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1.  N-Terminal Pro-B Type Natriuretic Peptide as a Marker of Bronchopulmonary Dysplasia or Death in Very Preterm Neonates: A Cohort Study 
PLoS ONE  2015;10(10):e0140079.
Background
Bronchopulmonary dysplasia (BPD) is a serious complication of preterm birth. Plasma N-terminal pro-B type natriuretic peptide (NT-proBNP) has been suggested as a marker that may predict BPD within a few days after birth.
Objectives
To investigate the association between NT-proBNP day three and bronchopulmonary dysplasia (BPD) or death and further to assess the impact of patent ductus arteriosus (PDA) on this association in neonates born before 32 gestational weeks.
Methods
A cohort study of 183 neonates born before 32 gestational weeks consecutively admitted to the Neonatal Intensive Care Unit, Aarhus University Hospital, Denmark. On day three plasma samples were collected and echocardiography carried out. NT-proBNP was measured by routine immunoassays. The combined outcome BPD or death was assessed at 36 weeks of postmenstrual age. Receiver operator characteristic (ROC) analysis was performed to determine the discrimination ability of NT-proBNP by the natural log continuous measure to recognize BPD or death. The association of BPD or death was assessed in relation to natural log NT-proBNP levels day three.
Results
The risk of BPD or death increased 1.7-fold with one unit increase of natural log NT-proBNP day three when adjusted for gestational age at birth (OR = 1.7, 95% CI 1.3; 2.3). The association was found both in neonates with and without a PDA. Adjusting for GA, PDA diameter, LA:Ao-ratio, or early onset sepsis did not change the estimate.
Conclusion
We found NT-proBNP to be associated with BPD or death in very preterm neonates. This association was not only explained by the PDA. We speculate that NT-proBNP may help the identification of neonates at risk of BPD as early as postnatal day three.
doi:10.1371/journal.pone.0140079
PMCID: PMC4599729  PMID: 26452045
2.  No excess risk of adverse pregnancy outcomes among women with serological markers of previous infection with Coxiella burnetii: evidence from the Danish National Birth Cohort 
Background
Q fever caused by Coxiella burnetii is transmitted to humans by inhalation of aerosols from animal birth products. Q fever in pregnancy is suspected to be a potential cause of fetal and maternal morbidity and fetal mortality but the pathogenesis is poorly understood, and even in Q fever endemic areas, the magnitude of a potential association is not established.
We aimed to examine if presence of antibodies to C. burnetii during pregnancy or seroconversion were associated with adverse pregnancy outcomes.
Methods
The Danish National Birth Cohort collected blood samples and interview data from 100,418 pregnant women (1996–2002). We sampled 397 pregnant women with occupational or domestic exposure to cattle or sheep and a random sample of 459 women with no animal exposure. Outcome measures were spontaneous abortion, preterm birth, birth weight and Small for Gestational Age (SGA).
Blood samples collected in pregnancy were screened for antibodies against C. burnetii by enzyme-linked immunosorbent assay (ELISA). Samples positive for IgG or IgM antibodies in the ELISA were confirmed by immunofluorescence antibody test (IFA).
Results
Among the 856 women, 169 (19.7%) women were IFA positive; 147 (87%) of these had occupational or domestic contact with livestock (IFA cutoff > =1:128).
Two abortions were IFA positive vs. 6 IFA negative (OR: 1.5; 95%CI: 0.3-7.6). Three preterm births were IFA positive vs. 38 IFA negative (OR: 0.4; 95% CI: 0.1-1.1). There was a significant difference in birth weight of 168 g (95% CI: 70-267 g) with IFA positive being heavier, and the risk of being SGA was not increased in the newborns of IFA positive women (OR: 0.4; 95%CI: 0.8-1.0).
Most seropositive women were IgG positive indicating previous exposure. Seroconversion during pregnancy was found in 10 women; they all delivered live babies at term, but two were SGA.
