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1.  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
2.  In-Utero Exposure to Bereavement and Offspring IQ: A Danish National Cohort Study 
PLoS ONE  2014;9(2):e88477.
Background
Intelligence is a life-long trait that has strong influences on lifestyle, adult morbidity and life expectancy. Hence, lower cognitive abilities are therefore of public health interest. Our primary aim was to examine if prenatal bereavement measured as exposure to death of a close family member is associated with the intelligence quotient (IQ) scores at 18-years of age of adult Danish males completing a military cognitive screening examination.
Methods
We extracted records for the Danish military screening test and found kinship links with biological parents, siblings, and maternal grandparents using the Danish Civil Registration System (N = 167,900). The prenatal exposure period was defined as 12 months before conception until birth of the child. We categorized children as exposed in utero to severe stress (bereavement) during prenatal life if their mothers lost an elder child, husband, parent or sibling during the prenatal period; the remaining children were included in the unexposed cohort. Mean score estimates were adjusted for maternal and paternal age at birth, residence, income, maternal education, gestational age at birth and birth weight.
Results
When exposure was due to death of a father the offsprings' mean IQ scores were lower among men completing the military recruitment exam compared to their unexposed counterparts, adjusted difference of 6.5 standard IQ points (p-value = 0.01). We did not observe a clinically significant association between exposure to prenatal maternal bereavement caused by death of a sibling, maternal uncle/aunt or maternal grandparent even after stratifying deaths only due to traumatic events.
Conclusion
We found maternal bereavement to be adversely associated with IQ in male offspring, which could be related to prenatal stress exposure though more likely is due to changes in family conditions after death of the father. This finding supports other literature on maternal adversity during fetal life and cognitive development in the offspring.
doi:10.1371/journal.pone.0088477
PMCID: PMC3928249  PMID: 24558394
3.  Epidemiologic methods for investigating male fecundity 
Asian Journal of Andrology  2013;16(1):17-22.
Fertility is a couple concept that has been measured since the beginning of demography, and male fecundity (his biological capacity to reproduce) is a component of the fertility rate. Unfortunately, we have no way of measuring the male component directly, although several indirect markers can be used. Population registers can be used to monitor the proportion of childless couples, couples who receive donor semen, trends in dizygotic twinning, and infertility diagnoses. Studies using time-to-pregnancy (TTP) may identify couple subfecundity, and TTP data will correlate with sperm quality and quantity as well as sexual activity and a number of other conditions. Having exposure data available for couples with a fecund female partner would make TTP studies of interest in identifying exposures that may affect male fecundity. Biological indicators such as sperm quality and quantity isolate the male component of fertility, and semen data therefore remain an important source of information for research. Unfortunately, often over half of those invited to provide a sperm sample will refuse, and the study is then subject to a selection that may introduce bias. Because the most important time windows for exposures that impair semen production could be early fetal life, puberty, and the time of ejaculation; longitudinal data over decades of time are required. The ongoing monitoring of semen quality and quantity should continue, and surveys monitoring fertility and waiting TTP should also be designed.
doi:10.4103/1008-682X.122198
PMCID: PMC3901876  PMID: 24369129
data collection; epidemiology; epidemiological monitoring; fertility; sperm count; time-to-pregnancy (TTP)
4.  Congenital Cerebral Palsy, Child Sex and Parent Cardiovascular Risk 
PLoS ONE  2013;8(11):e79071.
Objective
Genes associated with cardiovascular disease may also be risk factors for congenital cerebral palsy (CP) and these associations may be modified by sex, since there is an increased risk of CP in male children. We investigated the association between CP of the child with cardiovascular disease in parents, taking sex of the child into consideration.
Methods
All parents of non-adopted singletons born in Denmark between 1973 and 2003 were included. Parents of a child with CP, confirmed by the Danish National CP registry, were considered exposed. Cox proportional hazards regressions were used to model risk of cardiovascular outcomes for exposed parents compared to all other parents beginning at the child’s 10th birthday.
