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1.  Pregnancy serum concentrations of perfluorinated alkyl substances and offspring behaviour and motor development at age 5–9 years – a prospective study 
Environmental Health  2015;14:2.
Background
In animal studies, perfluorinated alkyl substances affect growth and neuro-behavioural outcomes. Human epidemiological studies are sparse. The aim was to investigate the association between pregnancy serum concentrations of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) and offspring behaviour and motor development at 5–9 years of age.
Methods
Maternal sera from the INUENDO cohort (2002–2004) comprising 1,106 mother-child pairs from Greenland, Kharkiv (Ukraine) and Warsaw (Poland) were analysed for PFOS and PFOA, using liquid-chromatography-tandem-mass-spectrometry. Exposures were grouped into country specific as well as pooled tertiles as well as being used as continuous variables for statistical analyses. Child motor development and behaviour at follow-up (2010–2012) were measured by the Developmental Coordination Disorder Questionnaire 2007 (DCDQ) and Strength and Difficulties Questionnaire (SDQ), respectively. Exposure-outcome associations were analysed by multiple logistic and linear regression analyses.
Results
In the pooled analysis, odds ratio (OR) (95% confidence interval (CI)) for hyperactivity was 3.1 (1.3, 7.2) comparing children prenatally exposed to the highest PFOA tertile with those exposed to the lowest PFOA tertile. Comparing children in the highest PFOS tertile with those in the lowest PFOS tertile showed elevated but statistically non-significant OR of hyperactivity (OR (95% CI) 1.7 (0.9, 3.2)). In Greenland, elevated PFOS was associated with higher SDQ-total scores indicating more behavioural problems (β (95% CI) =1.0 (0.1, 2.0)) and elevated PFOA was associated with higher hyperactivity sub-scale scores indicating more hyperactive behaviour (β (95% CI) = 0.5 (0.1, 0.9)). Prenatal PFOS and PFOA exposures were not associated with motor difficulties.
Conclusions
Prenatal exposure to PFOS and PFOA may have a small to moderate effect on children’s neuro-behavioural development, specifically in terms of hyperactive behaviour. The associations were strongest in Greenland where exposure contrast is largest.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-069X-14-2) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-069X-14-2
PMCID: PMC4298045  PMID: 25567242
Behaviour; Child; Child development; Cohort study; Motor development; Perfluorooctanoate (PFOA); Perfluorooctane sulfonate (PFOS); Prenatal exposure, Delayed effects
2.  Mortality after Parental Death in Childhood: A Nationwide Cohort Study from Three Nordic Countries 
PLoS Medicine  2014;11(7):e1001679.
Jiong Li and colleagues examine mortality rates in children who lost a parent before 18 years old compared with those who did not using population-based data from Denmark, Sweden, and Finland.
Please see later in the article for the Editors' Summary
Background
Bereavement by spousal death and child death in adulthood has been shown to lead to an increased risk of mortality. Maternal death in infancy or parental death in early childhood may have an impact on mortality but evidence has been limited to short-term or selected causes of death. Little is known about long-term or cause-specific mortality after parental death in childhood.
Methods and Findings
This cohort study included all persons born in Denmark from 1968 to 2008 (n = 2,789,807) and in Sweden from 1973 to 2006 (n = 3,380,301), and a random sample of 89.3% of all born in Finland from 1987 to 2007 (n = 1,131,905). A total of 189,094 persons were included in the exposed cohort when they lost a parent before 18 years old. Log-linear Poisson regression was used to estimate mortality rate ratio (MRR). Parental death was associated with a 50% increased all-cause mortality (MRR = 1.50, 95% CI 1.43–1.58). The risks were increased for most specific cause groups and the highest MRRs were observed when the cause of child death and the cause of parental death were in the same category. Parental unnatural death was associated with a higher mortality risk (MRR = 1.84, 95% CI 1.71–2.00) than parental natural death (MRR = 1.33, 95% CI 1.24–1.41). The magnitude of the associations varied according to type of death and age at bereavement over different follow-up periods. The main limitation of the study is the lack of data on post-bereavement information on the quality of the parent-child relationship, lifestyles, and common physical environment.
