Increase in thyroglobulin antibody and thyroid peroxidase antibody levels, but not preterm birth-rate, in pregnant Danish women upon iodine fortification.

OBJECTIVE: The presence of thyroid antibodies in pregnancy has been associated with preterm birth. In the non-pregnant population, the implementation of the Danish iodine fortification program has increased the prevalence of thyroid antibodies. This study investigated the prevalence of thyroid peroxidase antibodies (TPOAbs) and thyroglobulin antibodies (TgAbs) in pregnant Danish women before, during and after implementation of the iodine fortification program and association with preterm birth. DESIGN: Comparative cohort study of 1368 pregnancies from three cohorts gathered before (1996-1998), during (2000-2003) and after (2008-2009) the iodine fortification program. METHODS: In cohort 1 (n = 297), TPOAbs were measured (DYNOtest (BRAHMS)). In cohorts 2 (n = 148) and 3 (n = 923), both TPOAbs and TgAbs were measured (Kryptor immunofluorescent assay (BRAHMS)). The prevalence and effect of antibody positivity were explored using three cut-offs: TPOAbs and/or TgAbs >100 kU/L, TPOAbs and/or TgAbs >60 kU/L and TPOAbs >30 and/or TgAbs >20 kU/L. National preterm birth data were extracted from the National Birth Registry. RESULTS: In the three cohorts, TPOAb levels >60 kU/L were found in 5.4, 8.1 and 12.0% (χ2(2, n = 1367) = 11.7, P = 0.003) respectively, and TPOAbs and/or TgAbs >60 kU/L in 8.1 and 16.2% in cohorts 2 and 3 respectively (χ2(2, n = 1070) = 6.5, P = 0.01). TgAb levels (>20 kU/L) had increased plenty-fold from cohort 2 to 3 (χ2(1, n = 1071) = 136.5, P < 0.001). Preterm birth occurred in 4.1% of all pregnancies with no effect from antibody positivity (TPOAbs and/or TgAbs >60 kU/L, χ2(1, n = 1039) = 0.0, P = 0.98, aOR = 1.1, 95% CI (0.4-2.7)). The national preterm birth-rate showed no increase over the same period. CONCLUSIONS: Thyroid antibody positivity in Danish pregnant women has more than doubled upon the implementation of the iodine fortification program without an increase in preterm birth-rate.

Gestational age-specific reference ranges from different laboratories misclassify pregnant women's thyroid status: comparison of two longitudinal prospective cohort studies.

OBJECTIVES: Correct interpretation of thyroid status during pregnancy is vital to secure fetal development. Pregnancy-related changes in maternal thyroid status necessitate the use of gestational age-specific reference ranges. In this study, we investigated between-laboratory reproducibility of thyroid reference ranges in pregnant women. DESIGN: Comparison of two longitudinal prospective cohort studies including 255 (cohort 1) and 101 (cohort 2) healthy antibody-negative Danish pregnant women attending prenatal care at Copenhagen University Hospital. METHODS: Different immunoassays were used to measure thyroid hormone levels in the two cohorts. Thyroid hormone reference ranges were established for every 5 weeks of gestation. Differences between cohorts were explored through mixed-model repeated measures regression analyses. By applying reference ranges from one cohort to the other, the proportion of women who would be misclassified by doing so was investigated. RESULTS: TSH increased and free thyroxine (FT4) decreased as pregnancy progressed. Results indicated highly significant differences between cohorts in free triiodothyronine (F=21.3, P<0.001) and FT4 (F=941, P<0.001). TSH levels were comparable (P=0.09). Up to 90.3% of the women had FT4 levels outside their laboratory's nonpregnant reference range, and up to 100% outside the other cohort's gestational-age-specific reference ranges. Z-score-based reference ranges markedly improved comparison between cohorts. CONCLUSION: Even in the same region, the use of gestational-age-specific reference ranges from different laboratories led to misclassification. Up to 100% of maternal FT4 levels fell outside the other cohort's reference range despite similar TSH levels. In clinical practice, thyroid testing of pregnant women without adding method specificity to gestational age-dependent reference ranges will compromise patient safety.

