Behavioral Problems at Age 11 Years After Prenatal and Postnatal Exposure to Acetaminophen: Parent-Reported and Self-Reported Outcomes.

Several studies have reported associations between prenatal acetaminophen exposure and behavioral outcomes in young children. We aimed to evaluate the associations of prenatal and postnatal exposures to acetaminophen with behavioral problems in children at age 11 years, using behavioral measures reported by parents and children. We studied 40,934 mother-child pairs from the Danish National Birth Cohort enrolled during 1996-2002. Parent-reported and child-reported Strengths and Difficulties Questionnaire (SDQ) responses were collected during the 11-year follow-up. We estimated risk ratios for behavioral problems including total difficulties as well as internalizing or externalizing behaviors following prenatal (during pregnancy) or postnatal (within the first 18 months after birth) acetaminophen exposure. Parent-reported and child-reported SDQ scores were moderately correlated; higher for externalizing (r = 0.59) than internalizing (r = 0.49) behaviors. Prenatal acetaminophen exposure was associated with 10%-40% higher risks for total difficulties and internalizing and externalizing problems based on parent- or child-reported SDQ, with the association being stronger for greater cumulative weeks of acetaminophen use. Postnatal exposure was associated with 16%-19% higher risks for parent-reported internalizing behaviors, but the associations were weak or null for child-reported scores except for prosocial behavior. Our study corroborates published associations between prenatal exposures to acetaminophen and behavioral problems and extends the literature to early adolescence.

Predicted vitamin D status during pregnancy in relation to offspring forearm fractures in childhood: a study from the Danish National Birth Cohort.

In a prospective cohort study, the association between maternal vitamin D status during pregnancy and offspring forearm fractures during childhood and adolescence was analysed in 30 132 mother and child pairs recruited to the Danish National Birth Cohort between 1996 and 2002. Data on characteristics, dietary factors and lifestyle factors were collected on several occasions during pregnancy. We analysed the association between predicted vitamin D status, based on a subsample with 25-hydroxyvitamin D (25(OH)D) biomarker measurements (n 1497) from gestation week 25, and first-time forearm fractures among offspring between birth and end of follow-up. Diagnoses were extracted from the Danish National Patient Register. Multivariable Cox regression models using age as the underlying time scale indicated no overall association between predicted vitamin D status (based on smoking, season, dietary and supplementary vitamin D intake, tanning bed use and outdoor physical activity) in pregnancy and offspring forearm fractures. Likewise, measured 25(OH)D, tanning bed use and dietary vitamin D intake were not associated with offspring forearm fractures. In mid-pregnancy, 91 % of the women reported intake of vitamin D from dietary supplements. Offspring of women who took >10 µg/d in mid-pregnancy had a significantly increased risk for fractures compared with the reference level of zero intake (hazard ratios (HR) 1·31; 95% CI 1·06, 1·62), but this was solely among girls (HR 1·48; 95% CI 1·10, 2·00). Supplement use in the peri-conceptional period exhibited similar pattern, although not statistically significant. In conclusion, our data indicated no protective effect of maternal vitamin D status with respect to offspring forearm fractures.

Maternal intake of folate during pregnancy and risk of cerebral palsy in the MOBAND-CP cohort.

BACKGROUND: Folate prevents neural tube defects and may play a role in some neurodevelopmental disorders. OBJECTIVES: We investigated whether higher intakes of periconceptional or midpregnancy folate, as recommended, were associated with a reduced risk of offspring cerebral palsy (CP). METHODS: We included participants from the Nordic collaboration cohort consisting of mother-child dyads in the Danish National Birth Cohort and the Norwegian Mother, Father, and Child Cohort Study [combined as MOthers and BAbies in Norway and Denmark (MOBAND-CP)]. A total of 190,989 live-born children surviving the first year of life were included. Missing covariate data were multiply imputed. Our exposures were defined as any or no folic acid supplementation in gestational weeks (GWs) -4 to 8 (periconceptional), 9 to 12, and -4 to 12, and supplemental, dietary, and total folate during midpregnancy (GWs 22-25). CP overall and the unilateral and bilateral spastic subtypes, as well as CP with low or moderate/high gross motor function impairments, were our outcomes of interest. RESULTS: Periconceptional folic acid supplementation was not associated with CP [adjusted odds ratio (aOR), 1.02; 95% CI: 0.82-1.28]. However, supplementation in GWs 9 to 12 was associated with a reduced risk of CP (aOR, 0.74; 95% CI: 0.57-0.96), and inverse associations were indicated for both the unilateral (aOR, 0.68; 95% CI: 0.46-1.02) and bilateral (aOR, 0.70; 95% CI: 0.49-1.02) spastic subtypes, although the associations were not statistically significant. Supplemental or dietary folate in midpregnancy alone were not associated with CP. Strong inverse associations were observed with low gross motor function impairment (aOR, 0.49; 95% CI: 0.29-0.83), while for unilateral CP the aOR was 0.63 (95% CI: 0.34-1.22) for intakes of ≥500 compared to ≤199 dietary folate equivalents/day during midpregnancy. CONCLUSIONS: Our findings suggest that folate intakes in GWs 9 to 12 and midpregnancy were associated with lower risks of CP, while no association was observed for periconceptional supplementation.

Old Question Revisited: Are High-Protein Diets Safe in Pregnancy?

