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author:("Olsen, bjørn")
1.  Mid-pregnancy Circulating Immune Biomarkers in Women with Preeclampsia and Normotensive Controls 
Pregnancy hypertension  2015;6(1):72-78.
To determine if mid-pregnancy circulating immune biomarkers are associated with preeclampsia.
Study Design
Nested case-control study of 410 preeclamptic women and 297 normotensive controls with primiparous singleton pregnancies enrolled in the Danish National Birth Cohort. The mean gestational age in our cohort is 16 weeks (range 9–26).
Main Outcome Measures
Preeclampsia was defined by blood pressure ≥ 140/90mmHg and proteinuria ≥3g/24h. Serum immune biomarkers included interleukin (IL)-6, IL-6 receptor, IL-4, IL-4 receptor, IL-5, IL-12, IL-2, TNF-α, TNF-β, TNF-receptor, IL-1β, IL-1α, IL-8, IL-10, IFN-γ, IL-18, macrophage migration inhibitory factor, macrophage inflammatory protein, transforming growth factor-beta (TGF-β), and RANTES. Associations with preeclampsia, term preeclampsia and preterm preeclampsia were determined using two logistic regression models; 1) biomarkers were dichotomized by the limit of detection (LOD): 2) on the continuous scale, non-detectable values were imputed by LOD/2 and transformed (base 2). All models were adjusted for body mass index and smoking.
IL1β was significantly associated with a decrease in the log odds of preeclampsia (p=0.0065), term preeclampsia (p=0.0230) and preterm preeclampsia (p=0.0068). Results were similar for IL4r and preeclampsia (p=0.0383). In the dichotomized models, detectable TNF-β was significantly associated with preeclampsia (ORadj 1.6, 95% CI 1.1–2.3) and term preeclampsia (ORadj 1.7, 95% CI 1.1–2.5) but not preterm preeclampsia. Detectable IL6 was significantly associated with term preeclampsia only (ORadj 1.5, 95% CI 1.1–2.2).
Mid-pregnancy circulating IL1β, IL4r, IL6, and TNFβ were associated with preeclampsia. However, results were not consistent across statistical models. As the relationship is complex, future studies should explore cytokine clusters in preeclampsia risk.
PMCID: PMC4785833  PMID: 26955776
Cytokines; Inflammation; Preeclampsia; Pregnancy
2.  Maternal Antenatal Bereavement and Neural Tube Defect in Live-Born Offspring: A Cohort Study 
PLoS ONE  2016;11(9):e0163355.
Maternal emotional stress during pregnancy has previously been associated with congenital neural malformations, but most studies are based on data collected retrospectively. The objective of our study was to investigate associations between antenatal maternal bereavement due to death of a close relative and neural tube defects (NTDs) in the offspring.
We performed a register-based cohort study including all live-born children (N = 1,734,190) from 1978–2008. Exposure was bereavement due to loss of a close relative from one year before conception to the end of the first trimester of pregnancy. The outcome was NTDs in the offspring according to the International Classification of Disease. We used multivariate logistic regression to estimate prevalence odds ratios (ORs).
A total of 2% children were born to mothers who lost a close relative prenatally. During 30 years of follow-up, 1,115 children were diagnosed with any NTDs: spina bifida (n = 889), anencephaly (n = 85) and encephalocele (n = 164). And 23 children were diagnosed with two types of NTDs. Overall, when comparing bereaved mothers to non-bereaved mothers, no significant increased prevalence of NTDs in the offspring was seen (OR = 0.84; 95% confidence interval: 0.52–1.33).
Overall maternal bereavement in the antenatal period was not related to NTDs in liveborn offspring.
PMCID: PMC5042438  PMID: 27685943
3.  Cohort profile: cerebral palsy in the Norwegian and Danish birth cohorts (MOBAND-CP) 
BMJ Open  2016;6(9):e012777.
The purpose of MOthers and BAbies in Norway and Denmark cerebral palsy (MOBAND-CP) was to study CP aetiology in a prospective design.
MOBAND-CP is a cohort of more than 210 000 children, created as a collaboration between the world's two largest pregnancy cohorts—the Norwegian Mother and Child Cohort study (MoBa) and the Danish National Birth Cohort. MOBAND-CP includes maternal interview/questionnaire data collected during pregnancy and follow-up, plus linked information from national health registries.
Findings to date
Initial harmonisation of data from the 2 cohorts has created 140 variables for children and their mothers. In the MOBAND-CP cohort, 438 children with CP have been identified through record linkage with validated national registries, providing by far the largest such sample with prospectively collected detailed pregnancy data. Several studies investigating various hypotheses regarding CP aetiology are currently on-going.
