Fetal sex-specific differences in gestational age at delivery in pre-eclampsia: a meta-analysis.

Background: : Pre-eclampsia (PE) is a major pregnancy disorder complicating up to 8% of pregnancies. Increasing evidence indicates a sex-specific interplay between the mother, placenta and fetus. This may lead to different adaptive mechanisms during pregnancy. Methods: We performed an individual participant data meta-analysis to determine associations of fetal sex and PE, with specific focus on gestational age at delivery in PE. This was done on 219 575 independent live-born singleton pregnancies, with a gestational age at birth between 22.0 and 43.0 weeks of gestation, from 11 studies participating in a worldwide consortium of international research groups focusing on pregnancy. Results: Of the women, 9033 (4.1%) experienced PE in their pregnancy and 48.8% of the fetuses were female versus 51.2% male. No differences in the female/male distribution were observed with respect to term PE (delivered ≥ 37 weeks). Preterm PE (delivered < 37 weeks) was slightly more prevalent among pregnancies with a female fetus than in pregnancies with a male fetus [odds ratio (OR) 1.11, 95% confidence interval (CI) 1.02-1.21]. Very preterm PE (delivered < 34 weeks) was even more prevalent among pregnancies with a female fetus as compared with pregnancies with a male fetus (OR 1.36, 95% CI 1.17-1.59). Conclusions: Sexual dimorphic differences in the occurrence of PE exist, with preterm PE being more prevalent among pregnancies with a female fetus as compared with pregnancies with a male fetus and with no differences with respect to term PE.

Cohort Profile Update: The Norwegian Mother and Child Cohort Study (MoBa).

This is an update of the Norwegian Mother and Child Cohort Study (MoBa) cohort profile which was published in 2006. Pregnant women attending a routine ultrasound examination were initially invited. The first child was born in October 1999 and the last in July 2009. The participation rate was 41%. The cohort includes more than 114 000 children, 95 000 mothers and 75 000 fathers. About 1900 pairs of twins have been born. There are approximately 16 400 women who participate with more than one pregnancy. Blood samples were obtained from both parents during pregnancy and from mothers and children (umbilical cord) after birth. Samples of DNA, RNA, whole blood, plasma and urine are stored in a biobank. During pregnancy, the mother responded to three questionnaires and the father to one. After birth, questionnaires were sent out when the child was 6 months, 18 months and 3 years old. Several sub-projects have selected participants for in-depth clinical assessment and exposure measures. The purpose of this update is to explain and describe new additions to the data collection, including questionnaires at 5, 7, 8 and 13 years as well as linkages to health registries, and to point to some findings and new areas of research. Further information can be found at [www.fhi.no/moba-en]. Researchers interested in collaboration and access to the data can complete an electronic application available on the MoBa website above.

Validity of pre-eclampsia registration in the medical birth registry of norway for women participating in the norwegian mother and child cohort study, 1999-2010.

BACKGROUND: The Norwegian Mother and Child Cohort Study (MoBa), a prospective population-based pregnancy cohort, is a valuable database for studying causes of pre-eclampsia. Pre-eclampsia data in MoBa come from the Medical Birth Registry of Norway (MBRN); thus, we wanted to study the validity of MBRN pre-eclampsia registration for MoBa women. METHODS: We selected all MoBa pregnancies with pre-eclampsia registered in the MBRN (n = 4081) and a random control group (n = 2000) without pre-eclampsia registrations. After excluding two delivery units not participating in MoBa and one no longer operating, units were asked to provide copies of antenatal charts with blood pressure and urinary measurements from all antenatal visits during pregnancy, and hospital discharge codes from the delivery stay. We received data for 5340 pregnancies delivered 1999-2010 (87% of all eligible). We calculated positive predictive value (PPV), and sensitivity and specificity of MBRN registration, using hypertension and proteinuria on the antenatal charts and/or hospital discharge codes indicating pre-eclampsia as gold standard. RESULTS: Overall PPV was 83.9% [95% CI 82.7, 85.1] and was higher when women were primiparous, or delivered preterm or low birthweight infants. Severe pre-eclampsia in the MBRN was found to be a true severe pre-eclampsia in 70% of cases. Extrapolating to the total MoBa population, the estimated sensitivity was low - 43.0% (38.7, 48.2) - while specificity was high - 99.2% (99.2, 99.3). False negative cases seemed to have mild forms of pre-eclampsia. CONCLUSIONS: PPV and specificity of pre-eclampsia registration in the MBRN during 1999-2010 was satisfactory, while sensitivity was low.