Conclusions
Parental death in childhood or adolescence is associated with increased all-cause mortality into early adulthood. Since an increased mortality reflects both genetic susceptibility and long-term impacts of parental death on health and social well-being, our findings have implications in clinical responses and public health strategies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
When someone close dies, it is normal to grieve, to mourn the loss of that individual. Initially, people who have lost a loved one often feel numb and disorientated and find it hard to grasp what has happened. Later, people may feel angry or guilty, and may be overwhelmed by feelings of sadness and despair. They may become depressed or anxious and may even feel suicidal. People who are grieving can also have physical reactions to their loss such as sleep problems, changes in appetite, and illness. How long bereavement—the period of grief and mourning after a death—lasts and how badly it affects an individual depends on the relationship between the individual and the deceased person, on whether the death was expected, and on how much support the mourner receives from relatives, friends, and professionals.
Why Was This Study Done?
The loss of a life-partner or of a child is associated with an increased risk of death (mortality), and there is also some evidence that the death of a parent during childhood leads to an increased mortality risk in the short term. However, little is known about the long-term impact on mortality of early parental loss or whether the impact varies with the type of death—a natural death from illness or an unnatural death from external causes such as an accident—or with the specific cause of death. A better understanding of the impact of early bereavement on mortality is needed to ensure that bereaved children receive appropriate health and social support after a parent's death. Here, the researchers undertake a nationwide cohort study in three Nordic countries to investigate long-term and cause-specific mortality after parental death in childhood. A cohort study compares the occurrence of an event (here, death) in a group of individuals who have been exposed to a particular variable (here, early parental loss) with the occurrence of the same event in an unexposed cohort.
What Did the Researchers Do and Find?
The researchers obtained data on everyone born in Denmark from 1968 to 2008 and in Sweden from 1973 to 2006, and on most people born in Finland from 1987 to 2007 (more than 7 million individuals in total) from national registries. They identified 189,094 individuals who had lost a parent between the age of 6 months and 18 years. They then estimated the mortality rate ratio (MRR) associated with parental death during childhood or adolescence by comparing the number of deaths in this exposed cohort (after excluding children who died on the same day as a parent or shortly after from the same cause) and in the unexposed cohort. Compared with the unexposed cohort, the exposed cohort had 50% higher all-cause mortality (MRR = 1.50). The risk of mortality in the exposed cohort was increased for most major categories of cause of death but the highest MRRs were seen when the cause of death in children, adolescents, and young adults during follow-up and the cause of parental death were in the same category. Notably, parental unnatural death was associated with a higher mortality risk (MRR = 1.84) than parental natural death (MRR = 1.33). Finally, the exposed cohort had increased all-cause MRRs well into early adulthood irrespective of child age at parental death, and the magnitude of MRRs differed by child age at parental death and by type of death.
What Do These Findings Mean?
These findings show that in three high-income Nordic countries parental death during childhood and adolescence is associated with an increased risk of all-cause mortality into early adulthood, irrespective of sex and age at bereavement and after accounting for baseline characteristics such as socioeconomic status. Part of this association may be due to “confounding” factors—the people who lost a parent during childhood may have shared other unknown characteristics that increased their risk of death. Because the study was undertaken in high-income countries, these findings are unlikely to be the result of a lack of material or health care needs. Rather, the increased mortality among the exposed group reflects both genetic susceptibility and the long-term impacts of parental death on health and social well-being. Given that increased mortality probably only represents the tip of the iceberg of the adverse effects of early bereavement, these findings highlight the need to provide long-term health and social support to bereaved children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001679.
The UK National Health Service Choices website provides information about bereavement, including personal stories; it also provides information about children and bereavement and about young people and bereavement, including links to not-for-profit organizations that support children through bereavement
The US National Cancer Institute has detailed information about dealing with bereavement for the public and for health professionals that includes a section on children and grief (in English and Spanish)
The US National Alliance for Grieving Children promotes awareness of the needs of children and teens grieving a death and provides education and resources for anyone who wants to support them
MedlinePlus provides links to other resources about bereavement (in English and Spanish)
doi:10.1371/journal.pmed.1001679
PMCID: PMC4106717  PMID: 25051501
3.  Severe Maternal Stress Exposure Due to Bereavement before, during and after Pregnancy and Risk of Overweight and Obesity in Young Adult Men: A Danish National Cohort Study 
PLoS ONE  2014;9(5):e97490.