Results
We identified 733,730 mothers and 666,652 fathers among whom 1,592 and 1,484, respectively, had a child with CP. The mean age for mothers at end of follow up was 50±8 years. After adjustment for maternal age, parental education, child’s sex, child’s residence, child being small for gestational age and maternal hypertensive disorder during pregnancy, mothers of CP male children had an excess risk of cardiovascular disease (HR: 1.52, 95% CI: 1.16-2.00), attributable mostly to an increased incidence of hypertension and cerebrovascular disease. After additional adjustment for preterm birth, the association was markedly attenuated for cardiovascular disease (1.34, 95%CI: 1.02 - 1.76), became nonsignificant for hypertension, but remained significant for cerebrovascular disease (HR: 2.73, 95% CI: 1.45- 5.12). There was no increased risk of cardiovascular events in mothers of female CP children, or fathers of CP children of any sex.
Conclusions
Women that have a male child with CP are at increased risk for premature cardiovascular disease. Part of this association may be related to risk factors for preterm births.
doi:10.1371/journal.pone.0079071
PMCID: PMC3815096  PMID: 24223882
5.  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
6.  Prenatal Antidepressant Exposure and Risk of Spontaneous Abortion – A Population-Based Study 
PLoS ONE  2013;8(8):e72095.
Purpose
To estimate the risk of spontaneous abortion after use of antidepressant medication during pregnancy.
Methods
From the Danish Medical Birth Registry and the Danish National Hospital Registry, we identified all pregnancies leading to in- or outpatient contacts in Denmark from February 1997 to December 2008. The Danish Registry of Medicinal Product Statistics provided information on the women's prescriptions for antidepressants during pregnancy. We obtained information on women who were diagnosed with depression from the Danish Psychiatric Central Registry. Adjusted relative risks (aRR) of spontaneous abortion were estimated according to exposure to antidepressants or maternal depression using binomial regression.
Results
Of the 1,005,319 pregnancies (547,300 women) identified, 114,721 (11.4%) ended in a spontaneous abortion. We identified 22,061 pregnancies exposed to antidepressants and 1,843 with a diagnosis of depression with no antidepressant use, of which 2,637 (12.0%) and 205 (11.1%) ended in a spontaneous abortion, respectively. Antidepressant exposure was associated with an aRR of 1.14 (95% confidence interval (CI) 1.10–1.18) for spontaneous abortion compared with no exposure to antidepressants. Among women with a diagnosis of depression, the aRR for spontaneous abortion after any antidepressant exposure was 1.00 (95% CI 0.80–1.24). No individual selective serotonin reuptake inhibitor (SSRI) was associated with spontaneous abortions. In unadjusted analyses, we found that mirtazapine, venlafaxine, and duloxetine were associated with spontaneous abortions among women with depression but we had no information on potential differences in disease severity and only few pregnancies were exposed in the population.
Conclusion
We identified a slightly increased risk of spontaneous abortion associated with the use of antidepressants during pregnancy. However, among women with a diagnosis of depression, antidepressants in general or individual SSRI in particular were not associated with spontaneous abortions. Further studies are warranted on the newer non-SSRI antidepressants, as we had insufficient data to adjust for important confounding factors.
doi:10.1371/journal.pone.0072095
PMCID: PMC3756033  PMID: 24015208
7.  Correction: Prenatal Exposure to Bereavement and Type-2 Diabetes: A Danish Longitudinal Population Based Study 
PLoS ONE  2013;8(8):10.1371/annotation/dbd21894-4722-499c-afaf-b03015fae7d8.
doi:10.1371/annotation/dbd21894-4722-499c-afaf-b03015fae7d8
PMCID: PMC3744642  PMID: 23976927
8.  Maternal Thyroid Dysfunction and Risk of Seizure in the Child: A Danish Nationwide Cohort Study 
Journal of Pregnancy  2013;2013:636705.
