No association between long-chain n-3 fatty acid intake during pregnancy and risk of type 1 diabetes in offspring in two large Scandinavian pregnancy cohorts.

AIMS/HYPOTHESIS: The aim of this study was to investigate whether higher dietary intake of marine n-3 fatty acids during pregnancy is associated with a lower risk of type 1 diabetes in children. METHODS: The Danish National Birth Cohort (DNBC) and the Norwegian Mother, Father and Child Cohort Study (MoBa) together include 153,843 mother-child pairs with prospectively collected data on eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake during pregnancy from validated food frequency questionnaires. Type 1 diabetes diagnosis in children (n=634) was ascertained from national diabetes registries. RESULTS: There was no association between the sum of EPA and DHA intake during pregnancy and risk of type 1 diabetes in offspring (pooled HR per g/day of intake: 1.00, 95% CI 0.88, 1.14), with consistent results for both the MoBa and the DNBC. Robustness analyses gave very similar results. CONCLUSIONS/INTERPRETATION: Initiation of a trial of EPA and DHA during pregnancy to prevent type 1 diabetes in offspring should not be prioritised.

Association of common maternal infections with birth outcomes: a multinational cohort study.

PURPOSE: It is unclear whether common maternal infections during pregnancy are risk factors for adverse birth outcomes. We assessed the association between self-reported infections during pregnancy with preterm birth and small-for-gestational-age (SGA) in an international cohort consortium. METHODS: Data on 120,507 pregnant women were obtained from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA. Self-reported common infections during pregnancy included influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections, cystitis, urinary tract infection, and the symptoms fever and diarrhoea. Birth outcomes included preterm birth, low birth weight and SGA. Associations between maternal infections and birth outcomes were first assessed using Poisson regression in each cohort and then pooled using random-effect meta-analysis. Risk ratios (RR) and 95% confidence intervals (CI) were calculated, adjusted for potential confounders. RESULTS: Vaginal infections (pooled RR, 1.10; 95% CI, 1.02-1.20) and urinary tract infections (pooled RR, 1.17; 95% CI, 1.09-1.26) during pregnancy were associated with higher risk of preterm birth. Similar associations with low birth weight were also observed for these two infections. Fever during pregnancy was associated with higher risk of SGA (pooled RR, 1.07; 95% CI, 1.02-1.12). No other significant associations were observed between maternal infections/symptoms and birth outcomes. CONCLUSION: Vaginal infections and urinary infections during pregnancy were associated with a small increased risk of preterm birth and low birth weight, whereas fever was associated with SGA. These findings require confirmation in future studies with laboratory-confirmed infection diagnosis.

Parental occupational exposure to pesticides, animals and organic dust and risk of childhood leukemia and central nervous system tumors: Findings from the International Childhood Cancer Cohort Consortium (I4C).

Parental occupational exposures to pesticides, animals and organic dust have been associated with an increased risk of childhood cancer based mostly on case-control studies. We prospectively evaluated parental occupational exposures and risk of childhood leukemia and central nervous system (CNS) tumors in the International Childhood Cancer Cohort Consortium. We pooled data on 329,658 participants from birth cohorts in five countries (Australia, Denmark, Israel, Norway and United Kingdom). Parental occupational exposures during pregnancy were estimated by linking International Standard Classification of Occupations-1988 job codes to the ALOHA+ job exposure matrix. Risk of childhood (<15 years) acute lymphoblastic leukemia (ALL; n = 129), acute myeloid leukemia (AML; n = 31) and CNS tumors (n = 158) was estimated using Cox proportional hazards models to generate hazard ratios (HR) and 95% confidence intervals (CI). Paternal exposures to pesticides and animals were associated with increased risk of childhood AML (herbicides HR = 3.22, 95% CI = 0.97-10.68; insecticides HR = 2.86, 95% CI = 0.99-8.23; animals HR = 3.89, 95% CI = 1.18-12.90), but not ALL or CNS tumors. Paternal exposure to organic dust was positively associated with AML (HR = 2.38 95% CI = 1.12-5.07), inversely associated with ALL (HR = 0.55, 95% CI = 0.31-0.99) and not associated with CNS tumors. Low exposure prevalence precluded evaluation of maternal pesticide and animal exposures; we observed no significant associations with organic dust exposure. This first prospective analysis of pooled birth cohorts and parental occupational exposures provides evidence for paternal agricultural exposures as childhood AML risk factors. The different risks for childhood ALL associated with maternal and paternal organic dust exposures should be investigated further.

Sodium Intake during Pregnancy, but Not Other Diet Recommendations Aimed at Preventing Cardiovascular Disease, Is Positively Related to Risk of Hypertensive Disorders of Pregnancy.

