Erik T. Parner

Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders

OBJECTIVES: Recent studies suggest that familial autoimmunity plays a part in the pathogenesis of ASDs. In this study we investigated the association between family history of autoimmune diseases (ADs) and ASDs/infantile autism. We perform confirmatory analyses based on results from previous studies, as well as various explorative analyses. METHODS: The study cohort consisted of all of the children born in Denmark from 1993 through 2004 (689 196 children). Outcome data consisted of both inpatient and outpatient diagnoses reported to the Danish National Psychiatric Registry. Information on ADs in parents and siblings of the cohort members was obtained from the Danish National Hospital Register. The incidence rate ratio of autism was estimated by using log-linear Poisson regression. RESULTS: A total of 3325 children were diagnosed with ASDs, of which 1089 had an infantile autism diagnosis. Increased risk of ASDs was observed for children with a maternal history of rheumatoid arthritis and celiac disease. Also, increased risk of infantile autism was observed for children with a family history of type 1 diabetes. CONCLUSIONS: Associations regarding family history of type 1 diabetes and infantile autism and maternal history of rheumatoid arthritis and ASDs were confirmed from previous studies. A significant association between maternal history of celiac disease and ASDs was observed for the first time. The observed associations between familial autoimmunity and ASDs/infantile autism are probably attributable to a combination of a common genetic background and a possible prenatal antibody exposure or alteration in fetal environment during pregnancy.

Autism After Infection, Febrile Episodes, and Antibiotic Use During Pregnancy: An Exploratory Study

OBJECTIVES: Results of animal studies suggest that maternal immune activation during pregnancy causes deficiencies in fetal neurodevelopment. Infectious disease is the most common path to maternal immune activation during pregnancy. The goal of this study was to determine the occurrence of common infections, febrile episodes, and use of antibiotics reported by the mother during pregnancy and the risk for autism spectrum disorder (ASD) and infantile autism in the offspring. METHODS: We used a population-based cohort consisting of 96 736 children aged 8 to 14 years and born from 1997 to 2003 in Denmark. Information on infection, febrile episodes, and use of antibiotics was self-reported through telephone interviews during pregnancy and early postpartum. Diagnoses of ASD and infantile autism were retrieved from the Danish Psychiatric Central Register; 976 children (1%) from the cohort were diagnosed with ASD. RESULTS: Overall, we found little evidence that various types of mild common infectious diseases or febrile episodes during pregnancy were associated with ASD/infantile autism. However, our data suggest that maternal influenza infection was associated with a twofold increased risk of infantile autism, prolonged episodes of fever caused a threefold increased risk of infantile autism, and use of various antibiotics during pregnancy were potential risk factors for ASD/infantile autism. CONCLUSIONS: Our results do not suggest that mild infections, febrile episodes, or use of antibiotics during pregnancy are strong risk factors for ASD/infantile autism. The results may be due to multiple testing; the few positive findings are potential chance findings.

Explaining the Increase in the Prevalence of Autism Spectrum Disorders: The Proportion Attributable to Changes in Reporting Practices

IMPORTANCE The prevalence of autism spectrum disorders (ASDs) has increased markedly in recent decades, which researchers have suggested could be caused in part by nonetiologic factors such as changes in diagnosis reporting practices. To our knowledge, no study has quantified the degree to which changes in reporting practices might explain this increase. Danish national health registries have undergone a change in diagnostic criteria in 1994 and the inclusion of outpatient contacts to health registries in 1995. OBJECTIVE To quantify the effect of changes in reporting practices in Denmark on reported ASD prevalence. DESIGN, SETTING, AND PARTICIPANTS We used a population-based birth cohort approach that includes information on all individuals with permanent residence in Denmark. We assessed all children born alive from January 1, 1980, through December 31, 1991, in Denmark (n=677915). The children were followed up from birth until ASD diagnosis, death, emigration, or the end of follow-up on December 31, 2011, whichever occurred first. The analysis uses a stratified Cox proportional hazards regression model with the changes in reporting practices modeled as time-dependent covariates. EXPOSURES The change in diagnostic criteria in 1994 and the inclusion of outpatient diagnoses in 1995. MAIN OUTCOMES AND MEASURES Autism spectrum disorders. RESULTS For Danish children born during the study period, 33% (95% CI, 0%-70%) of the increase in reported ASD prevalence could be explained by the change in diagnostic criteria alone; 42% (95% CI, 14%-69%), by the inclusion of outpatient contacts alone; and 60% (95% CI, 33%-87%), by the change in diagnostic criteria and the inclusion of outpatient contacts. CONCLUSIONS AND RELEVANCE Changes in reporting practices can account for most (60%) of the increase in the observed prevalence of ASDs in children born from 1980 through 1991 in Denmark. Hence, the study supports the argument that the apparent increase in ASDs in recent years is in large part attributable to changes in reporting practices.

