Thorhallur I. Halldorsson

Prenatal Exposure to Perfluorooctanoate and Risk of Overweight at 20 Years of Age: A Prospective Cohort Study

Background: Perfluoroalkyl acids 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 biomarkers of adiposity were quantified in a subset (n = 422) of participants. Results: After adjusting for covariates, including maternal pre-pregnancy 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.

Associations of in utero exposure to perfluorinated alkyl acids with human semen quality and reproductive hormones in adult men.

Background: Perfluorinated alkyl acids (PFAAs), persistent chemicals with unique water-, dirt-, and oil-repellent properties, are suspected of having endocrine-disrupting activity. The PFAA compounds perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are found globally in humans; because they readily cross the placental barrier, in utero exposure may be a cause for concern. Objectives: We investigated whether in utero exposure to PFOA and PFOS affects semen quality, testicular volume, and reproductive hormone levels. Methods: We recruited 169 male offspring (19–21 years of age) from a pregnancy cohort established in Aarhus, Denmark, in 1988–1989, corresponding to 37.6% of the eligible sons. Each man provided a semen sample and a blood sample. Semen samples were analyzed for sperm concentration, total sperm count, motility, and morphology, and blood samples were used to measure reproductive hormones. As a proxy for in utero exposure, PFOA and PFOS were measured in maternal blood samples from pregnancy week 30. Results: Multivariable linear regression analysis suggested that in utero exposure to PFOA was associated with lower adjusted sperm concentration (ptrend = 0.01) and total sperm count (ptrend = 0.001) and with higher adjusted levels of luteinizing hormone (ptrend = 0.03) and follicle-stimulating hormone (ptrend = 0.01). PFOS did not appear to be associated with any of the outcomes assessed, before or after adjustment. Conclusions: The results suggest that in utero exposure to PFOA may affect adult human male semen quality and reproductive hormone levels.

Intake of artificially sweetened soft drinks and risk of preterm delivery: a prospective cohort study in 59,334 Danish pregnant women

BACKGROUND Sugar-sweetened soft drinks have been linked to a number of adverse health outcomes such as high weight gain. Therefore, artificially sweetened soft drinks are often promoted as an alternative. However, the safety of artificial sweeteners has been disputed, and consequences of high intakes of artificial sweeteners for pregnant women have been minimally addressed. OBJECTIVE We examined the association between intakes of sugar-sweetened and artificially sweetened soft drinks and preterm delivery. DESIGN We conducted prospective cohort analyses of 59,334 women from the Danish National Birth Cohort (1996-2002). Soft drink intake was assessed in midpregnancy by using a food-frequency questionnaire. Preterm delivery ( lt 37 wk) was the primary outcome measure. Covariate information was assessed by telephone interviews. RESULTS There was an association between intake of artificially sweetened carbonated and noncarbonated soft drinks and an increased risk of preterm delivery (P for trend: le 0.001, both variables). In comparison with women with no intake of artificially sweetened carbonated soft drinks, the adjusted odds ratio for women who consumed ge 1 serving of artificially sweetened carbonated soft drinks/d was 1.38 (95% CI: 1.15, 1.65). The corresponding odds ratio for women who consumed ge 4 servings of artificially sweetened carbonated soft drinks/d was 1.78 (95% CI: 1.19, 2.66). The association was observed for normal-weight and overweight women. A stronger increase in risk was observed for early preterm and moderately preterm delivery than with late-preterm delivery. No association was observed for sugar-sweetened carbonated soft drinks (P for trend: 0.29) or for sugar-sweetened noncarbonated soft drinks (P for trend: 0.93). CONCLUSIONS Daily intake of artificially sweetened soft drinks may increase the risk of preterm delivery. Further studies are needed to reject or confirm these findings.

High dietary intake of saturated fat is associated with reduced semen quality among 701 young Danish men from the general population

BACKGROUND Saturated fat intake has been associated with both cardiovascular disease and cancer risk, and a newly published study found an association between saturated fat intake and a lower sperm concentration in infertile men. OBJECTIVE The objective was to examine the association between dietary fat intake and semen quality among 701 young Danish men from the general population. DESIGN In this cross-sectional study, men were recruited when they were examined to determine their fitness for military service from 2008 to 2010. They delivered a semen sample, underwent a physical examination, and answered a questionnaire comprising a quantitative food-frequency questionnaire to assess food and nutrient intakes. Multiple linear regression analyses were performed with semen variables as outcomes and dietary fat intakes as exposure variables, adjusted for confounders. RESULTS A lower sperm concentration and total sperm count in men with a high intake of saturated fat was found. A significant dose-response association was found, and men in the highest quartile of saturated fat intake had a 38% (95% CI: 0.1%, 61%) lower sperm concentration and a 41% (95% CI: 4%, 64%) lower total sperm count than did men in the lowest quartile. No association between semen quality and intake of other types of fat was found. CONCLUSIONS Our findings are of potentially great public interest, because changes in diet over the past decades may be part of the explanation for the recently reported high frequency of subnormal human sperm counts. A reduction in saturated fat intake may be beneficial for both general and reproductive health.

