Background: Perfluoroalkyl adds are persistent compounds used in various industrial applications. Of these compounds, perfluorooctanoate (PFOA) is currently detected in humans worldwide. A recent ...study on low-dose developmental exposure to PFOA in mice reported increased weight and elevated biomarkers of adiposity in postpubertal female offspring. Objective: We examined whether the findings of increased weight in postpubertal female mice could be replicated in humans. Methods: A prospective cohort of 665 Danish pregnant women was recruited in 1988-1989 with offspring follow-up at 20 years. PFOA was measured in serum from gestational week 30. Offspring body mass index (BMI) and waist circumference were recorded at follow-up (n = 665), and bio-markers of adiposity were quantified in a subset (n = 422) of participants. Results: After adjusting for covariates, including maternal prepregnancy BMI, smoking, education, and birth weight, in utero exposure to PFOA was positively associated with anthropometry at 20 years in female but not male offspring. Adjusted relative risks comparing the highest with lowest quartile (median: 5.8 vs. 2.3 ng/mL) of maternal PFOA concentration were 3.1 95% confidence interval (CI): 1.4, 6.9 for overweight or obese (BMI ≥ 25 kg/m²) and 3.0 (95% CI: 1.3, 6.8) for waist circumference > 88 cm among female offspring. This corresponded to estimated increases of 1.6 kg/m² (95% CI: 0.6, 2.6) and 4.3 cm (95% CI: 1.4, 7.3) in average BMI and waist circumference, respectively. In addition, maternal PFOA concentrations were positively associated with serum insulin and leptin levels and inversely associated with adiponectin levels in female offspring. Similar associations were observed for males, although point estimates were less precise because of fewer observations. Maternal perfluorooctane sulfonate (PFOS), perfluorooctane sulfonamide (PFOSA), and perfluorononanoate (PFNA) concentrations were not independently associated with offspring anthropometry at 20 years. Conclusions: Our findings on the effects of low-dose developmental exposures to PFOA are in line with experimental results suggesting obesogenic effects in female offspring at 20 years of age.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Objective To study the association between endometriosis and risk of pre-eclampsia, cesarean section, postpartum hemorrhage, preterm birth, and small for gestational age (SGA), in a large Danish ...birth cohort, while taking fertility treatment into account. Design Population-based study. Setting Not applicable. Patient(s) A total population of 82,793 singleton pregnancies from the Aarhus Birth Cohort (1989 through 2013); 1,213 women had a diagnosis of endometriosis, affecting 1,719 pregnancies. Intervention(s) None. Main Outcome Measure(s) Pre-eclampsia, cesarean section, postpartum hemorrhage, preterm birth, and SGA. Result(s) Endometriosis was associated with an increased risk of preterm birth (adjusted odds ratio AOR 1.67, 95% confidence interval CI 1.37–2.05), with the risk being highest for very preterm birth (AOR 1.91, 95% CI 1.16–3.15). Compared with unaffected women, women with endometriosis also had an increased risk of pre-eclampsia (AOR 1.37, 95% CI 1.06–1.77) and cesarean section (AOR 1.83, 95% CI 1.60–2.09). Assisted reproductive technology did not explain these findings. No association was found between endometriosis and postpartum hemorrhage or SGA. Conclusion(s) Women with endometriosis were at increased risk of pre-eclampsia, preterm birth, and cesarean section, irrespective of use of assisted reproductive technology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Perfluoroalkyl substances (PFASs) are persistent pollutants found to be endocrine disruptive and neurotoxic in animals. Positive correlations between PFASs and neurobehavioral problems in children ...were reported in cross-sectional data, but findings from prospective studies are limited.
We investigated whether prenatal exposure to PFASs is associated with attention deficit/hyperactivity disorder (ADHD) or childhood autism in children.
Among 83,389 mother-child pairs enrolled in the Danish National Birth Cohort during 1996-2002, we identified 890 ADHD cases and 301 childhood autism cases from the Danish National Hospital Registry and the Danish Psychiatric Central Registry. From this cohort, we randomly selected 220 cases each of ADHD and autism, and we also randomly selected 550 controls frequency matched by child's sex. Sixteen PFASs were measured in maternal plasma collected in early or mid-pregnancy. We calculated risk ratios (RRs) using generalized linear models, taking into account sampling weights.
Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples; four other PFASs were quantified in ≥ 90% of the samples. We did not find consistent evidence of associations between mother's PFAS plasma levels and ADHD per natural log nanograms per milliliter increase: PFOS RR = 0.87 (95% CI: 0.74, 1.02); PFOA RR = 0.98 (95% CI: 0.82, 1.16) or autism per natural log nanograms per milliliter increase: PFOS RR = 0.92 (95% CI: 0.69, 1.22); PFOA RR = 0.98 (95% CI: 0.73, 1.31). We found positive as well as negative associations between higher PFAS quartiles and ADHD in models that simultaneously adjusted for all PFASs, but these estimates were imprecise.
In this study we found no consistent evidence to suggest that prenatal PFAS exposure increases the risk of ADHD or childhood autism in children.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Background: Participation rates in large cohort studies have decreased during the last 2 decades. The consequences of this trend for relative risk estimation are unknown. Methods: The impact of a low ...participation rate (30%) on the Danish National Birth Cohort was examined among 49,751 women from the source population, including 15,373 participants in the cohort study. On the basis of independent data collection, we estimated odds ratios (ORs) in the source population and among participants for 3 exposure-risk associations: (a) in vitro fertilization and preterm birth, (b) smoking during pregnancy and birth of a small-for-gestational-age infant, and (c) prepregnancy body mass index and antepartum stillbirth. The effect of nonparticipation was described by a relative odds ratio (ROR), calculated as the OR (participants)/OR (source population). Two methods for calculation of confidence intervals for the relative odds ratio also were assessed. Results: The effect of nonparticipation on the selected ORs was small. The relative ORs were close to one and the bias was never larger than 16%, although some of the confidence intervals were wide. The 2 methods for calculation of confidence intervals gave very similar results and a small simulation study showed that the coverage probabilities were close to the 95% nominal level. Conclusion: For the 3 chosen associations, the ORs were not biased by nonparticipation. The results are reassuring for studies based on the Danish cohort and similar cohorts of pregnant women. The methodology used to compute confidence intervals for the relative odds ratios performed well in the scenarios considered.
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BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Results of animal studies suggest that maternal immune activation during pregnancy causes deficiencies in fetal neurodevelopment. Infectious disease is the most common path to maternal immune ...activation during pregnancy. The goal of this study was to determine the occurrence of common infections, febrile episodes, and use of antibiotics reported by the mother during pregnancy and the risk for autism spectrum disorder (ASD) and infantile autism in the offspring.
We used a population-based cohort consisting of 96 736 children aged 8 to 14 years and born from 1997 to 2003 in Denmark. Information on infection, febrile episodes, and use of antibiotics was self-reported through telephone interviews during pregnancy and early postpartum. Diagnoses of ASD and infantile autism were retrieved from the Danish Psychiatric Central Register; 976 children (1%) from the cohort were diagnosed with ASD.
Overall, we found little evidence that various types of mild common infectious diseases or febrile episodes during pregnancy were associated with ASD/infantile autism. However, our data suggest that maternal influenza infection was associated with a twofold increased risk of infantile autism, prolonged episodes of fever caused a threefold increased risk of infantile autism, and use of various antibiotics during pregnancy were potential risk factors for ASD/infantile autism.
Our results do not suggest that mild infections, febrile episodes, or use of antibiotics during pregnancy are strong risk factors for ASD/infantile autism. The results may be due to multiple testing; the few positive findings are potential chance findings.
ObjectiveA theory has emerged, suggesting that abnormalities in the auditory system may be associated with sudden infant death syndrome (SIDS). However, current clinical evidence has never been ...systematically reviewed.DesignA systematic review was conducted according to the guideline of Preferred Reporting Items for Systematic Reviews and Meta-Analyses.Data sourcesPubMed, Embase and Web of Science were systematically searched through 7 September 2020.Eligibility criteria for selecting studiesOnly human studies with a reference group were included. Studies were eligible for inclusion if they examined infants exposed to otoacoustic emissions (OAEs), auditory brainstem response (ABR) or had autopsies with brainstem histology of the auditory system. SIDS was the primary outcome, while the secondary outcome was near-miss sudden infant death syndrome episodes.Data extraction and synthesisTwo independent reviewers extracted data and assessed risk of bias, and the quality of evidence. Due to high heterogeneity, a narrative synthesis was conducted. Risk of bias and quality of evidence was assessed using the Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development and Evaluation.ResultsTwelve case–control studies were included. Seven studies on OAEs or ABR had a high degree of inconsistency. Contrarily, four out of five studies reporting on brainstem histology found that auditory brainstem abnormalities were more prevalent in SIDS cases than in controls. However, the quality of evidence across all studies was very low.ConclusionThis systematic review found no clear association between auditory system pathology and SIDS. The higher prevalence of histological abnormalities in the auditory system of SIDS may indicate an association. However, further studies of higher quality and larger study populations are needed to determine whether these findings are valid.PROSPERO registration numberCRD42020208045.