BACKGROUND: The role of diet on hypertensive disorders of pregnancy (HDPs), including preeclampsia and gestational hypertension (GHTN), remains unclear. OBJECTIVES: We evaluated whether adherence during pregnancy to dietary recommendations that reduce cardiovascular disease (CVD) in the general population is related to the risk of HDPs. METHODS: We followed 66,651 singleton pregnancies from 62,774 women participating in the Danish National Birth Cohort. Diet was assessed during week of gestation 25 with an FFQ from which we created 2 dietary pattern scores: 1) AHA, based on the diet recommendations from the AHA 2020 Strategic Impact Goals; and 2) the Dietary Approaches to Stop Hypertension (DASH) diet. Cases of HDPs were identified through linkage with the Danish National Patient Registry. RRs and 95% CIs of HDPs were estimated by increasing quintiles of adherence to the AHA and DASH scores using log-Poisson regression models with generalized estimating equations-to account for repeated pregnancies per woman-while adjusting for potential confounders. RESULTS: We identified 1809 cases of HDPs: n = 1310 preeclampsia (n = 300 severe preeclampsia) and n = 499 cases of GHTN. Greater adherence to AHA or DASH scores was not related to the risk of HDPs. However, when each component of the scores was separately evaluated, there were positive linear relations of sodium intake with HDPs (P-linearity < 0.01). Women with the highest sodium intake [median 3.70 g/d (range: 3.52, 7.52 g/d)] had 54% (95% CI:16%, 104%) higher risk of GHTN and 20% (95% CI:1%, 42%) higher risk of preeclampsia than women with the lowest intake [median 2.60 g/d (range: 0.83, 2.79 g/d)]. In addition, intake of whole grains was positively related to the risk of GHTN but not to preeclampsia ( P-heterogeneity = 0.002). CONCLUSION: Sodium intake during pregnancy, but no other diet recommendations to prevent CVD among nonpregnant adults, is positively related to the occurrence of HDPs among pregnant Danish women.

Nut Consumption and Renal Function Among Women With a History of Gestational Diabetes.

OBJECTIVE: Nut intake has been associated with reduced cardiometabolic risk, but few studies have examined its association with renal function. We examined associations between nut intake and renal function among women with previous gestational diabetes mellitus (GDM), a population with an increased risk for renal dysfunction. DESIGN AND METHODS: This study included 607 women with a history of GDM who participated in the Diabetes & Women's Health Study (2012-2014) follow-up clinical examination in Denmark. At the clinic, biospecimens were collected, and habitual intake of nuts (9 types) in the past year was assessed using a food frequency questionnaire. A total of 330 women free of major chronic diseases were included in the analysis. Total nut intake was classified as none (≤1 serving/month), monthly (2-3 servings/month), weekly (1-6 servings/week), and daily (≥1 serving/day). One serving was defined as 28 g. Renal function markers included estimated glomerular rate (eGFR) and urinary albumin-to-creatinine ratio (UACR), calculated based on plasma creatinine (mg/dL), and urinary albumin (mg/L), and creatinine (mg/dL) measurements, respectively. We estimated percent differences with 95% confidence intervals for each outcome by nut intake, adjusted for current body mass index, age, physical activity, energy intake, alcohol consumption, and vegetables intake. RESULTS: We observed a nonlinear association between total nut intake and UACR with lowest UACR values among women with weekly intake. Compared to women with weekly intake (n = 222), the adjusted UACR values were higher by 86% [95% confidence interval: 15%, 202%], 24% [-1%, 54%], and 117% [22%, 288%] among women with no (n = 13), monthly (n = 86), and daily (n = 9) intake, respectively. Compared to weekly consumers, daily nut consumers also had 9% [0%, 19%] significantly higher eGFR values, but eGFR values were similar among women with no and monthly intake. CONCLUSION: Moderate nut consumption may be beneficial to kidney health among women with prior GDM.

The association between birth order and childhood leukemia may be modified by paternal age and birth weight. Pooled results from the International Childhood Cancer Cohort Consortium (I4C).

The "delayed infection hypothesis" states that a paucity of infections in early childhood may lead to higher risks of childhood leukemia (CL), especially acute lymphoblastic leukemia (ALL). Using prospectively collected data from six population-based birth cohorts we studied the association between birth order (a proxy for pathogen exposure) and CL. We explored whether other birth or parental characteristics modify this association. With 2.2 × 106 person-years of follow-up, 185 CL and 136 ALL cases were ascertained. In Cox proportional hazards models, increasing birth order (continuous) was inversely associated with CL and ALL; hazard ratios (HR) = 0.88, 95% confidence interval (CI): (0.77-0.99) and 0.85: (0.73-0.99), respectively. Being later-born was associated with similarly reduced hazards of CL and ALL compared to being first-born; HRs = 0.78: 95% CI: 0.58-1.05 and 0.73: 0.52-1.03, respectively. Successive birth orders were associated with decreased CL and ALL risks (P for trend 0.047 and 0.055, respectively). Multivariable adjustment somewhat attenuated the associations. We found statistically significant and borderline interactions between birth weight (p = 0.024) and paternal age (p = 0.067), respectively, in associations between being later-born and CL, with the lowest risk observed for children born at <3 kg with fathers aged 35+ (HR = 0.18, 95% CI: 0.06-0.50). Our study strengthens the theory that increasing birth order confers protection against CL and ALL risks, but suggests that this association may be modified among subsets of children with different characteristics, notably advanced paternal age and lower birth weight. It is unclear whether these findings can be explained solely by infectious exposures.