Thyroid hormones are essential for brain development, and maternal thyroid disease may affect child neurocognitive development. Some types of seizures may also depend upon early exposure of the developing central nervous system, and we hypothesized that maternal thyroid dysfunction could increase the risk of seizure in the child. In a Danish population-based study we included 1,699,693 liveborn singletons, and from the Danish National Hospital Register we obtained information on maternal diagnosis of hyper- or hypothyroidism and neonatal seizure, febrile seizure, and epilepsy in the child. Maternal diagnosis of thyroid dysfunction before or after birth of the child was registered in two percent of the singleton births. In adjusted analyses, maternal hyperthyroidism and hypothyroidism first time diagnosed after birth of the child were associated with a significant increased risk of epilepsy in the child. Moreover, hypothyroidism diagnosed after birth of the child was associated with a significant increased risk of neonatal and febrile seizures. No significant association was seen for maternal diagnosis prior to birth of the child. We speculate if some degree of maternal thyroid dysfunction was already present during the pregnancy in mothers diagnosed after birth of the child and if this untreated condition may present a neurodevelopmental risk.
doi:10.1155/2013/636705
PMCID: PMC3745964  PMID: 23984072
9.  Early life bereavement and childhood cancer: a nationwide follow-up study in two countries 
BMJ Open  2013;3(5):e002864.
Objective
Childhood cancer is a leading cause of child deaths in affluent countries, but little is known about its aetiology. Psychological stress has been suggested to be associated with cancer in adults; whether this is also seen in childhood cancer is largely unknown. We investigated the association between bereavement as an indicator of severe childhood stress exposure and childhood cancer, using data from Danish and Swedish national registers.
Design
Population-based cohort study.
Setting
Denmark and Sweden.
Participants
All live-born children born in Denmark between 1968 and 2007 (n=2 729 308) and in Sweden between 1973 and 2006 (n=3 395 166) were included in this study. Exposure was bereavement by the death of a close relative before 15 years of age. Follow-up started from birth and ended at the first of the following: date of a cancer diagnosis, death, emigration, day before their 15th birthday or end of follow-up (2007 in Denmark, 2006 in Sweden).
Outcome measures
Rates and HRs for all childhood cancers and specific childhood cancers.
Results
A total of 1 505 938 (24.5%) children experienced bereavement at some point during their childhood and 9823 were diagnosed with cancer before the age of 15 years. The exposed children had a small (10%) increased risk of childhood cancer (HR 1.10; 95% CI 1.04 to 1.17). For specific cancers, a significant association was seen only for central nervous system tumours (HR 1.14; 95% CI 1.02 to 1.28).
Conclusions
Our data suggest that psychological stress in early life is associated with a small increased risk of childhood cancer.
doi:10.1136/bmjopen-2013-002864
PMCID: PMC3664350  PMID: 23793702
Childhood cancer; bereavement; psychological stress; risk factor; follow up
10.  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
11.  Ambient Air Pollution and Autism in Los Angeles County, California 
Environmental Health Perspectives  2012;121(3):380-386.
Background: The prevalence of autistic disorder (AD), a serious developmental condition, has risen dramatically over the past two decades, but high-quality population-based research addressing etiology is limited.
Objectives: We studied the influence of exposures to traffic-related air pollution during pregnancy on the development of autism using data from air monitoring stations and a land use regression (LUR) model to estimate exposures.
Methods: Children of mothers who gave birth in Los Angeles, California, who were diagnosed with a primary AD diagnosis at 3–5 years of age during 1998–2009 were identified through the California Department of Developmental Services and linked to 1995–2006 California birth certificates. For 7,603 children with autism and 10 controls per case matched by sex, birth year, and minimum gestational age, birth addresses were mapped and linked to the nearest air monitoring station and a LUR model. We used conditional logistic regression, adjusting for maternal and perinatal characteristics including indicators of SES.
Results: Per interquartile range (IQR) increase, we estimated a 12–15% relative increase in odds of autism for ozone [odds ratio (OR) = 1.12, 95% CI: 1.06, 1.19; per 11.54-ppb increase] and particulate matter ≤ 2.5 µm (OR = 1.15; 95% CI: 1.06, 1.24; per 4.68-μg/m3 increase) when mutually adjusting for both pollutants. Furthermore, we estimated 3–9% relative increases in odds per IQR increase for LUR-based nitric oxide and nitrogen dioxide exposure estimates. LUR-based associations were strongest for children of mothers with less than a high school education.
Conclusion: Measured and estimated exposures from ambient pollutant monitors and LUR model suggest associations between autism and prenatal air pollution exposure, mostly related to traffic sources.
doi:10.1289/ehp.1205827
PMCID: PMC3621187  PMID: 23249813
air pollution; autism; land-use regression; pregnancy; traffic
12.  Risk of Cerebral Palsy and Childhood Epilepsy Related to Infections before or during Pregnancy 
PLoS ONE  2013;8(2):e57552.