Recurrence of Autism Spectrum Disorders in Full- and Half-Siblings and Trends Over Time: A Population-Based Cohort Study

IMPORTANCE To date, this is the first population-based study to examine the recurrence risk for autism spectrum disorders (ASDs), including time trends, and the first study to consider the ASDs recurrence risk for full- and half-siblings. OBJECTIVES To estimate the relative recurrence risk for ASDs in a Danish population, including recurrence in full- and half-siblings, and to examine time trends in ASDs relative to the recurrence risk. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study in Denmark. All children (about 1.5 million) born in Denmark between January 1, 1980, and December 31, 2004, were identified and followed up to December 31, 2010. We identified a maternal sibling subcohort derived from mothers with at least 2 children and a paternal sibling subcohort derived from fathers with at least 2 children. EXPOSURES Children having an older sibling with ASDs are compared with children not having an older sibling with ASDs. MAIN OUTCOMES AND MEASURES The adjusted hazard ratio for ASDs among children having an older sibling with ASDs compared with children not having an older sibling with ASDs. RESULTS The overall relative recurrence risk for ASDs was 6.9 (95% CI, 6.1-7.8), and it did not change significantly over time; similar risks were observed in maternal and paternal full-siblings. The relative recurrence risks were 2.4 (95% CI, 1.4-4.1) for maternal half-siblings and 1.5 (95% CI, 0.7-3.4) for paternal half-siblings. CONCLUSIONS AND RELEVANCE Our population-based recurrence risk estimate is lower than the recently reported estimates from clinical samples. Our results demonstrate no time trend in the ASDs recurrence risk as seen in the ASDs prevalence. The difference in the recurrence risk between full- and half-siblings supports the role of genetics in ASDs, while the significant recurrence risk in maternal half-siblings may support the role of factors associated with pregnancy and the maternal intrauterine environment in ASDs.

Is maternal smoking during pregnancy a risk factor for Hyperkinetic disorder?—findings from a sibling design

BACKGROUND Studies have consistently shown that pregnancy smoking is associated with twice the risk of hyperactivity/inattention problems in the offspring. An association of this magnitude may indicate behavioural difficulties as one of the most important health effects related to smoking during pregnancy. However, social and genetic confounders may fully or partially account for these findings. METHODS A cohort including all singletons born in Finland from 1 January 1987 through 31 December 2001 was followed until 1 January 2006 based on linkage of national registers. Data were available for 97% (N = 868,449) of the population. We followed singleton children of smoking and non-smoking mothers until they had an International Classification of Diseases, 10th revision, diagnosis of hyperkinetic disorder (HKD) or to the end of the observation period. We used sibling-matched Cox regression analyses to control for social and genetic confounding. RESULTS We found a much smaller association between exposure to maternal smoking during pregnancy and risk of HKD in children using the sibling-matched analysis [hazards ratio (HR) = 1.20, 95% confidence interval (CI) 0.97-1.49] than was observed in the entire cohort (HR 2.01, 95% CI 1.90-2.12). CONCLUSIONS Our findings suggest that the strong association found in previous studies may be due to time-stable familial factors, such as environmental and genetic factors. If smoking is a causal factor, the effect is small and less important than what the previous studies indicate.