Conclusion
We found no increased risk of adverse pregnancy outcome in women with verified exposure to C. burnetii.
To our knowledge, this is the first population-based seroepidemiologic study evaluating pregnancy outcome in women with serologically verified exposure to C. burnetii against a comparable reference group of seronegative women.
doi:10.1186/1471-2334-13-87
PMCID: PMC3585700  PMID: 23413787
Q fever; Coxiella burnetii; Infection; Human; Pregnancy; Spontaneous abortion; Preterm birth
6.  Perfluoroalkyl Acid Concentrations in Blood Samples Subjected to Transportation and Processing Delay 
PLoS ONE  2015;10(9):e0137768.
Background
In studies of perfluoroalkyl acids, the validity and comparability of measured concentrations may be affected by differences in the handling of biospecimens. We aimed to investigate whether measured plasma levels of perfluoroalkyl acids differed between blood samples subjected to delay and transportation prior to processing and samples with immediate processing and freezing.
Methods
Pregnant women recruited at Aarhus University Hospital, Denmark, (n = 88) provided paired blood samples. For each pair of samples, one was immediately processed and plasma was frozen, and the other was delayed and transported as whole blood before processing and freezing of plasma (similar to the Danish National Birth Cohort). We measured 12 perfluoroalkyl acids and present results for compounds with more than 50% of samples above the lower limit of quantification.
Results
For samples taken in the winter, relative differences between the paired samples ranged between -77 and +38% for individual perfluoroalkyl acids. In most cases concentrations were lower in the delayed and transported samples, e.g. the relative difference was -29% (95% confidence interval -30; -27) for perfluorooctane sulfonate. For perfluorooctanoate there was no difference between the two setups [corresponding estimate 1% (0, 3)]. Differences were negligible in the summer for all compounds.
Conclusions
Transport of blood samples and processing delay, similar to conditions applied in some large, population-based studies, may affect measured perfluoroalkyl acid concentrations, mainly when outdoor temperatures are low. Attention to processing conditions is needed in studies of perfluoroalkyl acid exposure in humans.
doi:10.1371/journal.pone.0137768
PMCID: PMC4565678  PMID: 26356420
7.  Perfluoroalkyl acids and time to pregnancy revisited: An update from the Danish National Birth Cohort 
Environmental Health  2015;14:59.
Background
We previously demonstrated an association between plasma perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and longer time to pregnancy (TTP) in a sample from the Danish National Birth Cohort (DNBC, 1996-2002). In this study we investigated this association in a new sample from the same cohort.
Methods
Sample 1 consisted of 440 women, and Sample 2 consisted of 1161 women from whom we previously published the associations between PFOS or PFOA and TTP. We performed sample-specific and pooled analyses using discrete-time survival analyses to estimate fecundability ratios according to PFOS and PFOA quartiles, adjusted for potential confounders chosen guided by a directed acyclic graph. We also estimated odds ratios for infertility (TTP > 12 months or infertility treatment) according to PFOS and PFOA by multivariable logistic regression.
Results
In Sample 1 PFOS was not associated with lower fecundability ratios or infertility, and there was a tendency towards longer TTP with increasing PFOA only in parous women. In Sample 2 previously reported associations were again seen. In the pooled analyses including both parous and nulliparous women fecundability ratios were 13-22 % lower for the three higher quartiles of PFOS or PFOA compared to the reference quartile.
Conclusions
The pooled analyses were driven by the larger old sample, but we did not corroborate our previous finding of an association between high PFOS and longer TTP in the new sample. The tendency towards an association for PFOA and TTP in parous women may be due to reverse causation. Results from the new sample are more in line with the recent literature.