Background
Perinatal stress may programme overweight and obesity. We examined whether maternal pre- and post-natal bereavement was associated with overweight and obesity in young men.
Methods
A cohort study was conducted including 119,908 men born from 1976 to 1993 and examined for military service between 2006 and 2011. Among them, 4,813 conscripts were born to mothers bereaved by death of a close relative from 12 months preconception to birth of the child (exposed group). Median body mass index (BMI) and prevalence of overweight and obesity were estimated. Odds ratio of overweight (BMI≥25 kg/m2) and obesity (BMI≥30 kg/m2) were estimated by logistic regression analysis adjusted for maternal educational level.
Results
Median BMI was similar in the exposed and the unexposed group but the prevalence of overweight (33.3% versus 30.4%, p = 0.02) and obesity (9.8% versus 8.5%, p = 0.06) was higher in the exposed group. Conscripts exposed 6 to 0 months before conception and during pregnancy had a higher risk of overweight (odds ratio 1.15, 95% confidence interval (CI): 1.03; 1.27 and odds ratio 1.13, 95% CI: 1.03; 1.25, respectively). Conscripts born to mothers who experienced death of the child’s biological father before child birth had a two-fold risk of obesity (odds ratio 2.00, 95% CI: 0.93; 4.31). There was no elevated risk in those who experienced maternal bereavement postnatally.
Conclusion
Maternal bereavement during the prenatal period was associated with increased risk of overweight or obesity in a group of young male conscripts, and this may possibly be reflected to severe stress exposure early in life. However, not all associations were clear, and further studies are warranted.
doi:10.1371/journal.pone.0097490
PMCID: PMC4020839  PMID: 24828434
4.  Stability of the Associations between Early Life Risk Indicators and Adolescent Overweight over the Evolving Obesity Epidemic 
PLoS ONE  2014;9(4):e95314.
Background
Pre- and perinatal factors and preschool body size may help identify children developing overweight, but these factors might have changed during the development of the obesity epidemic.
Objective
We aimed to assess the associations between early life risk indicators and overweight at the age of 9 and 15 years at different stages of the obesity epidemic.
Methods
We used two population-based Northern Finland Birth Cohorts including 4111 children born in 1966 (NFBC1966) and 5414 children born in 1985–1986 (NFBC1986). In both cohorts, we used the same a priori defined prenatal factors, maternal body mass index (BMI), birth weight, infant weight (age 5 months and 1 year), and preschool BMI (age 2–5 years). We used internal references in early childhood to define percentiles of body size (<50, 50–75, 75–90 and >90) and generalized linear models to study the association with overweight, according to the International Obesity Taskforce (IOTF) definitions, at the ages of 9 and 15 years.
Results
The prevalence of overweight at the age of 15 was 9% for children born in 1966 and 16% for children born in 1986. However, medians of infant weight and preschool BMI changed little between the cohorts, and we found similar associations between maternal BMI, infant weight, preschool BMI, and later overweight in the two cohorts. At 5 years, children above the 90th percentile had approximately a 12 times higher risk of being overweight at the age of 15 years compared to children below the 50th percentile in both cohorts.
Conclusions
The associations between early body size and adolescent overweight showed remarkable stability, despite the increase in prevalence of overweight over the 20 years between the cohorts. Using consequently defined internal percentiles may be a valuable tool in clinical practice.
doi:10.1371/journal.pone.0095314
PMCID: PMC3991687  PMID: 24748033
5.  Preschool Weight and Body Mass Index in Relation to Central Obesity and Metabolic Syndrome in Adulthood 
PLoS ONE  2014;9(3):e89986.
Background
If preschool measures of body size routinely collected at preventive health examinations are associated with adult central obesity and metabolic syndrome, a focused use of these data for the identification of high risk children is possible. The aim of this study was to test the associations between preschool weight and body mass index (BMI) and adult BMI, central obesity and metabolic alterations.
Methods
The Northern Finland Birth Cohort 1966 (NFBC1966) (N = 4111) is a population-based cohort. Preschool weight (age 5 months and 1 year) and BMI (age 2–5 years) were studied in relation to metabolic syndrome as well as BMI, waist circumference, lipoproteins, blood pressure, and fasting glucose at the age of 31 years. Linear regression models and generalized linear regression models with log link were used.
