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1.  Prenatal Exposure to Perfluorooctanoate and Risk of Overweight at 20 Years of Age: A Prospective Cohort Study 
Environmental Health Perspectives  2012;120(5):668-673.
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.
PMCID: PMC3346773  PMID: 22306490
offspring obesity; overweight; perfluoroalkyl compounds; PFOA; pregnancy; prenatal exposure
2.  Infertility, infertility treatment, and mixed-handedness in children 
Early human development  2009;85(12):745-749.
Mixed-handedness, which may reflect atypical brain laterality, has been linked to a number of medical conditions as well as prenatal stress.
The aim of the study was to examine whether infertility or infertility treatment was associated with an increased risk of mixed-handedness in children.
Study design, subjects and outcome measures
We used data from three population-based birth cohorts in Denmark: the Aalborg-Odense Birth Cohort (1984-1987), the Aarhus Birth Cohort (1990-1992) and the Danish National Birth Cohort (1996-2002) (N=7728, 5720 and 29486, respectively). Data on time to pregnancy and infertility treatment was collected during pregnancy. Handedness was reported in a follow-up questionnaire when the children were at least 7 years old. Children were categorized as mixed-handed if the mothers reported that they used both hands equally.
Children born after infertility treatment, particularly intrauterine insemination, had a higher risk of being mixed-handed compared to children of fertile couples with a time to pregnancy ≤12 months (odds ratio 1.41, 95% confidence interval 1.09-1.82). Children of couples with unplanned pregnancies, particularly after an oral contraceptives failure, were also more likely to be mixed-handed. There was no association between a long waiting time to pregnancy and mixed-handedness in children.
Children born after infertility treatment, particularly intrauterine insemination, and children exposed to oral contraceptives during early gestation may have a higher risk of being mixed-handed.
PMCID: PMC2788033  PMID: 19875254
Infertility; Infertility treatment; Mixed-handedness; Oral contraceptives; Time to pregnancy
3.  Parental infertility and sexual maturation in children 
The reproductive health of children born of infertile couples may be affected by infertility treatment or factors associated with infertility. We examined sexual maturation in children of parents with infertility.
We used data from a follow-up of 3382 girls and 2810 boys born between 1984 and 1987 in the Aalborg–Odense Birth Cohort. We had mothers’ report of time to pregnancy (TTP) and infertility treatment (at the time, mostly hormonal) from the pregnancy questionnaire administered in 1984–1987, and the children’s report of their own sexual maturation from the follow-up questionnaire administered in 2005, when they were between 18 and 21 years old. Many reported age only in year when they had the events related to sexual maturation, and for each event, we imputed the month based on the median month at each year of age among those reporting both years and months.
In girls, the mean age at menarche was 13.3 years and, in boys, the mean age at appearance of acne, voice break, regular shaving and first nocturnal emission were 14.5, 14.5, 17.2 and 14.7 years, respectively. We saw no significant differences in age at these events among children born of either fertile (with TTP of 0–12 months and no treatment), untreated infertile (with TTP of more than 12 months and no treatment) or treated infertile couples (with a history of examination or treatment for infertility).
Our data suggest no significant association between parental infertility or hormonal treatment and timing of sexual maturation in the offspring.
PMCID: PMC2733842  PMID: 18840889
infertility; infertility treatment; puberty; time to pregnancy
4.  Handedness and time to pregnancy 
Non-right handedness, particularly mixed-handedness, has been associated with a number of medical conditions. We examined whether handedness was associated with fecundity, measured by time to pregnancy.
We used data on parental handedness and time to pregnancy from two regional birth cohorts in Denmark: the Aalborg-Odense Birth Cohort (1984–1987) and the Aarhus Birth Cohort (1990–1992) (N=5808 and 3426, respectively). We applied discrete-time survival analysis to assess fecundity in relation to handedness.
In both cohorts, we saw a slightly lower fecundity in individuals who reported being mixed-handed. Left handedness was not significantly associated with fecundity.
Our data showed a modest association between mixed-handedness and subfecundity, which suggests that these traits may share a common prenatal etiology.