Background and Aim
Maternal infections during pregnancy have been associated with several neurological disorders in the offspring. However, given the lack of specificity for both the exposures and the outcomes, other factors related to infection such as impaired maternal immune function may be involved in the causal pathway. If impaired maternal immune function plays a role, we would expect infection before pregnancy to be associated with these neurological outcomes.
Methods/Principal Findings
The study population included all first-born singletons in Denmark between January 1 1982 and December 31 2004. We identified women who had hospital-recorded infections within the 5 year period before pregnancy, and women who had hospital-recorded infections during pregnancy. We grouped infections into either infections of the genitourinary system, or any other infections. Cox models were used to estimate adjusted hazard ratios (aHRs) with 95% confidence interval (CI). Maternal infection of the genitourinary system during pregnancy was associated with an increased risk of cerebral palsy (aHR = 1.63, 95% CI: 1.34–1.98) and epilepsy (aHR = 1.27, 95% CI: 1.13–1.42) in the children, compared to children of women without infections during pregnancy. Among women without hospital-recorded infections during pregnancy, maternal infection before pregnancy was associated with an increased risk of epilepsy (aHR = 1.35, 95% CI: 1.21–1.50 for infections of the genitourinary system, and HR = 1.12, 95% CI: 1.03–1.22 for any other infections) and a slightly higher risk of cerebral palsy (aHR = 1.20, 95% CI: 0.96–1.49 for infections of the genitourinary system, and HR = 1.23, 95% CI: 1.06–1.43 for any other infections) in the children, compared to children of women without infections before (and during) pregnancy.
Conclusions
These findings indicate that the maternal immune system, maternal infections, or factors related to maternal immune function play a role in the observed associations between maternal infections before pregnancy and cerebral diseases in the offspring.
doi:10.1371/journal.pone.0057552
PMCID: PMC3583873  PMID: 23460873
13.  Sex Differences in Response to Anti-TNF Therapy in Early and Established Rheumatoid Arthritis – Results from the Longitudinal Danish DANBIO Registry 
The Journal of rheumatology  2011;39(1):46-53.
Objective
To investigate sex differences in response to anti-tumor necrosis factor (TNF) therapy over time in early versus established rheumatoid arthritis (RA).
Methods
RA patients who initiated anti-TNF therapy between January 2003 and June 2008 in Denmark were selected from the DANBIO Registry. Sex differences in baseline disease features were examined using Chi-square, Mann-Whitney and t-tests. Using a generalized estimating equations (GEE) model for repeated measures, we examined EULAR responses in men and women over 48 months of follow up, adjusting for baseline values of age, disease activity (DAS28), disease duration and anti-TNF, methotrexate and prednisolone use.
Results
At initiation of anti-TNF therapy (baseline), 328 women and 148 men had early RA (≤2 years), and 1,245 women and 408 men had established RA (>2 years). In both early and established RA, men and women had active disease with similar DAS28 scores (mean±SD: 5.2±1.1), physician global scores, swollen joint counts and radiographic changes. In early RA, men were significantly more likely to achieve a EULAR good/moderate response over 48 months compared to women (GEE: p=0.003), and a significant interaction between sex and follow up time (GEE: p<0.0005) suggested that men achieved this response sooner than women.
Conclusion
Better responses to anti-TNF therapy among men compared to women in early but not established RA suggest that disease duration at initiation of therapy may be an important factor to consider when investigating sex differences in treatment responses.
doi:10.3899/jrheum.110548
PMCID: PMC3563108  PMID: 22089458
Rheumatoid arthritis; Sex; Anti-TNF response
14.  Spontaneous Abortion and a Diet Drug Containing Caffeine and Ephedrine: A Study within the Danish National Birth Cohort 
PLoS ONE  2012;7(11):e50372.
Background
Medications may be consumed periconceptionally before a woman knows she is pregnant. In this study, the authors evaluate the association of a prescription diet drug (Letigen) containing ephedrine (20 mg) and caffeine (200 mg) with spontaneous abortion (SAB) in the Danish National Birth Cohort.