Folic acid supplementation and interpregnancy interval.

BACKGROUND: Maternal folic acid supplementation between subsequent pregnancies may be important to reduce the risk of low folate status associated with short interpregnancy intervals. We examined how the prevalence of preconception folic acid use for a given pregnancy in Norwegian women varied according to the time interval from the previous pregnancy. METHODS: Analysis was based on 48 855 pairs of pregnancies with the second pregnancy included in the Norwegian Mother and Child Cohort Study (birth years 1999-2009). Interpregnancy interval was defined as the time from birth of a child to the conception of the subsequent sibling. Preconception folic acid use was defined as any use of folic acid-containing supplements within the last 4 weeks before the second pregnancy. RESULTS: The prevalence of preconception folic acid use was 31%. Among women with a term birth (≥37 weeks) in the previous pregnancy (92%), those with interpregnancy intervals ≤12 and ≥49 months were associated with up to 35% lower prevalence of preconception folic acid use for the second pregnancy, relative to the reference group (13-24 months). The low use in short intervals was mainly attributable to lower proportion of planned pregnancies and fewer women with higher education. Among women with a preterm birth (<37 weeks) in the previous pregnancy (8%), preconception folic acid use significantly decreased with increasing pregnancy spacing. CONCLUSIONS: Our finding of a lower preconception folic acid use in women with both short and long interpregnancy intervals might help identifying those with higher risk of folate deficiency and preventing unwanted pregnancy outcomes.

Analysis of self-selection bias in a population-based cohort study of autism spectrum disorders.

BACKGROUND: This study examined potential self-selection bias in a large pregnancy cohort by comparing exposure-outcome associations from the cohort to similar associations obtained from nationwide registry data. The outcome under study was specialist-confirmed diagnosis of autism spectrum disorders (ASDs). METHODS: The cohort sample (n = 89 836) was derived from the population-based prospective Norwegian Mother and Child Cohort Study and its substudy of ASDs, the Autism Birth Cohort (ABC) study. The nationwide registry data were derived from the Medical Birth Registry of Norway (n = 507 856). The children were born in 1999­2007, and seven prenatal and perinatal exposures were selected for analyses. RESULTS: ASDs were reported for 234 (0.26%) children in the cohort and 2072 (0.41%) in the nationwide population. Compared with the nationwide population, the cohort had an under-representation of the youngest women (<25 years), those who had single status, mothers who smoked during pregnancy, and non-users of prenatal folic acid supplements. The ratios of the adjusted odds ratios (ORs) in the cohort over the adjusted ORs in the nationwide population were as follows; primipara pregnancy: 1.39/1.22, prenatal folic acid use: 0.85/0.86, prenatal smoking: 1.20/1.17, preterm birth (<37 weeks): 1.48/1.42, low birthweight (<2500 g): 1.60/1.58, male sex: 4.39/4.59 (unadjusted only); and caesarean section history: 1.03/1.04. CONCLUSIONS: Associations estimated between ASDs and perinatal and prenatal exposures in the cohort are close to those estimated in the nationwide population. Self-selection does not appear to compromise validity of exposure-outcome associations in the ABC study.

Maternal active and passive smoking and hypertensive disorders of pregnancy: risk with trimester-specific exposures.