Fish Oil-Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring.

BACKGROUND: Reduced intake of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. We assessed the effect of supplementation with n-3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring. METHODS: We randomly assigned 736 pregnant women at 24 weeks of gestation to receive 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day. Their children formed the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) cohort and were followed prospectively with extensive clinical phenotyping. Neither the investigators nor the participants were aware of group assignments during follow-up for the first 3 years of the children's lives, after which there was a 2-year follow-up period during which only the investigators were unaware of group assignments. The primary end point was persistent wheeze or asthma, and the secondary end points included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization. RESULTS: A total of 695 children were included in the trial, and 95.5% completed the 3-year, double-blind follow-up period. The risk of persistent wheeze or asthma in the treatment group was 16.9%, versus 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.97; P=0.035), corresponding to a relative reduction of 30.7%. Prespecified subgroup analyses suggested that the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011). Analyses of secondary end points showed that supplementation with n-3 LCPUFA was associated with a reduced risk of infections of the lower respiratory tract (31.7% vs. 39.1%; hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.033), but there was no statistically significant association between supplementation and asthma exacerbations, eczema, or allergic sensitization. CONCLUSIONS: Supplementation with n-3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third. (Funded by the Lundbeck Foundation and others; ClinicalTrials.gov number, NCT00798226 .).

Examining the Effect of Fish Oil Supplementation in Chinese Pregnant Women on Gestation Duration and Risk of Preterm Delivery.

BACKGROUND: Intervention studies have shown that long-chain (LC) n-3 PUFA intake can prolong gestation but the dose-time-effect relations remain unresolved. OBJECTIVES: We examined the effect on gestation duration of 2 doses of supplemental LC n-3 PUFAs. METHODS: We undertook a 3-group parallel randomized controlled trial in areas of China with low (median: 2.1 g/d) and higher (14.3 g/d) fish intake. Unselected women (median: age, 26.2 y; BMI, 20. kg/m2) were randomly assigned at midgestation to take four 0.72-g identical gelatin capsules per day until the last day of the preterm period (<259 days of gestation), when they were asked to stop. Capsules contained fish oil [high fish oil (HFO) group (60% w/w LC n-3 PUFAs)], a 1:3 mixture of fish oil to olive oil [low fish oil (LFO) group (20%)], or olive oil [control (CON) group (0%)], providing 2.0, 0.5, and 0 g/d of LC n-3 PUFAs, respectively. Habitual fish intake was recorded at baseline. Hazard rate ratios (HRRs) for spontaneous delivery <259 days of gestation and <273 days of gestation across groups were estimated by Cox regression. RESULTS: Among 5531 women randomly assigned, 92.5% were included in analyses (1706/1825, 1695/1851, and 1717/1855, respectively). The groups were similar with respect to hazard rates <259 days of gestation [HRR: 1.04 (95% CI: 0.70, 1.53) for LFO compared with CON and 0.90 (95% CI: 0.60, 1.35) for HFO compared with CON], hazard rates <273 days of gestation [HRR: 1.00 (95% CI: 0.86, 1.18) and 0.91 (95% CI: 0.77, 1.07), respectively], and mean gestation durations [differences: 0.2 d (95% CI: -0.5, 0.8) and 0.6 d (95% CI: -0.06, 1.2), respectively]. Inspection of pregnancy survival curves suggested that LC n-3 PUFAs delayed delivery in low fish consumers by 5-10 d and that this effect ceased rapidly after stopping taking the capsules. CONCLUSION: This trial could not substantiate that fish oil prevents preterm birth in Chinese women, possibly because statistical power was too low. This trial was registered at clinicaltrials.gov as NCT02770456.

Telomere length is reduced in 9- to 16-year-old girls exposed to gestational diabetes in utero.