Results
Throughout preschool ages, weight and BMI were significantly linearly associated with adult BMI and waist circumference. Preschool BMI was inversely associated with high-density lipoprotein levels from the age of 3 years. Compared with children in the lower half of the BMI range, the group of children with the 5% highest BMI at the age of 5 years had a relative risk of adult obesity of 6.2(95% CI:4.2–9.3), of adult central obesity of 2.4(95% CI:2.0–2.9), and of early onset adult metabolic syndrome of 2.5(95% CI:1.7–3.8).
Conclusions
High preschool BMI is consistently associated with adult obesity, central obesity and early onset metabolic syndrome. Routinely collected measures of body size in preschool ages can help to identify children in need of focused prevention due to their increased risk of adverse metabolic alterations in adulthood.
doi:10.1371/journal.pone.0089986
PMCID: PMC3940896  PMID: 24595022
6.  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
7.  Web-Based Versus Traditional Paper Questionnaires: A Mixed-Mode Survey With a Nordic Perspective 
Background
Survey response rates have been declining over the past decade. The more widespread use of the Internet and Web-based technologies among potential health survey participants suggests that Web-based questionnaires may be an alternative to paper questionnaires in future epidemiological studies.
Objective
To compare response rates in a population of parents by using 4 different modes of data collection for a questionnaire survey of which 1 involved a nonmonetary incentive.
Methods
A random sample of 3148 parents of Danish children aged 2-17 years were invited to participate in the Danish part of the NordChild 2011 survey on their children’s health and welfare. NordChild was conducted in 1984 and 1996 in collaboration with Finland, Iceland, Norway, and Sweden using mailed paper questionnaires only. In 2011, all countries used conventional paper versions only except Denmark where the parents were randomized into 4 groups: (1) 789 received a paper questionnaire only (paper), (2) 786 received the paper questionnaire and a log-in code to the Web-based questionnaire (paper/Web), (3) 787 received a log-in code to the Web-based questionnaire (Web), and (4) 786 received log-in details to the Web-based questionnaire and were given an incentive consisting of a chance to win a tablet computer (Web/tablet). In connection with the first reminder, the nonresponders in the paper, paper/Web, and Web groups were also present with the opportunity to win a tablet computer as a means of motivation. Descriptive analysis was performed using chi-square tests. Odds ratios were used to estimate differences in response rates between the 4 modes.
Results
In 2011, 1704 of 3148 (54.13%) respondents answered the Danish questionnaire. The highest response rate was with the paper mode (n=443, 56.2%). The other groups had similar response rates: paper/Web (n=422, 53.7%), Web (n=420, 53.4%), and Web/tablet (n=419, 53.3%) modes. Compared to the paper mode, the odds for response rate in the paper/Web decreased by 9% (OR 0.91, 95% CI 0.74-1.10) and by 11% (OR 0.89, 95% CI 0.73-1.09) in the Web and Web/tablet modes. The total number of responders for NordChild declined from 10,291 of 15,339 (67.09%) in 1984 and 10,667 of 15,254 (69.93%) in 1996 to 7805 of 15,945 (48.95%) in 2011 with similar declines in all 5 Nordic countries.
Conclusions
Web-based questionnaires could replace traditional paper questionnaires with minor effects on response rates and lower costs. The increasing effect on the response rate on participants replying for a nonmonetary incentive could only be estimated within the 2 Web-based questionnaire modes before the first reminder. Alternative platforms to reach higher participation rates in population surveys should reflect the development of electronic devices and the ways in which the population primarily accesses the Internet.
doi:10.2196/jmir.2595
PMCID: PMC3757995  PMID: 23978658
mixed-mode survey; patient participation rate; Web-based; paper; questionnaires; nonmonetary incentive
8.  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
9.  Evaluation of general practitioners’ assessment of overweight among children attending the five-year preventive child health examination: A cross-sectional survey 
Objective
To evaluate general practitioners’ (GPs’) assessment of potential overweight among children attending the five-year preventive child health examination (PCHE) by comparing their assessment of the children's weight-for-stature with overweight defined by body mass index (BMI) according to paediatric standard definitions.