Antidepressant exposure in pregnancy and risk of autism spectrum disorders

Background Both the use of antidepressant medication during pregnancy and the prevalence of autism spectrum disorder have increased during recent years. A causal link has recently been suggested, but the association may be confounded by the underlying indication for antidepressant use. We investigated the association between maternal use of antidepressant medication in pregnancy and autism, controlling for potential confounding factors. Methods We identified all children born alive in Denmark 1996–2006 (n=668,468) and their parents in the Danish Civil Registration System. We obtained information on the mother’s prescriptions filled during pregnancy from the Danish National Prescription Registry, and on diagnoses of autism spectrum disorders in the children and diagnoses of psychiatric disorders in the parents from the Danish Psychiatric Central Register. In a cohort analysis, we estimated hazard ratios of autism spectrum disorders in children exposed to antidepressant medication during pregnancy compared with children who were not exposed, using Cox proportional hazards regression analysis. Furthermore, we estimated the risk for autism spectrum disorder in a sibling design. Results Children exposed prenatally to antidepressants had an adjusted hazard ratio of 1.5 (95% confidence interval [CI] 1.2–1.9) for autism spectrum disorder compared with unexposed children. Restricting the analysis to children of women with a diagnosis of affective disorder, the adjusted hazard ratio was 1.2 (95% CI 0.7–2.1), and the risk was further reduced when exposed children were compared with their unexposed siblings (adjusted hazard ratio 1.1; 95% CI 0.5–2.3). Conclusion After controlling for important confounding factors, there was no significant association between prenatal exposure to antidepressant medication and autism spectrum disorders in the offspring.

Parental age and autism spectrum disorders.

PURPOSE We sought to study the possible association between parental age and autism spectrum disorder (ASD) by using both a cohort design and a sibling design. METHODS Our cohort included all singleton births in Denmark from January 1, 1980, through December 31, 2003, a total of 1,311,736 children. Cases of ASDs were obtained from the Danish National Psychiatric Register using International Classification of Diseases (ICD)-8 and ICD-10. RESULTS A total of 9556 children were diagnosed with an ASD. Both maternal and paternal age were associated with a greater risk of ASD in the offspring (hazard ratios ranging from 1.21 (1.10-1.34) to 1.65 (1.09-2.48) depending on combinations of parental age categories; <35, 35-39, and 40+ years). For mothers younger than 35 years, the risk of ASD increased with increasing fathers age group. For fathers younger than 35 years, the risk of ASD increased with increasing maternal age. CONCLUSIONS We found an association between parental age and ASD in the cohort study, but the combined underlying mechanisms through which paternal and maternal age impact ASD risk do not seem to act synergistically. The results of the sibling analysis suggest that the association between parental age and ASD found in the cohort study cannot be accounted for by common genetic and environmental factors.

Autism Prevalence Trends Over Time in Denmark Changes in Prevalence and Age at Diagnosis

OBJECTIVE To examine the effect of changing age at diagnosis on the diagnosed prevalence of autism among different birth cohorts. DESIGN Population-based cohort study. SETTING Children were identified in the Danish Medical Birth Registry and psychiatric outcomes were obtained via linkage with the Danish National Psychiatric Register. PARTICIPANTS All children born in Denmark from January 1, 1994, through December 31, 1999 (N = 407 458). MAIN OUTCOME MEASURES The age-specific prevalence, hazard ratio, and relative risk by age. RESULTS Statistically significant shifts in age at diagnosis were observed for autism spectrum disorder; children diagnosed before age 9 years in the cohorts born between January 1, 1994, and December 31, 1995, between January 1, 1996, and December 31, 1997, and between January 1, 1998, and December 31, 1999, were on average diagnosed at ages 5.9 (95% confidence interval [CI], 5.8-6.0), 5.8 (95% CI, 5.7-5.9), and 5.3 (95% CI, 5.2-5.4) years, respectively. The relative risk comparing the 1996-1997 birth cohort with the 1994-1995 birth cohort at age 3 years was 1.20 (95% CI, 0.86-1.67), which decreased to 1.10 (95% CI, 1.00-1.20) at age 11 years. Similarly, the relative risk comparing the 1998-1999 birth cohort with the 1994-1995 birth cohort at age 3 years was 1.69 (95% CI, 1.24-2.31), which decreased to 1.23 (95% CI, 1.11-1.37) at age 11 years. Similar results were observed for childhood autism. CONCLUSIONS Shifts in age at diagnosis inflated the observed prevalence of autism in young children in the more recent cohorts compared with the oldest cohort. This study supports the argument that the apparent increase in autism in recent years is at least in part attributable to decreases in the age at diagnosis over time.

