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1.  Psychological Stress and Hospitalization for Childhood Asthma-a Nationwide Cohort Study in Two Nordic Countries 
PLoS ONE  2013;8(10):e78816.
Objective
Exposures to psychological stress in early life may contribute to the development or exacerbation of asthma. We undertook a cohort study based on data from several population-based registers in Denmark and Sweden to examine whether bereavement in childhood led to increased asthma hospitalization.
Methods
All singleton children born in Denmark during 1977-2008 and in Sweden during 1973-2006 were included in the study (N=5,202,576). The children were followed from birth to the date of first asthma hospitalization, emigration, death, their 18th birthday, or the end of study (31 December 2007 in Sweden and 31 December 2008 in Denmark), whichever came first. All the children were assigned to the non-bereaved group until they lost a close relative (mother, father or a sibling), from when they were included in the bereaved group. We evaluated the hazard ratio (HR) of first hospitalization for asthma in bereaved children using Cox proportional hazards regression models, compared to those who were in the non-bereaved group. We also did a sub-analysis on the association between bereavement and first asthma medication.
Results
A total of 147,829 children were hospitalized for asthma. The overall adjusted HR of asthma hospitalization in bereaved children was 1.10 (95% confidence interval (CI): 1.04-1.16), compared to non-bereaved children. The risk of asthma hospitalization was increased in those who lost a close relative at age of 14-17 years (HR=1.54, 95% CI: 1.23-1.92), but not in younger age groups. The association between bereavement and asthma hospitalization did not change over time since bereavement. In the sub-analysis in singleton live births during 1996-2008 recorded in the DMBR, bereavement was associated with a lower use of asthma medication (HR=0.87, 95% CI: 0.80-0.95).
Conclusions
Our data suggests that psychological stress following bereavement in late adolescence is associated with an increased risk of asthma hospitalization or lowers the threshold for asthma hospitalization.
doi:10.1371/journal.pone.0078816
PMCID: PMC3808299  PMID: 24205324
2.  Use of corticosteroids during pregnancy and risk of asthma in offspring: a nationwide Danish cohort study 
BMJ Open  2014;4(6):e005053.
Objective
To examine whether in utero exposure to local and systemic corticosteroids is associated with asthma development in offspring.
Design
Cohort study.
Setting
Denmark.
Participants
We included all singletons born alive in Denmark between 1996 and 2009. Data on maternal corticosteroid use, asthma in offspring and covariates were obtained from medical registries.
Main outcome measures
We compared asthma risks of children prenatally exposed to corticosteroids and of children of former corticosteroid users with that of unexposed children. We computed absolute risks and used proportional-hazards regression to compute adjusted HRs (aHRs). Using logistic regression we compared exposed children with unexposed siblings in a ‘within-mother-between-pregnancy’ analysis. Adjustment addressed varying length of follow-up.
Results
We identified 877 778 children, 3.6% of whom were prenatally exposed to systemic (n=5327) or local (n=24 436) corticosteroids. A total of 105 677 children developed asthma during follow-up with a 10-year risk of 18.4% among the exposed and 13.5% among the unexposed. The aHR was 1.54 (95% CI 1.45 to 1.65) for systemic use, 1.45 (95% CI 1.40 to 1.50) for local use and 1.32 (95% CI 1.30 to 1.34) for former use. The adjusted OR of the ‘within-mother-between-pregnancy’ analysis was 1.11 (95% CI 0.98 to 1.25).
Conclusions
These population-based data do not support a strong causal association between maternal corticosteroid use during pregnancy and increased asthma risk in offspring.
doi:10.1136/bmjopen-2014-005053
PMCID: PMC4054622  PMID: 24902733
CLINICAL PHARMACOLOGY; EPIDEMIOLOGY; PERINATOLOGY; RESPIRATORY MEDICINE (see Thoracic Medicine)
3.  Maternal Use of Antibiotics, Hospitalisation for Infection during Pregnancy, and Risk of Childhood Epilepsy: A Population-Based Cohort Study 
PLoS ONE  2012;7(1):e30850.
Background
Maternal infection during pregnancy may be a risk factor for epilepsy in offspring. Use of antibiotics is a valid marker of infection.
Methodology/Principal Findings
To examine the relationship between maternal infection during pregnancy and risk of childhood epilepsy we conducted a historical cohort study of singletons born in northern Denmark from 1998 through 2008 who survived ≥29 days. We used population-based medical databases to ascertain maternal use of antibiotics or hospital contacts with infection during pregnancy, as well as first-time hospital contacts with a diagnosis of epilepsy among offspring. We compared incidence rates (IR) of epilepsy among children of mothers with and without infection during pregnancy. We examined the outcome according to trimester of exposure, type of antibiotic, and total number of prescriptions, using Poisson regression to estimate incidence rate ratios (IRRs) while adjusting for covariates. Among 191 383 children in the cohort, 948 (0.5%) were hospitalised or had an outpatient visit for epilepsy during follow-up, yielding an IR of 91 per 100 000 person-years (PY). The five-year cumulative incidence of epilepsy was 4.5 per 1000 children. Among children exposed prenatally to maternal infection, the IR was 117 per 100 000 PY, with an adjusted IRR of 1.40 (95% confidence interval (CI): 1.22–1.61), compared with unexposed children. The association was unaffected by trimester of exposure, antibiotic type, or prescription count.