Future plans
Additional data can be harmonised as necessary to meet requirements of new projects. Biological specimens collected during pregnancy and at delivery are potentially available for assay, as are results from assays conducted on these specimens for other projects. The study size allows consideration of CP subtypes, which is rare in aetiological studies of CP. In addition, MOBAND-CP provides a platform within the context of a merged birth cohort of exceptional size that could, after appropriate permissions have been sought, be used for cohort and case-cohort studies of other relatively rare health conditions of infants and children.
PMCID: PMC5020679  PMID: 27591025
4.  Maternal Infections during Pregnancy and Cerebral Palsy: A Population-based Cohort Study 
Cerebral palsy (CP) is a common motor disability in childhood. We examined the association between maternal infections during pregnancy and the risk of congenital CP in the child.
Liveborn singletons in Denmark between 1997 and 2003 were identified from the Danish National Birth Registry and followed from 1 year of life until 2008. Redemption of antibiotics from the National Register of Medicinal Product Statistics and maternal infections reported by the National Hospital Register were used as markers of maternal infection during pregnancy. CP diagnoses were obtained from the Danish Cerebral Palsy Registry. Adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated by Cox proportional hazard models.
Of the 440 564 singletons with follow-up data, 840 were diagnosed with congenital CP. Maternal genito-urinary tract infections (HR 2.1, 95% CI 1.4, 3.2) were associated with CP in all births, in term births (HR 1.9, 95% CI 1.1, 3.2), in children with spastic CP (HR 2.1, 95% CI 1.4, 3.3), and among first-born children (HR 1.9, 95% CI 1.4, 3.3). Overall, we found associations between redeemed nitrofurantoin (HR 1.7, 95% CI 1.1, 2.8) and CP. Among trimester-specific exposures, CP risk was associated with prescriptions redeemed in the first trimester for any antibacterials, beta-lactam antibacterials, and nitrofurantoin, an antibiotic commonly used to treat lower urinary tract infection, and genito-urinary tract infections in the third trimester.
Genito-urinary tract infections and antibiotic use during pregnancy were associated with increased risks of CP, indicating that some maternal infections or causes of maternal infections present in prenatal life may be part of a causal pathway leading to CP.
PMCID: PMC4997608  PMID: 24117888
maternal infections; bacterial infections; pregnancy; congenital cerebral palsy
5.  Perfluoroalkyl Acids in Maternal Serum and Indices of Fetal Growth: The Aarhus Birth Cohort 
Environmental Health Perspectives  2015;124(6):848-854.
Previous studies indicated an association between intrauterine exposure to perfluorooctane sulfonate (PFOS) or perfluorooctanoate (PFOA) and lower birth weight. However, these perfluoroalkyl acids (PFAAs) have to some extent been substituted by other compounds on which little is known.
We investigated the association between specific PFAAs and birth weight, birth length, and head circumference at birth.
We studied 1,507 mothers and their children from the Aarhus Birth Cohort (2008–2013). Nulliparous women were included during pregnancy, and serum levels of 16 PFAAs were measured between 9 and 20 completed gestational weeks (96% within 13 weeks). For compounds with quantifiable values in > 50% of samples (7 compounds), we report the associations with birth weight, birth length, and head circumference at birth determined by multivariable linear regression.
Estimated mean birth weights were lower among women with serum perfluorohexane sulfonate, perfluoroheptane sulfonate, and PFOS concentrations above the lowest exposure quartile, but we found no consistent monotonic dose–response patterns. These associations were stronger when the population was restricted to term births (n = 1,426). For PFOS, the birth weight estimates for the highest versus lowest quartile were –50 g (95% CI: –123, 23 g) in all births and –62 g (95% CI: –126, 3 g) in term births. For the other PFAAs, the direction of the associations was inconsistent, and no overall association with birth weight was apparent. No PFAAs were associated with birth length or head circumference at birth.
Overall, we did not find strong or consistent associations between PFAAs and birth weight or other indices of fetal growth, though estimated mean birth weights were lower among those with exposures above the lowest quartile for some compounds.
Bach CC, Bech BH, Nohr EA, Olsen J, Matthiesen NB, Bonefeld-Jørgensen EC, Bossi R, Henriksen TB. 2016. Perfluoroalkyl acids in maternal serum and indices of fetal growth: the Aarhus Birth Cohort. Environ Health Perspect 124:848–854;
PMCID: PMC4892925  PMID: 26495857
7.  Prenatal and early life stress and risk of eating disorders in adolescent girls and young women 
European Child & Adolescent Psychiatry  2016;25(11):1245-1253.
