectrum disorders (ASD). However, the shape of the association remains unclear, and results on the joint associations is lacking. This study tests if advancing paternal and maternal ages are independently associated with ASD risk and estimates the functional form of the associations. In a population-based cohort study from five countries (Denmark, Israel, Norway, Sweden and Western Australia) comprising 5 766 794 children born 1985-2004 and followed up to the end of 2004-2009, the relative risk (RR) of ASD was estimated by using logistic regression and splines. Our analyses included 30 902 cases of ASD. Advancing paternal and maternal age were each associated with increased RR of ASD after adjusting for confounding and the other parent's age (mothers 40-49 years vs 20-29 years, RR=1.15 (95% confidence interval (CI): 1.06-1.24), P-value<0.001; fathers⩾50 years vs 20-29 years, RR=1.66 (95% CI: 1.49-1.85), P-value<0.001). Younger maternal age was also associated with increased risk for ASD (mothers <20 years vs 20-29 years, RR=1.18 (95% CI: 1.08-1.29), P-value<0.001). There was a joint effect of maternal and paternal age with increasing risk of ASD for couples with increasing differences in parental ages. We did not find any support for a modifying effect by the sex of the offspring. In conclusion, as shown in multiple geographic regions, increases in ASD was not only limited to advancing paternal or maternal age alone but also to differences parental age including younger or older similarly aged parents as well as disparately aged parents.

Degree of fetal growth restriction associated with schizophrenia risk in a national cohort.

BACKGROUND: Accumulating evidence suggests that fetal growth restriction may increase risk of later schizophrenia but this issue has not been addressed directly in previous studies. We examined whether the degree of fetal growth restriction was linearly related to risk of schizophrenia, and also whether maternal pre-eclampsia, associated with both placental dysfunction and poor fetal growth, was related to risk of schizophrenia. METHOD: A population-based cohort of single live births in the Medical Birth Registry of Norway (MBRN) between 1967 and 1982 was followed to adulthood (n=873 612). The outcome was schizophrenia (n=2207) registered in the National Insurance Scheme (NIS). The degree of growth restriction was assessed by computing sex-specific z scores (standard deviation units) of ' birth weight for gestational age' and ' birth length for gestational age'. Analyses were adjusted for potential confounders. Maternal pre-eclampsia was recorded in the Medical Birth Registry by midwives or obstetricians using strictly defined criteria. RESULTS: The odds ratio (OR) for schizophrenia increased linearly with decreasing birth weight for gestational age z scores (p value for trend=0.005). Compared with the reference group (z scores 0.01­1.00), the adjusted OR [95% confidence interval (CI)] for the lowest z-score category (

Remission, continuation and incidence of eating disorders during early pregnancy: a validation study in a population-based birth cohort.

BACKGROUND: We internally validated previously published rates of remission, continuation and incidence of broadly defined eating disorders during pregnancy in the Norwegian Mother and Child Cohort (MoBa) at the Norwegian Institute of Public Health. METHOD: A total of 77 267 pregnant women enrolled at 17 weeks gestation between 2001 and 2009 were split into a training sample (n = 41 243) from the version 2 dataset and a validation sample (n = 36 024) from the version 5 dataset who were not in the original study. Internal validation of original rate models involved fitting a calibration model to compare model parameters between the two samples and bootstrap estimates of bias in the entire version 5 dataset. RESULTS: Remission, continuation and incidence estimates remained stable. Pre-pregnancy prevalence estimates in the validation sample were: anorexia nervosa (AN; 0.1%), bulimia nervosa (BN; 1.0%), binge eating disorder (BED; 3.3%) and eating disorder not otherwise specified-purging disorder (EDNOS-P; 0.1%). In early pregnancy, estimates were: BN (0.2%), BED (4.8%) and EDNOS-P (<0.01%). Incident BN and EDNOS-P during pregnancy were rare. The highest rates were for full or partial remission for BN and EDNOS-P and continuation for BED. CONCLUSIONS: We validated previously estimated rates of remission, continuation and incidence of eating disorders during pregnancy. Eating disorders, especially BED, during pregnancy were relatively common, occurring in nearly one in every 20 women. Pregnancy was a window of remission from BN but a window of vulnerability for BED. Training to detect eating disorders by obstetricians/gynecologists and interventions to enhance pregnancy and neonatal outcomes warrant attention.

Male-mediated infertility in sons of building painters and gardeners: a nationwide register-based follow-up study.