Design
A cross-sectional survey. Data were obtained from a questionnaire survey of children's health in general and their growth in particular.
Setting
The five-year preventive child health examination (PCHE) in general practice in the Central Denmark Region.
Subjects
Children attending the five-year PCHE in general practice, regardless of their weight status.
Main outcome measures
Paediatric standard definitions for childhood overweight based on BMI were used as the gold standard for categorizing weight-for-stature. Identification of overweight was analysed with regard to sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the GPs’ assessment of weight-for-stature.
Results
A total of 165 GPs conducted 1138 PCHEs. GPs assessed that 171 children had a weight-for-stature above normal. Use of the Danish Standards (DS), i.e. the Danish national growth charts for BMI, as the gold standard yielded a sensitivity of 70.1% (95% CI 62.0–77.3) and a specificity of 92.4% (95% CI 90.6–93.9). The sensitivity was influenced by the GPs’ use of BMI and the presence of previous notes regarding abnormal weight development.
Conclusion
At the five-year PCHE almost one-third of overweight children were assessed to be normal weight by GPs. Use of BMI and presence of notes on abnormal weight in medical records were positively associated with a higher identification. Hence, utilization of medical record data and BMI charts may refine GPs’ assessment of childhood overweight.
doi:10.3109/02813432.2012.704811
PMCID: PMC3443942  PMID: 22934817
Assessment; children; Denmark; general practice; overweight; preventive child health examination
10.  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
11.  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
12.  Psychometric Properties of the Danish Strength and Difficulties Questionnaire: The SDQ Assessed for More than 70,000 Raters in Four Different Cohorts 
PLoS ONE  2012;7(2):e32025.
Background
The Strength and Difficulties Questionnaire (SDQ) is a brief behavioural five factor instrument developed to assess emotional and behavioural problems in children and adolescents. The aim of the current study was to evaluate the psychometric properties for parent and teacher ratings in the Danish version of SDQ for different age groups of boys and girls.
Methods
The Danish versions of the SDQ were distributed to a total of 71,840 parent and teacher raters of 5-, 7- and 10- to 12-year-old children included in four large scale Danish cohorts. The internal reliability was assessed and exploratory factor analyses were carried out to replicate the originally proposed five factor structure. Mean scores and percentiles were examined in order to differentiate between low, medium and high levels of emotional and behavioural difficulties.
Results
The original five factor structure could be substantially confirmed. The Conduct items however did not solely load on the proposed Conduct scale and the Conduct scale was further contaminated by non-conduct items. Positively worded items tended to load on the Prosocial scale. This was more so the case for teachers than for parents. Parent and teacher means and percentiles were found to be lower compared to British figures but similar to or only slightly lower than those found in the other Nordic countries. The percentiles for girls were generally lower than for boys, markedly so for the teacher hyperactivity ratings.
Conclusions
The study supports the usefulness of the SDQ as a screening tool for boys and girls across age groups and raters in the general Danish population.
doi:10.1371/journal.pone.0032025
PMCID: PMC3288071  PMID: 22384129
13.  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
14.  Testing the association between psychosocial job strain and adverse birth outcomes - design and methods 
BMC Public Health  2011;11:255.
Background
A number of studies have examined the effects of prenatal exposure to stress on birth outcomes but few have specifically focused on psychosocial job strain. In the present protocol, we aim to examine if work characterised by high demands and low control, during pregnancy, is associated with the risk of giving birth to a child born preterm or small for gestational age.
Methods and design
We will use the Danish National Birth Cohort where 100.000 children are included at baseline. In the present study 49,340 pregnancies will be included. Multinomial logistic regression will be applied to estimate odds ratios for the outcomes: preterm; full term but small for gestational age; full term but large for gestational age, as a function of job-strain (high strain, active and passive versus low strain). In the analysis we control for maternal age, Body Mass Index, parity, exercise, smoking, alcohol use, coffee consumption, type of work (manual versus non-manual), maternal serious disease and parents' heights as well as gestational age at interview.