Females are more likely than males to develop eating disorders (EDs) in the adolescence and youth, and the etiology remains unclear. We aimed to estimate the effect of severe early life stress following bereavement, the death of a close relative, on the risk of EDs among females aged 10–26 years. This population-based cohort study included girls born in Denmark (from 1973 to 2000) or Sweden (from 1970 to 1997). Girls were categorized as exposed if they were born to mothers who lost a close relative 1 year prior to or during pregnancy or if the girl herself lost a parent or a sibling within the first 10 years of life. All other girls were included in unexposed group. An ED case was defined by a diagnosis of EDs at ages of 10–26 years, including broadly defined bulimia nervosa, broadly defined anorexia nervosa and mixed EDs. Poisson regression models were used to estimate the incidence rate ratio (IRR) between exposed group and unexposed group.A total of 64453 (3.05 %) girls were included in the exposed group. We identified 9477 girls with a diagnosis of EDs, of whom 307 (3.24 %) were from the exposed group. Both prenatal and postnatal exposure following bereavement by unexpected death was associated with an increased overall risk of EDs (IRRprenatal: 1.49, 95 % CI: 1.01–2.19 and IRRpostnatal: 1.34, 95 % CI: 1.05–1.71). We observed similar results for subtypes of broadly defined bulimia nervosa (IRR: 2.47, 95 % CI: 1.67–3.65) and mixed EDs (IRR: 1.45, 95 % CI: 1.02–2.07).Our findings suggest that prenatal and early postnatal life stress due to unexpected death of a close relative is associated with an increased overall risk of eating disorders in adolescent girls and young women. The increased risk might be driven mainly by differences in broadly defined bulimia nervosa and mixed eating disorders, but not broadly defined anorexia nervosa.
PMCID: PMC5083758  PMID: 27083434
Bereavement; Eating disorders; Cohort study; Prenatal stress; Postnatal stress
Hypertension  2014;65(3):594-599.
Leptin, an adipocyte-derived hormone, plays an important role in reproduction and angiogenesis. Studies examining leptin in preeclampsia are inconsistent, possibly due to small sample sizes and variability in sampling and outcome. We conducted a nested case-control study to examine associations between serum leptin (measured: 9–26 weeks gestation) and preeclampsia among 430 primiparous preeclamptic women and 316 primiparous normotensive controls from the Danish National Birth Cohort. Median [interquartile range] leptin concentrations were calculated. Associations between leptin and preeclampsia (blood pressure ≥ 140/90mmHg), term preeclampsia (preeclampsia and delivery ≥ 37 weeks gestation), or preterm (preeclampsia and delivery < 37 weeks gestation) preeclampsia were examined using generalized linear models adjusting for body mass index, gestational age at blood draw, maternal age, smoking, and socio-occupational status. As leptin is increased in obese women and the risk of preeclampsia increases with body mass index, we used the Sobel test to examine if leptin is a mediator of this relationship. After adjustments, leptin concentrations were significantly higher in women with preeclampsia [30.5(24.6) p=0.0117] and term preeclampsia [30.4(24.9) p=0.0228] compared to controls [20.9(28.3)]. There was no significant difference between preterm preeclampsia [30.6(23.4) p=0.2210] and controls. Leptin is a possible mediator of the association between body mass index and preeclampsia (p=0.0276). Leptin concentrations are higher in women with preeclampsia compared to normotensive controls and may mediate some of the relationship between body mass index and preeclampsia.
PMCID: PMC4326535  PMID: 25510827
Body Mass Index; Hypertension; Leptin; Preeclampsia; Pregnancy
9.  Bias from conditioning on live birth in pregnancy cohorts: an illustration based on neurodevelopment in children after prenatal exposure to organic pollutants 
Only 60–70% of fertilized eggs may result in a live birth, and very early fetal loss mainly goes unnoticed. Outcomes that can only be ascertained in live-born children will be missing for those who do not survive till birth. In this article, we illustrate a common bias structure (leading to ‘live-birth bias’) that arises from studying the effects of prenatal exposure to environmental factors on long-term health outcomes among live births only in pregnancy cohorts. To illustrate this we used prenatal exposure to perfluoroalkyl substances (PFAS) and attention-deficit/hyperactivity disorder (ADHD) in school-aged children as an example. PFAS are persistent organic pollutants that may impact human fecundity and be toxic for neurodevelopment. We simulated several hypothetical scenarios based on characteristics from the Danish National Birth Cohort and found that a weak inverse association may appear even if PFAS do not cause ADHD but have a considerable effect on fetal survival. The magnitude of the negative bias was generally small, and adjusting for common causes of the outcome and fetal loss can reduce the bias. Our example highlights the need to identify the determinants of pregnancy loss and the importance of quantifying bias arising from conditioning on live birth in observational studies.
PMCID: PMC4339763  PMID: 25604449
Bias analysis; live-birth bias; reproductive epidemiology; birth cohort; prenatal exposure; perfluoroalkyl substances; attention-deficit/hyperactivity disorder
10.  Early Life Bereavement and Schizophrenia 
Medicine  2016;95(3):e2434.