Methods
Women were recruited during their first prenatal visit from 1996–2002. Pre-conception and early pregnancy medication use was reported on the enrollment form, and pregnancy outcome was determined by linking the mother's Civil Registration Number to the Medical Birth Registry and the National Hospital Discharge Register. Of 97,903 eligible pregnancies, 4,443 ended in SAB between 5 and 20 completed gestational weeks, inclusive. Letigen use was reported for 565 pregnancies. Cox regression models accounting for left truncation were fit to estimate the effect of pre-conception and early pregnancy Letigen use on SAB.
Principal Findings
The estimated maternal age-adjusted hazard ratio for SAB was 1.1 (95% confidence interval 0.8–1.6) for any periconceptional Letigen use compared to no periconceptional use.
Conclusions
Although Letigen has high levels of caffeine (the recommended 3 pills/day are approximately equivalent to caffeine from 6 cups of coffee), periconceptional use does not appear to be associated with an appreciably increased hazard of clinically recognized SAB.
doi:10.1371/journal.pone.0050372
PMCID: PMC3500353  PMID: 23166844
15.  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
16.  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
17.  Socio-demographic characteristics of women sustaining injuries during pregnancy: a study from the Danish National Birth Cohort 
BMJ Open  2012;2(4):e000826.
Objectives
To describe adverse birth outcomes associated with hospital-treated injuries that took place among women in the Danish National Birth Cohort.
Design
Longitudinal cohort study.
Setting
Denmark.
Participants
90 452 women and their offspring selected from the Danish National Birth Cohort.
Primary and secondary outcome measures
To determine if injured women were more likely to deliver an infant preterm, with low birth weight, stillborn or have a spontaneous abortion, the authors estimated HRs. ORs were generated to assess APGAR scores and infants born small for gestational age (SGA). Models were adjusted for maternal smoking and drinking during pregnancy, household socioeconomic status, eclampsia/pre-eclampsia or gestational diabetes status during pregnancy and maternal age at birth; estimates for preterm birth were also adjusted for prior history of preterm birth.
Results
In the cohort of 90 452 pregnant women, 3561 (3.9%) received medical treatment for an injury during pregnancy. Injured pregnant women were more likely to deliver infants that were stillborn or have pregnancies terminated by spontaneous abortion. The authors did not detect an adverse effect between injuries sustained during pregnancy and delivery of preterm, low birth weight or SGA infants, or infants with an APGAR score of <7.
Conclusions
The study shows that injuries occurring among women from an unselected population may not have an adverse effect on birth weight, gestational age, APGAR score or SGA status but may adversely affect the risk of stillbirth and spontaneous abortions in some situations.
Article summary
Article focus
We describe adverse birth outcomes associated with injuries that took place among pregnant women in the Danish National Birth Cohort and include in our assessment injury severity, cause and mechanism.
Key messages
Injured pregnant women were more likely to deliver infants that were stillborn or have pregnancies that were terminated by spontaneous abortion. We did not detect an adverse effect between injuries sustained during pregnancy and delivery of preterm, low birth weight or SGA infants, or infants with an APGAR score of <7.
Women sustaining head or neck injuries were more likely to deliver an infant SGA and have a stillbirth, though these results were not statistically significant.
Strengths and limitations of this study
Previous studies have selected pregnant trauma patients or emergency room patients; our study, however, presents injuries among pregnant women from a general population.
We only have data on late spontaneous abortions, and if injured fetuses are aborted early, we would not detect an association.
doi:10.1136/bmjopen-2012-000826
PMCID: PMC3391365  PMID: 22761281
18.  Dietary fats may impact semen quantity and quality 
Asian Journal of Andrology  2012;14(4):511-512.
doi:10.1038/aja.2012.52
PMCID: PMC3720090  PMID: 22635159
19.  Time to Pregnancy among Women with Rheumatoid Arthritis 
Arthritis and rheumatism  2011;63(6):1517-1521.
Objective
To assess whether onset of rheumatoid arthritis (RA) prior to conception is associated with a delayed time to pregnancy (TTP).
Methods
The study included pregnant women from across Denmark enrolled in the Danish National Birth Cohort (DNBC) between 1996 and 2002, who had planned or partly planned the cohort pregnancy. RA diagnosis was identified using the Danish National Hospital Discharge Registry. Self-reported data including TTP, maternal age, parity, pre-pregnancy height and weight, maternal occupational status, smoking and alcohol consumption were collected using a detailed computer-assisted telephone interview at approximately 16 weeks of gestation. We used logistic regression analyses as well as a complementary log regression model to examine whether TTP was influenced by RA, adjusting for the above-mentioned variables.
