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Background: Adequate thyroid function during pregnancy is essential for optimal fetal growth. Gestational exposure to perfluoroalkyl substances (PFAS) can negatively affect birth size and disrupt maternal and neonatal thyroid function, although the interrelationship is unclear., Objective: We aimed to quantify the associations between maternal serum-PFAS concentrations and birth weight, birth length, and cranial circumference. We also aimed to estimate associations between PFAS and thyroid hormone (TH) concentrations, thereby elucidating whether THs potentially mediate the associations between PFAS concentrations and birth size., Methods: We studied a population-based prospective cohort of 172 mother-singleton pairs from the Faroe Islands. Twelve PFAS were measured in maternal serum obtained at 34 weeks of gestation. THs were measured in maternal and cord serum. Associations between PFAS concentrations and birth size and TH concentrations were estimated using multivariable linear regressions. Sex-stratified analyses along with a mediation analysis were performed to estimate potential mediating effects of THs in the association between PFAS and birth outcomes., Results: Several PFASs were negatively associated with birth weight, length, and head circumference, and a general positive association between maternal serum-PFASs and cord serum-thyroid-stimulating hormone (TSH; also known as thyrotropin) was found. For instance, a doubling in perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) was associated with a 53% (95% CI, 18%-99%) and 40% (95% CI, 8%-81%) increases in TSH concentrations, respectively. There was little evidence of sexually dimorphic associations. Overall, THs were not found to mediate associations between PFASs and birth size., Conclusion: In this study, several PFASs were negatively associated with birth size and increased THs; however, this did not explain lower birth weight among children exposed to PFAS., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Higher concentrations of single perfluorinated alkyl acids (PFAAs) have been associated with lower birth weight (BW), but few studies have examined the combined effects of PFAA mixtures. PFAAs have been reported to induce estrogen receptor (ER) transactivity, and estrogens may influence human fetal growth. We hypothesize that mixtures of PFAAs may affect human fetal growth by disrupting the ER., Objectives: We aimed to study the associations between the combined xenoestrogenic activity of PFAAs in pregnant women's serum and offspring BW, length, and head circumference., Methods: We extracted the actual mixture of PFAAs from the serum of 702 Danish pregnant women (gestational wk 11–13) enrolled in the Aarhus Birth Cohort (ABC) using solid phase extraction, high-performance liquid chromatography (HPLC), and weak anion exchange. PFAA-induced xenoestrogenic receptor transactivation (XER) was determined using the stable transfected MVLN cell line. Associations between XER and measures of fetal growth were estimated using multivariable linear regression with primary adjustment for maternal age, body mass index (BMI), educational level, smoking, and alcohol intake, and sensitivity analyses with additional adjustment for gestational age (GA) (linear and quadratic)., Results: On average, an interquartile range (IQR) increase in XER was associated with a [Formula: see text] [95% confidence interval (CI): [Formula: see text], [Formula: see text]] decrease in BW and a [Formula: see text] (95% CI: 0.1, 0.5) decrease in birth length. Upon additional adjustment for GA, the estimated mean differences were [Formula: see text] (95% CI: [Formula: see text], 4) and [Formula: see text] (95% CI: [Formula: see text], 0.0), respectively., Conclusion: Higher-serum PFAA-induced xenoestrogenic activities were associated with lower BW and length in offspring, suggesting that PFAA mixtures may affect fetal growth by disrupting ER function. https://doi.org/10.1289/EHP1884.

Few studies have evaluated the association between pregravid oral contraceptive (OC) use and birth weight, and findings have been conflicting. We conducted a prospective cohort study of 5921 pregnancy planners in Denmark to evaluate recency, duration, and type of OC used before conception in relation to infant birth weight. Participants completed online questionnaires and reported detailed information on contraceptive history and covariates at baseline. Participants completed bimonthly follow-up questionnaires to update their pregnancy status for up to 12 months or until conception occurred. Birth weight data were ascertained from the Danish Medical Birth Registry for 4046 live births delivered by study participants between 2008 and 2010. We used multivariable linear and log-binomial regression analyses to control for confounding. Mean birth weight was higher among women who had used OCs within 0-1 months (mean difference = 97 g, CI 26, 168) or 2-6 months (mean difference = 40 g, CI -5, 85) before conception, compared with more than 12 months before conception. Mean birth weight was lower among women who had used OCs for long durations (mean difference comparing ≥12 with <4 years of OC use = -85 g, CI -158, -11). Our findings indicate that pregravid OC use within 6 months of conception may be associated with a small increase in birth weight, but that long duration of use may have the opposite effect. Results were stronger among male infants, among 2nd and 4th generation OC users, and among users of OCs with a higher estrogen dose.