Prenatal stress and cerebral palsy: a nationwide cohort study in Denmark.

OBJECTIVES: Exposure to prenatal stress may affect neurodevelopment of the fetus, but whether this exposure increases the risk of cerebral palsy (CP) later in life is unknown. We aimed to examine the association between maternal bereavement during the prenatal time period and CP in childhood. METHODS: We conducted a nationwide cohort study by linking information from nationwide registers. All 1,501,894 singletons born in Denmark from 1979 to 2004 were followed up from birth to the end of 2006. We identified 39,601 children whose mothers lost a close relative (child, spouse, parent, sibling) during pregnancy or up to 1 year before pregnancy and they were classified as the exposed group. The outcome of interest was the diagnosis of CP as registered in the National Hospital Register. We used Cox Regression to estimate the hazard ratios (HRs). RESULTS: Exposure to maternal bereavement after the loss of a child during the prenatal period was associated with an increased risk of CP among children born preterm without intrauterine growth retardation (HR 2.26, 95% CI, 1.09-3.79) and among children born at term with intrauterine growth retardation (HR 2.01, 95% CI, 1.04-3.89). Prenatal stress after maternal bereavement by loss of other relatives was not associated with an increased risk of CP. CONCLUSIONS: Our data suggest that extremely severe stress in prenatal life could increase the susceptibility for CP among children born preterm or with impaired fetal growth.

A nationwide study on the risk of autism after prenatal stress exposure to maternal bereavement.

OBJECTIVE: Prenatal stress has been linked to several adverse neurobehavioral outcomes, which may share a common pathophysiology with autism. We aimed to examine whether prenatal stress exposure after maternal bereavement is associated with an increased risk of autism later in life. METHODS: We conducted a nationwide population-based cohort study of all 1492709 singletons in Denmark born from 1978 to 2003. A total of 37275 children were born to women who lost a close relative during pregnancy or up to 1 year before pregnancy. These children were included in the exposed group, and the remaining children were in the unexposed group. All children were followed up from birth until their death, migration, onset of autism, or the end of 2006. Information on autism was obtained from the Danish Psychiatric Central Register. We used Cox regression models to estimate hazard ratios in the exposed group compared with those in the unexposed group. RESULTS: Maternal bereavement during the prenatal period was not associated with an increased risk of autism in the offspring. The hazard ratios did not differ by the nature of the exposure (maternal relationship to the deceased or cause of death). The hazard ratios were comparable between the 5 prenatal exposure periods under study (7-12 months before pregnancy, 0-6 months before pregnancy, first trimester, second trimester, and third trimester). CONCLUSIONS: This is the first population-based cohort study to examine the effect of prenatal stress on autism in childhood. Our data do not support any strong association between prenatal stress after maternal bereavement and the risk of autism.

Prenatal stress and risk of febrile seizures in children: a nationwide longitudinal study in Denmark.

We aimed to examine whether exposure to prenatal stress following maternal bereavement is associated with an increased risk of febrile seizures. In a longitudinal population-based cohort study, we followed 1,431,175 children born in Denmark. A total of 34,777 children were born to women who lost a close relative during pregnancy or within 1 year before the pregnancy and they were included in the exposed group. The exposed children had a risk of febrile seizures similar to that of the unexposed children (hazard ratio (HR) 1.00, 95% CI 0.94-1.06). The HRs did not differ according to the nature or timing of bereavement. Our data do not suggest any causal link between exposure to prenatal stress and febrile seizures in childhood.

Prenatal stress and epilepsy in later life: a nationwide follow-up study in Denmark.

PURPOSE: To examine whether prenatal exposure to maternal bereavement is associated with an increased risk of epilepsy in the first decades of life. METHODS: We conducted a population-based cohort study of children (N=1,553,966) born in Denmark from 1978 to 2004. A total of 39,867 children born to women who lost a close relative while pregnant or within 1 year before the pregnancy were included in the exposed cohort. The main outcome of interest was hospitalization due to epilepsy (ICD 8 codes 345.00-345.99, ICD 10 codes G40.0-G41.9). We used log-linear Poisson models to estimate incidence rate ratios (IRRs). RESULTS: The exposed children had a risk of epilepsy similar to that of unexposed children (IRR 1.06, 95% CI 0.96-1.18). The IRRs were 1.08 (95% CI 0.89-1.31) for the children of women who lost a child, and 1.02 (95% CI 0.91-1.15) for the children of women who lost a partner, parent or sibling. The IRRs did not differ according to the timing of exposure or the causes of death (unexpected causes and other causes). CONCLUSIONS: Our data do not suggest any strong association between prenatal stress and epilepsy in the first decades of life.