Conclusions/Significance
Prenatal exposure to maternal infection is associated with an increased risk of epilepsy in childhood. The similarity of estimates across types of antibiotics suggests that processes common to all infections underlie this outcome, rather than specific pathogens or drugs.
doi:10.1371/journal.pone.0030850
PMCID: PMC3266299  PMID: 22295115
4.  Early Life Disease Programming during the Preconception and Prenatal Period: Making the Link between Stressful Life Events and Type-1 Diabetes 
PLoS ONE  2010;5(7):e11523.
Background
To assess the risk of developing Type-1 diabetes among children who were exposed to maternal bereavement during the prenatal or 1-year preconception period.
Methods
We identified N = 1,548,746 singleton births born in Denmark between January 1st 1979 through December 31st 2004, and their next of kin. Altogether, 39,857 children were exposed to bereavement during their prenatal life. The main outcome of interest was hospitalization for type-1 diabetes (ICD 8: 249; ICD 10: E10).
Results
We found the strongest association for type-1 diabetes among children exposed to traumatic father or sibling deaths (aIRR: 2.03, 1.22–3.38); the association was mainly seen for girls (aIRR: 2.91, 1.61–5.26).
Conclusions
We found evidence to suggest that female fetuses exposed to severe prenatal stress are at increased risk for developing type-1 diabetes.
doi:10.1371/journal.pone.0011523
PMCID: PMC2901388  PMID: 20634978
5.  Prenatal Exposure to Bereavement and Type-2 Diabetes: A Danish Longitudinal Population Based Study 
PLoS ONE  2012;7(8):e43508.
Background
The etiology of type-2 diabetes is only partly known, and a possible role of prenatal stress in programming offspring for insulin resistance has been suggested by animal models. Previously, we found an association between prenatal stress and type-1 diabetes. Here we examine the association between prenatal exposure to maternal bereavement during preconception and pregnancy and development of type-2 diabetes in the off-spring.
Methods
We utilized data from the Danish Civil Registration System to identify singleton births in Denmark born January 1st 1979 through December 31st 2008 (N = 1,878,246), and linked them to their parents, grandparents, and siblings. We categorized children as exposed to bereavement during prenatal life if their mothers lost an elder child, husband or parent during the period from one year before conception to the child’s birth. We identified 45,302 children exposed to maternal bereavement; the remaining children were included in the unexposed cohort. The outcome of interest was diagnosis of type-2 diabetes. We estimated incidence rate ratios (IRRs) from birth using log-linear poisson regression models and used person-years as the offset variable. All models were adjusted for maternal residence, income, education, marital status, sibling order, calendar year, sex, and parents’ history of diabetes at the time of pregnancy.
Results
We found children exposed to bereavement during their prenatal life were more likely to have a type-2 diabetes diagnosis later in life (aIRR: 1.31, 1.01–1.69). These findings were most pronounced when bereavement was caused by death of an elder child (aIRR: 1.51, 0.94–2.44). Results also indicated the second trimester of pregnancy to be the most sensitive period of bereavement exposure (aIRR:2.08, 1.15–3.76).
Conclusions
Our data suggests that fetal exposure to maternal bereavement during preconception and the prenatal period may increase the risk for developing type-2 diabetes in childhood and young adulthood.
doi:10.1371/journal.pone.0043508
PMCID: PMC3429491  PMID: 22952698
6.  Infant and childhood neurodevelopmental outcomes following prenatal exposure to selective serotonin reuptake inhibitors: overview and design of a Finnish Register-Based Study (FinESSI) 
BMC Psychiatry  2012;12:217.
Background
Experimental animal studies and one population-based study have suggested an increased risk for adverse neurodevelopmental outcome after prenatal exposure to SSRIs. We describe the methods and design of a population-based study examining the association between prenatal SSRI exposure and neurodevelopment until age 14.
Methods and design
This is a cohort study of national registers in Finland: the Medical Birth Register, the Register of Congenital Malformations, the Hospital Discharge Register including inpatient and outpatient data, the Drug Reimbursement Register, and the Population Register. The total study population includes 845,345 women and their live-born, singleton offspring aged 14 or younger and born during Jan 1st 1996-Dec 31st 2010. We will compare the prevalence of psychiatric and neurodevelopmental outcomes in offspring exposed prenatally to SSRIs to offspring exposed to prenatal depression and unexposed to SSRIs. Associations between exposure and outcome are assessed by statistical methods including specific modeling to account for correlated outcomes within families and differences in duration of follow-up between the exposure groups. Descriptive results. Of all pregnant women with pregnancy ending in delivery (n = 859,359), 1.9% used SSRIs. The prevalence of diagnosed depression and depression-related psychiatric disorders within one year before or during pregnancy was 1.7%. The cumulative incidence of registered psychiatric or neurodevelopmental disorders was 6.9% in 2010 among all offspring born during the study period (age range 0–14 years).
Discussion
The study has the potential for significant public health importance in providing information on prenatal exposure to SSRIs and long-term neurodevelopment.
doi:10.1186/1471-244X-12-217
PMCID: PMC3564781  PMID: 23206294
SSRI; Pregnancy; Neurodevelopment
7.  Prenatal Stress and Risk of Febrile Seizures in Children: A Nationwide Longitudinal Study in Denmark 
We aimed to examine whether exposure to prenatal stress following maternal bereavement is associated with an increased risk of febrile seizures. In a longitudinal population-based cohort study, we followed 1,431,175 children born in Denmark. A total of 34,777 children were born to women who lost a close relative during pregnancy or within 1 year before the pregnancy and they were included in the exposed group. The exposed children had a risk of febrile seizures similar to that of the unexposed children (hazard ratio (HR) 1.00, 95% CI 0.94–1.06). The HRs did not differ according to the nature or timing of bereavement. Our data do not suggest any causal link between exposure to prenatal stress and febrile seizures in childhood.
doi:10.1007/s10803-009-0717-4
PMCID: PMC2694316  PMID: 19291382
Prenatal stress; Bereavement; Febrile seizures; Fetal programming; Longitudinal study
8.  Intrauterine growth pattern and risk of childhood onset insulin dependent (type I) diabetes: population based case-control study. 