Results
Overall, compared to women with no recorded RA (n=68,170), women with prevalent RA (onset prior to conception) (n=112) were slightly older (30.8±4.3 vs. 29.7±4.1 years), were more likely to have been treated for infertility (9.8% vs. 7.6%) and were more likely to have taken longer than 12 months to conceive (25.0% vs. 15.6%). The association between RA and TTP was borderline significant after adjusting for covariates in the regression analyses (OR=1.6, 95% CI: 1.0, 2.4). Similar results were obtained after restricting the analyses to women who had planned the pregnancy or those who were nulliparous before the cohort pregnancy.
Conclusion
Women with RA onset prior to conception had a slightly longer TTP compared to those who did not have RA, indicating a slight reduction in fecundity.
doi:10.1002/art.30327
PMCID: PMC3106134  PMID: 21380995
20.  Long-Term Health Outcomes in Children Born to Mothers with Diabetes: A Population-Based Cohort Study 
PLoS ONE  2012;7(5):e36727.
Background
To examine whether prenatal exposure to parental type 1 diabetes, type 2 diabetes, or gestational diabetes is associated with an increased risk of malignant neoplasm or diseases of the circulatory system in the offspring.
Methods/Principal Findings
We conducted a population-based cohort study of 1,781,576 singletons born in Denmark from 1977 to 2008. Children were followed for up to 30 years from the day of birth until the onset of the outcomes under study, death, emigration, or December 31, 2009, whichever came first. We used Cox proportional hazards model to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) for the outcomes under study while adjusting for potential confounders. An increased risk of malignant neoplasm was found in children prenatally exposed to maternal type 2 diabetes (HR = 2.2, 95%CI: 1.5–3.2). An increased risk of diseases of the circulatory system was found in children exposed to maternal type 1 diabetes (HR = 2.2, 95%CI: 1.6–3.0), type 2 diabetes (HR = 1.4, 95%CI: 1.1–1.7), and gestational diabetes (HR = 1.3, 95%CI: 1.1–1.6), but results were attenuated after excluding children with congenital malformations. An increased risk of diseases of the circulatory system was also found in children exposed to paternal type 2 diabetes (HR = 1.5, 95%CI: 1.1–2.2) and the elevated risk remained after excluding children with congenital malformations.
Conclusions
This study suggests that susceptibility to malignant neoplasm is modified partly by fetal programming. Diseases of the circulatory system may be modified by genetic factors, other time-stable family factors, or fetal programming.
doi:10.1371/journal.pone.0036727
PMCID: PMC3359312  PMID: 22649497
21.  Parental infertility and cerebral palsy in children 
Human Reproduction (Oxford, England)  2010;25(12):3142-3145.
BACKGROUND
Children born after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) have been reported to have a higher risk of cerebral palsy (CP), perhaps due to the higher frequency of preterm birth, multiple births or vanishing embryo in the pregnancies. However, it has been suggested that the underlying infertility may be part of the pathway. In this study, we examined whether untreated subfecundity (measured by time to pregnancy) or infertility treatment was associated with an increased risk of CP in the offspring.
METHODS
Using the Danish National Birth Cohort (1997–2003), we compared children born after 0–2 months of waiting time to pregnancy (n = 35 848) with those born after a time to pregnancy of 3–5 months (n = 15 361), 6–12 months (n = 11 528) and >12 months (n = 7387), as well as those born after IVF/ICSI (n = 3617), ovulation induction with or without intrauterine insemination (n = 3000), and unplanned pregnancies (n = 13 462). CP cases were identified through the Danish CP Register.
RESULTS
In total, 165 (0.18%) children were diagnosed with CP in the entire cohort. We found no significant association between time to pregnancy and the risk of CP in children conceived spontaneously. Children born after IVF/ICSI had an increased risk of CP, even after adjustment for preterm birth and multiplicity (hazard ratio 2.30, 95% confidence interval 1.12–4.73).