Fish and long-chain n−3 polyunsaturated fatty acid intakes during pregnancy and risk of postpartum depression: a prospective study based on a large national birth cohort

BACKGROUND Mothers may be reluctant to receive medical treatment of postpartum depression (PPD), despite the detrimental consequences the disorder can impose on mother and child. Research on alternative methods of prevention and treatment of PPD is warranted. Previous studies have suggested that long-chain n-3 polyunsaturated fatty acids (PUFAs) might have a beneficial effect on depression. OBJECTIVE The objective was to explore the association between intake of fish and n-3 PUFAs during pregnancy and PPD in the Danish National Birth Cohort (DNBC). DESIGN Exposure information from the DNBC was linked to the Danish patient and prescription registries for data on clinically identified cases of depression up to 1 y postpartum. Intake of fish and n-3 PUFAs was assessed in midpregnancy with a food-frequency questionnaire. Admission to the hospital for PPD (PPD-admission) and prescription of antidepressants (PPD-prescription) were treated as separate outcomes. A total of 54,202 women were included in the present study sample. RESULTS Rates of depression were 0.3% (PPD-admission) and 1.6% (PPD-prescription). No association was observed between fish intake and risk of PPD-admission [crude odds ratio of 1.01 (95% CI: 0.52, 1.97) and adjusted odds ratio of 0.82 (95% CI: 0.42, 1.64)], whereas a higher risk of PPD-prescription was found for the lowest compared with the highest fish intake group [crude odds ratio of 1.61 (95% CI: 1.26, 2.06) and adjusted odds ratio of 1.46 (95% CI: 1.12, 1.90)]. No association was observed with respect to n-3 PUFA intake. CONCLUSION Overall, our data from a large prospective cohort linked with high-quality registers showed little evidence to support an association between intake of fish or n-3 PUFAs and PPD.

Does leisure time physical activity in early pregnancy protect against pre‐eclampsia? Prospective cohort in Danish women

Objective  To examine the association between physical activity in early pregnancy and risk of pre‐eclampsia.

Fish intake during pregnancy, fetal growth, and gestational length in 19 European birth cohort studies.

BACKGROUND Fish is a rich source of essential nutrients for fetal development, but in contrast, it is also a well-known route of exposure to environmental pollutants. OBJECTIVE We assessed whether fish intake during pregnancy is associated with fetal growth and the length of gestation in a panel of European birth cohort studies. DESIGN The study sample of 151,880 mother-child pairs was derived from 19 population-based European birth cohort studies. Individual data from cohorts were pooled and harmonized. Adjusted cohort-specific effect estimates were combined by using a random- and fixed-effects meta-analysis. RESULTS Women who ate fish >1 time/wk during pregnancy had lower risk of preterm birth than did women who rarely ate fish (≤ 1 time/wk); the adjusted RR of fish intake >1 but <3 times/wk was 0.87 (95% CI: 0.82, 0.92), and for intake ≥ 3 times/wk, the adjusted RR was 0.89 (95% CI: 0.84, 0.96). Women with a higher intake of fish during pregnancy gave birth to neonates with a higher birth weight by 8.9 g (95% CI: 3.3, 14.6 g) for >1 but <3 times/wk and 15.2 g (95% CI: 8.9, 21.5 g) for ≥ 3 times/wk independent of gestational age. The association was greater in smokers and in overweight or obese women. Findings were consistent across cohorts. CONCLUSION This large, international study indicates that moderate fish intake during pregnancy is associated with lower risk of preterm birth and a small but significant increase in birth weight.

Linking Exposure to Polychlorinated Biphenyls With Fatty Fish Consumption and Reduced Fetal Growth Among Danish Pregnant Women: A Cause for Concern?