BACKGROUND: The inverse association between prenatal smoking and preeclampsia is puzzling, given the increased risks of prematurity and low birthweight associated with both smoking and preeclampsia. We analyzed the Norwegian Mother and Child Birth Cohort (MoBa) to determine whether the associations varied by timing of prenatal smoking. METHODS: We conducted an analysis of 74,439 singleton pregnancies with completed second- and third- trimester questionnaires. Active and passive smoke exposure by trimester were determined by maternal self-report, and covered the period of preconception through approximately 30 weeks' gestation. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Rates of active smoking declined dramatically during pregnancy: for trimester 1, 23%; trimester 2, 9%; and trimester 3, 8%. Active smoking in the third trimester was associated with reduced odds of preeclampsia and gestational hypertension, with the strongest association among continuous smokers (for preeclampsia, OR= 0.57 [95% CI = 0.46-0.70]). Women who quit smoking before the third trimester had approximately the same risk of preeclampsia and gestational hypertension as nonsmokers. There was some evidence of dose-response, with the heaviest smokers (more than eight cigarettes per day) having the lowest risks of preeclampsia (0.48 [0.32-0.73]) and gestational hypertension (0.51 [0.28-0.95]). There was little evidence of an association with passive smoking exposure. CONCLUSION: The association between smoking and preeclampsia varies substantially according to the timing and intensity of exposure. A better understanding of the biologic pathways that underlie these associations may provide important clues to the etiology of preeclampsia and the development of effective clinical interventions.

Self-selection and bias in a large prospective pregnancy cohort in Norway.

Self-selection in epidemiological studies may introduce selection bias and influence the validity of study results. To evaluate potential bias due to self-selection in a large prospective pregnancy cohort in Norway, the authors studied differences in prevalence estimates and association measures between study participants and all women giving birth in Norway. Women who agreed to participate in the Norwegian Mother and Child Cohort Study (43.5% of invited; n = 73 579) were compared with all women giving birth in Norway (n = 398 849) using data from the population-based Medical Birth Registry of Norway in 2000-2006. Bias in the prevalence of 23 exposure and outcome variables was measured as the ratio of relative frequencies, whereas bias in exposure-outcome associations of eight relationships was measured as the ratio of odds ratios. Statistically significant relative differences in prevalence estimates between the cohort participants and the total population were found for all variables, except for maternal epilepsy, chronic hypertension and pre-eclampsia. There was a strong under-representation of the youngest women (<25 years), those living alone, mothers with more than two previous births and with previous stillbirths (relative deviation 30-45%). In addition, smokers, women with stillbirths and neonatal death were markedly under-represented in the cohort (relative deviation 22-43%), while multivitamin and folic acid supplement users were over-represented (relative deviation 31-43%). Despite this, no statistically relative differences in association measures were found between participants and the total population regarding the eight exposure-outcome associations. Using data from the Medical Birth Registry of Norway, this study suggests that prevalence estimates of exposures and outcomes, but not estimates of exposure-outcome associations are biased due to self-selection in the Norwegian Mother and Child Cohort Study.

Fish consumption and breast cancer risk. The European Prospective Investigation into Cancer and Nutrition (EPIC).

There is current interest in fish consumption and marine omega-3 (n-3) fatty acids and breast cancer risk. Some in vitro and animal studies have suggested an inhibitory effect of marine n-3 fatty acids on breast cancer growth, but the results from epidemiological studies that have examined the association between fish consumption and breast cancer risk in humans are inconsistent. We examined fish consumption and breast cancer risk in 310,671 women aged between 25 and 70 yr at recruitment into the European Prospective Investigation Into Cancer and Nutrition (EPIC). The participants completed a dietary questionnaire between 1992-98 and were followed up for incidence of breast cancer for a median of 6.4 yr. Hazard ratio for breast cancer by intake of total and lean and fatty fish were estimated, stratified by study centre and adjusted for established breast cancer risk factors. During follow-up, 4,776 invasive incident breast cancers were reported. No significant associations between intake of total fish and breast cancer risk were observed, hazard ratio (HR) 1.01 (95% confidence interval [CI] 0.99-1.02; p = 0.28 per 10 g fish/day). When examining lean and fatty fish separately, we found a positive significant association only in the highest quintile for fatty fish (HR 1.13, 95% CI 1.01-1.26), but test for trend was not significant (p = 0.10). No associations with breast cancer risk were observed when the study participants were subdivided by menopausal status. Although the period of follow-up is relatively short, the results provide no evidence for an association between fish intake and breast cancer risk.

[Estrogen replacement therapy and breast cancer]. / Østrogenbehandling og brystkreft.