AIM: To investigate whether sons of gardeners and building painters have increased risk of infertility in comparison with sons of bricklayers, carpenters and electricians. METHODS: Participants were men born 1965-1984 in Denmark whose fathers the year before birth had worked as gardeners, painters, bricklayers, carpenters or electricians (N=22,978). Cases of infertility were identified by Danish registers, and participants were followed-up for up to 24 years after their 20th birthday. RESULTS: Sons of gardeners did not have increased risk of infertility. Hazard ratios for sons of painters fluctuated around the null in main analyses but were 1.6 (98% CI: 1.0-2.5) and 1.7 (95% CI: 0.9-3.2) in the subset of participants with smallest risk of paternal exposure misclassification. CONCLUSIONS: Working as gardener or building painter was not related to increased risk of infertility among the next generation of males in main analyses. However, inherent limitations in data may have attenuated true associations.

The Autism Birth Cohort: a paradigm for gene-environment-timing research.

The reported prevalence of autism spectrum disorders (ASDs) has increased by 5- to 10-fold over the past 20 years. Whether ASDs are truly more frequent is controversial; nonetheless, the burden is profound in human and economic terms. Although autism is among the most heritable of mental disorders, its pathogenesis remains obscure. Environmental factors are proposed; however, none is implicated. Furthermore, there are no biomarkers to screen for ASD or risk of ASD. The Autism Birth Cohort (ABC) was initiated to analyze gene x environment x timing interactions and enable early diagnosis. It uses a large, unselected birth cohort in which cases are prospectively ascertained through population screening. Samples collected serially through pregnancy and childhood include parental blood, maternal urine, cord blood, milk teeth and rectal swabs. More than 107,000 children are continuously screened through questionnaires, referral, and a national registry. Cases are compared with a control group from the same cohort in a 'nested case-control' design. Early screening and diagnostic assessments and re-assessments are designed to provide a rich view of longitudinal trajectory. Genetic, proteomic, immunologic, metagenomic and microbiological tools will be used to exploit unique biological samples. The ABC is a paradigm for analyzing the role of genetic and environmental factors in complex disorders.

The effect of recurrent miscarriage and infertility on the risk of pre-eclampsia.

OBJECTIVE: Pre-eclampsia, recurrent miscarriage and infertility may all partly be caused by unsuccessful placentation early in pregnancy. If so, one will expect these disorders to be associated in population studies. The aim of the present investigation was to estimate the risk of pre-eclampsia in women with recurrent miscarriage and infertility. DESIGN: Cohort study. SETTING: The Norwegian Mother and Child Cohort Study (MoBa), a large population-based pregnancy cohort. SAMPLE: The sample consisted of 20,846 singleton pregnancies to nulliparous women participating in the MoBa, 1999-2005. METHODS: Information on miscarriage, infertility and potential confounders was self-reported in postal questionnaires, whereas the diagnosis of pre-eclampsia was retrieved from the Medical Birth Registry of Norway. Risk estimation and confounder control was performed with multiple logistic regression. MAIN OUTCOME MEASURES: Pre-eclampsia according to history of miscarriage and infertility. RESULTS: An increased risk of pre-eclampsia, although not statistically significant, was found for women with recurrent miscarriages (adjusted OR 1.51, 95% CI 0.80-2.83). Women who had ever been treated for infertility also had increased risk (adjusted OR 1.29, 95% CI 1.05-1.60). When these two risk factors were combined, the adjusted odds ratio for pre-eclampsia was 2.40 (95% CI 1.11-5.18). CONCLUSIONS: The study supports the hypothesis that infertility, recurrent miscarriage and pre-eclampsia share elements of the same aetiological factors.

Back-neck pain and symptoms of anxiety and depression: a population-based twin study.

BACKGROUND: Clinical and epidemiological studies have shown an association between anxiety and depression and pain in the back and neck. The nature of this relationship is not clear. This study aimed to investigate the extent to which common genetic and environmental aetiological factors contribute to the covariance between symptoms of anxiety and depression and back-neck pain. METHODS: Measures of back-neck pain and symptoms of anxiety and depression were part of a self-report questionnaire sent in 1992 to twins born in Norway between 1967 and 1974 (3996 pairs). Structural equation modelling was applied to determine to what extent back-neck pain and symptoms of anxiety and depression share genetic and environmental liability factors. RESULTS: The phenotypic correlation between symptoms of anxiety and depression and back-neck pain was 0.31. Individual differences in both anxiety and depression and back-neck pain were best accounted for by additive genetic and individual environmental factors. Heritability estimates were 0.53 and 0.30 respectively. For back-neck pain, however, a model specifying only shared- and individual environmental effects could not be rejected. Bivariate analyses revealed that the correlation between back-neck pain and symptoms of anxiety and depression was best explained by additive genetic and individual environmental factors. Genetic factors affecting both phenotypes accounted for 60% of the covariation. There were no significant sex differences. CONCLUSION: The results support previous findings of a moderate association between back-neck pain and symptoms of anxiety and depression, and suggest that this association is primarily due to common genetic effects.