Objective: To investigate the association between exposure to mothers smoking during prenatal and early postnatal life and risk of overweight at age 7 years, while taking birth weight into account., Methods: From the Danish National Birth Cohort a total of 32,747 families were identified with available information on maternal smoking status in child's pre- and postnatal life and child's birth weight, and weight and height at age 7 years. Outcome was overweight according to the International Obesity Task Force gender and age specific body mass index. Smoking exposure was categorized into four groups: no exposure (n = 25,076); exposure only during pregnancy (n = 3,343); exposure only postnatally (n = 140); and exposure during pregnancy and postnatally (n = 4,188). Risk of overweight according to smoking status as well as dose-response relationships were estimated by crude and adjusted odds ratios using logistic regression models., Results: Exposure to smoking only during pregnancy, or both during pregnancy and postnatally were both significantly associated with overweight at 7 years of age (OR: 1.31, 95% CI: 1.15-1.48, and OR: 1.76, 95% CI: 1.58-1.97, respectively). Analyses excluding children with low birth weight (<2,500 gram) revealed similar results. A significant prenatal dose-response relationship was found. Per one additional cigarette smoked per day an increase in risk of overweight was observed (OR: 1.02, 95% CI: 1.01-1.03). When adjusting for quantity of smoking during pregnancy, prolonged exposure after birth further increased the risk of later overweight in the children (OR 1.28, 95% CI:1.09-1.50) compared with exposure only in the prenatal period., Conclusions: Mother's perinatal smoking increased child's OR of overweight at age 7 years irrespective of birth weight, and with higher OR if exposed both during pregnancy and in early postnatal life. Clear dose-response relationships were observed, which emphasizes the need for prevention of any tobacco exposure of infants.

Background: The intake of periconceptional multivitamins may decrease the risk of preterm births (PTBs) or small-for-gestational-age (SGA) births., Objective: We related the timing and frequency of periconceptional multivitamin use to SGA births and PTBs and its clinical presentations (ie, preterm labor, premature rupture of membranes, and medical induction)., Design: Women in the Danish National Birth Cohort (n = 35,897) reported the number of weeks of multivitamin use during a 12-wk periconceptional period. Cox regression was used to estimate the relation between any multivitamin use and PTBs (<37 wk) or SGA births (birth weight adjusted for gestational age >2 SDs below the mean on the basis of fetal growth curves). The timing (preconception and postconception) and frequency of use were also analyzed. Regular users (4-6 wk) and partial users (1-3 wk) in each period were compared with nonusers., Results: The association between periconceptional multivitamin use and PTBs varied according to prepregnancy overweight status (P-interaction = 0.07). Regular preconception and postconception multivitamin use in women with a prepregnancy BMI (in kg/m(2)) <25 was associated with reduced risks of a PTB (HR: 0.84; 95% CI: 0.73, 0.95) and preterm labor (HR: 0.80; 95% CI: 0.69, 0.94). No similar associations were shown for overweight women. The adjusted risk of an SGA birth was reduced in multivitamin users regardless of their prepregnancy BMI (HR: 0.83; 95% CI: 0.73, 0.95), with the strongest association in regular users in the postconception period., Conclusion: Regular periconceptional multivitamin use was associated with reduced risk of SGA births and PTBs in nonoverweight women.

The aim of this study was to identify dietary predictors of plasma dioxin-like activity in women from the Danish National Birth Cohort. Associations between exposure and birth weight and infant development at 6 months were also explored. Diet was assessed in mid-pregnancy by a food-frequency questionnaire. One hundred nulliparous 25-35-year-old women of normal pre-pregnancy body-mass-index were chosen according to their intake of fatty fish, as fatty fish is a potential route of exposure. Intake of other foods of animal origin was also explored. Dioxin-like activity was measured in plasma using the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR-CALUX) and quantified in toxic equivalents (CALUX-TEQs). Information on infant attainment of specific milestones was obtained by maternal report in a standardized interview. The sample mean was 46 pg CALUX-TEQ/g lipid. Plasma dioxin-like activity increased by 10.7 pg CALUX-TEQ/g lipid (95% CI: 1.8; 19.7) for the highest compared to the lowest tertile of total dietary fat intake but decreased by -9.8 pg CALUX-TEQ/g lipid (95% CI: -19.4; -0.2) for fatty fish intake. The inverse association for fatty fish was explained by lower intake of high-fat food groups such as red meat, fats and oils, which were also predictors of dioxin-like activity. Plasma dioxin-like activity was not associated with birth weight, but an inverse correlation was observed with total developmental score (Spearman r=-0.23, p=0.046). Our study indicates that dietary patterns associated with high fat intake may lead to increased plasma dioxin-like activity and in utero exposure might be related to early infant development.

The authors examined the relation between fish consumption during pregnancy and fetal growth among 44,824 women from the Danish National Birth Cohort (1996-2002). They evaluated the associations between consumption of total fish, fatty fish, and lean fish in midpregnancy and birth weight, birth length, and head circumference among singleton full-term infants. Fish consumption was ascertained by food frequency questionnaire. The birth of infants classified below the 10th percentile for gestational age and gender was significantly increased among women who consumed more than 60 g of fish per day, as compared with women who consumed 5 g or less per day. Adjusted odds ratios were 1.24 (95% confidence interval (CI): 1.03, 1.49) for birth weight and 1.21 (95% CI: 1.01, 1.43) for head circumference. The adjusted odds ratio was borderline significant for birth length (odds ratio = 1.20, 95% CI: 1.00, 1.45). These increases in risk were followed by small decreases in average values for these growth measures. Furthermore, the inverse association for total fish consumption could be explained by consumption of fatty fish, while no association was found for lean fish. These results indicate that consumption of fatty fish, a known route of exposure to persistent organic pollutants, could be associated with reduced fetal growth.