Electronic supplementary material
The online version of this article (doi:10.1186/s12940-015-0040-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12940-015-0040-9
PMCID: PMC4493954  PMID: 26148742
Female infertility; Fecundity; Reproduction; Perfluorooctane sulfonate; Perfluorooctanoate; Perfluorinated chemicals; Epidemiology; Humans
8.  Autism After Infection, Febrile Episodes, and Antibiotic Use During Pregnancy: An Exploratory Study 
Pediatrics  2012;130(6):e1447-e1454.
OBJECTIVES
Results of animal studies suggest that maternal immune activation during pregnancy causes deficiencies in fetal neurodevelopment. Infectious disease is the most common path to maternal immune activation during pregnancy. The goal of this study was to determine the occurrence of common infections, febrile episodes, and use of antibiotics reported by the mother during pregnancy and the risk for autism spectrum disorder (ASD) and infantile autism in the offspring.
METHODS
We used a population-based cohort consisting of 96 736 children aged 8 to 14 years and born from 1997 to 2003 in Denmark. Information on infection, febrile episodes, and use of antibiotics was self-reported through telephone interviews during pregnancy and early postpartum. Diagnoses of ASD and infantile autism were retrieved from the Danish Psychiatric Central Register; 976 children (1%) from the cohort were diagnosed with ASD.
RESULTS
Overall, we found little evidence that various types of mild common infectious diseases or febrile episodes during pregnancy were associated with ASD/infantile autism. However, our data suggest that maternal influenza infection was associated with a twofold increased risk of infantile autism, prolonged episodes of fever caused a threefold increased risk of infantile autism, and use of various antibiotics during pregnancy were potential risk factors for ASD/infantile autism.
CONCLUSIONS
Our results do not suggest that mild infections, febrile episodes, or use of antibiotics during pregnancy are strong risk factors for ASD/infantile autism. The results may be due to multiple testing; the few positive findings are potential chance findings.
doi:10.1542/peds.2012-1107
PMCID: PMC4451062  PMID: 23147969
antibiotics; autism; autistic disorder; fever; infection; pregnancy
9.  Attention Deficit/Hyperactivity Disorder and Childhood Autism in Association with Prenatal Exposure to Perfluoroalkyl Substances: A Nested Case–Control Study in the Danish National Birth Cohort 
Environmental Health Perspectives  2014;123(4):367-373.
Background:
Perfluoroalkyl substances (PFASs) are persistent pollutants found to be endocrine disruptive and neurotoxic in animals. Positive correlations between PFASs and neurobehavioral problems in children were reported in cross-sectional data, but findings from prospective studies are limited.
Objectives:
We investigated whether prenatal exposure to PFASs is associated with attention deficit/hyperactivity disorder (ADHD) or childhood autism in children.
Methods:
Among 83,389 mother–child pairs enrolled in the Danish National Birth Cohort during 1996–2002, we identified 890 ADHD cases and 301 childhood autism cases from the Danish National Hospital Registry and the Danish Psychiatric Central Registry. From this cohort, we randomly selected 220 cases each of ADHD and autism, and we also randomly selected 550 controls frequency matched by child’s sex. Sixteen PFASs were measured in maternal plasma collected in early or mid-pregnancy. We calculated risk ratios (RRs) using generalized linear models, taking into account sampling weights.
Results:
Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples; four other PFASs were quantified in ≥ 90% of the samples. We did not find consistent evidence of associations between mother’s PFAS plasma levels and ADHD [per natural log nanograms per milliliter increase: PFOS RR = 0.87 (95% CI: 0.74, 1.02); PFOA RR = 0.98 (95% CI: 0.82, 1.16)] or autism [per natural log nanograms per milliliter increase: PFOS RR = 0.92 (95% CI: 0.69, 1.22); PFOA RR = 0.98 (95% CI: 0.73, 1.31)]. We found positive as well as negative associations between higher PFAS quartiles and ADHD in models that simultaneously adjusted for all PFASs, but these estimates were imprecise.
Conclusions:
In this study we found no consistent evidence to suggest that prenatal PFAS exposure increases the risk of ADHD or childhood autism in children.