Discussion
The prospective nature of the design and the high number of participants strengthen the study. The large statistical power allows for interpretable results regardless of whether or not the hypotheses are confirmed. This is, however, not a controlled study since all kinds of 'natural' interventions takes place throughout pregnancy (e.g. work absence, medical treatment and job-redesign). The analysis will be performed from a public health perspective. From this perspective, we are not primarily interested in the effect of job strain per se but if there is residual effect of job strain after naturally occurring preventive measures have been taken.
doi:10.1186/1471-2458-11-255
PMCID: PMC3111377  PMID: 21510894
15.  Prevalence of the ADHD phenotype in 7- to 9-year-old children: effects of informant, gender and non-participation 
Purpose
To estimate the prevalence of the ADHD phenotype based on parent and teacher reports in a general population sample of 7- to 9-year-old Norwegian children and evaluate the effect of parent attrition, gender and informant on the prevalence estimate.
Methods
The population consisted of all children (N = 9,430) attending 2nd–4th grade in the City of Bergen, Norway. The 18 symptoms of ADHD corresponding to the SNAP-IV and DSM-IV were included in the Bergen Child Study questionnaire to teachers and parents. Teacher information was available for 9,137 children (97%) and information from both informants was available for the 6,237 children (66%) whose parents agreed to participate in the study.
Results
The prevalence of the ADHD phenotype based on the combination of parent and teacher reports was 5.2% among participants. Teacher ratings of non-participants had a doubled rate of ADHD high scorers with an OR of 2.1 (95% CI, 1.9–2.4). The non-participant ADHD high scorers had more inattentive and fewer hyperactive/impulsive symptoms as compared to participating ADHD high scorers. Teachers reported high scores of hyperactivity/impulsivity and the combined symptom constellation much more frequently in boys than girls, while the difference between genders was less marked according to parent reports.
Conclusions
The ADHD phenotype was twice as prevalent among non-participants as among participants. Reported prevalences in population studies are therefore likely to be underestimates, if such attrition bias is not accounted for. Choice of informant, criteria for symptom count, definitions of subtypes and gender differences influence the prevalence estimates of the ADHD phenotype.
doi:10.1007/s00127-011-0379-3
PMCID: PMC3328684  PMID: 21499807
Attention-deficit/hyperactivity disorder; Child psychiatry; Epidemiology; Attrition; Gender
16.  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
17.  Infertility, infertility treatment, and mixed-handedness in children 
Early human development  2009;85(12):745-749.
Background
Mixed-handedness, which may reflect atypical brain laterality, has been linked to a number of medical conditions as well as prenatal stress.
Aims
The aim of the study was to examine whether infertility or infertility treatment was associated with an increased risk of mixed-handedness in children.
Study design, subjects and outcome measures
We used data from three population-based birth cohorts in Denmark: the Aalborg-Odense Birth Cohort (1984-1987), the Aarhus Birth Cohort (1990-1992) and the Danish National Birth Cohort (1996-2002) (N=7728, 5720 and 29486, respectively). Data on time to pregnancy and infertility treatment was collected during pregnancy. Handedness was reported in a follow-up questionnaire when the children were at least 7 years old. Children were categorized as mixed-handed if the mothers reported that they used both hands equally.
Results
Children born after infertility treatment, particularly intrauterine insemination, had a higher risk of being mixed-handed compared to children of fertile couples with a time to pregnancy ≤12 months (odds ratio 1.41, 95% confidence interval 1.09-1.82). Children of couples with unplanned pregnancies, particularly after an oral contraceptives failure, were also more likely to be mixed-handed. There was no association between a long waiting time to pregnancy and mixed-handedness in children.
Conclusions
Children born after infertility treatment, particularly intrauterine insemination, and children exposed to oral contraceptives during early gestation may have a higher risk of being mixed-handed.
