Bodil Hammer Bech

Prepregnancy obesity and fetal death: a study within the Danish National Birth Cohort.

Objective: To examine the association between high prepregnancy body mass index and fetal death, allowing for the effects of gestational age, weight gain, and maternal diseases in pregnancy. Methods: Prepregnancy body mass index (BMI) and fetal death were examined in the Danish National Birth Cohort among 54,505 pregnant women who participated in a comprehensive interview during the second trimester. Pregnancy outcomes were obtained from registers and medical records. Cox regression analyses with delayed entry and time-dependent covariates were used to estimate the risk of fetal death. Results: Compared with normal-weight women (18.5 ≤ BMI < 25), the risks of fetal death among obese women (BMI ≥ 30), expressed as adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were as follows: before week 14: 0.8 (0.5–1.4), weeks 14–19: 1.6 (1.0–2.5), weeks 20–27: 1.9 (1.1–3.3), weeks 28–36: 2.1 (1.0–4.4), weeks 37–39: 3.5 (1.9–6.4), and weeks 40+: 4.6 (1.6–13.4). Overweight women (25 ≤ BMI < 30) also experienced a higher risk after 28 weeks, and especially after 40 weeks of gestation (HR 2.9, 95% CI 1.1–7.7). Analysis of stillbirth (fetal death at 28+ completed weeks of gestation) indicated that the effects were not due to obesity-related diseases in pregnancy, nor was weight gain associated with stillbirth. The increased risk of stillbirth among overweight and obese women was partly attributable to inadequate placental function (crude odds ratios 2.1, 95% CI 1.0–4.4, and 5.2, 95% CI 2.5–10.9, respectively). Conclusion: Prepregnancy obesity was associated with an increasing excess risk of fetal death with advancing gestation, and placental dysfunction may be a possible contributing factor. Level of Evidence: II-2

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.

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.

Health of children born to mothers who had preeclampsia: a population-based cohort study

OBJECTIVE We assessed whether preeclampsia correlates with the long-term postnatal health of the offspring. STUDY DESIGN We conducted a population-based cohort study of 1,618,481 singletons born in Denmark (1978-2004) with up to 27 years of follow-up. We used Cox regression to estimate the associations between preeclampsia and long-term health outcomes of the offspring. RESULTS Children born at term exposed to preeclampsia had an increased risk of a variety of diseases, such as endocrine, nutritional, and metabolic diseases (incidence rate ratio, 1.6; 95% confidence interval, 1.5-1.7), and diseases of the blood and blood-forming organs (incidence rate ratio, 1.5; 95% confidence interval, 1.3-1.8). Children born preterm exposed to preeclampsia had a similar pattern of hospitalizations compared with the children born preterm unexposed to preeclampsia, although they had a decreased risk of cerebral palsy (incidence rate ratio, 0.7; 95% confidence interval, 0.6-0.9). CONCLUSION Preeclampsia was associated with an increased risk of being hospitalized for a number of diseases, especially in the children born at term.

Neonatal jaundice, autism, and other disorders of psychological development.

OBJECTIVES: The goals were to study the association between neonatal jaundice and disorders of psychological development in a national, population-based cohort and to study whether gestational age, parity, and season of birth influenced that association. METHODS: A population-based, follow-up study of all children born alive in Denmark between 1994 and 2004 (N = 733 826) was performed, with data collected from 4 national registers. Survival analysis was used to calculate hazard ratios (HRs). RESULTS: Exposure to jaundice in neonates was associated with increased risk of disorders of psychological development for children born at term. The excess risk of developing a disorder in the spectrum of psychological development disorders after exposure to jaundice as a neonate was between 56% (HR: 1.56 [95% confidence interval [CI]: 1.05–2.30]) and 88% (HR: 1.88 [95% CI: 1.17–3.02]). The excess risk of infantile autism was 67% (HR: 1.67 [95% CI: 1.03–2.71]). This risk for infantile autism was higher if the child was conceived by a parous woman (HR: 2.71 [95% CI: 1.57–4.66]) or was born between October and March (HR: 2.21 [95% CI: 1.24–3.94]). The risk for infantile autism disappeared if the child was conceived by a primiparous woman (HR: 0.58 [95% CI: 0.18–1.83]) or was born between April and September (HR: 1.02 [95% CI: 0.41–2.50]). Similar risk patterns were found for the whole spectrum of autistic disorders. CONCLUSIONS: Neonatal jaundice in children born at term is associated with disorders of psychological development. Parity and season of birth seem to play important roles.

Maternal obesity and neonatal mortality according to subtypes of preterm birth.