Citation:
Liew Z, Ritz B, von Ehrenstein OS, Bech BH, Nohr EA, Fei CY, Bossi R, Henriksen TB, Bonefeld-Jørgensen EC, Olsen J. 2015. Attention deficit/hyperactivity disorder and childhood autism in association with prenatal exposure to perfluoroalkyl substances: a nested case–control study in the Danish National Birth Cohort. Environ Health Perspect 123:367–373; http://dx.doi.org/10.1289/ehp.1408412
doi:10.1289/ehp.1408412
PMCID: PMC4383573  PMID: 25616253
10.  Fetal Growth and Schizophrenia: A Nested Case-Control and Case-Sibling Study 
Schizophrenia Bulletin  2012;39(6):1337-1342.
The association between low birth weight and schizophrenia has been suggested by many studies. Small for gestational age (SGA) is a measure used as a proxy for intrauterine growth restriction. We aim to examine if children who are born SGA are at increased risk of developing schizophrenia and whether an association may be explained by factors shared among siblings. We linked 3 population-based registers: the Danish National Medical Birth Register, the Danish Psychiatric Central Register, and the Danish Civil Registration register to identify all persons born between 1978 and 2000. A nested case-control study and a case-sibling study design were used. There were 4650 cases of schizophrenia. Incidence rate ratios (IRRs) were estimated using conditional logistic regression. SGA was defined as the lowest 10th birth weight percentile for a given sex and gestational age. SGA was associated with an IRR of 1.23 (95% CI: 1.11–1.37) for schizophrenia in the case-control study. An IRR of 1.28 (95% CI: 0.97–1.68) was found in the case-sibling study. There is a modest association between SGA and schizophrenia. Our results indicate that this association is due to an independent effect of factors associated with low birth weight for gestational age per se, rather than other factors shared by siblings.
doi:10.1093/schbul/sbs148
PMCID: PMC3796081  PMID: 23236080
register; Denmark; cohort study; epidemiology
11.  Predictors for an unsuccessful INtubation-SURfactant-Extubation procedure: a cohort study 
BMC Pediatrics  2014;14:155.
Background
The INtubation-SURfactant-Extubation (INSURE) is a procedure that is increasingly being used to treat the respiratory distress syndrome in preterm infants. The objective of this study was to identify predictors for an unsuccessful INSURE procedure.
Methods
The neonates included were less than 32 weeks’ gestation, treated with surfactant in the neonatal intensive care unit, and born 1998–2010. INSURE was defined as surfactant administration during intubation for less than 2 hours without the need for mechanical ventilation. INSURE success was defined as no re-intubation within 72 hours after INSURE, and INSURE failure was defined as re-intubation within 72 hours after INSURE. An unsuccessful INSURE procedure was either INSURE failure or mechanical ventilation for more than 24 hours immediately after surfactant administration. All predictors were defined a priori and were present before surfactant administration. Multivariate logistic regression was performed.
Results
In total, 322 neonates were included: 31% (n = 100) had INSURE success, 10% (n = 33) had INSURE failure, 49% (n = 158) needed mechanical ventilation for more than 24 hours, and the remaining 10% (n = 31) needed mechanical ventilation for less than 24 hours. Predictors for INSURE failure were low gestational age and hemoglobin below 8.5 mmol/l. Predictors for mechanical ventilation for more than 24 hours were low gestational age, Apgar at 5 minutes below 7, oxygen need above 50%, CO2 pressure above 7 kPa (~53 mmHg), pH below 7.3, lactate above 2.5 mmol/l, need for inotropes, and surfactant administration shortly after birth, whereas preeclampsia reduced the risk.