BACKGROUND: A previous randomized dietary intervention in pregnant women from the 1970s, the Harlem Trial, reported retarded fetal growth and excesses of very early preterm births and neonatal deaths among those receiving high-protein supplementation. Due to ethical challenges, these findings have not been addressed in intervention settings. Exploring these findings in an observational setting requires large statistical power due to the low prevalence of these outcomes. The aim of this study was to investigate if the findings on high protein intake could be replicated in an observational setting by combining data from two large birth cohorts. METHODS: Individual participant data on singleton pregnancies from the Danish National Birth Cohort (DNBC) (n = 60,141) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (n = 66,302) were merged after a thorough harmonization process. Diet was recorded in mid-pregnancy and information on birth outcomes was extracted from national birth registries. RESULTS: The prevalence of preterm delivery, low birth weight and fetal and neonatal deaths was 4.77%, 2.93%, 0.28% and 0.17%, respectively. Mean protein intake (standard deviation) was 89 g/day (23). Overall high protein intake (>100 g/day) was neither associated with low birth weight nor fetal or neonatal death. Mean birth weight was essentially unchanged at high protein intakes. A modest increased risk of preterm delivery [odds ratio (OR): 1.10 (95% confidence interval (CI): 1.01, 1.19)] was observed for high (>100 g/day) compared to moderate protein intake (80-90 g/day). This estimate was driven by late preterm deliveries (weeks 34 to <37) and greater risk was not observed at more extreme intakes. Very low (<60 g/day) compared to moderate protein intake was associated with higher risk of having low-birth weight infants [OR: 1.59 (95%CI: 1.25, 2.03)]. CONCLUSIONS: High protein intake was weakly associated with preterm delivery. Contrary to the results from the Harlem Trial, no indications of deleterious effects on fetal growth or perinatal mortality were observed.

Effects of early childhood otitis media and ventilation tubes on psychosocial wellbeing - A prospective cohort study within the Danish National Birth Cohort.

BACKGROUND: Otitis Media (OM) is one of the most common infections among children in developed countries and may result in temporary conductive hearing loss (HL) if accompanied by middle ear effusion (MEE). Ventilation tube insertion (VTI) is recommended as treatment for recurrent acute OM or chronic MEE with HL. HL may lead to impaired development of psychosocial skills. However, evidence for the developmental consequences of OM and the effect of VTI is inconsistent. The objectives of this study were to investigate 1) whether OM in early childhood is associated with long-term consequences of psychosocial development and 2) if VTI prevents the possible negative consequences of OM. METHODS: This study examined prospectively collected data from 52.877 children registered in the Danish National Birth Cohort (DNBC). Information about previous OM-episodes and VTI was obtained through systematic follow-up interviews at seven years, and The Strength and Difficulties Questionnaire (SDQ) containing questions about psychological wellbeing was completed. Five groups were defined based on OM-exposure and the presence of VTI. Baseline characteristics were analysed, and comparison of mean SDQ-scores for the five exposure groups was conducted. Means were adjusted for à priori defined confounding factors. RESULTS: Data from 52,877 children in the DNBC showed an association between OM and poorer SDQ-scores. VTI was associated with an additional increase, i.e. worsening, of the SDQ-score for boys, and only a slight beneficial effect on the girls' outcome. The groups differed in their baseline characteristics in e.g. maternal education, socio-economic status, breastfeeding, and prematurity. CONCLUSION: Significant associations between parent-reported OM in early childhood and later psychosocial health difficulties were found. VTI did not resolve this association.

Childhood epilepsy and maternal antibodies to microbial and tissue antigens during pregnancy.

INTRODUCTION: Several epidemiologic studies show associations between mother's infections during pregnancy and an increased risk of mental and neurological disorders in the offspring. Such associations could be due to the direct or indirect effects of infectious agents, including immune responses to infectious agents that display molecular mimicry with host antigens. We measured a range of antigen-specific maternal IgG antibodies to examine if any were associated with risk for childhood epilepsy in offspring. METHODS: We used a case-cohort design within the Danish National Birth Cohort (DNBC) to examine maternal IgG antibodies to 25 microbial and tissue antigens during pregnancy and their association with the risk of epilepsy in offspring. The source population of this study was 68,250 live born singletons with up to 10 years of follow up. We randomly identified a sample of 282 children as a subcohort and included 275 children with a verified diagnosis of epilepsy as cases. Maternal antibodies were categorized into 6 groups (<50, 50-59, 60-69, 70-79, 80-89, ≥90 percentile) according to the level in the subcohort. We used a Prentice-weighted Cox regression model to estimate the hazard ratio (HR) and 95% confidence interval (CI) for epilepsy according to measured antibodies. RESULTS: Higher levels of maternal antibodies against herpes simples virus type 1 (anti-HSV1) were associated with a slightly higher risk of childhood epilepsy (HR for trend=1.09, 95% CI: 0.99-1.21), while higher levels of maternal antibodies against pneumococcal polysaccharide 18 (anti-PnPS18) were associated with a lower risk of childhood epilepsy (HR for trend=0.90, 95% CI: 0.81-1.01). Among the subtypes, a significantly higher risk associated with anti-HSV1 antibodies was seen for childhood absence epilepsy (HR for trend=2.08, 95% CI: 1.12-3.85) and for epileptic encephalopathies (HR for trend=1.49, 95% CI: 1.01-2.22). The significantly lower risk associated with anti-PnPS18 antibodies was observed for infantile spasms (HR for trend=0.47, 95% CI: 0.27-0.83). CONCLUSIONS: Maternal anti-HSV1and anti-PnPS18 antibodies during pregnancy may be associated with the risk of epilepsy in offspring, but any potential etiologic and preventative implications of these associations warrant further exploration.