BMJ : British Medical Journal  1996;313(7066):1174-1177.
OBJECTIVE: To investigate whether prenatal growth affects the risk of development of childhood onset insulin dependent (type I) diabetes mellitus. DESIGN: Population based case-control study. SETTING: Data from a nationwide childhood diabetes case register were linked with data from the nationwide Swedish Medical Birth Registry. SUBJECTS: Data from a total of 4584 diabetic children born after 1973 and diagnosed with diabetes from 1978 to 1992 were studied. For each child with insulin dependent diabetes three control children were randomly selected from among all infants born in the same year and at the same hospital as the proband. MAIN OUTCOME MEASURES: Birth weight, gestation, maternal age and parity, number of previous spontaneous abortions, and sex specific birth weight by gestational week expressed as multiples of the standard deviation (SD). RESULTS: There was a clear trend in the odds ratio for childhood onset diabetes according to SD of birth weight. The odds ratio (95% confidence interval) for small for gestational age after stratification for maternal age, parity, smoking habits, and maternal diabetes was 0.81 (0.65 to 0.99) and for large for gestational age after similar stratification was 1.20 (1.02 to 1.42). CONCLUSIONS: Intrauterine conditions that affect prenatal growth seem also to affect the risk of development of childhood diabetes in the way previously described for postnatal growth: a poor growth decreases and an excess growth increases the risk. The mechanism for this association is unclear.
PMCID: PMC2352527  PMID: 8916747
9.  Prenatal Stress Exposure Related to Maternal Bereavement and Risk of Childhood Overweight 
PLoS ONE  2010;5(7):e11896.
Background
It has been suggested that prenatal stress contributes to the risk of obesity later in life. In a population–based cohort study, we examined whether prenatal stress related to maternal bereavement during pregnancy was associated with the risk of overweight in offspring during school age.
Methodology/Principal Findings
We followed 65,212 children born in Denmark from 1970–1989 who underwent health examinations from 7 to 13 years of age in public or private schools in Copenhagen. We identified 459 children as exposed to prenatal stress, defined by being born to mothers who were bereaved by death of a close family member from one year before pregnancy until birth of the child. We compared the prevalence of overweight between the exposed and the unexposed. Body mass index (BMI) values and prevalence of overweight were higher in the exposed children, but not significantly so until from 10 years of age and onwards, as compared with the unexposed children. For example, the adjusted odds ratio (OR) for overweight was 1.68 (95% confidence interval [CI] 1.08–2.61) at 12 years of age and 1.63 (95% CI 1.00–2.61) at 13 years of age. The highest ORs were observed when the death occurred in the period from 6 to 0 month before pregnancy (OR 3.31, 95% CI 1.71–6.42 at age 12, and OR 2.31, 95% CI 1.08–4.97 at age 13).
Conclusions/Significance
Our results suggest that severe pre-pregnancy stress is associated with an increased risk of overweight in the offspring in later childhood.
doi:10.1371/journal.pone.0011896
PMCID: PMC2912844  PMID: 20689593
10.  Birth weight, gestational age, fetal growth and childhood asthma hospitalization 
Background
Childhood asthma may have a fetal origin through fetal growth and development of the immunocompetence or respiratory organs.
Objective
We examined to which extent short gestational age, low birth weight and fetal growth restriction were associated with an increased risk of asthma hospitalization in childhood.
Methods
We undertook a cohort study based on several national registers in Denmark, Sweden and Finland. We included all live singleton born children in Denmark during 1979-2005 (N = 1,538,093), in Sweden during 1973-2004 (N = 3,067,670), and a 90% random sample of singleton children born in Finland during 1987-2004 (N = 1,050,744). The children were followed from three years of age to first hospitalization for asthma, emigration, death, their 18th birthday, or the end of study (the end of 2008 in Denmark, and the end of 2007 in Sweden or Finland), whichever came first. We computed the pseudo-values for each observation and used them in a generalized estimating equation to estimate relative risks (RR) for asthma hospitalization.
Results
A total of 131,783 children were hospitalized for asthma during follow-up. The risk for asthma hospitalization consistently increased with lower birth weight and shorter gestational age. A 1000-g decrease in birth weight corresponded to a RR of 1.17 (95% confidence interval (CI) 1.15-1.18). A one-week decrease in gestational age corresponded to a RR of 1.05 (95% CI 1.04-1.06). Small for gestational age was associated with an increased risk of asthma hospitalization in term but not in preterm born children.
Conclusions
Fetal growth and gestational age may play a direct or indirect causal role in the development of childhood asthma.
doi:10.1186/1710-1492-10-13
PMCID: PMC3973844  PMID: 24602245
Asthma; Birth weight; Gestational age; Hospitalization; Small for gestational age
11.  No effect of season of birth on risk of type 1 diabetes, cancer, schizophrenia and ischemic heart disease, while some variations may be seen for pneumonia and multiple sclerosis 
Dermato-endocrinology  2013;5(2):309-316.