Conclusions
We identified specific predictors associated with an unsuccessful INSURE procedure. Keeping high-risk neonates with one or several predictors intubated and treated with mechanical ventilation after surfactant may prevent a re-intubation procedure.
doi:10.1186/1471-2431-14-155
PMCID: PMC4072617  PMID: 24947477
Respiratory distress syndrome; Pulmonary surfactants; Premature neonates; Mechanical ventilation; Continuous positive airway pressure
12.  Adverse Pregnancy Outcomes and Coxiella burnetii Antibodies in Pregnant Women, Denmark 
Emerging Infectious Diseases  2014;20(6):925-931.
Q fever may be associated with complications, but overall risk is low.
A high risk for obstetric complications has been reported among women infected with Coxiella burnetii, the causative agent of Q fever, but recent studies have failed to confirm these findings. We reviewed national data collected in Denmark during 2007–2011 and found 19 pregnancies in 12 women during which the mother had a positive or equivocal test for antibodies to C. burnetii (IgM phase I and II titers >64, IgG phase I and II titers >128). Of these 12 women, 4 experienced obstetric complications (miscarriage, preterm delivery, infant small for gestational age, oligohydramnion, fetal growth restriction, or perinatal death); these complications occurred in 9 pregnancies (47% of the 19 total pregnancies identified). Our findings suggest an association between Q fever and adverse pregnancy outcomes, but complications were identified in only 9 pregnancies during the study’s 5-year period, indicating that the overall risk is low.
doi:10.3201/eid2006.130584
PMCID: PMC4036770  PMID: 24856281
Q fever; Coxiella burnetii; Denmark; pregnancy; fetus; infant; mother; bacteria; zoonoses; infertility; seropositivity; antibodies; miscarriage
13.  Seasonal Variation of Dystocia in a Large Danish Cohort 
PLoS ONE  2014;9(4):e94432.
Background
Dystocia is one of the most frequent causes of cesarean delivery in nulliparous women. Despite this, its causes are largely unknown. Vitamin D receptor (VDR) has been found in the myometrium. Thus, it is possible that vitamin D affects the contractility of the myometrium and may be involved in the pathogenesis of dystocia. Seasonal variation of dystocia in areas with distinct seasonal variation in sunlight exposure, like Denmark, could imply that vitamin D may play a role. This study examined whether there was seasonal variation in the incidence of dystocia in a Danish population.
Method
We used information from a cohort of 34,261 nulliparous women with singleton pregnancies, spontaneous onset of labor between 37 and 42 completed gestational weeks, and vertex fetal presentation. All women gave birth between 1992 and 2010 at the Department of Obstetrics and Gynecology, Aarhus University Hospital, Skejby. Logistic regression combined with cubic spline was used to estimate the seasonal variation for each outcome after adjusting for calendar time.
Results
No evidence for seasonal variation was found for any of the outcomes: acute cesarean delivery due to dystocia (p = 0.44); instrumental vaginal delivery due to dystocia (p = 0.69); oxytocin augmentation due to dystocia (p = 0.46); and overall dystocia (p = 0.91).
Conclusion
No seasonal variation in the incidence of dystocia was observed in a large cohort of Danish women. This may reflect no association between vitamin D and dystocia, or alternatively that other factors with seasonal variation and influence on the occurrence of dystocia attenuate such an association.
doi:10.1371/journal.pone.0094432
PMCID: PMC3988070  PMID: 24736600
14.  The Danish neonatal clinical database is valuable for epidemiologic research in respiratory disease in preterm infants 
BMC Pediatrics  2014;14:47.
Background
We examined the quality of the information on the use of surfactant and the use of and duration of nasal continuous positive airway pressure (nCPAP), oxygen supplementation, and mechanical ventilation in the Danish Neonatal Clinical Database (NeoBase).