Aims: The diabetogenic effect of diuretics, as well as the indication for prescribing them, may impact on fetal growth. We analysed whether the purchase of prescription drugs for diuretics during pregnancy was associated with measures of fetal growth., Methods: During 1991-98 all women who purchased prescription drugs for diuretics during pregnancy were identified in the Northern Jutland Prescription Database (NJDP), Denmark, and in the Medicines Monitoring Unit's Database (MEMO), Scotland. Information on birth weight and gestational age was obtained from the Danish Birth Registry, the Danish Hospital Discharge Registry and the Scottish Tayside Neonatal Database. Information on diabetes, hypertension and prepregnancy weight were obtained by hospital record review in a sample of women in the Danish cohort. Women who did not purchase prescription diuretics during pregnancy were used as a reference group in both cohorts., Results: Danish women who purchased prescription loop diuretics during pregnancy gave birth to infants with higher birth weights than women who did not use diuretics; mean difference 104.7 g (95% CI; 2.6, 206.9). However, the high prevalence of diabetes (10.3%) among Danish women who purchased prescription loop diuretics during pregnancy might explain this result. Both the Danish and the Scottish women who purchased prescription diuretics during their pregnancy were at increased risk of preterm delivery (< 37 completed weeks); ORs: 1.8 (CI; 1.2, 2.7)NJDP, 1.9 (CI; 0.9, 4.3)MEMO. The proportion of hypertension among women who purchased prescription thiazides was 15.8%, and the risk of having an infant with a birth weight (BW) < 2500 g was increased; ORs: 2.6 (CI; 1.4, 5.0)NJDP, 2.4 (CI; 0.8, 7.8)MEMO., Conclusions: Prescribing diuretics during pregnancy was associated with differences in birth weight and incidence of preterm delivery. Confounding by indication may explain the findings.

Objective: To investigate the impact of epilepsy and antiepileptic drugs on length of gestation and anthropometric measures of the newborn., Design: Cohort study based on questionnaires mailed to all pregnant women who attended for prenatal care at our department from August 1989 to January 1997., Setting: Department of Obstetrics and Gynaecology at Aarhus University Hospital, Denmark., Participants: One hundred and ninety-three singleton pregnancies in women with epilepsy were compared with 24,094 singleton pregnancies in women without epilepsy., Main Outcome Measures: Preterm delivery, small for gestational age, mean gestational age, gestational age-adjusted birthweight, head circumference, and body length., Results: Children of women with epilepsy who smoked had lower gestational age and were at increased risk of preterm delivery (OR 3.4; 95% CI 1.8-6.5), compared with children born by nonepileptic women who smoked. Birthweight adjusted for gestational age was reduced by 102 g (95% CI 40-164) in women with epilepsy, and the risk of delivering a child who was small for gestational age was increased (adjusted OR 1.9, 95% CI 1.3-2.7), compared with women without epilepsy. Newborn babies of women with epilepsy treated by drugs had a reduced adjusted birthweight (208 g, 95% CI 116-300), head circumference (0.4 cm, 95% CI 0.0-0.7), and body length (0.5 cm, 95% CI 0.1-1.0), compared with the newborn infants of women without epilepsy., Conclusions: Women with epilepsy who smoked were at increased risk of preterm delivery compared with healthy smokers. Children of women with drug treated epilepsy had lower birthweight, length, and head circumference than children of women without epilepsy.

During the past decades conclusive evidence has accumulated that alkylating antineoplastic drugs (ADs) can cause cancer, most notably acute non-lymphocytic leukaemia, and that most ADs are reprotoxic. Studies on health workers handling ADs have shown significantly increased risks for miscarriages (two studies) and malformations (two studies). The present study monitored the risk for cancer and adverse reproductive outcome among Danish nurses handling ADs. No increased risks were found for miscarriages, malformations, low birth weight, or preterm birth among the offspring of nurses handling ADs during pregnancy. The sex ratio was normal. The relative risk (RR) for leukaemia was significantly increased (10.65) but based on only two cases, one of acute myeloblastic and one of chronic myeloid leukaemia. From the available exposure data occupational exposures to ADs were apparently higher in the studies that have reported increased risks for miscarriages and malformations than in the present one. Regarding reproductive outcome the study gives some confidence that the safety measures which were implemented in the oncology departments around 1980 can protect the health personnel against adverse effects of ADs on reproduction. As the study is as yet the only negative one in a well protected setting, it should be followed up by other studies of well protected health personnel handling ADs. The findings concerning the leukaemia risk, although based on small numbers, encourage larger studies.