Background: The risk of type 1 diabetes (T1DM), infections, cancer, schizophrenia and multiple sclerosis (MS) has been associated with environmental factors including vitamin D status.
Materials and Methods: Data were obtained from all children born in Denmark in 1940 (n = 72,839), 1977 (n = 89,570), and 1996 (n = 74,015). Information on contacts to hospitals (1977–2009) was obtained from the National Hospital Discharge Register. The main exposure variable was season of birth as a proxy variable for vitamin D status (summer: April–September and winter: October–March).
Results: No associations between season of birth and risk of MS were seen in the 1940 cohort or the 1996 cohort. In the 1977 cohort, there was a borderline statistically significant decreased risk of MS in those born during wintertime compared with those born during summertime (HR = 0.70, 95% CI: 0.47–1.04, p = 0.07). There were no significant differences within the groups regarding season and risk of T1DM at any age, T1DM before 10 y, infection, any type of cancer, schizophrenia and myocardial infarction. In the 1977 cohort the risk of pneumonia was significantly lower among those born in the summer compared with the winter at any age (HR 0.91, 95% CI 0.85–0.97, p < 0.01) and at age < 10 y (HR 0.90, 95% CI 0.84–0.97, p < 0.01).
Conclusion: MS and pneumonia in young subjects may be related to season of birth and thus maternal vitamin D exposure. Low sunlight exposure in the winter time leading to low vitamin D levels during pregnancy may be a potential explanation.
doi:10.4161/derm.22779
PMCID: PMC3772919  PMID: 24194971
Vitamin D and Multiple Sclerosis; type 1 Diabetes; cancer; schizophrenia; pneumonia; myocardial infarction
12.  The 5-minute Apgar score as a predictor of childhood cancer: a population-based cohort study in five million children 
BMJ Open  2012;2(4):e001095.
Objective
The aetiology of childhood cancer remains largely unknown but recent research indicates that uterine environment plays an important role. We aimed to examine the association between the Apgar score at 5 min after birth and the risk of childhood cancer.
Design
Nationwide population-based cohort study.
Setting
Nationwide register data in Denmark and Sweden.
Study population
All live-born singletons born in Denmark from 1978 to 2006 (N=1 771 615) and in Sweden from 1973 to 2006 (N=3 319 573). Children were followed up from birth to 14 years of age.
Main outcome measures
Rates and HRs for all childhood cancers and for specific childhood cancers.
Results
A total of 8087 children received a cancer diagnosis (1.6 per 1000). Compared to children with a 5-min Apgar score of 9–10, children with a score of 0–5 had a 46% higher risk of cancer (adjusted HR 1.46, 95% CI 1.15 to 1.89). The potential effect of low Apgar score on overall cancer risk was mostly confined to children diagnosed before 6 months of age. Children with an Apgar score of 0–5 had higher risks for several specific childhood cancers including Wilms’ tumour (HR 4.33, 95% CI 2.42 to 7.73).
Conclusions
A low 5 min Apgar score was associated with a higher risk of childhood cancers diagnosed shortly after birth. Our data suggest that environmental factors operating before or during delivery may play a role on the development of several specific childhood cancers.
doi:10.1136/bmjopen-2012-001095
PMCID: PMC3425910  PMID: 22874628
Oncology; Epidemiology; Paediatric oncology; Preventive Medicine
13.  Influence of maternal age at delivery and birth order on risk of type 1 diabetes in childhood: prospective population based family study 
BMJ : British Medical Journal  2000;321(7258):420-424.
Objectives
To examine the influence of parental age at delivery and birth order on subsequent risk of childhood diabetes.
Design
Prospective population based family study.
Setting
Area formerly administered by the Oxford Regional Health Authority.
Participants
1375 families in which one child or more had diabetes. Of 3221 offspring, 1431 had diabetes (median age at diagnosis 10.5 years, range 0.4-28.5) and 1790 remained non-diabetic at a median age of 16.1 years.
Main outcome measures
Disease free survival and hazard ratios for the development of type 1 diabetes in all offspring, assessed by Cox proportional hazard regression.
Results
Maternal age at delivery was strongly related to risk of type 1 diabetes in the offspring; risk increased by 25% (95% confidence interval 17% to 34%) for each five year band of maternal age, so that maternal age at delivery of 45 years or more was associated with a relative risk of 3.11 (2.07 to 4.66) compared with a maternal age of less than 20 years. Paternal age was also associated with a 9% (3% to 16%) increase for each five year increase in paternal age. The relative risk of diabetes, adjusted for parental age at delivery and sex of offspring, decreased with increasing birth order; the overall effect was a 15% risk reduction (10% to 21%) per child born.
Conclusions
A strong association was found between increasing maternal age at delivery and risk of diabetes in the child. Risk was highest in firstborn children and decreased progressively with higher birth order. The fetal environment seems to have a strong influence on risk of type 1 diabetes in the child. The increase in maternal age at delivery in the United Kingdom over the past two decades could partly account for the increase in incidence of childhood diabetes over this period.
PMCID: PMC27456  PMID: 10938050
14.  Pragmatic controlled trial to prevent childhood obesity in maternity and child health care clinics: pregnancy and infant weight outcomes (The VACOPP Study) 
BMC Pediatrics  2013;13:80.