Methods
We included all neonates born with a gestational age < 32 weeks admitted to a Neonatal Intensive Care Unit (NICU) at two university hospitals in 2005. On discharge, the clinicians complete a structured form with information related to the delivery and course of stay in the NICU. These forms were entered into the NeoBase. The nurses’ daily bedside documentation was used as reference standard. Concordance was used as a measure of agreement between the NeoBase and the reference standard. For the dichotomous variables the concordance was defined as the sensitivity of the information registered in the NeoBase. For the continuous variables, it was based on the discrepancy in days between the NeoBase and the reference standard. The percentage of concordance was described as high (> 90), moderate (70–90) or low (< 70).
Results
Overall, 153 infants participated in the study. Concordance was high for all dichotomous variables. The NeoBase slightly underestimated the duration of nCPAP and mechanical ventilation. The duration of oxygen therapy was neither over- nor underestimated in the NeoBase. Concordance was low for all continuous variables if we assumed that the registered information was identical. It was 100% for duration of mechanical ventilation and moderate for nCPAP and oxygen supplementation if we allowed for a discrepancy of 1 day.
Conclusion
The NeoBase is a valuable tool for clinical and epidemiologic research and quality assurance regarding neonatal respiratory disease.
doi:10.1186/1471-2431-14-47
PMCID: PMC3930301  PMID: 24528529
Respiratory variables; Very preterm infants; Validation; Epidemiology; Quality assurance
15.  Randomised Trial of Planned Caesarean Section Prior to Versus after 39 Weeks: Unscheduled Deliveries and Facility Logistics - A Secondary Analysis 
PLoS ONE  2013;8(12):e84744.
Objectives
To compare the impact of scheduling caesarean section prior to versus after 39 completed weeks of gestation on the occurrence of unscheduled caesarean section and rescheduling of the procedure.
Methods
Secondary analysis from a multicentre randomised open-label trial including singleton pregnant women with a healthy foetus and a reliable due date. Women were allocated by computerized telephone randomisation to planned caesarean section at 38 weeks and three days or 39 weeks and three days. The outcomes were unscheduled deliveries with provided reasons, such as spontaneous labour onset or supervening complications, and any changes in the scheduled delivery date. Statistical analyses were according to intention-to-treat using Fisher’s exact test.
Results
From March 2009 to June 2011 1,274 women were included. Median difference in gestational age at delivery was six days. Compared to the 38 weeks group, the women in the 39 weeks group were more likely to have an unscheduled caesarean section (15.2% vs. 9.3%; RR 1.64, 95% CI 1.21; 2.22), to deliver between 6 pm and 8 am (10 % vs. 6%; RR 1.68, 95% CI 1.14; 2.47), or to have the procedure rescheduled (36.7% vs. 23%; RR 1.6, 95% CI 1.34;1.90).
Conclusions
Scheduling caesarean section after 39 weeks leads to a 60% increase in unscheduled caesarean sections and a 70% increase in delivery outside regular work hours as compared to scheduling of the procedure prior to 39 weeks.
Trial Registration
www.clinicaltrials.gov NCT00835003 http://www.clinicaltrials.gov/ct2/show/NCT00835003?term=NCT00835003&rank=1
doi:10.1371/journal.pone.0084744
PMCID: PMC3869904  PMID: 24376842
17.  Dietary Glycemic Index during Pregnancy Is Associated with Biomarkers of the Metabolic Syndrome in Offspring at Age 20 Years 
PLoS ONE  2013;8(5):e64887.
Objective
Growing evidence indicates that metabolic syndrome is rooted in fetal life with a potential key role of nutrition during pregnancy. The objective of the study was to assess the possible associations between the dietary glycemic index (GI) and glycemic load (GL) during pregnancy and biomarkers of the metabolic syndrome in young adult offspring.
Methods
Dietary GI and GL were assessed by questionnaires and interviews in gestation week 30 and offspring were clinically examined at the age of 20 years. Analyses based on 428 mother-offspring dyads were adjusted for maternal smoking during pregnancy, height, pre-pregnancy body mass index (BMI), education, energy intake, and the offspring’s ambient level of physical activity. In addition, possible confounding by gestational diabetes mellitus was taken into account.