doi:10.1016/j.earlhumdev.2009.10.001
PMCID: PMC2788033  PMID: 19875254
Infertility; Infertility treatment; Mixed-handedness; Oral contraceptives; Time to pregnancy
18.  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
19.  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
20.  Infertility, infertility treatment and psychomotor development: Danish National Birth Cohort 
Summary
Babies born of infertile couples, regardless of treatment, have a higher risk of preterm birth and low birthweight, conditions associated with delayed development. We examined developmental milestones in singletons as a function of parental infertility [time to pregnancy (TTP) >12 months] and infertility treatment. From the Danish National Birth Cohort (1997–2003), we identified 37,897 singletons born of fertile couples (TTP ≤12 months), 4351 born of infertile couples conceiving naturally (TTP >12 months), and 3309 born after infertility treatment. When the children were about 18 months old, mothers reported 12 developmental milestones by responding to structured questions. We defined a failure to achieve the assessed milestone or the minimal numbers of milestones in a summary (motor, or cognitive/language skills) as delay. Naturally conceived children born of infertile couples had a pattern of psychomotor development similar to that of children born of fertile couples, but increasing TTP correlated with a modest delay. When the analysis was restricted to infertile couples (treated and untreated), children born after treatment showed a slight delay in cognitive/language development (odds ratio 1.24, [95% confidence interval 1.01, 1.53] for not meeting at least three out of six cognitive/language milestones); children born after intracytoplasmic sperm injection (ICSI) had the highest estimated relative risk of delay for most milestones, especially motor milestones. These results suggest that a long TTP may be associated with a modest developmental delay. Infertility treatment, especially ICSI, may be associated with a slight delay for some of these early milestones.
doi:10.1111/j.1365-3016.2008.00989.x
PMCID: PMC2706001  PMID: 19159396
child development; infertility; assisted reproductive techniques
21.  Parental infertility and sexual maturation in children 
BACKGROUND
The reproductive health of children born of infertile couples may be affected by infertility treatment or factors associated with infertility. We examined sexual maturation in children of parents with infertility.
METHODS
We used data from a follow-up of 3382 girls and 2810 boys born between 1984 and 1987 in the Aalborg–Odense Birth Cohort. We had mothers’ report of time to pregnancy (TTP) and infertility treatment (at the time, mostly hormonal) from the pregnancy questionnaire administered in 1984–1987, and the children’s report of their own sexual maturation from the follow-up questionnaire administered in 2005, when they were between 18 and 21 years old. Many reported age only in year when they had the events related to sexual maturation, and for each event, we imputed the month based on the median month at each year of age among those reporting both years and months.
RESULTS
In girls, the mean age at menarche was 13.3 years and, in boys, the mean age at appearance of acne, voice break, regular shaving and first nocturnal emission were 14.5, 14.5, 17.2 and 14.7 years, respectively. We saw no significant differences in age at these events among children born of either fertile (with TTP of 0–12 months and no treatment), untreated infertile (with TTP of more than 12 months and no treatment) or treated infertile couples (with a history of examination or treatment for infertility).
CONCLUSIONS
Our data suggest no significant association between parental infertility or hormonal treatment and timing of sexual maturation in the offspring.
doi:10.1093/humrep/den366
PMCID: PMC2733842  PMID: 18840889
infertility; infertility treatment; puberty; time to pregnancy
22.  Handedness and time to pregnancy 
Background
Non-right handedness, particularly mixed-handedness, has been associated with a number of medical conditions. We examined whether handedness was associated with fecundity, measured by time to pregnancy.
Methods
We used data on parental handedness and time to pregnancy from two regional birth cohorts in Denmark: the Aalborg-Odense Birth Cohort (1984–1987) and the Aarhus Birth Cohort (1990–1992) (N=5808 and 3426, respectively). We applied discrete-time survival analysis to assess fecundity in relation to handedness.
Results
In both cohorts, we saw a slightly lower fecundity in individuals who reported being mixed-handed. Left handedness was not significantly associated with fecundity.
Conclusions
Our data showed a modest association between mixed-handedness and subfecundity, which suggests that these traits may share a common prenatal etiology.
doi:10.1097/EDE.0b013e31818b47d1
PMCID: PMC2662690  PMID: 19057386
handedness; fecundity; time to pregnancy
23.  Infertility, Infertility Treatment and Fetal Growth Restriction 
Obstetrics and gynecology  2007;110(6):1326-1334.
OBJECTIVE
To examine the association between infertility, with or without treatment, and fetal growth, as well as perinatal and infant mortality.
METHODS
From the Danish National Birth Cohort (1997–2003), we identified 51,041 singletons born of fertile couples (time to pregnancy ≤12 months), 5787 born of infertile couples conceiving naturally (time to pregnancy >12 months), and 4317 born after treatment. We defined SGA as the lowest 5% of birth weight by sex and gestational age.