Background
According to current evidence, the prevention of obesity should start early in life. Even the prenatal environment may expose a child to unhealthy weight gain; maternal gestational diabetes is known to be among the prenatal risk factors conducive to obesity. Here we report the effects of antenatal dietary and physical activity counselling on pregnancy and infant weight gain outcomes.
Methods
The study was a non-randomised controlled pragmatic trial aiming to prevent childhood obesity, the setting being municipal maternity health care clinics. The participants (n = 185) were mothers at risk of developing gestational diabetes mellitus and their offspring. The children of the intervention group mothers were born between 2009 and 2010, and children of the control group in 2008. The intervention started between 10–17 gestational weeks and consisted of individual counselling on diet and physical activity by a public health nurse, and two group counselling sessions by a dietician and a physiotherapist. The expectant mothers also received a written information leaflet to motivate them to breastfeed their offspring for at least 6 months. We report the proportion of mothers with pathological glucose tolerance at 26–28 weeks’ gestation, the mother’s gestational weight gain (GWG) and newborn anthropometry. Infant weight gain from 0 to 12 months of age was assessed as weight-for-length standard deviation scores (SDS) and mixed effect linear regression models.
Results
Intervention group mothers had fewer pathological oral glucose tolerance test results (14.6% vs. 29.2%; 95% CI 8.9 to 23.0% vs. 20.8 to 39.4%; p-value 0.016) suggesting that the intervention improved gestational glucose tolerance. Mother’s GWG, newborn anthropometry or infant weight gain did not differ significantly between the groups.
Conclusion
Since the intervention reduced the prevalence of gestational diabetes mellitus, it may have the potential to diminish obesity risk in offspring. However, results from earlier studies suggest that the possible effect on the offspring’s weight gain may manifest only later in childhood.
Trial registration
Clinical Trials gov: NCT00970710
doi:10.1186/1471-2431-13-80
PMCID: PMC3664621  PMID: 23688259
Childhood obesity; Gestational diabetes mellitus; Diet; Physical activity; Intervention; Prevention
15.  Fertility treatment and risk of childhood and adolescent mental disorders: register based cohort study 
Objective To assess the mental health of children born after fertility treatment by comparing their risk of mental disorders with that of spontaneously conceived children.
Design Prospective register based cohort study.
Setting Nationwide register based information from Danish National Health Registers cross linked by a unique personal identification number assigned to all citizens in Denmark.
Participants All children born in Denmark in 1995-2003 with follow-up in 2012 when the children were aged 8-17; 33 139 children were conceived after fertility treatment and 555 828 children were born after spontaneous conception.
Main outcome measures Absolute risks and hazard ratios for overall and specific mental disorders estimated with adjustment for potential confounding variables. Estimated association between the risk of mental disorders and subtypes of procedures, hormone treatments, gamete types, and cause of infertility.
Results The risk of mental disorders in children born after in vitro fertilisation or intracytoplasmic sperm injection was low, and was no higher than in spontaneously conceived children, except for a borderline significant increased risk of tic disorders (hazard ratio 1.40, 95% confidence interval 1.01 to 1.95; absolute risk 0.3%). In contrast, children born after ovulation induction with or without insemination had low but significantly increased risks of any mental disorder (1.20, 1.11 to 1.31; absolute risk 4.1%), autism spectrum disorders (1.20, 1.05 to 1.37; 1.5%), hyperkinetic disorders (1.23, 1.08 to 1.40; 1.7%), conduct, emotional, or social disorder (1.21, 1.02 to 1.45; 0.8%), and tic disorders (1.51, 1.16 to 1.96; 0.4%). There was no risk systematically related to any specific type of hormone drug treatment.
Conclusions There was a small increase in the incidence of mental disorders in children born after ovulation induction/intrauterine insemination. Children born after in vitro fertilisation/intracytoplasmic sperm injection were found to have overall risk comparable with children conceived spontaneously.
doi:10.1136/bmj.f3978
PMCID: PMC3702157  PMID: 23833075
16.  In utero exposure to antidepressant drugs and risk of attention deficit hyperactivity disorder: a nationwide Danish cohort study 
BMJ Open  2013;3(9):e003507.
Objective
To investigate whether in utero exposure to antidepressants is associated with increased risk of attention deficit hyperactivity disorder (ADHD).
Design
Cohort study.
Setting
Denmark.
Participants
All Danish singletons born alive from 1996 to 2009 were included. Using national medical registries, we defined in utero exposure to antidepressants as redemption of an antidepressant prescription by the mother 30 days prior to or during pregnancy. We defined maternal former users of antidepressants as women, who had redeemed a prescription up to 30 days prior to pregnancy, and never users as women who had never redeemed a prescription.
Main outcome measures
ADHD was defined as redemption of a prescription for ADHD medication or an ADHD hospital diagnosis. Children were followed through 2010, and we used proportional-hazards regression to compute adjusted HRs comparing children exposed in utero and children born to former antidepressant users with children born to never users. To adjust for confounding from family-related factors, we conducted a within-mother between-pregnancy analysis comparing exposed children with unexposed siblings using conditional logistic regression.
Results
We identified a cohort of 877 778 children, of whom 1.7% were exposed in utero. The overall median follow-up time was 8 years; selective serotonin reuptake inhibitors were the most commonly used class of antidepressant during pregnancy (78% of users). The adjusted HR comparing children exposed to any antidepressant in utero with children born to never users was 1.2 (95% CI 1.1 to 1.4), and 1.6 (95% CI 1.5 to 1.8) comparing children born to former users to children born to never users of antidepressants. In the within-mother between-pregnancy analysis (n=867), the adjusted OR was 0.7 (95% CI 0.4 to 1.4).