Outcome Measures
Waist circumference, blood pressure, HOMA insulin resistance (HOMA-IR) and plasma levels of fasting glucose, triglycerides, HDL cholesterol, LDL cholesterol, total cholesterol, insulin, and leptin were measured in the offspring.
Results
Significant associations were found between dietary GI in pregnancy and HOMA-IR (the relative increase in HOMA-IR per 10 units’ GI increase was 1.09 [95% CI: 1.01, 1.16], p = 0.02), insulin (1.09 [95% CI: 1.02, 1.16], p = 0.01) and leptin (1.21 [95% CI: 1.06, 1.38], p = 0.01) in the offspring; whereas no associations were detected for GL.
Conclusions
Our data suggests that high dietary GI in pregnancy may affect levels of markers for the metabolic syndrome in young adult offspring in a potentially harmful direction.
doi:10.1371/journal.pone.0064887
PMCID: PMC3669023  PMID: 23741411
18.  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.
doi:10.1289/ehp.1104034
PMCID: PMC3346773  PMID: 22306490
offspring obesity; overweight; perfluoroalkyl compounds; PFOA; pregnancy; prenatal exposure
19.  Presence of Antibodies Against Coxiella burnetii and Risk of Spontaneous Abortion: A Nested Case-Control Study 
PLoS ONE  2012;7(2):e31909.
Background and Aims
Q fever is a bacterial zoonosis caused by infection with Coxiella burnetii. It is well established that Q fever causes fetal loss in small ruminants. The suspicion has been raised that pregnant women may also experience adverse pregnancy outcome when the infection is acquired or reactivated during pregnancy. The purpose of this study was to assess the potential association between serologic markers of infection with C.burnetii and spontaneous abortion.
Methods
A nested case-control study within the Danish National Birth Cohort, a cohort of 100,418 pregnancies recruited from 1996–2002. Women were recruited in first trimester of pregnancy and followed prospectively. Median gestational age at enrolment was 8 weeks (25 and 75 percentiles: 7 weeks; 10 weeks). During pregnancy, a blood sample was collected at gestational week 6–12 and stored in a bio bank. For this study, a case sample of 218 pregnancies was drawn randomly among the pregnancies in the cohort which ended with a miscarriage before 22 gestational weeks, and a reference group of 482 pregnancies was selected in a random fashion among all pregnancies in the cohort. From these pregnancies, serum samples were screened for antibodies against C. burnetii in a commercial enzyme-linked immunosorbent assay (ELISA). Samples that proved IgG or IgM antibody positive were subsequently confirmatory tested by an immunofluorescence (IFA) test.
Results
Among cases, 11 (5%) were C. burnetii positive in ELISA of which one was confirmed in the IFA assay compared to 29 (6%) ELISA positive and 3 IFA confirmed in the random sample.
Conclusions
We found no evidence of a higher prevalence of C.burnetii antibodies in serum samples from women who later miscarried and the present study does not indicate a major association between Q fever infection and spontaneous abortion in humans. Very early first trimester abortions were, however, not included in the study.
doi:10.1371/journal.pone.0031909
PMCID: PMC3283715  PMID: 22363769
20.  Infertility, infertility treatment, and mixed-handedness in children 
Early human development  2009;85(12):745-749.
Background
Mixed-handedness, which may reflect atypical brain laterality, has been linked to a number of medical conditions as well as prenatal stress.
Aims
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.
Results
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.
Conclusions
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.
doi:10.1016/j.earlhumdev.2009.10.001
PMCID: PMC2788033  PMID: 19875254
Infertility; Infertility treatment; Mixed-handedness; Oral contraceptives; Time to pregnancy
21.  Handedness and time to pregnancy 
Background
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.
Methods
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.
Results
In both cohorts, we saw a slightly lower fecundity in individuals who reported being mixed-handed. Left handedness was not significantly associated with fecundity.