OBJECTIVE: To examine the association between prepregnancy body mass index (BMI) and neonatal mortality while accounting for the timing of delivery and subtypes of preterm birth. METHODS: The study population included 85,375 liveborn singletons of mothers in the Danish National Birth Cohort (1996–2002) who were interviewed during the second trimester. Information about pregnancy outcomes and neonatal deaths (n=230) was obtained from national registers. The association was estimated by Cox regression analyses and results were presented as hazard ratios with 95% confidence intervals (CIs). RESULTS: Compared with infants of mothers who were at a normal weight before pregnancy (BMI of 18.5 or more but less than 25), neonatal mortality was increased in infants of mothers who were overweight (BMI of 25 or more but less than 30) or obese (BMI of 30 or more) (adjusted hazard ratios 1.7, CI 1.2–2.5, and 1.6, CI 1.0–2.4, respectively). For preterm infants (n=3,934, 136 deaths), neonatal mortality in infants born after preterm premature rupture of membranes (PROM) was significantly increased if they were born to an overweight or obese mother (adjusted hazard ratios 3.5, CI 1.4–8.7, and 5.7, CI 2.2–14.8). There were no associations between high BMI and neonatal mortality in infants born after spontaneous preterm birth without preterm PROM or in infants born after induced preterm delivery. CONCLUSION: High maternal weight seems to increase the risk of neonatal mortality, especially in infants born after preterm PROM. Inflammation or infection related to obesity may be part of the causal pathway. LEVEL OF EVIDENCE: II

Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3

Objective To assess the association between a patent ductus arteriosus (PDA) on day 3 of life and severe morbidity and mortality. Design Cohort study. Setting Neonatal Intensive Care Unit, Aarhus University Hospital, Denmark. Patients All neonates with a gestational age less than 32 weeks admitted from 2010 to 2012. Interventions All neonates (n=183) were routinely screened with echocardiography for PDA on day 3 of life. Information on baseline characteristics and outcome was collected by structured coding sheets and medical records. Main outcome measures The association among PDA diameter and pulmonary haemorrhage, intraventricular haemorrhage (IVH), necrotising enterocolitis, bronchopulmonary dysplasia (BPD), death, and the composite outcome of death or severe morbidity was assessed. Results In neonates, born prior to 28 gestational weeks, a PDA on day 3 of life was associated with a threefold increase in odds of death or severe morbidity compared with neonates without PDA (OR=3.4; CI 1.1 to 11). The odds were highest in neonates with a large PDA (diameter ≥1.5 mm). Neonates with a large PDA were also found to have increased odds of IVH (OR 4.2; CI 1.3 to 14) and BPD (OR 3.7; CI 1.0 to 14) compared with neonates with no PDA. Conclusions In neonates born with a gestational age below 28 weeks the presence of a PDA on day 3 of life was associated with adverse outcome; this association was even more pronounced with a large PDA. Thus, early echocardiography may facilitate the identification of neonates suitable for a targeted approach to intervention in future randomised controlled trials.

Prenatal antidepressant exposure and risk of spontaneous abortion - a population-based study.

Purpose To estimate the risk of spontaneous abortion after use of antidepressant medication during pregnancy. Methods 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 womens 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. Results 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. Conclusion 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.

Infertility, infertility treatment, and fetal growth restriction.

OBJECTIVE: To examine the association between infertility, with or without treatment, and fetal growth, as well as perinatal and infant mortality. METHODS: From the Danish National Birth Cohort (1997–2003), we identified 51,041 singletons born of fertile couples (time to pregnancy 12 months or less), 5,787 born of infertile couples conceiving naturally (time to pregnancy more than 12 months), and 4,317 born after treatment. We defined small for gestational age (SGA) as the lowest 5% of birth weight by sex and gestational age. RESULTS: 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. CONCLUSION: 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. LEVEL OF EVIDENCE: II

Semen quality according to prenatal coffee and present caffeine exposure: two decades of follow-up of a pregnancy cohort

BACKGROUND A few studies have investigated the association between male caffeine consumption in adult life and semen quality with conflicting results, but so far no studies have explored the effect of prenatal coffee exposure. We studied the association between prenatal coffee and current caffeine exposure and semen quality and levels of reproductive hormones. METHODS From a Danish pregnancy cohort established in 1984-1987, 347 sons out of 5109 were selected for a follow-up study conducted 2005-2006. Semen and blood samples were analyzed for conventional semen characteristics and reproductive hormones and were related to information on maternal coffee consumption during pregnancy and present caffeine consumption. Data were available for 343 men. RESULTS There was a tendency toward decreasing crude median semen volume (P = 0.06) and adjusted mean testosterone (P = 0.06) and inhibin B (P = 0.09) concentrations with increasing maternal coffee consumption during pregnancy. Sons of mothers drinking 4-7 cups/day had lower testosterone levels than sons of mothers drinking 0-3 cups/day (P = 0.04). Current male caffeine intake was associated with increasing testosterone levels (P = 0.007). Men with a high caffeine intake had approximately 14% higher concentration of testosterone than those with a low caffeine intake (P = 0.008). CONCLUSIONS The results observed in this study are only tentative, but they do not exclude a small to moderate effect of prenatal coffee exposure on semen volume and levels of reproductive hormones. Present adult caffeine intake did not show any clear associations with semen quality, but high caffeine intake was associated with a higher testosterone concentration.