Supplemental Digital Content is available in the text
We aimed to examine whether early life bereavement, as indicator of severe stress, was associated with an increased risk of schizophrenia later in life.
Based on population registers, we established a cohort of all children born in Denmark (N = 1 686 416) and Sweden (N = 2 563 659) from 1973 to 1997. Children were categorized as exposed if they lost a first-degree relative during the first 18 years of life. Outcome is the first diagnosis of schizophrenia as either inpatient or outpatient. Log-linear Poisson regression models were used to estimate incidence rate ratios (IRRs).
A total of 188,850 children (4.6%) experienced death of a first-degree relative from birth to 18 years of age. Compared with unexposed children, those exposed had overall a 39% higher risk of schizophrenia (= 1.39, 95% CI [confidence interval]: 1.32–1.47). The IRR was particularly high if the family member committed suicide (aIRR = 2.11, 95% CI: 1.90–2.34) or died due to an injury or accident (aIRR = 1.44, 95% CI: 1.27–1.63). The IRR of schizophrenia decreased with increasing child's age at bereavement (P < 0.0001). Children who experienced >1 death during the first 18 years of life (aIRR = 1.79, 95% CI: 1.46–2.19) had a higher risk than those with a single death (aIRR = 1.37, 95% CI: 1.30–1.45).
The study suggested that exposure to death of a first-degree relative before 18 years was associated with an increased risk of schizophrenia in later life. The complex mechanisms behind these associations remain to be elucidated.
PMCID: PMC4998249  PMID: 26817875
11.  Mortality in Children Aged 0-9 Years: A Nationwide Cohort Study from Three Nordic Countries 
PLoS ONE  2016;11(1):e0146669.
Mortality in children under five years has been widely studied, whereas mortality at 5–9 years has received little attention. Using unique data from national registers in three Nordic countries, we aimed to characterize mortality directionality in children aged 0 to 9 years.
Methods and Findings
The cohort study included all children born in Denmark from 1973 to 2008 (n = 2,433,758), Sweden from 1973 to 2006 (n = 3,400,212), and a random sample of 89.3% of children born in Finland from 1987 to 2007 (n = 1,272,083). Children were followed from 0 to 9 years, and cumulative mortality and mortality rates were compared by age, gender, cause of death, and calendar periods. Among the 7,105,962 children, there were 48,299 deaths during study period. From 1981–1985 to 2001–2005, all-cause mortality rates were reduced by between 34% and 62% at different ages. Overall mortality rate ratio between boys and girls decreased from 1.25 to 1.21 with the most prominent reduction in children aged 5–9 years (from 1.59 to 1.19). Neoplasms, diseases of the nervous system and transport accidents were the most frequent cause of death after the first year of life. These three leading causes of death declined by 42% (from 6.2 to 3.6 per 100,000 person years), 43% (from 3.7 to 2.1) and 62% (from 3.9 to 1.5) in boys, and 25% (from 4.1 to 3.1 per 100000 person years), 42% (from 3.4 to 1.9) and 63% (from 3.0 to 1.1) in girls, respectively. Mortality from neoplasms was the highest in each age except infants when comparing cause-specific mortality, and half of deaths from diseases of the nervous system occurred in infancy. Mortality rate due to transport accidents increased with age and was highest in boys aged 5–9 years.
Mortality rate in children aged 0–9 years has been decreasing with diminished difference between genders over the past decades. Our results suggest the importance of further research on mortality by causes of neoplasms, and causes of transport accidents—especially in children aged 5–9 years.
PMCID: PMC4706349  PMID: 26744840
12.  Pregnancy-Induced Changes in Systemic Gene Expression among Healthy Women and Women with Rheumatoid Arthritis 
PLoS ONE  2015;10(12):e0145204.
Pregnancy induces drastic biological changes systemically, and has a beneficial effect on some autoimmune conditions such as rheumatoid arthritis (RA). However, specific systemic changes that occur as a result of pregnancy have not been thoroughly examined in healthy women or women with RA. The goal of this study was to identify genes with expression patterns associated with pregnancy, compared to pre-pregnancy as baseline and determine whether those associations are modified by presence of RA.
In our RNA sequencing (RNA-seq) dataset from 5 healthy women and 20 women with RA, normalized expression levels of 4,710 genes were significantly associated with pregnancy status (pre-pregnancy, first, second and third trimesters) over time, irrespective of presence of RA (False Discovery Rate (FDR)-adjusted p value<0.05). These genes were enriched in pathways spanning multiple systems, as would be expected during pregnancy. A subset of these genes (n = 256) showed greater than two-fold change in expression during pregnancy compared to baseline levels, with distinct temporal trends through pregnancy. Another 98 genes involved in various biological processes including immune regulation exhibited expression patterns that were differentially associated with pregnancy in the presence or absence of RA.