AIMS/HYPOTHESIS: Shortened telomere length is a marker of cell damage and is associated with oxidative stress, chronic inflammation and metabolic disease. We hypothesised that the offspring of women with gestational diabetes mellitus (GDM) with increased risk of cardiovascular and metabolic diseases might exhibit shorter telomere length. METHODS: We investigated telomere length in 439 GDM and 469 control group offspring, aged between 9 and 16 years, recruited from the Danish National Birth Cohort. Relative telomere length was measured in peripheral blood DNA (n = 908) using a quantitative PCR approach. Multivariate regression analysis was used to investigate the association between mothers' GDM status and telomere length in the offspring. RESULTS: Female offspring had longer telomeres than males. Offspring of mothers with GDM had significantly shorter telomere length than control offspring, but this difference was observed only in girls. There was a negative association between telomere length and GDM exposure among the female offspring (14% shorter telomeres, p = 0.003) following adjustment for the age of the offspring. Telomere length in female offspring was negatively associated with fasting insulin levels and HOMA-IR (p = 0.03). Maternal age, smoking, gestational age, birthweight and the offspring's anthropometric characteristics were not associated with telomere length (p ≥ 0.1). CONCLUSIONS/INTERPRETATION: The 9- to 16-year-old girls of mothers with GDM had shorter telomeres than those from the control population. Further studies are needed to understand the extent to which shortened telomere length predicts and/or contributes to the increased risk of disease later in life among the offspring of women with GDM.

Lack of Association Between Maternal or Neonatal Vitamin D Status and Risk of Childhood Type 1 Diabetes: A Scandinavian Case-Cohort Study.

Studies on vitamin D status during pregnancy and risk of type 1 diabetes mellitus (T1D) lack consistency and are limited by small sample sizes or single measures of 25-hydroxyvitamin D (25(OH)D). We investigated whether average maternal 25(OH)D plasma concentrations during pregnancy are associated with risk of childhood T1D. In a case-cohort design, we identified 459 children with T1D and a random sample (n = 1,561) from the Danish National Birth Cohort (n = 97,127) and Norwegian Mother and Child Cohort Study (n = 113,053). Participants were born between 1996 and 2009. The primary exposure was the estimated average 25(OH)D concentration, based on serial samples from the first trimester until delivery and on umbilical cord plasma. We estimated hazard ratios using weighted Cox regression adjusting for multiple confounders. The adjusted hazard ratio for T1D per 10-nmol/L increase in the estimated average 25(OH)D concentration was 1.00 (95% confidence interval: 0.90, 1.10). Results were consistent in both cohorts, in multiple sensitivity analyses, and when we analyzed mid-pregnancy or cord blood separately. In conclusion, our large study demonstrated that normal variation in maternal or neonatal 25(OH)D is unlikely to have a clinically important effect on risk of childhood T1D.

Parental Smoking and Risk of Childhood-onset Type 1 Diabetes.

BACKGROUND: A few prospective studies suggest an association between maternal smoking during pregnancy and lower risk of type 1 diabetes. However, the role of unmeasured confounding and misclassification remains unclear. METHODS: We comprehensively evaluated whether maternal smoking in pregnancy predicts lower risk of childhood-onset type 1 diabetes in two Scandinavian pregnancy cohorts (185,076 children; 689 cases) and a Norwegian register-based cohort (434,627 children; 692 cases). We measured cord blood cotinine as an objective marker of nicotine exposure during late pregnancy in 154 cases and 476 controls. We also examined paternal smoking during pregnancy, in addition to environmental tobacco smoke exposure the first 6 months of life, to clarify the role of characteristics of smokers in general. RESULTS: In the pregnancy cohorts, maternal smoking beyond gestational week 12 was inversely associated with type 1 diabetes, pooled adjusted hazard ratio (aHR) 0.66 (95% CI = 0.51, 0.85). Similarly, in the Norwegian register-based cohort, children of mothers who still smoked at the end of pregnancy had lower risk of type 1 diabetes, aHR 0.65 (95% CI = 0.47, 0.89). Cord blood cotinine ≥30 nmol/L was also associated with reduced risk of type 1 diabetes, adjusted odds ratio 0.42 (95% CI = 0.17, 1.0). We observed no associations of paternal smoking during pregnancy, or environmental tobacco smoke exposure, with childhood-onset type 1 diabetes. CONCLUSION: Maternal sustained smoking during pregnancy is associated with lower risk of type 1 diabetes in children. This sheds new light on the potential intrauterine environmental origins of the disease.

Relative validity of a web-based food frequency questionnaire for Danish adolescents.

BACKGROUND: With increased focus on dietary intake among youth and risk of diseases later in life, it is of importance, prior to assessing diet-disease relationships, to examine the validity of the dietary assessment tool. This study's objective was to evaluate the relative validity of a self-administered web-based FFQ among Danish children aged 12 to 15 years. METHODS: From a nested sub-cohort within the Danish National Birth Cohort, 124 adolescents participated. Four weeks after completion of the FFQ, adolescents were invited to complete three telephone-based 24HRs; administered 4 weeks apart. Mean or median intakes of nutrients and food groups estimated from the FFQ were compared with the mean of 3x24HRs. To assess the level of ranking we calculated the proportion of correctly classified into the same quartile, and the proportion of misclassified (into the opposite quartile). Spearman's correlation coefficients and de-attenuated coefficients were calculated to assess agreement between the FFQ and 24HRs. RESULTS: The mean percentage of all food groups, for adolescents classified into the same and opposite quartile was 35 and 7.5%, respectively. Mean Spearman's correlation was 0.28 for food groups and 0.35 for nutrients, respectively. Adjustment for energy and within-person variation in the 24HRs had little effect on the magnitude of the correlations for food groups and nutrients. We found overestimation by the FFQ compared with the 24HRs for fish, fruits, vegetables, oils and dressing and underestimation by the FFQ for meat/poultry and sweets. Median intake of beverages, dairy, bread, cereals, the mean total energy and carbohydrate intake did not differ significantly between the two methods. CONCLUSION: The relative validity of the FFQ compared with the 3x24HRs showed that the ranking ability differed across food groups and nutrients with best ranking for estimated intake of dairy, fruits, and oils and dressing. Larger variation was observed for fish, sweets and vegetables. For nutrients, the ranking ability was acceptable for fatty acids and iron. When evaluating estimates from the FFQ among Danish adolescents these findings should be considered.