RESULTS
Crude estimates suggested an increased risk of perinatal mortality and SGA among infertile couples (treated and untreated), but the odds ratios (ORs) of perinatal mortality among infertile couples were attenuated after adjustment for maternal age and body mass index [1.32, 95% confidence interval (CI) 0.95–1.84 among untreated and 1.26, 95% CI 0.86–1.85 among treated couples]. The elevated risk of SGA among infertile couples persisted after adjustment for maternal age, parity and smoking (OR 1.24, 95% CI 1.10–1.40 among untreated, and OR 1.40, 95% CI 1.23–1.60 among treated). The risk of SGA increased with time to pregnancy, and a longer time to pregnancy was associated with a small reduction in birth weight across the whole distribution.
CONCLUSION
The increased risk of SGA observed among infertile couples with or without infertility treatment suggests that infertility may be a risk factor for intrauterine growth restriction. Treatment per se may have little effect on fetal growth. A small to moderate increased risk of perinatal mortality in infertile couples cannot be ruled out due to the small number of cases.
doi:10.1097/01.AOG.0000290330.80256.97
PMCID: PMC2365892  PMID: 18055728
24.  Mental health among children seeking asylum in Denmark – the effect of length of stay and number of relocations: a cross-sectional study 
BMC Public Health  2008;8:293.
Background
The process of seeking asylum and the related organisational conditions in the host country may adversely affect the children's mental health. The objective of this study was to examine the mental health of children seeking asylum in relation to organisational factors of the asylum system including length of stay and number of relocations.
Methods
The population included all 260 parent-accompanied asylum-seeking children aged 4–16 years living in the asylum centres managed by the Danish Red Cross in October–December 2006. Mental health was evaluated using the Strengths and Difficulties Questionnaire. School teachers evaluated children aged 4–16; and the 11–16-year-olds completed the self-report version. To assess the association between organisational factors and mental health, binary logistic regression analyses were done using backwards elimination. We received responses for 246 children equivalent to 95% of the study population.
Results
Using teachers' reports, we found that children who had been asylum-seeking for more than one year in Denmark had an increased risk of having mental difficulties (odds ratio 5.5, 95% CI 1.8–16.3); four or more relocations in the asylum system were also associated with a higher risk (3.0, 1.4–6.7). When the self-report data were included, the associations were even stronger.
Conclusion
Protracted stays at asylum centres and multiple relocations within the asylum system appear to have an adverse effect on asylum-seeking children's mental health. A limit to the duration of the children's stay in the asylum system should be ensured. Follow-up studies with inclusion of other conditions, such as parental mental health and the children's previous trauma, are needed to clarify the influence of the different factors and their interactions.
doi:10.1186/1471-2458-8-293
PMCID: PMC2535781  PMID: 18713455
25.  Infertility, infertility treatment and twinning: the Danish National Birth Cohort 
Human reproduction (Oxford, England)  2007;22(4):1086-1090.
BACKGROUND
We have previously observed that an increasing time to pregnancy (TTP) is associated with a reduced frequency of twin deliveries in couples not receiving infertility treatment. By using updated information, we assessed the frequencies of dizygotic and monozygotic twin deliveries as a function of infertility (TTP>12 months), as well as infertility treatment.
METHODS
From the Danish National Birth Cohort (1997−2003), we identified 51730 fertile couples with TTP12 months, and 5163 infertile couples who conceived after treatment. Information on zygosity, available for part of the cohort (1997−2000), was based on standardized questions on the similarities between the twins at the age of 3−5 years.
RESULTS
Compared with fertile couples, the frequency of dizygotic twin deliveries was lower for infertile couples conceiving naturally (Odds ratio 0.4, 95% confidence interval 0.2−0.7) and was much higher for infertile couples conceiving after treatment (17.3, 14.4−20.7). The frequency of dizygotic twin deliveries decreased with TTP in untreated couples, while the frequency of monozygotic twin deliveries remained constant.
CONCLUSIONS
The frequency of dizygotic twin deliveries decreased with time to pregnancy and substantially increased with infertility treatment, whereas monozygotic twin deliveries remained substantially unchanged.
doi:10.1093/humrep/del495
PMCID: PMC2077299  PMID: 17204529
infertility; infertility treatment; time to pregnancy; twinning; zygosity

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