Our findings support the hypothesis that the maternal immune system plays an active role during pregnancy, and also provide insight into other systemic changes that occur in the maternal transcriptome during pregnancy compared to the pre-pregnancy state. Only a small proportion of genes modulated by pregnancy were influenced by presence of RA in our data.
PMCID: PMC4684291  PMID: 26683605
13.  Trends in All-Cause Mortality across Gestational Age in Days for Children Born at Term 
PLoS ONE  2015;10(12):e0144754.
Term birth is a gestational age from 259 days to 293 days. However trends in mortality according to gestational ages in days have not yet been described in this time period.
Methods and Findings
Based on nation-wide registries, we conducted a population-based cohort study among all children born at term in Denmark from 1997 to 2004 to estimate differences in mortality across gestational ages in days among singletons born at term. We studied early-neonatal mortality, neonatal mortality, infant mortality, and five-year mortality. Children were followed from birth up to the last day of the defined mortality period or December 31, 2009. A total of 360,375 singletons born between 259 and 293 days of gestation were included in the study. Mortality decreased with increasing gestational age in days and the highest mortality was observed among children born at 37 week of gestation. A similar pattern was observed when analyses were restricted to children born to by mothers without pregnancy complications.
This study demonstrates heterogeneity in mortality rates even among singletons born at term. The highest mortality was observed among children born 37 weeks of gestation, which call for cautions when inducing labor in term pregnancies just reaching 37 weeks of gestation. The findings support that 37 weeks of gestation should be defined as early term.
PMCID: PMC4684378  PMID: 26656842
14.  Fetal growth and preterm birth in children exposed to maternal or paternal rheumatoid arthritis. A nationwide cohort study 
To assess indicators of fetal growth and risk of preterm birth in children of parents with rheumatoid arthritis (RA).
Through linkage of Danish national registries we identified all children born in Denmark between 1977 and 2008. We used general linear regression models to estimate mean differences in indicators of fetal growth among children having a parent with RA compared to unexposed children. Odds ratios of preterm birth were calculated by a logistic regression model.
Of the 1,917,723 children included, a total of 13,556 children were exposed to maternal RA or maternal preclinical RA. Children exposed to maternal RA (2,101) had approximately similar length, head and abdominal circumference at birth, compared with children of mothers without RA. Birth weight was 87 gram lower (−87.04 g; 95% CI, −111.23; −62.84) and placenta weight was 14 gram lower (−13.45 g; 95% CI, −21.46; −5.43). Rather similar results were found in children exposed to maternal preclinical RA (11,455). Compared with unexposed children a higher risk of preterm birth was found in children exposed to maternal RA and maternal preclinical RA respectively (OR, 1.48; 95% CI,1.20;1.84 and OR, 1.32; 95% CI,1.07;1.64). No associations were found with paternal RA.
Children exposed to either maternal RA or maternal preclinical RA are more often born preterm. However, indicators of fetal growth measured at birth were only slightly lower than in unexposed children.
PMCID: PMC4245456  PMID: 25393524
Rheumatoid arthritis; birth weight; birth length; indicators of fetal growth; preterm birth; pregnancy outcome
15.  Severity of Birth Defects After Propylthiouracil Exposure in Early Pregnancy 
Thyroid  2014;24(10):1533-1540.
Background: Propylthiouracil (PTU) used in the treatment of maternal hyperthyroidism in early pregnancy may be associated with a higher prevalence of birth defects in the face and neck region and in the urinary system but the severity of these complications remains to be elucidated.
Methods: Review of hospital-registered cases of birth defects in the face and neck region and in the urinary system after PTU exposure in early pregnancy. We obtained information on maternal redeemed prescription of PTU and child diagnosis of birth defect from nationwide registers for all children born in Denmark between 1996 and 2008 (n=817,093). The children were followed until December 31, 2010 (median age, 8.3 years) and the Cox proportional hazards model was used to estimate adjusted hazard ratio (HR) with 95% confidence interval (CI) for having a birth defect after PTU exposure versus nonexposed children (n=811,730).
Results: Fourteen cases of birth defects were identified in the face and neck region and in the urinary system after PTU exposure in early pregnancy; 11 children were exposed to PTU only (n=564), whereas 3 children were born to mothers who switched from methimazole (MMI)/carbimazole (CMZ) to PTU in early pregnancy (n=159). Among children exposed to PTU only, the adjusted HR for having a birth defect in the face and neck region was 4.92 (95% CI 2.04–11.86) and in the urinary system 2.73 (1.22–6.07). Looking into details of the 14 cases, 7 children were diagnosed with a birth defect in the face and neck region (preauricular and branchial sinus/fistula/cyst) and 7 children had a birth defect in the urinary system (single cyst of kidney and hydronephrosis). Surgical treatment was registered in 6 of the cases with a birth defect in the face and neck region and 3 of the cases with a birth defect in the urinary system. Two of the children with a birth defect in the urinary system also had other birth defects (genital organs).