CONCLUSIONS
Subfecundity per se did not appear to be associated with the risk of CP in children, whereas being born after IVF/ICSI conferred an increased risk.
doi:10.1093/humrep/deq206
PMCID: PMC2989872  PMID: 21045245
cerebral palsy; infertility; infertility treatment; time to pregnancy; Danish National Birth Cohort
22.  Stress during Pregnancy and Offspring Pediatric Disease: A National Cohort Study 
Environmental Health Perspectives  2011;119(11):1647-1652.
Background: Identifying risk factors for adverse health outcomes in children is important. The intrauterine environment plays a pivotal role for health and disease across life.
Objectives: We conducted a comprehensive study to determine whether common psychosocial stress during pregnancy is a risk factor for a wide spectrum of pediatric diseases in the offspring.
Methods: The study was conducted using prospective data in a population-based sample of mothers with live singleton births (n = 66,203; 71.4% of those eligible) from the Danish National Birth Cohort. We estimated the association between maternal stress during pregnancy (classified based on two a priori–defined indicators of common stress forms, life stress and emotional stress) and offspring diseases during childhood (grouped into 16 categories of diagnoses from the International Classification of Diseases, 10th Revision, based on data from national registries), controlling for maternal stress after pregnancy.
Results: Median age at end of follow-up was 6.2 (range, 3.6–8.9) years. Life stress (highest compared with lowest quartile) was associated with an increased risk of conditions originating in the perinatal period [odds ratio (OR) = 1.13; 95% confidence interval (CI): 1.06, 1.21] and congenital malformations (OR=1.17; CI: 1.06, 1.28) and of the first diagnosis of infection [hazard ratio (HR) = 1.28; CI: 1.17, 1.39], mental disorders (age 0–2.5 years: HR = 2.03; CI: 1.32, 3.14), and eye (age 0–4.5 years: HR = 1.27; CI: 1.06, 1.53), ear (HR = 1.36; CI: 1.23, 1.51), respiratory (HR = 1.27; CI; 1.19, 1.35), digestive (HR = 1.23; CI: 1.11, 1.37), skin (HR = 1.24; CI: 1.09, 1.43), musculoskeletal (HR = 1.15; CI: 1.01–1.30), and genitourinary diseases (HR = 1.25; CI; 1.08, 1.45). Emotional stress was associated with an increased risk for the first diagnosis of infection (HR = 1.09; CI: 1.01, 1.18) and a decreased risk for the first diagnosis of endocrine (HR = 0.81; CI; 0.67, 0.99), eye (HR = 0.84; CI; 0.71, 0.99), and circulatory diseases (age 0–3 years: HR = 0.63; CI: 0.42, 0.95).
Conclusions: Maternal life stress during pregnancy may be a common risk factor for impaired child health. The results suggest new approaches to reduce childhood diseases.
doi:10.1289/ehp.1003253
PMCID: PMC3226491  PMID: 21775267
antenatal stress; child health and development; intrauterine exposure; prenatal exposure delayed effects; prenatal programming; psychosocial stress
23.  An investigation of the apparent breast cancer epidemic in France: screening and incidence trends in birth cohorts 
BMC Cancer  2011;11:401.
Background
Official descriptive data from France showed a strong increase in breast-cancer incidence between 1980 to 2005 without a corresponding change in breast-cancer mortality. This study quantifies the part of incidence increase due to secular changes in risk factor exposure and in overdiagnosis due to organised or opportunistic screening. Overdiagnosis was defined as non progressive tumours diagnosed as cancer at histology or progressive cancer that would remain asymptomatic until time of death for another cause.
Methods
Comparison between age-matched cohorts from 1980 to 2005. All women residing in France and born 1911-1915, 1926-1930 and 1941-1945 are included. Sources are official data sets and published French reports on screening by mammography, age and time specific breast-cancer incidence and mortality, hormone replacement therapy, alcohol and obesity. Outcome measures include breast-cancer incidence differences adjusted for changes in risk factor distributions between pairs of age-matched cohorts who had experienced different levels of screening intensity.