Severe life events and impaired fetal growth: a nation-wide study with complete follow-up.

BACKGROUND: To estimate the association between severe maternal life events and infants small for gestational age at different gestational ages at birth. METHODS: From 1980 to 1992 all women exposed to severe life events such as death or first hospitalization for cancer or acute myocardial infarction in partners or children during pregnancy or up to 485 days before were identified through national registers. We included all 3,402 exposed pregnancies and 19,551 unexposed pregnancies randomly selected to the control cohort and performed adjusted stratified Cox proportional hazards regression analyses with time-dependent covariates. RESULTS: These life events were not associated with SGA in general, but exposed infants born before 32 weeks of gestation had twice the risk for being born with a birth weight

Smoking among upper secondary pupils with asthma: reasons for their smoking behavior: a population-based study.

We compared why adolescent pupils with and without asthma started smoking and currently smoke. Girls with asthma started smoking less often because of friends smoking, and asthmatics started more often because of pressure, especially asthmatic boys. Fewer asthmatics smoked currently for social reasons and more to stay slim, mainly asthmatic boys.

Hospitalization for mental illness among parents after the death of a child.

BACKGROUND: The loss of a child is considered one of the most stressful events in the life of a parent. We hypothesized that parental bereavement increases the risk of hospital admission for a psychiatric disorder, especially for affective disorders. METHODS: We studied a cohort of 1,082,503 persons identified from national registers in Denmark who were born between 1952 and 1999 and had at least one child under 18 years of age during the follow-up period, from 1970 to 1999. Parents who lost a child during follow-up were categorized as "bereaved" from the date of death of the child. RESULTS: As compared with parents who did not lose a child, parents who lost a child had an overall relative risk of a first psychiatric hospitalization for any disorder of 1.67 (95 percent confidence interval, 1.53 to 1.83). Bereaved mothers had a higher relative risk of being hospitalized for any psychiatric disorder than bereaved fathers (relative risks, 1.78 [95 percent confidence interval, 1.60 to 1.98] and 1.38 [95 percent confidence interval, 1.17 to 1.63], respectively; P value for interaction, 0.01). The relative risks of hospitalization specifically for affective disorders were 1.91 (95 percent confidence interval, 1.59 to 2.30) and 1.61 (95 percent confidence interval, 1.15 to 2.27) for bereaved mothers and fathers, respectively. Among mothers, the relative risk of being hospitalized for any psychiatric disorder was highest during the first year after the death of the child but remained significantly elevated five years or more after the death. CONCLUSIONS: The risk of psychiatric hospitalization was increased among parents, especially mothers, who lost a child.

Psychological stress and inflammatory bowel disease: a follow-up study in parents who lost a child in Denmark.

OBJECTIVES: Little is known about the association between psychological stress and the risk of inflammatory bowel disease (IBD). This study aimed to examine whether the death of a child is related to the development and exacerbation of IBD in bereaved parents. METHODS: We undertook a follow-up study based on national registers. All 21,062 parents who lost a child (younger than 18 yr) from 1980 to 1996 in Denmark were included in the exposed cohort, and 293,745 parents matched on family structure were selected randomly from the general population to the unexposed cohort. Cox's proportional-hazards regression models were used to evaluate the relative risks (RRs) of first IBD hospitalization in the exposed parents, compared to the unexposed. Poisson regression models were fitted to estimate the frequency of IBD readmission between the exposed and the unexposed IBD parents. We used Wilcoxon tests to compare the mean duration of hospitalizations in the two groups of patients. RESULTS: There were 32 prevalent IBD patients at the study entry in the exposed cohort and 451 prevalent cases in the unexposed cases. We observed 301 incident cases of Crohn's disease (20 in the exposed, 281 in the unexposed) and 766 incident cases of ulcerative colitis (51 in the exposed, 715 in the unexposed). The RRs of first hospitalization for Crohn's disease and ulcerative colitis were 0.97 (95% CI = 0.62-1.53) and 1.01 (95% CI = 0.76-1.34), respectively. For incident or prevalent IBD patients, we did not observe any differences in the frequency or duration of hospitalization in the exposed and unexposed patients. CONCLUSIONS: Our findings do not support an association between psychological stress and the development of IBD in young-to-middle-aged adults.