Conclusions
Our data showed a modest association between mixed-handedness and subfecundity, which suggests that these traits may share a common prenatal etiology.
doi:10.1097/EDE.0b013e31818b47d1
PMCID: PMC2662690  PMID: 19057386
handedness; fecundity; time to pregnancy
22.  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.
doi:10.1136/bmj.b3569
PMCID: PMC2749925  PMID: 19776103
23.  Risk of respiratory morbidity in term infants delivered by elective caesarean section: cohort study 
BMJ : British Medical Journal  2007;336(7635):85-87.
Objective To investigate the association between elective caesarean sections and neonatal respiratory morbidity and the importance of timing of elective caesarean sections.
Design Cohort study with prospectively collected data from the Aarhus birth cohort, Denmark.
Setting Obstetric department and neonatal department of a university hospital in Denmark.
Participants All liveborn babies without malformations, with gestational ages between 37 and 41 weeks, and delivered between 1 January 1998 and 31 December 2006 (34 458 babies).
Main outcome measures Respiratory morbidity (transitory tachypnoea of the newborn, respiratory distress syndrome, persistent pulmonary hypertension of the newborn) and serious respiratory morbidity (oxygen therapy for more than two days, nasal continuous positive airway pressure, or need for mechanical ventilation).
Results 2687 infants were delivered by elective caesarean section. Compared with newborns intended for vaginal delivery, an increased risk of respiratory morbidity was found for infants delivered by elective caesarean section at 37 weeks’ gestation (odds ratio 3.9, 95% confidence interval 2.4 to 6.5), 38 weeks’ gestation (3.0, 2.1 to 4.3), and 39 weeks’ gestation (1.9, 1.2 to 3.0). The increased risks of serious respiratory morbidity showed the same pattern but with higher odds ratios: a fivefold increase was found at 37 weeks (5.0, 1.6 to16.0). These results remained essentially unchanged after exclusion of pregnancies complicated by diabetes, pre-eclampsia, and intrauterine growth retardation, or by breech presentation.
Conclusion Compared with newborns delivered vaginally or by emergency caesarean sections, those delivered by elective caesarean section around term have an increased risk of overall and serious respiratory morbidity. The relative risk increased with decreasing gestational age.
doi:10.1136/bmj.39405.539282.BE
PMCID: PMC2190264  PMID: 18077440
24.  Do inattention and hyperactivity symptoms equal scholastic impairment? evidence from three European cohorts 
BMC Public Health  2007;7:327.
Background
Attention Deficit/Hyperactivity Disorder (ADHD) affects many children, adolescents, and adults and is associated with a number of impairments. Poor academic performance is related to ADHD in clinical samples. However, it is unclear to what extent core ADHD symptoms and scholastic impairment are related in non-referred school-aged children.
Methods
Data come from three population-based cohorts from Sweden, Denmark, and Finland, which are part of the Nordic Network on ADHD. The combined sample size was 13,087 children who were studied at ages 7–8 or 10–12 years. Teachers rated children on inattention and hyperactivity symptoms and reported children's scholastic performance on basic skills.
Results
There was a significant association in all cohorts between core ADHD symptoms and scholastic impairment in reading, writing, and mathematics. Particularly, inattention was related to a two to tenfold increase in scholastic impairment. Prevalence of hyperactivity symptoms was similar across the three cohorts, but inattention was lowest among children from the Finnish cohort, after stratification on living conditions.
Conclusion
These results extend previous reports of scholastic impairment among children with clinically diagnosed ADHD to non-referred population samples from three European countries. Surveillance policies should be implemented in school systems to catch children in need of behavioral or scholastic support early.
doi:10.1186/1471-2458-7-327
PMCID: PMC2216016  PMID: 17999767
25.  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.
doi:10.1136/bmj.39062.520648.BE
PMCID: PMC1804137  PMID: 17259189

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