BACKGROUND: Sales of HRT in Norway have increased considerably over the last 10 to 15 years, as has the incidence of breast cancer. The aim of this study was to investigate the relationship between use of HRT and risk of breast cancer in a Norwegian cohort of women. MATERIAL AND METHODS: The Norwegian Women and Cancer (NOWAC) study is a representative, national, population-based cohort study involving 31,451 postmenopausal women aged 45-64 who contributed information on reproduction, lifestyle and use of HRT. The women are followed up for breast cancer. RESULTS: Current users of HRT, 35% of those included, had an adjusted relative risk of breast cancer of 2.1 (95% CI 1.5-2.5). A continuous regimen of estrogen/progestagen implied an increased risk compared to a sequential regimen. Longer use increased the risk (test for trend p<0.0001). The population-attributable risk of breast cancer due to use of HRT was estimated at 27%, which equals approximately 300 cases of breast cancer per year among Norwegian women aged 45-64. INTERPRETATION: Our results suggest that current use of HRT could be considered a major determinant of the increasing incidence of breast cancer in postmenopausal women in Norway. Treatment should, accordingly, be restricted to women with serious vasomotor complaints. The dosage should be individually tailored according to potential risks and benefits, and treatment given over a short period of time.

Consumption of vegetables and fruits and risk of breast cancer.

CONTEXT: The intake of vegetables and fruits has been thought to protect against breast cancer. Most of the evidence comes from case-control studies, but a recent pooled analysis of the relatively few published cohort studies suggests no significantly reduced breast cancer risk is associated with vegetable and fruit consumption. OBJECTIVE: To examine the relation between total and specific vegetable and fruit intake and the incidence of breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 285,526 women between the ages of 25 and 70 years, participating in the European Prospective Investigation Into Cancer and Nutrition (EPIC) study, recruited from 8 of the 10 participating European countries. Participants completed a dietary questionnaire in 1992-1998 and were followed up for incidence of cancer until 2002. MAIN OUTCOME MEASURES: Relative risks for breast cancer by total and specific vegetable and fruit intake. Analyses were stratified by age at recruitment and study center. Relative risks were adjusted for established breast cancer risk factors. RESULTS: During 1,486,402 person-years (median duration of follow-up, 5.4 years), 3659 invasive incident breast cancer cases were reported. No significant associations between vegetable or fruit intake and breast cancer risk were observed. Relative risks for the highest vs the lowest quintile were 0.98 (95% confidence interval [CI], 0.84-1.14) for total vegetables, 1.09 (95% CI , 0.94-1.25) for total fruit, and 1.05 (95% CI , 0.92-1.20) for fruit and vegetable juices. For 6 specific vegetable subgroups no associations with breast cancer risk were observed either. CONCLUSION: Although the period of follow-up is limited for now, the results suggest that total or specific vegetable and fruit intake is not associated with risk for breast cancer.

Hormone replacement therapy and incidence of hormone-dependent cancers in the Norwegian Women and Cancer study.

Increasing use of HRT over the last 2 decades could have contributed to the increasing incidence of cancer in women. Our aim was to investigate the relation between use of HRT and risk of hormone-dependent cancers in a Norwegian cohort of women. The Norwegian Women and Cancer (NOWAC) study is a representative, national, population-based cohort study. This report includes 35,456 postmenopausal women aged 45-64 years who answered a postal questionnaire in 1996-1998 providing information on reproduction, lifestyle and use of HRT. The women were followed up for cancer incidence. The main analyses were restricted to 31,451 postmenopausal women with complete information. Ever use of HRT was reported by 43.5% and current use, by 35% of the women. Current users had an increased risk of breast cancer (adjusted RR=2.1, 95% CI 1.5-2.5). The risk increased with increasing duration of use (ptrend < 0.0001). Using a regimen of continuous estrogen-progestagen implied an increased risk. Adjusted RRs associated with <5 and > or =5 years' duration of use were 2.6 (95% CI 1.9-3.7) and 3.2 (95% CI 2.2-4.6), respectively. The population-attributable risk of breast cancer due to current use of HRT was 27%. We found no significant increase in risk of ovarian cancer. Neither did we find users of estrogen-progestagen preparations to have any increase in risk of endometrial cancer. Our results suggest that HRT could be considered a major determinant for the increasing incidence of breast cancer in Norway.