Smoking patterns among adolescents with asthma attending upper secondary schools: a community-based study.

OBJECTIVE: Smoking among people who have asthma may be a serious health problem. We studied the prevalence of smoking and the relations between smoking and asthma, symptoms, medicine, and gender differences among adolescents with asthma. METHODS: A national cross-sectional study on health and lifestyles was performed in 1996-1997 using a computerized questionnaire in upper secondary schools in Denmark. We included 1887 pupils with asthma (defined as self-reported asthma diagnosed by a physician) and 20 688 controls. Smoking was categorized as daily, occasional, ex-smokers, and never smoked. We adjusted for age, gender, parents' job and smoking, family type, body mass index, and exercise habits. RESULTS: In total, 37.7% smoked currently and 16.5% smoked daily; more girls than boys smoked. More pupils with asthma than without smoked daily (adjusted odds ratio [OR]: 1.15; 95% confidence interval [CI]: 1.04-1.33), they smoked significantly more cigarettes daily (10.3 vs 9.6), and more were heavy smokers (> or =15 cigarettes daily; adjusted OR: 1.47; 95% CI:1.14-1.91). Furthermore, nearly twice as many pupils who had asthma with symptoms but were not using medicine smoked as pupils who had asthma without symptoms and were using medicine (adjusted OR: 1.84; 95% CI: 0.99-3.41). More boys with asthma than without started smoking before 14 years of age (adjusted OR: 1.75; 95% CI: 1.09-2.81). However, more pupils with asthma had tried to quit (adjusted OR: 1.26; 95% CI: 0.99-1.60). Pupils with and without asthma were occasional smokers and ex-smokers at a similar prevalence. CONCLUSIONS: More pupils with asthma than without smoked daily, and they also smoked more cigarettes per day. This is a major health concern, as adolescents have a high smoking prevalence in Denmark.

Mortality in parents after death of a child in Denmark: a nationwide follow-up study.

BACKGROUND: Little is known about the effect of parental bereavement on physical health. We investigated whether the death of a child increased mortality in parents. METHODS: We undertook a follow-up study based on national registers. From 1980 to 1996, we enrolled 21062 parents in Denmark who had a child who had died (exposed cohort), and 293745 controls--ie, parents whose children were alive, and whose family structure matched that of the exposed cohort. Natural deaths were defined with ICD8 codes 0000-7969 and ICD10 codes A00-R99, and unnatural deaths with codes 8000-9999 and V01-Y98. We used Cox's proportional-hazards regression models to assess the mortality rate of parents up to 18 years after bereavement. FINDINGS: We observed an increased overall mortality rate in mothers whose child had died (hazards ratio 1.43, 95% CI 1.24-1.64; p<0.0001). An excess mortality from natural causes (1.44, 1.15-1.78; p<0.0001) was noted in mothers only during the 10th-18th year of follow-up. Mothers had increased mortality rates from unnatural causes throughout follow-up, with the highest rate recorded during the first 3 years (3.84, 2.48-5.88; p<0.0001). Bereaved fathers had only an early excess mortality from unnatural causes (1.57, 1.06-2.32; p=0.04). Mothers who lost a child due to an unnatural death or an unexpected death had a hazard ratio of 1.72 (1.38-2.15; p=0.0040) and 1.67 (1.37-2.03; p=0.0037), respectively. INTERPRETATION: The death of a child is associated with an overall increased mortality from both natural and unnatural causes in mothers, and an early increased mortality from unnatural causes in fathers.