Background
A secular trend towards earlier puberty has been observed in girls, while a similar trend has been more uncertain in boys. We estimated current ages at pubertal development in both boys ...and girls.
Methods
In this population‐based cohort study, 14 759 of 22 439 invited boys and girls born from 2000 to 2003 in the Danish National Birth Cohort gave half‐yearly self‐reported information on puberty from the age of 11.5 years and throughout puberty. This late start of follow‐up limits the estimation of age at onset of puberty but not later pubertal milestones. We estimated mean age at attaining the following pubertal milestones in years with 95% confidence intervals (CI): age at menarche, voice break, first ejaculation of semen and Tanner stages for pubic hair development and breast development or genital development. Further, the difference in mean age at menarche between mothers and daughters was estimated.
Results
In boys, voice break occurred at 13.1 (95% CI 13.0, 13.1) years, first ejaculation of semen occurred at 13.4 (95% CI 13.3, 13.4) years, and Tanner Genital Stage 5 occurred at 15.6 (95% CI 15.5, 15.6) years. In girls, age at menarche occurred at 13.0 (95% CI 13.0, 13.1) years and Tanner Breast Stage 5 occurred at 15.8 (95% CI 15.7, 15.9) years. Daughters had menarche 3.6 (95% CI 3.1, 4.2) months earlier than their mothers had.
Conclusion
These data indicate that age at menarche has declined and to some extent support a decline in age at attaining other markers of pubertal development among boys.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction
Hypertensive disorders of pregnancy, including gestational hypertension and preeclampsia, are leading causes of morbidity and mortality for both mother and fetus. It has been proposed ...that vitamin D affects a number of biological processes involved in the pathogenesis of hypertensive disorders of pregnancy. Therefore, a seasonal variation in the risk of these disorders might be expected in areas such as Denmark with marked seasonal variation in sunlight exposure. In this study, we aimed to evaluate the existence of this association.
Material and methods
We used information from a cohort of 50 665 previously healthy, nulliparous women with singleton pregnancies. All women gave birth between 1989 and 2010 at Aarhus University Hospital, Denmark. Logistic regression analyses combined with the cubic spline method were used to estimate the seasonal variation for each outcome: gestational hypertension and preeclampsia, after adjusting for calendar time.
Results
Of the 50 665 women included, 8.5% were diagnosed with a hypertensive disorder of pregnancy. The overall tendency was towards increasing risk when conceiving during spring and early summer, peaking midsummer, and subsequently decreasing steadily during late summer and fall to reach the nadir by winter. Seasonal variation was found for; gestational hypertension (P = .01); preeclampsia (P = .001) and early‐onset preeclampsia (P = .014).
Conclusions
We found a seasonal variation in the risk of the hypertensive disorders of pregnancy in a large cohort of Danish nulliparous women. The highest risk was seen in women with the estimated date of conception in June and August, that is, during summer. Seasonal variation in vitamin D status may explain this association.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Previous studies have investigated the associations between perfluoroalkyl acids (PFAAs) in women and time to pregnancy (TTP). Inconsistent results may be explained by differences in conditioning on ...parity.
We used causal directed acyclic graphs to illustrate potential confounding related to previous pregnancies and exposure measurement error due to differences in the interpregnancy interval in pregnancy-based studies that include parous women. We exemplified the potential importance of these issues using data from the Danish National Birth Cohort.
We used discrete time survival models to estimate associations between maternal plasma PFAAs in early pregnancy and TTP in 638 nulliparous and 613 parous women.
PFAA quartiles were not associated with the TTP in nulliparous women. In parous women, higher PFAA quartiles were associated with longer TTP. The strongest associations were estimated for perfluorohexane sulfonate and perfluorooctane sulfonate. PFAA concentrations were higher in women with longer interpregnancy intervals. Accounting for the interpregnancy interval attenuated the estimated associations.
Associations between PFAAs and TTP in parous women may be biased by confounders related to previous pregnancies and exposure measurement error. To avoid these biases, studies that include parous women may need to condition on a) common causes of PFAAs and the TTP in the index pregnancy, b) previous births (a descendant of a collider), c) PFAA levels or common causes of PFAA levels and the TTP in the previous pregnancy (to alleviate collider stratification bias caused by conditioning on previous births), and d) the interpregnancy interval (in pregnancy-based studies). Alternatives would be to restrict studies to nulliparous women or to use toxicokinetic modeling to correct exposure estimates in parous women. These recommendations may be extended to studies of other chemicals with similar toxicokinetic properties. https://doi.org/10.1289/EHP1493.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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