Cesarean section among immigrants in Norway.

OBJECTIVE: We studied prevalences and risk factors for cesarean section among different groups of immigrants from countries outside Western Europe and North America in comparison to ethnic Norwegians. METHODS: The study is population based using data from the Medical Birth Registry of Norway. A total of 553,491 live births during the period 1986-1995 were studied, including 17,891 births to immigrant mothers. RESULTS: The prevalences of cesarean section ranged from 10.1% among women from Vietnam to 25.8% in the group of Filipino origin. The use of abdominal delivery was also high in the groups from Sri Lanka/India (21.3%), Somalia/Eritrea/Ethiopia (20.5%) and Chile/Brazil (24.3%), while the frequency among women from Turkey/Morocco (12.6%) and Pakistan (13.2%) was approximately the same as among ethnic Norwegians (12.4%). Feto-pelvic disproportion, fetal distress and prolonged labor were the most important diagnoses associated with the high prevalences, but the significance of these diagnoses differed among the groups. Other unknown factors come into play, particularly among women from Somalia/Eritrea/Ethiopia and Chile/Brazil. CONCLUSION: There was substantial variation in the use of cesarean section among ethnic groups in Norway. The diagnoses feto-pelvic disproportion, fetal distress and prolonged labor may be confounded by a number of factors including maternal request for cesarean section and difficulties in handling the delivery. Further research is needed to explain the observed differences.

Consanguinity and recurrence risk of stillbirth and infant death.

OBJECTIVES: The aim of this study was to estimate the recurrence risk for stillbirth and infant death and compare results for offspring of first-cousin parents with results for offspring of unrelated parents. METHODS: The study population consisted of all single births with a previous sibling born in Norway between 1967 and 1994. Altogether, 629,888 births were to unrelated parents, and 3466 births were to parents who were first cousins. The risk of stillbirth and infant death was estimated for subsequent siblings contingent on parental consanguinity and survival of the previous sibling. RESULTS: For unrelated parents, the risk of early death (stillbirth plus infant death) for the subsequent sibling was 17 of 1000 if the previous child survived and 67 of 1000 if the previous child died before 1 year of age. For parents who were first cousins, the risk of early death for the subsequent sibling was 29 of 1000 if the previous child survived and 116 of 1000 if the previous child died. CONCLUSIONS: The risk of recurrence of stillbirth and infant death is higher for offspring of first-cousin parents compared with offspring of unrelated parents.

Consanguinity and recurrence risk of birth defects: a population-based study.

Recurrence risks give insight into the causes of birth defects and are useful in genetic counseling. There are few population-based studies of recurrence of birth defects for subsequent sibs with consanguineous parents. The aim of this study was to estimate and compare the recurrence risk of birth defects for offspring of first cousins and nonconsanguineous parents. The study population consisted of all single births with a previous sib born in Norway between 1967 and 1995. Altogether 660,398 children had nonconsanguineous parents, and 3,583 had parents who were first cousins. For nonconsanguineous parents the risk of a birth defect for the subsequent sib was 15 per 1,000 births (95% confidence interval: 14.5-15.1) if the previous child did not have a birth defect and 33 (95% confidence interval: 30-37) if the previous child had a birth defect. For parents who were first cousins the risk of a birth defect for the subsequent sib was 36 per 1,000 (95% confidence interval: 30-42) if the previous child did not have a birth defect and 68 (95% confidence interval: 33-122) if the previous child had a birth defect. The risk of recurrence of birth defects is higher for subsequent sibs with first-cousin parents than for those with nonconsanguineous parents. This difference indicates the degree to which the increased homozygosity among offspring of consanguineous parents influences the risk of recurrence of birth defects.

Complaints and complications in pregnancy: a study of ethnic Norwegian and ethnic Pakistani women in Oslo.