Conclusions: We report details on possible PTU-associated birth defects. They tend to be less severe than the defects observed after MMI/CMZ exposure. Yet, the majority of affected children had to undergo surgery.
PMCID: PMC4195247  PMID: 24963758
16.  Prenatal maternal bereavement and risk of eating disorders in infants and toddlers: a population-based cohort study 
BMC Psychiatry  2015;15:229.
Prenatal stress has been associated to a number of neuropsychiatric diseases but its role on the development of eating disorders (ED) remains unknown. Infants and toddlers with feeding or eating disorders are also at an increased risk of such diseases in later childhood and adolescence. We aimed to examine whether prenatal stress following maternal bereavement is associated with ED in infants and toddlers.
This population-based cohort study included children born from 1977 to 2008 in Denmark (N = 2,127,126) and from 1977 to 2006 in Sweden (N = 2,974,908). Children were categorized as exposed if they were born to mothers who lost a close relative one year prior to or during pregnancy and were categorized as unexposed otherwise. They were followed until the age of 3 for a first diagnosis of ED. Poisson regression models were used to examine incidence rate ratio (IRR) between the exposed and the unexposed cohort.
A total of 9,403 ED cases were identified and 179 of whom were in the exposed cohort. Offspring born to mothers bereaved by loss of a core family member (older child or spouse) within the six months before pregnancy had a higher risk of ED than the unexposed offspring (IRR: 1.63, 95 % confidence intervals (CI): 1.07–2.47). In stratified analyses, bereavement during the six months before pregnancy was associated with an increased risk of ED in boys (IRR: 2.21, 95 % CI: 1.28–3.82), but not in girls (IRR: 1.18, 95 % CI: 0.61–2.27).
This is the first population-based study to explore the association between prenatal stress and the risk of ED in infants and toddlers within two Nordic countries. This study added new evidence of early life stress for etiology of ED while the potential mechanism still needs further studies.
Prenatal stress following maternal bereavement by loss of a core family member is associated with an increased risk of ED among infants and toddlers. The six months before conception may be a susceptible time window, especially for boys.
PMCID: PMC4582887  PMID: 26403981
Bereavement; Eating disorders; Hypothalamus-pituitary-adrenal axis; Prenatal stress
17.  Cancer Mortality in People Treated with Antidepressants before Cancer Diagnosis: A Population Based Cohort Study 
PLoS ONE  2015;10(9):e0138134.
Depression is common after a cancer diagnosis and is associated with an increased mortality, but it is unclear whether depression occurring before the cancer diagnosis affects cancer mortality. We aimed to study cancer mortality of people treated with antidepressants before cancer diagnosis.
Methods and Findings
We conducted a population based cohort study of all adults diagnosed with cancer between January 2003 and December 2010 in Denmark (N = 201,662). We obtained information on cancer from the Danish Cancer Registry, on the day of death from the Danish Civil Registry, and on redeemed antidepressants from the Danish National Prescription Registry. Current users of antidepressants were defined as those who redeemed the latest prescription of antidepressant 0–4 months before cancer diagnosis (irrespective of earlier prescriptions), and former users as those who redeemed the latest prescription five or more months before cancer diagnosis. We estimated an all-cause one-year mortality rate ratio (MRR) and a conditional five-year MRR for patients who survived the first year after cancer diagnosis and confidence interval (CI) using a Cox proportional hazards regression model. Overall, 33,111 (16.4%) patients redeemed at least one antidepressant prescription in the three years before cancer diagnosis of whom 21,851 (10.8%) were current users at the time of cancer diagnosis. Current antidepressant users had a 32% higher one-year mortality (MRR = 1.32, 95% CI: 1.29–1.35) and a 22% higher conditional five-year mortality (MRR = 1.22, 95% CI: 1.17–1.26) if patients survived the first year after the cancer diagnosis than patients not redeeming antidepressants. The one-year mortality was particularly high for patients who initiated antidepressant treatment within four months before cancer diagnosis (MRR = 1.54, 95% CI: 1.47–1.61). Former users had no increased cancer mortality.
Initiation of antidepressive treatment prior to cancer diagnosis is common and is associated with an increased mortality.
PMCID: PMC4569483  PMID: 26367120
18.  Perfluoroalkyl Acid Concentrations in Blood Samples Subjected to Transportation and Processing Delay 
PLoS ONE  2015;10(9):e0137768.
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.
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.
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.
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.