In a selected group of women from the Danish National Birth Cohort, the authors investigated the association between intake of fatty fish and plasma concentrations of polychlorinated biphenyls (PCBs) on the one hand and the association between maternal PCB concentrations and fetal growth on the other. Of 70,183 women who filled in a food frequency questionnaire during 1996-2002, 100 nulliparous women aged 25-35 years with normal prepregnancy body mass index were selected according to their intake of fatty fish (low (0 meals/month, n = 34), medium (1-3 meals/month, n = 33), or high (> or = meals/month, n = 33)). Women with a high intake of fatty fish had 50% (95% confidence interval (CI): 31, 72) higher plasma PCB concentrations than women with low intake. Maternal plasma PCB concentrations were inversely associated with birth weight and placental weight. The adjusted mean difference between the 75th and 25th PCB percentiles was -155 g (95% CI: -291, -19) for birth weight and -81 g (95% CI: -135, -26) for placental weight. These results support previous findings from this cohort, where fatty fish intake was inversely associated with fetal growth. Dietary recommendations often encourage weekly consumption of fatty fish. These results suggest that potential exposure to PCBs should be carefully considered before recommending such intakes among women of childbearing age.

Intake of vitamin C and E in pregnancy and risk of pre‐eclampsia: prospective study among 57 346 women

Objective  It has been suggested that vitamin C, alone or in combination with vitamin E, may protect against pre‐eclampsia, whereas the safety of high‐dose vitamin E supplements has been questioned. We investigated dietary intakes of vitamins C and E to see if they correlated with the incidence of pre‐eclampsia.

Long-term effects of prenatal exposure to perfluoroalkyl substances on female reproduction

STUDY QUESTION Does prenatal exposure to perfluoroalkyl substances (PFASs) have long-term effects on female reproductive function?. SUMMARY ANSWER Our results suggest an association between in utero exposure to perfluorooctanoic acid (PFOA) and delay in age of menarche. WHAT IS KNOWN ALREADY Previous cross-sectional studies have reported possible effects of PFASs on female reproduction including reduced fecundity, delayed puberty and accelerated age at menopause. Only limited data exist from follow-up studies on long-term implications of prenatal exposure to PFASs. STUDY DESIGN, SIZE, DURATION In this study we used data from a Danish population-based cohort established in 1988-1989. Of 1212 eligible pregnant women, 965 participated. Follow-up was initiated in 2008 on the female offspring at ∼20 years of age. Three hundred and sixty seven (84%) daughters answered a questionnaire and 267 (61%) daughters furthermore attended clinical examinations which were conducted in 2008-2009. PARTICIPANTS/MATERIALS, SETTING, METHODS The final study population consisted of 343 daughters of which 254 had attended the clinical examinations and 89 had answered the questionnaire only. Levels of PFASs in maternal serum from pregnancy week 30 were used as a measure of prenatal exposure and related to age of menarche, menstrual cycle length, levels of reproductive hormones and follicle number of the daughters. Data were divided into three groups according to tertiles of maternal concentrations of PFASs (low, medium, high). MAIN RESULTS AND THE ROLE OF CHANCE In adjusted regression analyses, daughters exposed to higher levels of PFOA in utero had a 5.3 (95% confidence interval: 1.3; 9.3) months later age of menarche compared with the reference group of lower PFOA. Crude (P = 0.05) and adjusted (P = 0.01) trend tests also indicated a relationship between higher prenatal PFOA exposure and delay of menarche. LIMITATIONS, REASONS FOR CAUTION We did not measure the exact amount of PFASs to which the daughters had been exposed prenatally. Instead we used PFAS concentrations in maternal serum as surrogates. However, PFASs are efficiently transferred to the fetus via placenta. Information on age of menarche was collected retrospectively but the time interval for recall in our study was relatively short (2-10 years). The remaining outcome measures depended on participation in clinical examination which reduced the number of observations leading to limited statistical power and risk of selection bias. WIDER IMPLICATIONS OF THE FINDINGS Since PFASs can be detected in humans all over the world, effects of prenatal exposure on female reproductive function later in life may have wide health implications. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by the Danish Council for Independent Research (271-05-0296, 09-065631), the Danish Ministry of Interior and Health (0-302-02-18/5), the Danish Council for Strategic Research (09-067124 (Centre for Fetal Programming), 09-063072, 2101-06-0005), the Novo Nordisk Foundation, the Aarhus University Research Foundation, the Frimodt-Heineke Foundation, the Foundation of Maria Dorthea and Holger From, the Beckett-Foundation, the Research Grant of Organon and the Foundation of Lily Benthine Lund. There are no competing interests. TRIAL REGISTRATION NUMBER Not applicable.