Omega-3 fatty acid addition during pregnancy.

BACKGROUND: Higher intakes of foods containing omega-3 long-chain polyunsaturated fatty acids (LCPUFA), such as fish, during pregnancy have been associated with longer gestations and improved perinatal outcomes. This is an update of a review that was first published in 2006. OBJECTIVES: To assess the effects of omega-3 LCPUFA, as supplements or as dietary additions, during pregnancy on maternal, perinatal, and neonatal outcomes and longer-term outcomes for mother and child. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 August 2018), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing omega-3 fatty acids (as supplements or as foods, stand-alone interventions, or with a co-intervention) during pregnancy with placebo or no omega-3, and studies or study arms directly comparing omega-3 LCPUFA doses or types. Trials published in abstract form were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data, assessed risk of bias in trials and assessed quality of evidence for prespecified birth/infant, maternal, child/adult and health service outcomes using the GRADE approach. MAIN RESULTS: In this update, we included 70 RCTs (involving 19,927 women at low, mixed or high risk of poor pregnancy outcomes) which compared omega-3 LCPUFA interventions (supplements and food) compared with placebo or no omega-3. Overall study-level risk of bias was mixed, with selection and performance bias mostly at low risk, but there was high risk of attrition bias in some trials. Most trials were conducted in upper-middle or high-income countries; and nearly half the trials included women at increased/high risk for factors which might increase the risk of adverse maternal and birth outcomes.Preterm birth < 37 weeks (13.4% versus 11.9%; risk ratio (RR) 0.89, 95% confidence interval (CI) 0.81 to 0.97; 26 RCTs, 10,304 participants; high-quality evidence) and early preterm birth < 34 weeks (4.6% versus 2.7%; RR 0.58, 95% CI 0.44 to 0.77; 9 RCTs, 5204 participants; high-quality evidence) were both lower in women who received omega-3 LCPUFA compared with no omega-3. Prolonged gestation > 42 weeks was probably increased from 1.6% to 2.6% in women who received omega-3 LCPUFA compared with no omega-3 (RR 1.61 95% CI 1.11 to 2.33; 5141 participants; 6 RCTs; moderate-quality evidence).For infants, there was a possibly reduced risk of perinatal death (RR 0.75, 95% CI 0.54 to 1.03; 10 RCTs, 7416 participants; moderate-quality evidence: 62/3715 versus 83/3701 infants) and possibly fewer neonatal care admissions (RR 0.92, 95% CI 0.83 to 1.03; 9 RCTs, 6920 participants; moderate-quality evidence - 483/3475 infants versus 519/3445 infants). There was a reduced risk of low birthweight (LBW) babies (15.6% versus 14%; RR 0.90, 95% CI 0.82 to 0.99; 15 trials, 8449 participants; high-quality evidence); but a possible small increase in large-for-gestational age (LGA) babies (RR 1.15, 95% CI 0.97 to 1.36; 6 RCTs, 3722 participants; moderate-quality evidence, for omega-3 LCPUFA compared with no omega-3. Little or no difference in small-for-gestational age or intrauterine growth restriction (RR 1.01, 95% CI 0.90 to 1.13; 8 RCTs, 6907 participants; moderate-quality evidence) was seen.For the maternal outcomes, there is insufficient evidence to determine the effects of omega-3 on induction post-term (average RR 0.82, 95% CI 0.22 to 2.98; 3 trials, 2900 participants; low-quality evidence), maternal serious adverse events (RR 1.04, 95% CI 0.40 to 2.72; 2 trials, 2690 participants; low-quality evidence), maternal admission to intensive care (RR 0.56, 95% CI 0.12 to 2.63; 2 trials, 2458 participants; low-quality evidence), or postnatal depression (average RR 0.99, 95% CI 0.56 to 1.77; 2 trials, 2431 participants; low-quality evidence). Mean gestational length was greater in women who received omega-3 LCPUFA (mean difference (MD) 1.67 days, 95% CI 0.95 to 2.39; 41 trials, 12,517 participants; moderate-quality evidence), and pre-eclampsia may possibly be reduced with omega-3 LCPUFA (RR 0.84, 95% CI 0.69 to 1.01; 20 trials, 8306 participants; low-quality evidence).For the child/adult outcomes, very few differences between antenatal omega-3 LCPUFA supplementation and no omega-3 were observed in cognition, IQ, vision, other neurodevelopment and growth outcomes, language and behaviour (mostly low-quality to very low-quality evidence). The effect of omega-3 LCPUFA on body mass index at 19 years (MD 0, 95% CI -0.83 to 0.83; 1 trial, 243 participants; very low-quality evidence) was uncertain. No data were reported for development of diabetes in the children of study participants. AUTHORS' CONCLUSIONS: In the overall analysis, preterm birth < 37 weeks and early preterm birth < 34 weeks were reduced in women receiving omega-3 LCPUFA compared with no omega-3. There was a possibly reduced risk of perinatal death and of neonatal care admission, a reduced risk of LBW babies; and possibly a small increased risk of LGA babies with omega-3 LCPUFA.For our GRADE quality assessments, we assessed most of the important perinatal outcomes as high-quality (e.g. preterm birth) or moderate-quality evidence (e.g. perinatal death). For the other outcome domains (maternal, child/adult and health service outcomes) GRADE ratings ranged from moderate to very low, with over half rated as low. Reasons for downgrading across the domain were mostly due to design limitations and imprecision.Omega-3 LCPUFA supplementation during pregnancy is an effective strategy for reducing the incidence of preterm birth, although it probably increases the incidence of post-term pregnancies. More studies comparing omega-3 LCPUFA and placebo (to establish causality in relation to preterm birth) are not needed at this stage. A further 23 ongoing trials are still to report on over 5000 women, so no more RCTs are needed that compare omega-3 LCPUFA against placebo or no intervention. However, further follow-up of completed trials is needed to assess longer-term outcomes for mother and child, to improve understanding of metabolic, growth and neurodevelopment pathways in particular, and to establish if, and how, outcomes vary by different types of omega-3 LCPUFA, timing and doses; or by characteristics of women.