Use of hormonal contraceptives and occurrence of pregnancy-related pelvic pain: a prospective cohort study in Norway.

BACKGROUND: Pregnancy-related pelvic pain is a common condition, and use of hormonal contraceptives before pregnancy has been proposed as a risk factor. We used data from a sub-sample of women participating in the "Norwegian Women and Cancer study" (NOWAC) to assess the association between hormonal contraceptive use and pelvic pain in pregnancy. METHODS: From a sub-group of 2078 parous women participating in the NOWAC study, information was collected from a self-instructive four-page questionnaire containing questions about lifestyle and medical conditions. We calculated odds ratios (OR) and 95% confidence intervals (CI), using unconditional logistic regression. RESULTS: In this study, the prevalence of pelvic pain in women was 26.5% during the first pregnancy and increased with parity. Use of hormonal contraceptives before a woman's first pregnancy was associated with an increased risk of pelvic pain in her first pregnancy (OR = 1.6; 95% confidence interval 1.2-2.2). There was no association between use of hormonal contraceptives and pelvic pain in the second or third pregnancy. Occurrence of pelvic pain in a previous pregnancy was the only factor associated with pelvic pain in subsequent pregnancies (OR = 51.1; 95% CI 32.9-79.5 in the second pregnancy and OR = 28.3; 95% CI 15.4-53.1 in the third pregnancy). CONCLUSION: Use of hormonal contraceptives was associated with an increased risk of pelvic pain in a woman's first pregnancy. The most important determinant of pelvic pain in the second or third pregnancy was the history of pelvic pain in the preceding pregnancy.

[Use of oral contraceptives and risk of cancer, a cohort study]. / Bruk av p-piller og risiko for kreft.

BACKGROUND: Use of oral contraceptives and the risk of cancer continues to be an issue. MATERIAL AND METHODS: The Norwegian Women and Cancer Cohort Study was initiated in order to study the use of oral contraceptives and risk of cancer. A total of 102 443 women aged 31-70 were included from 1991 to 1997. In the follow-up analysis through 1999, 851 of the 96 355 eligible women had developed breast cancer, 171 ovarian cancer, 118 cervical cancer, 110 endometrial cancer and 219 colorectal cancer. RESULTS: The risk of breast cancer increased with the duration of oral contraceptive use (p for trend p = 0.002), while risk of ovarian and endometrial cancer decreased (p for trend p = 0.03 for endometrial cancer and p < 0.0001 for ovarian cancer). No significant association between the use of oral contraceptives and the combined risk of breast/endometrial/ovarian cancer was revealed. INTERPRETATION: Use of oral contraceptives does not seem to change the overall risk of cancer. The increased risk of breast cancer is compensated by the protective effect in relation to endometrial and ovarian cancer.

Breast cancer and specific types of oral contraceptives: a large Norwegian cohort study.

The aim of our study was to examine the risk of breast cancer according to specific types of estrogens and progestagens in oral contraceptives (OCs) based on the prospective Norwegian Women and Cancer study (NOWAC). Between 1991-97 women aged 30-70 years were drawn at random from the central person register and mailed an invitation and a questionnaire. Women (102,443) were enrolled with follow-up information collected throughout 1999 by linkage with national registries of cancer, mortality and emigration based on the unique national identification number. Among the 96,362 women included in the present analysis 851 invasive breast cancer were diagnosed. The adjusted risk of breast cancer increased with 25% for ever use of OCs and the risk increased with increasing duration of use (test for trend: p = 0.007). No association between time since last use and breast cancer risk was found after stratification on duration of use. Positive trend was still found for total duration of use among women who used OCs more than 5 years ago. Second generation of OCs had an increased risk with increasing duration of use. Classifying progestagens according to chemical groups, the relative risk increased significantly with increasing cumulative dose of levonorgestrel progestagen. It was difficult to conclude for the other groups due to lack of power. In a multivariate analysis the cumulative dose for all progestagen groups were non-significant, although we observed a significant increased risk with increasing milligram-months of estrogen exposure (p = 0.002). In conclusion, the increased risk of breast cancer related with OC formulations could be due mostly to estrogen component.