PMCID: PMC2662690  PMID: 19057386
handedness; fecundity; time to pregnancy
5.  Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study 
Objective To investigate any association between selective serotonin reuptake inhibitors (SSRIs) taken during pregnancy and congenital major malformations.
Design Population based cohort study.
Participants 493 113 children born in Denmark, 1996-2003.
Main outcome measure Major malformations categorised according to Eurocat (European Surveillance of Congenital Anomalies) with additional diagnostic grouping of heart defects. Nationwide registers on medical redemptions (filled prescriptions), delivery, and hospital diagnosis provided information on mothers and newborns. Follow-up data available to December 2005.
Results Redemptions for SSRIs were not associated with major malformations overall but were associated with septal heart defects (odds ratio 1.99, 95% confidence interval 1.13 to 3.53). For individual SSRIs, the odds ratio for septal heart defects was 3.25 (1.21 to 8.75) for sertraline, 2.52 (1.04 to 6.10) for citalopram, and 1.34 (0.33 to 5.41) for fluoxetine. Redemptions for more than one type of SSRI were associated with septal heart defects (4.70, 1.74 to 12.7)). The absolute increase in the prevalence of malformations was low—for example, the prevalence of septal heart defects was 0.5% (2315/493 113) among unexposed children, 0.9% (12/1370) among children whose mothers were prescribed any SSRI, and 2.1% (4/193) among children whose mothers were prescribed more than one type of SSRI.
Conclusion There is an increased prevalence of septal heart defects among children whose mothers were prescribed an SSRI in early pregnancy, particularly sertraline and citalopram. The largest association was found for children of women who redeemed prescriptions for more than one type of SSRI.
PMCID: PMC2749925  PMID: 19776103
6.  Infertility, Infertility Treatment and Fetal Growth Restriction 
Obstetrics and gynecology  2007;110(6):1326-1334.
To examine the association between infertility, with or without treatment, and fetal growth, as well as perinatal and infant mortality.
From the Danish National Birth Cohort (1997–2003), we identified 51,041 singletons born of fertile couples (time to pregnancy ≤12 months), 5787 born of infertile couples conceiving naturally (time to pregnancy >12 months), and 4317 born after treatment. We defined SGA as the lowest 5% of birth weight by sex and gestational age.
Crude estimates suggested an increased risk of perinatal mortality and SGA among infertile couples (treated and untreated), but the odds ratios (ORs) of perinatal mortality among infertile couples were attenuated after adjustment for maternal age and body mass index [1.32, 95% confidence interval (CI) 0.95–1.84 among untreated and 1.26, 95% CI 0.86–1.85 among treated couples]. The elevated risk of SGA among infertile couples persisted after adjustment for maternal age, parity and smoking (OR 1.24, 95% CI 1.10–1.40 among untreated, and OR 1.40, 95% CI 1.23–1.60 among treated). The risk of SGA increased with time to pregnancy, and a longer time to pregnancy was associated with a small reduction in birth weight across the whole distribution.
The increased risk of SGA observed among infertile couples with or without infertility treatment suggests that infertility may be a risk factor for intrauterine growth restriction. Treatment per se may have little effect on fetal growth. A small to moderate increased risk of perinatal mortality in infertile couples cannot be ruled out due to the small number of cases.
PMCID: PMC2365892  PMID: 18055728
7.  Effect of reducing caffeine intake on birth weight and length of gestation: randomised controlled trial 
BMJ : British Medical Journal  2007;334(7590):409.
Objective To estimate the effect of reducing caffeine intake during pregnancy on birth weight and length of gestation.
Design Randomised double blind controlled trial.
Setting Denmark.
Participants 1207 pregnant women drinking at least three cups of coffee a day, recruited before 20 weeks' gestation.
Interventions Caffeinated instant coffee (568 women) or decaffeinated instant coffee (629 women).
Main outcome measures Birth weight and length of gestation.
Results Data on birth weight were obtained for 1150 liveborn singletons and on length of gestation for 1153 liveborn singletons. No significant differences were found for mean birth weight or mean length of gestation between women in the decaffeinated coffee group (whose mean caffeine intake was 182 mg lower than that of the other group) and women in the caffeinated coffee group. After adjustment for length of gestation, parity, prepregnancy body mass index, and smoking at entry to the study the mean birth weight of babies born to women in the decaffeinated group was 16 g (95% confidence interval −40 to 73) higher than those born to women in the caffeinated group. The adjusted difference (decaffeinated group−caffeinated group) of length of gestation was −1.31 days (−2.87 to 0.25).