Fish oil supplementation during pregnancy and allergic respiratory disease in the adult offspring.

BACKGROUND: Maternal supplementation with long-chain n-3 polyunsaturated fatty acids can have immunologic effects on the developing fetus through several anti-inflammatory pathways. However, there is limited knowledge of the long-term programming effects. OBJECTIVE: In a randomized controlled trial from 1990 with 24 years of follow-up, our aim was to determine whether supplementation with 2.7 g of long-chain n-3 polyunsaturated fatty acids in pregnancy can reduce the risk of asthma in offspring and allergic respiratory disease. METHODS: The randomized controlled trial included 533 women who were randomly assigned to receive fish oil during the third trimester of pregnancy, olive oil, or no oil in the ratio 2:1:1. The offspring were followed in a mandatory national prescription register, with complete follow-up for prescriptions related to the treatment of asthma and allergic rhinitis as primary outcomes. Furthermore, the offspring were invited to complete a questionnaire (74% participated) and attend a clinical examination (47% participated) at age 18 to 19 years. RESULTS: In intention-to-treat analyses the probability of having had asthma medication prescribed was significantly reduced in the fish oil group compared with the olive oil group (hazard ratio, 0.54, 95% CI, 0.32-0.90; P = .02). The probability of having had allergic rhinitis medication prescribed was also reduced in the fish oil group compared with the olive oil group (hazard ratio, 0.70, 95% CI, 0.47-1.05; P = .09), but the difference was not statistically significant. Self-reported information collected at age 18 to 19 years supported these findings. No associations were detected with respect to lung function outcomes or allergic sensitization at 18 to 19 years of age. CONCLUSION: Maternal supplementation with fish oil might have prophylactic potential for long-term prevention of asthma in offspring.

Impact of Road Traffic Pollution on Pre-eclampsia and Pregnancy-induced Hypertensive Disorders.

BACKGROUND: Road traffic is a major source of air pollution and noise. Both exposures have been associated with hypertension in adults, but pregnant women have been less studied. METHODS: We examined single and joint effects of ambient air pollution and road traffic noise on pre-eclampsia and pregnancy-induced hypertensive disorders among 72,745 singleton pregnancies (1997-2002) from the Danish National Birth Cohort with complete covariate data and residential address history from conception until live born birth. Nitrogen dioxide (NO2) and noise from road traffic (Lden) were modeled at all addresses. Outcome and covariate data were derived from registries, hospital records, and questionnaires. RESULTS: A 10-µg/m increase in NO2 exposure during first trimester was associated with increased risk of pre-eclampsia (n = 1,880, adjusted odds ratio = 1.07 [95% confidence interval = 1.01, 1.14]) and pregnancy-induced hypertensive disorders (n = 2,430, adjusted odds ratio = 1.07 [1.01, 1.13]). A 10 dB higher road traffic noise was also associated with increased risk of pre-eclampsia (1.10 [1.02, 1.18]) and pregnancy-induced hypertensive disorders (1.08 [1.02, 1.15]). For both exposures, the associations were strongest for mild pre-eclampsia (n = 1,393) and early-onset pre-eclampsia (n = 671), whereas higher risk for severe pre-eclampsia (n = 487) was not evident. In mutually adjusted models, estimates for both exposures decreased and only the association between NO2 and mild pre-eclampsia remained. CONCLUSIONS: Road traffic may increase the risk of pre-eclampsia and hypertensive disorders in pregnancy through exposure to both ambient air pollution and noise, although associations with the two exposures were generally not found to be independent of one another. See video abstract, http://links.lww.com/EDE/B112.