Conclusions
This study provides no evidence to support a causal association between in utero exposure to antidepressants and risk of ADHD.
doi:10.1136/bmjopen-2013-003507
PMCID: PMC3780335  PMID: 24056487
17.  Association Between Prepartum Maternal Iron Deficiency and Offspring Risk of Schizophrenia: Population-Based Cohort Study With Linkage of Danish National Registers 
Schizophrenia Bulletin  2010;37(5):982-987.
Recent findings suggest that maternal iron deficiency may increase the risk of schizophrenia-spectrum disorder in offspring. We initiated this study to determine whether maternal prepartum anemia influences offspring risk of schizophrenia. We conducted a population-based study with individual record linkage of the Danish Civil Registration System, the Danish Psychiatric Central Register, and the Danish National Hospital Register. In a cohort of 1 115 752 Danish singleton births from 1978 to 1998, cohort members were considered as having a maternal history of anemia if the mother had received a diagnosis of anemia at any time during the pregnancy. Cohort members were followed from their 10th birthday until onset of schizophrenia, death, or December 31, 2008, whichever came first. Adjusted for relevant confounders, cohort members whose mothers had received a diagnosis of anemia during pregnancy had a 1.60-fold (95% confidence interval = 1.16–2.15) increased risk of schizophrenia. Although the underlying mechanisms are unknown and independent replication is needed, our findings suggest that maternal iron deficiency increases offspring risk of schizophrenia.
doi:10.1093/schbul/sbp167
PMCID: PMC3160221  PMID: 20093425
Schizophrenia; epidemiology; risk factor; Denmark; maternal iron deficiency; follow-up; cohort
18.  Low Birth Weight in Children Born to Mothers with Hyperthyroidism and High Birth Weight in Hypothyroidism, whereas Preterm Birth Is Common in Both Conditions: A Danish National Hospital Register Study 
European Thyroid Journal  2013;2(2):135-144.
Objectives
Maternal hyper- and hypothyroidism have been associated with increased risk of adverse pregnancy outcomes, but studies have led to inconsistent results. We aimed to identify children born to mothers with a hospital-recorded diagnosis of thyroid dysfunction in Denmark and to study the association with gestational age at delivery and birth weight of the child.
Study Design
Population-based cohort study using Danish nationwide registers. All singleton live births in Denmark between January 1, 1978 and December 31, 2006 were identified and stratified by maternal diagnosis of hyper- or hypothyroidism registered in the Danish National Hospital Register before January 1, 2007.
Results
Maternal first-time diagnosis of thyroid dysfunction before, during or after pregnancy was registered in 32,809 (2.0%) of the singleton live births (n = 1,638,338). Maternal diagnosis of hyperthyroidism (adjusted OR 1.22, 95% CI 1.15-1.30) and hypothyroidism (adjusted OR 1.17, 95% CI 1.08-1.27) were associated with increased risk of preterm birth. Moreover, birth weight in children born to mothers with a diagnosis of hyperthyroidism was lower (adjusted difference −51 g, 95% CI −58 to −43 g) and higher in relation to maternal hypothyroidism (adjusted difference 20 g, 95% CI 10-30 g). Hyperthyroidism was associated with small-for-gestational-age (adjusted OR 1.15, 95% CI 1.10-1.20) and hypothyroidism with large-for-gestational-age children (adjusted OR 1.24, 95% CI 1.17-1.31).
Conclusions
Based on Danish nationwide registers, both maternal hyper- and hypothyroidism were associated with increased risk of preterm birth. Actual birth weight of the child and birth weight for gestational age were low if the mother had a diagnosis of hyperthyroidism and high if the diagnosis was hypothyroidism.
doi:10.1159/000350513
PMCID: PMC3821508  PMID: 24783052
Thyroid disease; Hyperthyroidism; Hypothyroidism; Iodine; Pregnancy; Gestational age; Birth weight; Birth length; Danish National Hospital Register

19.  Cardiovascular risk factors in children exposed to maternal diabetes in utero 
Diabetologia  2010;54(3):504-507.
Aims/hypothesis
Recent studies have provided evidence that intrauterine exposure to maternal diabetes has lifelong effects on adult offspring, including increased risks of obesity, type 2 diabetes and cardiovascular disease. The aim of this study was to assess the relationship between exposure to maternal diabetes in utero and cardiovascular risk factors in healthy children and to investigate whether these associations are independent of maternal prepregnancy BMI and offspring attained BMI.
Methods
Data were from a retrospective cohort of children aged 6–13 years born during 1994–2002. Multiple linear regression was used to examine the associations between exposure and cardiovascular risk factors with adjustment for demographic factors and pubertal stage and additionally for maternal prepregnancy BMI and offspring attained BMI.
Results
Ninety-nine offspring of diabetic pregnancies had significantly increased E-selectin, vascular adhesion molecule 1 (VCAM1), leptin, waist circumference, BMI and systolic blood pressure and decreased adiponectin levels compared with 422 offspring of non-diabetic pregnancies after adjustment for age, sex and race/ethnicity (p<0.05 for each risk factor). Additional adjustment for maternal prepregnancy BMI substantially attenuated group differences in the risk factors except for E-selectin, VCAM1 and waist circumference, which remained significantly higher in exposed children.