PMCID: PMC4565678  PMID: 26356420
20.  Apgar-score in children prenatally exposed to antiepileptic drugs: a population-based cohort study 
BMJ Open  2015;5(9):e007425.
It is unknown if prenatal exposure to antiepileptic drugs (AEDs) increases the risk of low Apgar score in offspring.
Population-based study using health registers in Denmark.
We identified all 677 021 singletons born in Denmark from 1997 to 2008 and linked the Apgar score from the Medical Birth Register with information on the women's prescriptions for AEDs during pregnancy from the Danish Register of Medicinal Product Statistics. We used the Danish National Hospital Registry to identify mothers diagnosed with epilepsy before birth of the child. Results were adjusted for smoking and maternal age.
Among 2906 children exposed to AEDs, 55 (1.9%) were born with an Apgar score ≤7 as compared with 8797 (1.3%) children among 674 115 pregnancies unexposed to AEDs (adjusted relative risk (aRR)=1.41 (95% CI 1.07 to 1.85). When analyses were restricted to the 2215 children born of mothers with epilepsy, the aRR of having a low Apgar score associated with AED exposure was 1.34 (95% CI 0.90 to 2.01) When assessing individual AEDs, we found increased, unadjusted RR for exposure to carbamazepine (RR=1.86 (95% CI 1.01 to 3.42)), valproic acid (RR=1.85 (95% CI 1.04 to 3.30)) and topiramate (RR=2.97 (95% CI 1.26 to 7.01)) when compared to unexposed children.
Prenatal exposure to AEDs was associated with increased risk of being born with a low Apgar score, but the absolute risk of a low Apgar score was <2%. Risk associated with individual AEDs indicate that the increased risk is not a class effect, but that there may be particularly high risks of a low Apgar score associated with certain AEDs.
PMCID: PMC4567672  PMID: 26359281
21.  Geographic analysis of the variation in the incidence of ADHD in a country with free access to healthcare: a Danish cohort study 
The prevalence of citizens diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) has risen dramatically over the past decades in many countries, however, with large variations. Countries such as Denmark with centrally organized well fare systems, free access to health services and individual tracking based on unique personal identification may in particular contribute to our understanding of the reasons for this increase. Based on Danish registers we aimed to examine the geographical patterns of the distribution of ADHD diagnosis and medication use and explore the association with access to diagnostic services, diagnostic culture, neighbourhood socioeconomic status and municipal spending on health care for children.
We combined information on registered diagnosis of ICD-10 Hyperkinetic Disorder and ADHD medication use in a Danish register-based cohort of children born between 1990 and 2000. We mapped incidence proportions of diagnoses and medication use within the 98 Danish Municipalities. Global and local clustering of ADHD was identified using spatial analysis. Information on contextual factors in the municipalities was obtained from national registers. The associations between the incidence of ADHD and contextual factors were analysed using Bayesian spatial regression models.
We found a considerable variation in the incidence of ADHD across the municipalities. Significant clustering of both high and low incidence of ADHD was identified and mapped using the local Moran’s I. Clustering of low incidence of diagnosis and medication use was observed in less populated areas with limited diagnostic resources and in contrast clustering of high incidence in densely populated areas and greater diagnostic resources. When considering the spatial autocorrelation between neighbouring municipalities, no significant associations were found between ADHD and access to diagnostic services, different diagnostic culture, socioeconomic status at municipality level or the municipal spending on health care for children.
A large geographical variation of ADHD in the municipalities was observed despite tax-financed and free access to healthcare. Although not statistically significant, results indicate that accessibility to diagnostic resources might explain some of the variation in ADHD incidence. In contrast to US studies the observed variation was not statistically associated to contextual factors in terms of SES, municipal spending on health care for children or differences in diagnostic practices.
PMCID: PMC4546292  PMID: 26297014
Attention deficit hyperactivity disorder; Incidence proportion; GIS; Spatial analysis; Geographic variation; Diagnostic resources
22.  Survival among people with down syndrome: a nationwide population-based study in denmark 
Several studies have shown substantially longer survival among persons with Down syndrome in recent decades. We examined survival patterns among Danish persons with Down syndrome by karyotype.
A national cohort of 3,530 persons with Down syndrome identified from the Danish Cytogenetic Register and a reference cohort of persons without Down syndrome randomly selected from the general population were followed from 1 April 1968 to 15 January 2009 by linkages to the Register of Causes of Death and the Civil Registration System.
Overall, persons with Down syndrome had higher mortality than the reference cohort but to a lesser degree for persons with mosaic trisomy 21 than for persons with standard trisomy 21 or with Robertsonian translocations (hazard ratio 4.98 (95% confidence interval 3.51–7.08), 8.94 (8.32–9.60), and 10.23 (7.50–13.97), respectively). Among persons with Down syndrome born after April 1968, more recent birth cohorts had lower mortality rates than older birth cohorts, which was largely due to declining mortality among persons with Down syndrome who also had congenital heart defects.