Diagnosing gestational diabetes mellitus in the Danish National Birth Cohort.

INTRODUCTION: The Danish National Birth Cohort (DNBC) contains comprehensive information on diet, lifestyle, constitutional and other major characteristics of women during pregnancy. It provides a unique source for studies on health consequences of gestational diabetes mellitus. Our aim was to identify and validate the gestational diabetes mellitus cases in the cohort. MATERIAL AND METHODS: We extracted clinical information from hospital records for 1609 pregnancies included in the Danish National Birth Cohort with a diagnosis of diabetes during or before pregnancy registered in the Danish National Patient Register and/or from a Danish National Birth Cohort interview during pregnancy. We further validated the diagnosis of gestational diabetes mellitus in 2126 randomly selected pregnancies from the entire Danish National Birth Cohort. From the individual hospital records, an expert panel evaluated gestational diabetes mellitus status based on results from oral glucose tolerance tests, fasting blood glucose and Hb1c values, as well as diagnoses made by local obstetricians. RESULTS: The audit categorized 783 pregnancies as gestational diabetes mellitus, corresponding to 0.89% of the 87 792 pregnancies for which a pregnancy interview for self-reported diabetes in pregnancy was available. From the randomly selected group the combined information from register and interviews could correctly identify 96% (95% CI 80-99.9%) of all cases in the entire Danish National Birth Cohort population. Positive predictive value, however, was only 59% (56-61%). CONCLUSIONS: The combined use of data from register and interview provided a high sensitivity for gestational diabetes mellitus diagnosis. The low positive predictive value, however, suggests that systematic validation by hospital record review is essential not to underestimate the health consequences of gestational diabetes mellitus in future studies.

Plasma Concentrations of Ferritin in Early Pregnancy Are Associated with Risk of Gestational Diabetes Mellitus in Women in the Danish National Birth Cohort.

BACKGROUND: Evidence from experimental studies has demonstrated that higher than normal iron concentrations can lead to pancreatic ß cell dysfunction and impaired glucose metabolism. Studies on body iron stores in early pregnancy and subsequent gestational diabetes mellitus (GDM) risk are sparse. OBJECTIVE: Our objective was to determine whether biomarkers of body iron stores measured in early pregnancy are associated with GDM risk. METHODS: A case-control study of 350 GDM cases and 349 non-GDM controls was conducted in participants from the Danish National Birth Cohort. Blood was collected at a mean ± SD gestational age of 9.4 ± 3.2 wk. Plasma biomarkers of iron stores, including ferritin and soluble transferrin receptor (sTfR), were measured. Logistic regression was used to estimate the OR of GDM associated with quintiles of plasma biomarkers of body iron stores, controlling for maternal age, family history of diabetes, exercise in pregnancy, parity, and prepregnancy body mass index (BMI). RESULTS: Cases were older (mean ± SD age: 32.2 ± 4.3 compared with 29.9 ± 4.2 y) and had a higher BMI (in kg/m(2); mean ± SD: 28.7 ± 6.0 compared with 24.1 ± 4.6) than controls. Plasma concentrations of both ferritin and sTfR in early pregnancy were significantly higher in GDM cases than in controls [means ± SDs: 80.6 ± 56.0 compared with 71.8 ± 50.1 µg/L (P = 0.03) and 1.5 ± 0.7 compared with 1.4 ± 0.6 mg/L (P = 0.002) for ferritin and sTfR, respectively]. Ferritin was positively and significantly associated with GDM risk even after adjustment for major risk factors of GDM, including prepregnancy BMI. ORs across increasing quintiles of ferritin were 1.00 (reference), 1.25 (95% CI: 0.70, 2.22), 1.89 (95% CI: 1.06, 3.37), 0.82 (95% CI: 0.46, 1.48), and 2.34 (95% CI: 1.30, 4.21) (P-linear trend = 0.02). CONCLUSION: These findings suggest that plasma ferritin measured in early pregnancy is significantly and positively associated with GDM risk.

Maternal thyroid function in pregnancy may program offspring blood pressure, but not adiposity at 20 y of age.