Conclusions/interpretation
Compared with unexposed children, healthy offspring exposed to maternal diabetes in utero have a worse cardiovascular risk profile. In particular, offspring have substantially increased levels of circulating cellular adhesion molecules, which are biomarkers of adverse endothelium perturbation and may be related to the earliest preclinical stages of atherosclerosis and diabetes.
doi:10.1007/s00125-010-2008-1
PMCID: PMC3035850  PMID: 21153896
Adipokines; Adiposity; Blood pressure; Cardiovascular risk factors in children; Developmental origins of health and disease; Endothelial cell adhesion molecules; Gestational diabetes; Intrauterine exposure to maternal diabetes; Lipids; Pregnancy
20.  The trends and the risk of type 1 diabetes over the past 40 years: an analysis by birth cohorts and by parental migration background in Sweden 
BMJ Open  2013;3(10):e003418.
Objective
To investigate the trends and the risk of developing type 1 diabetes in the offspring of Swedes and immigrants by specific parental migration background, age, sex and birth cohort.
Design
Registry-based cohort study.
Setting
Using Swedish nationwide data we analysed the risk of developing type 1 diabetes in 3 457 486 female and 3 641 304 male offspring between 0 and 30 years of age, born to native Swedes or immigrants and born and living in Sweden between 1969 and 2009. We estimated incidence rate ratios (IRRs) with 95% CIs using Poisson regression models. We further calculated age-standardised rates (ASRs) of type 1 diabetes, using the world population as standard.
Results
We observed a trend of increasing ASRs among offspring below 15 years of age born to native Swedes and a less evident increase among offspring of immigrants. We further observed a shift towards a younger age at diagnosis in younger birth cohorts in both groups of offspring.Compared with offspring of Swedes, children (0–14 years) and young adults (15–30 years) with one parent born abroad had an overall 30% and 15–20% lower IRR, respectively, after multivariable adjustment. The reduction in IRR was even greater among offspring of immigrants if both parents were born abroad. Analysis by specific parental region of birth revealed a 45–60% higher IRR among male and female offspring aged 0–30 years of Eastern Africa.
Conclusions
Parental country of birth and early exposures to environmental factors play an important role in the aetiology of type 1 diabetes.
doi:10.1136/bmjopen-2013-003418
PMCID: PMC3816233  PMID: 24176793
Type 1 Diabetes; Birth Cohort; Incidence; Migration; Sweden
21.  Maternal Use of Antibiotics and the Risk of Childhood Febrile Seizures: A Danish Population-Based Cohort 
PLoS ONE  2013;8(4):e61148.
Objective
In a large population-based cohort in Denmark to examine if maternal use of antibiotics during pregnancy, as a marker of infection, increases the risk of febrile seizures in childhood in a large population-based cohort in Denmark.
Methods
All live-born singletons born in Denmark between January 1, 1996 and September 25, 2004 and who were alive on the 90th day of life were identified from the Danish National Birth Registry. Diagnoses of febrile seizures were obtained from the Danish National Hospital Register and maternal use of antibiotics was obtained from the National Register of Medicinal Product Statistics. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox proportional hazard regression models.
Results
We followed 551,518 singletons for up to 5 years and identified a total of 21,779 children with a diagnosis of febrile seizures. Slightly increased hazard ratios were observed among most exposure groups when compared to the unexposed group, ex. HR 1.08 95% CI: 1.05–1.11 for use of any systemic antibiotic during pregnancy.
Conclusion
We found weak associations between the use of pharmacologically different antibiotics during pregnancy and febrile seizures in early childhood which may indicate that some infections, or causes or effects of infections, during pregnancy could affect the fetal brain and induce susceptibility to febrile seizures.
doi:10.1371/journal.pone.0061148
PMCID: PMC3627381  PMID: 23613800
22.  Parental educational level and injury incidence and mortality among foreign-born children: a cohort study with 46 years follow-up 
Abstract:
Background:
Injury risk during childhood and adolescence vary depending on socio-economic factors. The aim of this study was to study if the risk of fatal and non-fatal unintentional injuries among foreign-born children was similar across parental educational level or not.
Methods:
In this retrospective cohort study we followed 907,335 children between 1961 and 2007 in Sweden. We established the cohort by linkage between Swedish national registers including cause of death register and in-patient register, through unique Personal Identification Numbers. The main exposure variable was parental (maternal and paternal) educational level. The cohorts was followed from start date of follow-up period, or date of birth whichever occurred last, until exit date from the cohort, which was date of hospitalization or death due to unintentional injury, first emigration, death due to other causes than injury or end of follow-up, whichever came first. We calculated hazard ratios (HR) with 95% confidence intervals (95% CI) by Cox proportional hazards regression models.
Results:
Overall, we found 705 and 78,182 cases of death and hospitalization due to unintentional injuries, respectively. Risk of death and hospitalization due to unintentional injuries was statistically significantly 1.48 (95% CI: 1.24-1.78) and 1.10 (95% CI: 1.08-1.12) times higher among children with lowest parental educational level (9 years and shorter years of study) compared to children with highest parental educational level (+13 years of study). We found similar results when stratified our study group by sex of children, by maternal and paternal educational level separately, and injury type (traffic-related, fall, poisoning, burn and drowning).