Results
There was an 8-fold increase in the number of mammography machines operating in France between 1980 and 2000. Opportunistic and organised screening increased over time. In comparison to age-matched cohorts born 15 years earlier, recent cohorts had adjusted incidence proportion over 11 years that were 76% higher [95% confidence limits (CL) 67%, 85%] for women aged 50 to 64 years and 23% higher [95% CL 15%, 31%] for women aged 65 to 79 years. Given that mortality did not change correspondingly, this increase in adjusted 11 year incidence proportion was considered as an estimate of overdiagnosis.
Conclusions
Breast cancer may be overdiagnosed because screening increases diagnosis of slowly progressing non-life threatening cancer and increases misdiagnosis among women without progressive cancer. We suggest that these effects could largely explain the reported "epidemic" of breast cancer in France. Better predictive classification of tumours is needed in order to avoid unnecessary cancer diagnoses and subsequent procedures.
doi:10.1186/1471-2407-11-401
PMCID: PMC3188513  PMID: 21936933
24.  Does weight loss improve semen quality and reproductive hormones? results from a cohort of severely obese men 
Reproductive Health  2011;8:24.
Background
A high body mass index (BMI) has been associated with reduced semen quality and male subfecundity, but no studies following obese men losing weight have yet been published. We examined semen quality and reproductive hormones among morbidly obese men and studied if weight loss improved the reproductive indicators.
Methods
In this pilot cohort study, 43 men with BMI > 33 kg/m2 were followed through a 14 week residential weight loss program. The participants provided semen samples and had blood samples drawn, filled in questionnaires, and had clinical examinations before and after the intervention. Conventional semen characteristics as well as sperm DNA integrity, analysed by the sperm chromatin structure assay (SCSA) were obtained. Serum levels of testosterone, estradiol, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH) and inhibin B (Inh-B) were measured.
Results
Participants were from 20 to 59 years of age (median = 32) with BMI ranging from 33 to 61 kg/m2. At baseline, after adjustment for potential confounders, BMI was inversely associated with sperm concentration (p = 0.02), total sperm count (p = 0.02), sperm morphology (p = 0.04), and motile sperm (p = 0.005) as well as testosterone (p = 0.04) and Inh-B (p = 0.04) and positively associated to estradiol (p < 0.005). The median (range) percentage weight loss after the intervention was 15% (3.5 - 25.4). Weight loss was associated with an increase in total sperm count (p = 0.02), semen volume (p = 0.04), testosterone (p = 0.02), SHBG (p = 0.03) and AMH (p = 0.02). The group with the largest weight loss had a statistically significant increase in total sperm count [193 millions (95% CI: 45; 341)] and normal sperm morphology [4% (95% CI: 1; 7)].
Conclusion
This study found obesity to be associated with poor semen quality and altered reproductive hormonal profile. Weight loss may potentially lead to improvement in semen quality. Whether the improvement is a result of the reduction in body weight per se or improved lifestyles remains unknown.
doi:10.1186/1742-4755-8-24
PMCID: PMC3177768  PMID: 21849026
25.  Parental infertility and developmental coordination disorder in children 
BACKGROUND
It has previously been reported that children born after infertility treatment had a slight delay in early motor milestones. In this study, we examined whether children of infertile couples with or without infertility treatment had a higher risk of developmental coordination disorder (DCD).
METHODS
We used data on parental infertility and DCD among 23 167 singletons from the Danish National Birth Cohort (1996–2002). Data on time to pregnancy (TTP) and infertility treatment were collected early in pregnancy. Data on DCD in children were collected using the Developmental Coordination Disorder Questionnaire, filled in by the mothers during follow-up when the children were 7 years old. We used the recommended cut-off for the age group to classify children.
RESULTS
Compared with children born of fertile couples, children conceived after a waiting TTP of longer than 12 months had a slightly higher risk of DCD [odds ratio (OR) 1.35, 95% confidence interval (CI) 1.03–1.77], but the estimated OR was not significant in children born after infertility treatment (OR 1.19, 95% CI 0.86–1.66). None of the individual treatment procedures was significantly associated with a higher risk of DCD. Children of parents who had not planned their pregnancy showed no elevated risk.
CONCLUSIONS
Our findings are overall reassuring, although it is possible that low fecundity may be associated with a modestly increased risk of DCD.
doi:10.1093/humrep/deq010
PMCID: PMC2839911  PMID: 20139428
assisted reproduction technologies; developmental coordination disorder; infertility

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