BACKGROUND: Experimental evidence exists indicating that maternal thyroid hormones during pregnancy may affect the metabolic set point and cardio-vascular function in the offspring. The objective of this study was to investigate the association between maternal thyroid function in week 30 of gestation and offspring adiposity and blood pressure at 20 y. METHODS: The study was based on the follow up of a Danish birth cohort from 1988 to 1989 (n = 965). A blood sample was drawn from the pregnant women in week 30 of gestation (N = 877). In 2008-2009, the offspring were followed up with self-reported anthropometrics (N = 645) and a clinically measured blood pressure (N = 425). Multiple linear regressions were used to estimate the association between maternal thyroid function and offspring BMI, waist circumference, and blood pressure. RESULTS: Offspring of subclinical hypothyroid women had higher systolic blood pressure (adjusted difference = 3.6, 95% confidence interval: 0.2, 7.0 mmHg) and a tendency toward higher diastolic blood pressure (adjusted difference = 2.3, 95% confidence interval: -0.2, 4.9 mmHg) compared to offspring of euthyroid women. No association was found with offspring BMI and waist circumference. CONCLUSION: Maternal thyroid function during third trimester of pregnancy may affect long-term blood pressure in the offspring.

The long-term programming effect of maternal 25-hydroxyvitamin D in pregnancy on allergic airway disease and lung function in offspring after 20 to 25 years of follow-up.

BACKGROUND: High prenatal vitamin D status has been linked to decreased risk of atopic diseases in early childhood, but whether such relations persist until adulthood has not been explored. OBJECTIVE: We sought to examine the association between maternal 25-hydryxovitamin D (25[OH]D) concentrations and outcomes of allergic airway disease and lung function in offspring with 20 to 25 years of follow-up. METHODS: In a prospective birth cohort with 965 pregnant women enrolled in 1988-1989, maternal 25(OH)D concentrations were quantified in serum from gestational week 30 (n = 850 [88%]). Offspring were followed in nationwide registries with complete follow-up to the age of 25 years (n = 850 [100%]). Additionally, at age 20 years, outcomes of allergic airway disease and lung function were assessed in a subset of offspring by using blood samples and spirometry (n = 410 [45%]) and a questionnaire (n = 641 [70%]). RESULTS: Exposure to a high maternal 25(OH)D concentration (≥125 nmol/L) was associated with an increased risk of asthma hospitalizations in offspring (hazard ratio [HR], 1.81; 95% CI, 0.78-4.16) during 25 years of follow-up compared with the reference group (75-<125 nmol/L). Furthermore, there were lower risks of asthma hospitalizations (HR, 0.29; 95% CI, 0.08-1.02) and asthma medication use (HR, 0.58; 95% CI, 0.35-0.95) in those exposed to a low maternal 25(OH)D concentration (<50 nmol/L). In a reduced set of participants, we found no associations between maternal 25(OH)D concentrations and offspring allergen-specific IgE, total IgE, and eosinophil cationic protein levels; self-reported doctor's diagnosis of asthma or hay fever; or lung function at 20 years of age. CONCLUSIONS: Our study does not provide support for a protective effect of a high maternal 25(OH)D concentration on outcomes of allergic airway disease and lung function at 20 to 25 years of age. In contrast, a high maternal 25(OH)D concentration might be associated with an increased risk of allergic diseases in offspring.

Long-term risk of type 2 diabetes mellitus in relation to BMI and weight change among women with a history of gestational diabetes mellitus: a prospective cohort study.

AIMS/HYPOTHESIS: Women with a history of gestational diabetes mellitus (GDM) are advised to control their weight after pregnancy. We aimed to examine how adiposity and weight change influence the long-term risk of developing type 2 diabetes after GDM. METHODS: We included 1,695 women who had incident GDM between 1991 and 2001, as part of the Diabetes & Women's Health study, and followed them until the return of the 2009 questionnaire. Body weight and incident type 2 diabetic cases were reported biennially. We defined baseline as the questionnaire period when women reported an incident GDM pregnancy. We estimated HRs and 95% CIs using Cox proportional hazards models. RESULTS: We documented 259 incident cases of type 2 diabetes during up to 18 years of follow-up. The adjusted HRs of type 2 diabetes associated with each 1 kg/m(2) increase in BMI were 1.16 (95% CI 1.12, 1.19) for baseline BMI and 1.16 (95% CI 1.13, 1.20) for most recent BMI. Moreover, each 5 kg increment of weight gain after GDM development was associated with a 27% higher risk of type 2 diabetes (adjusted HR 1.27; 95% CI 1.04, 1.54). Jointly, women who had a BMI ≥30.0 kg/m(2) at baseline and gained ≥5 kg after GDM had an adjusted HR of 43.19 (95% CI 13.60, 137.11), compared with women who had a BMI <25.0 kg/m(2) at baseline and gained <5 kg after GDM. CONCLUSIONS/INTERPRETATION: Baseline BMI, most recent BMI and weight gain after GDM were significantly and positively associated with risk of progression from GDM to type 2 diabetes.