Conclusion A moderate reduction in caffeine intake in the second half of pregnancy has no effect on birth weight or length of gestation.
Trial registration Clinical Trials NCT00131690.
PMCID: PMC1804137  PMID: 17259189
9.  Maternal consumption of coffee during pregnancy and stillbirth and infant death in first year of life: prospective study 
BMJ : British Medical Journal  2003;326(7386):420.
To study the association between coffee consumption during pregnancy and the risk of stillbirth and infant death in the first year of life.
Prospective follow up study.
Aarhus University Hospital, Denmark, 1989-96.
18 478 singleton pregnancies in women with valid information about coffee consumption during pregnancy.
Main outcome measures
Stillbirth (delivery of a dead fetus at ⩾28 weeks' gestation) and infant death (death of a liveborn infant during the first year of life).
Pregnant women who drank eight or more cups of coffee per day during pregnancy had an increased risk of stillbirth compared with women who did not drink coffee (odds ratio=3.0, 95% confidence interval 1.5 to 5.9). After adjustment for smoking habits and alcohol intake during pregnancy, the relative risk of stillbirth decreased slightly. Adjustment for parity, maternal age, marital status, years of education, occupational status, and body mass index did not substantially change the estimates of association. There was no significant association between coffee consumption and death in the first year of life after adjustment for smoking habits during pregnancy.
Drinking coffee during pregnancy is associated with an increased risk of stillbirth but not with infant death.
What is already known on this topicResults from studies in monkeys suggest that high daily doses of caffeine in pregnancy increase the risk of stillbirth, but evidence from studies in humans has been lackingWhat this study addsPregnant women who drank eight or more cups of coffee a day had more than twice the risk of stillbirth compared with women who did not drink coffee during pregnancy
PMCID: PMC149440  PMID: 12595379
10.  Prenatal Antidepressant Exposure and Risk of Spontaneous Abortion – A Population-Based Study 
PLoS ONE  2013;8(8):e72095.
To estimate the risk of spontaneous abortion after use of antidepressant medication during pregnancy.
From the Danish Medical Birth Registry and the Danish National Hospital Registry, we identified all pregnancies leading to in- or outpatient contacts in Denmark from February 1997 to December 2008. The Danish Registry of Medicinal Product Statistics provided information on the women's prescriptions for antidepressants during pregnancy. We obtained information on women who were diagnosed with depression from the Danish Psychiatric Central Registry. Adjusted relative risks (aRR) of spontaneous abortion were estimated according to exposure to antidepressants or maternal depression using binomial regression.
Of the 1,005,319 pregnancies (547,300 women) identified, 114,721 (11.4%) ended in a spontaneous abortion. We identified 22,061 pregnancies exposed to antidepressants and 1,843 with a diagnosis of depression with no antidepressant use, of which 2,637 (12.0%) and 205 (11.1%) ended in a spontaneous abortion, respectively. Antidepressant exposure was associated with an aRR of 1.14 (95% confidence interval (CI) 1.10–1.18) for spontaneous abortion compared with no exposure to antidepressants. Among women with a diagnosis of depression, the aRR for spontaneous abortion after any antidepressant exposure was 1.00 (95% CI 0.80–1.24). No individual selective serotonin reuptake inhibitor (SSRI) was associated with spontaneous abortions. In unadjusted analyses, we found that mirtazapine, venlafaxine, and duloxetine were associated with spontaneous abortions among women with depression but we had no information on potential differences in disease severity and only few pregnancies were exposed in the population.
We identified a slightly increased risk of spontaneous abortion associated with the use of antidepressants during pregnancy. However, among women with a diagnosis of depression, antidepressants in general or individual SSRI in particular were not associated with spontaneous abortions. Further studies are warranted on the newer non-SSRI antidepressants, as we had insufficient data to adjust for important confounding factors.
PMCID: PMC3756033  PMID: 24015208

Results 1-10 (10)