OBJECTIVES: To describe the pattern of complaints and complications in pregnancy among ethnic Norwegian and ethnic Pakistani women in Oslo in order to modify antenatal care services. DESIGN: A cross-sectional study of hospital patients conducted in community hospitals in Oslo, Norway. A total of 137 obstetrical patients, 66 ethnic Pakistani and 71 ethnic Norwegian women were included in the study. Medical complications and subjective reported physical complaints during pregnancy were the main outcome measures. RESULTS: Among the ethnic Pakistani women complications were more common and the risks were higher for gestational diabetes [crude odds ratio (OR) = 5.6, 95% confidence interval (CI) = 1.5-20.5), intrauterine growth retardation (crude OR = 5.0, 95% CI = 1.4-18.8), hyperemesis gravidarum (crude OR = 3.7, 95% CI = 1.1-12.2) and anaemia (crude OR = 10.2, 95% CI = 3.3-31.4). The frequency of congenital malformations (p = 0.048, OR not calculated) were also higher. Among the ethnic Norwegian women the frequency of subjective reported physical complaints were more common and the risks were higher for pelvic girdle pain (crude OR = 0.4, 95% CI = 0.2-0.8) and exhaustion (crude OR = 0.2, 95% CI = 0.04-0.1). Infections such as hepatitis and tuberculosis only occurred in the Pakistani study group. CONCLUSION: This study indicates that health personnel delivering antenatal care to women of Pakistani origin need to be watchful for the following conditions: gestational diabetes, hyperemesis gravidarum, early diagnosis of the type of anaemia, fetal malformations and infections like hepatitis and tuberculosis. In addition, a correct diagnosis of intrauterine growth retardation is important. Among ethnic Norwegian women pelvic girdle pain and exhaustion were common complaints.

Influence of consanguinity and maternal education on risk of stillbirth and infant death in Norway, 1967-1993.

To analyze the influence of consanguinity and maternal education on stillbirth and infant death for children born in Norway between 1967 and 1993, the authors studied 7,274 children of ethnic Pakistani origin and 1,431,055 children of Norwegian ethnic origin. Of these children, 31.0% of the Pakistani children and 0.1% of the Norwegian children had parents who were first cousins. Consanguinity increased the relative risk of stillbirth (odds ratio (OR) = 1.3, 95% confidence interval (CI) 1.0-1.6) and infant death (OR = 2.4, 95% CI 2.0-3.0), after adjustment for maternal education, maternal age, parity, and year of birth. In 1985-1993, 29% (95% CI 13-45) of stillbirths and infant deaths among the Pakistani group were attributable to consanguinity. In the Norwegian group, 17% (95% CI 13-21) of the deaths were attributable to factors associated with low maternal education, while in the Pakistani group, the corresponding estimate was nonsignificant. The risks of stillbirth and infant death were similar for children with non-consanguineous parents in both populations. This is an important observation considering the differences in socioeconomic status between the two groups. The authors conclude that consanguinity influenced stillbirth and infant death independent of maternal education, and that a large proportion of deaths could be attributed to consanguinity in the Pakistani group due to high frequencies of consanguinity.

Birth defects and parental consanguinity in Norway.

The study compares frequencies of birth defects between immigrant groups and the rest of the Norwegian population in Norway and estimates the influence of consanguinity and socioeconomic factors on these frequencies. The authors studied all 1.56 million births in Norway from 1967 to 1993. Of these, 7,494 children had two Pakistani parents, 84,688 had one Norwegian and one immigrant parent, and 25,891 had two immigrant parents from countries other than Pakistan. The risk of birth defects relative to the Norwegian group was 0.98 (95% confidence interval 0.92-1.03) in the group with one foreign and one Norwegian parent, 1.39 (95% confidence interval 1.22-1.60) in the group with two Pakistani parents, and 1.04 (95% confidence interval 0.95-1.14) in the group with two parents from other foreign countries; 0.1% of the Norwegian and 30.1% of the Pakistani children had parents who were first cousins. There was no difference in risk between children of nonconsanguineous Pakistani parents and the other groups. The relative risk of birth defects among children whose parents were first cousins was about 2 in all groups. Among the Pakistani, 28% of all birth defects could be attributed to consanguinity. Low paternal educational level was associated with a slightly increased risk in the Norwegian group, while independent effects of parental educational levels were not found in any other groups.

Ethnicity and use of obstetrical analgesia: do Pakistani women receive inadequate pain relief in labour?

OBJECTIVE: To study whether the use of analgesic treatment in labour is influenced by ethnicity. DESIGN: A cross-sectional study of hospital patients. Setting; the two municipal hospitals, Ullevål and Aker, in Oslo, Norway. Subjects; a total of 137 obstetrical patients, 67 Pakistani women and 70 Norwegian women. Main outcome measure; use of analgesics in labour. RESULTS: 30% of the Pakistani and 9% of the Norwegian women received no analgesia in labour. Pethidine injection was the preferred analgesic administered to Pakistani women. Women of Pakistani origin received epidural infusion or nitrous oxide and oxygen gas less frequently than Norwegian women. They also received fewer combinations of other analgesic methods. When adjusted for the mothers' age, parity and duration of delivery, Pakistani origin was the only significant predictor for receiving no analgesia in labour. CONCLUSION: Women of Pakistani origin were more than three times as likely not to receive analgesia in labour as Norwegian women. The health services offered to Pakistani women in labour were different from those offered to Norwegian women. These results indicate that women of Pakistani origin may be offered insufficient obstetrical analgesia, or that Norwegian women received unnecessary pain relief in labour.