Recent birth cohorts of persons with Down syndrome experienced declining mortality, likely due to treatment for congenital heart defects, and persons with mosaic trisomy 21 had better survival than persons with other Down syndrome karyotypes.
PMCID: PMC4532298  PMID: 22878506
congenital heart defects; Down syndrome; mortality; mosaic trisomy 21; survival
23.  Congenital cerebral palsy and prenatal exposure to self-reported maternal infections, fever, or smoking 
American journal of obstetrics and gynecology  2013;209(4):332.e1-332.e10.
The objective of the study was to investigate the association between maternal self-reported infections, fever, and smoking in the prenatal period and the subsequent risk for congenital cerebral palsy (CP).
We included the 81,066 mothers of singletons born between 1996 and 2003 who participated in the Danish National Birth Cohort. Children were followed up through December 2008. Information on maternal infections, fever, smoking, and other demographic and lifestyle factors during pregnancy were reported by mothers in computer-assisted telephone interviews in early and midgestation. We identified 139 CP cases including 121 cases of spastic CP (sCP) as confirmed by the Danish National Cerebral Palsy Register. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs).
Self-reported vaginal infections were associated with an increased risk of CP and sCP (aHR, 1.52; 95% CI, 1.04–2.24; and aHR, 1.73; 95% CI, 1.16–2.60, respectively) and particularly untreated vaginal infections were associated with an increased risk of sCP (aHR, 1.95; 95% CI, 1.16–3.26). Fever was associated with the risk of CP (aHR, 1.53; 95% CI, 1.06–2.21). Smoking 10 or more cigarettes per day during pregnancy was also associated with sCP (aHR, 1.80; 95% CI, 1.10–2.94). There was a modest excess in risk for children exposed to both heavy smoking and vaginal infections. No other self-reported infections were significantly associated with CP.
Self-reported vaginal infections, fever, and smoking 10 or more cigarettes per day during pregnancy were associated with a higher risk of overall CP and/or sCP.
PMCID: PMC4512233  PMID: 23791566
congenital cerebral palsy; maternal infections; pregnancy; smoking
24.  Risk of Fetal Death after Treatment with Antipsychotic Medications during Pregnancy 
PLoS ONE  2015;10(7):e0132280.
Antipsychotic medications are increasingly used during pregnancy. Nevertheless, fetal risks are still not fully studied. It is currently unclear whether the antipsychotic treatment might induce a higher risk of fetal death. We aimed to determine if use of antipsychotic medication during pregnancy is associated with an increased risk of spontaneous abortion or stillbirth.
In a historical cohort study, we identified all clinically recognized pregnancies registered in the nationwide Danish registries from 1997 to 2008 (N = 1,005,319). Exposure was defined as any prescription of antipsychotic medications redeemed by the pregnant women during the exposure window, and recorded in the Danish National Prescription Register. Outcome was defined as any spontaneous abortion or stillbirth recorded in the Danish National Hospital Register and the Danish Medical Birth Register respectively.
Women exposed to antipsychotic medications during pregnancy had a 34% higher risk of spontaneous abortion (adjusted relative risk = 1.34; 95% confidence interval = 1.22; 1.46) compared to unexposed women, but a similar risk compared to women exposed prior to (but not during) pregnancy (adjusted relative risk = 1.04; 95% confidence interval = 0.93; 1.17). The risk of spontaneous abortion was not increased in exposed pregnancies when compared to unexposed pregnancies in the same women (adjusted hazard ratio = 1.11; 95% CI = 0.94; 1.31). A twofold higher risk of stillbirth was found in women exposed to antipsychotic medications compared with unexposed women (relative risk = 2.27; 95% confidence interval = 1.45; 3.55) and compared with women exposed only prior to pregnancy (relative risk = 2.06; 95% confidence interval = 1.01; 4.19).
The increased risk of spontaneous abortion found in women treated with antipsychotic medications during pregnancy is most likely due to confounding factors. The risk of stillbirth was twofold higher in pregnancies exposed to antipsychotic medication during pregnancy. Treatment with antipsychotic medications during pregnancy requires careful consideration.
PMCID: PMC4498617  PMID: 26162087
25.  Perfluoroalkyl acids and time to pregnancy revisited: An update from the Danish National Birth Cohort 
Environmental Health  2015;14:59.
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.
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.
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.
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.
PMCID: PMC4493954  PMID: 26148742
Female infertility; Fecundity; Reproduction; Perfluorooctane sulfonate; Perfluorooctanoate; Perfluorinated chemicals; Epidemiology; Humans

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