Conclusions:
It seems injury prevention work against unintentional injuries is less effective among children with low parental education compared with those with higher parental education. We recommend designing specific preventive interventions aiming at children with low parental education.
doi:10.5249/jivr.v6i1.525
PMCID: PMC3865454  PMID: 24042970
Unintentional injury; Educational level; Relative risk; Cohort study
23.  Risk of human papillomavirus-related cancers among kidney transplant recipients and patients receiving chronic dialysis - an observational cohort study 
BMC Nephrology  2013;14:137.
Background
Individuals with end-stage renal disease (ESRD) have excess risk of various cancer types. However, the total burden of human papillomavirus-related cancers remains unknown.
Methods
We performed a nationwide observational cohort study during 1994–2010.
For each person with ESRD, we sampled 19 population controls (without ESRD) matched on age, gender and municipality. Participants were followed until first diagnosis of human papillomavirus-related cancer, death, emigration, or 31 December 2010, whichever came first.
Human papillomavirus-related cancers were extracted from Danish medical administrative databases. We considered cancers of the cervix, vulva, vagina, penis, anus, and subsets of head and neck cancers as human papillomavirus-related. We calculated incidence rates of human papillomavirus-related cancer and used Poisson regression to identify risk factors for human papillomavirus-related cancer.
Results
Among 12,293 persons with ESRD and 229,524 population controls we identified 62 and 798 human papillomavirus-related cancers, respectively. Incidence rates of human papillomavirus-related- cancer were 102 per 100,000 person-years (95% confidence interval [CI]; 79.5-131) among persons with ESRD and 40.8 per 100,000 person-years (95% CI; 38.1-43.7) among population controls. ESRD patients had 4.54 (95% CI, 2.48-8.31) fold increased risk of anal cancer and 5.81 fold (95% CI; 3.36-10.1) increased risk of vulvovaginal cancer. Adjusted for age, comorbidity, and sex, ESRD patients had 2.41 (95% CI; 1.83-3.16) fold increased risk of any human papillomavirus-related cancer compared with population controls. Compared with dialysis patients renal transplant recipients had an age-adjusted non-significant 1.53 (95% CI, 0.91-2.58) fold higher risk of human papillomavirus-related cancer.
Conclusions
Persons with ESRD have excess risk of potentially vaccine-preventable human papillomavirus-related cancers.
doi:10.1186/1471-2369-14-137
PMCID: PMC3710213  PMID: 23834996
24.  Apgar score and hospitalization for epilepsy in childhood: a registry-based cohort study 
BMC Public Health  2006;6:23.
Background
A depressed Apgar score at 5 minutes is a marker for perinatal insults, including neurologic damage. We examined the association between 5-minute Apgar score and the risk of epilepsy hospitalization in childhood.
Methods
Using records linked from population registries, we conducted a cohort study among singleton children born alive in the period 1978–2001 in North Jutland County, Denmark. The first hospital discharge diagnosis of epilepsy during the follow-up time was the main outcome. We followed each child for up to 12 years, calculated absolute risks and risk differences, and used a Poisson regression model to estimate risk ratios for epilepsy hospitalization. We adjusted risk ratio estimates for birth weight, gestational age, mode of delivery, birth presentation, mother's age at delivery, and birth defects.
Results
One percent of the 131,853 eligible newborns had a 5-minute Apgar score <7. These children were more likely to be hospitalized with epilepsy during the follow-up than were children with an Apgar score of 7 or greater. The crude risk difference for epilepsy hospitalization was 2.5 cases per 100 (95% confidence interval [CI] 1.3 to 3.8). The risk difference estimates were greater in the presence of other perinatal risk factors. The adjusted risk ratio was 2.4 (95% CI 1.5 to 3.8). Half of the 12-year risk for epilepsy hospitalization in those with a depressed Apgar score occurred during the first year of life. The risk ratio during the first year of life was 4.9 (95% CI 2.0 to 12.3).
Conclusion
An Apgar score <7 at five minutes predicts an increase in the subsequent risk of epilepsy hospitalization. This association is amplified by other perinatal risk factors.
doi:10.1186/1471-2458-6-23
PMCID: PMC1409783  PMID: 16451724
25.  Lung cancer in asbestos cement workers in Denmark. 
OBJECTIVES: To study the relative and absolute risks of main types of lung cancer in a cohort of asbestos cement workers from Denmark. METHOD: A cohort of 7887 men and 576 women employed between 1928 and 1984 was compiled from the personnel files of Danish Eternit Production. The cohort was followed up for deaths, emigrations, and incident cancer cases during the period 1943-90. The observed number of lung cancer cases in the cohort was compared with the expected number based on incidences for the Danish population. Internal comparison was made with Poisson modelling. RESULTS: A total of 226 lung cancer cases were observed (223 men and three women). The standardised incidence ratio (SIR) for all lung cancer among men was 1.7 (observed number 223, expected number 129.7, 95% confidence interval (95% CI) 1.5-2.0). The SIRs were raised for all main types of lung cancer; adenocarcinoma 2.6, squamous cell carcinoma 1.7, and anaplastic carcinoma 1.5. The higher SIR for adenocarcinomas was found particularly with a latency period of 25 years or more. Among the 93 excess lung cancer cases, 36 were squamous cell carcinomas and 32 were adenocarcinomas. CONCLUSION: Asbestos cement work is associated with an increased risk of lung cancer of all main types. During the first 25 years after the start of employment this excess risk is shared almost equally between the different histological types of lung cancer, but the risk of adenocarcinomas is clearly higher after this point.
PMCID: PMC1128496  PMID: 8758035

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