Association of Hospitalization for Infection in Childhood With Diagnosis of Autism Spectrum Disorders: A Danish Cohort Study

OBJECTIVE To investigate the association between hospitalization for infection in the perinatal/neonatal period or childhood and the diagnosis of autism spectrum disorders (ASDs). DESIGN A population-based cohort study. SETTING Denmark. PARTICIPANTS All children born in Denmark from January 1, 1980, through December 31, 2002, comprising a total of 1 418 152 children. EXPOSURE Infection requiring hospitalization. MAIN OUTCOME MEASURE The adjusted hazard ratio (HR) for ASDs among children hospitalized for infection compared with other children. RESULTS A total of 7379 children were diagnosed as having ASDs. Children admitted to the hospital for any infectious disease displayed an increased rate of ASD diagnoses (HR, 1.38 [95% confidence interval, 1.31-1.45]). This association was found to be similar for infectious diseases of bacterial and viral origin. Furthermore, children admitted to the hospital for noninfectious disease also displayed an increased rate of ASD diagnoses (HR, 1.76 [95% confidence interval, 1.68-1.86]), and admissions for infection increased the rate of mental retardation (2.18 [2.06-2.31]). CONCLUSIONS The association between hospitalization for infection and ASDs observed in this study does not suggest causality because a general association is observed across different infection groups. Also, the association is not specific for infection or for ASDs. We discuss a number of noncausal explanatory models.

Neonatal outcome and congenital malformations in children born after ICSI with testicular or epididymal sperm: a controlled national cohort study

STUDY QUESTION Does neonatal outcome including congenital malformations in children born after ICSI with epididymal and testicular sperm [testicular sperm extraction (TESE)/percutaneous epididymal sperm aspiration (PESA)/testicular sperm aspiration (TESA) (TPT)] differ from neonatal outcome in children born after ICSI with ejaculated sperm, IVF and natural conception (NC)? SUMMARY ANSWER Children born after TPT have similar neonatal outcome, including total malformation rates, as have children born after ICSI and IVF with ejaculated sperm. Testing for variance over the four groups may indicate smaller differences in specific malformation rates with TPT as the highest risk group. WHAT IS KNOWN ALREADY Regarding neonatal outcome as well as congenital malformations in children born after TPT, studies are few, with limited sample size, heterogeneous and often performed without relevant control groups. STUDY DESIGN, SIZE, DURATION Population-based cohort study including all Danish children born after TPT and fresh embryo transfer in Denmark from 1995 to 2009. Children born after transfer of frozen-thawed embryos were excluded. Control groups of children conceived by ICSI with ejaculated sperm, IVF and NC were identified by cross-linkage of the Danish IVF Register, Medical Birth Register (MBR) and National Hospital Discharge Register (HDR). PARTICIPANTS/MATERIALS, SETTING The study group consisted of 466 children born after TPT, while the control groups consisted of 8967 (ICSI with ejaculated sperm), 17 592 (IVF) and 63 854 (NC) children. Neonatal outcomes and congenital malformations were analysed for singletons and twins separately. Risk estimates for low birthweight (LBW, <2500 g) and preterm birth (PTB, <37 gestational weeks) were adjusted for maternal age, parity, child gender and year of childbirth. The study group was identified from the Danish national database on children born after TPT. Control groups were obtained from the IVF register and the MBR. All information included in the study was retrieved from the national registers. MAIN RESULTS AND THE ROLE OF CHANCE Considering singletons and twins as one group, the sex ratio (♂/♀) was significantly lower for children born after TPT (0.89) compared with conventional IVF (1.11; P = 0.017) but did not differ significantly when compared with ICSI with ejaculated sperm (0.94) and NC (1.05). The mean birthweight (BW) for singletons did not differ significantly between groups when including only first-born children. The mean gestational age (GA) in the TPT singletons (279 ± 12 days) was significantly higher compared with IVF (276 ± 18 days; P = 0.02), but similar to ICSI with ejaculated sperm and NC singletons when including only first-born children (277 ± 16 days and 279 ± 14 days, respectively). Rate of stillbirths, perinatal and neonatal mortality in the group of TPT singletons did not differ significantly from any of the control groups. Comparable results were found for the TPT twin group, except for perinatal mortality, which was significantly lower in the TPT group compared with naturally conceived twins. The adjusted risk of LBW was significantly higher for TPT versus NC singletons [adjusted odds ratio (AOR) = 0.67 (0.48-0.93)]; however AOR for PTB was similar in the two groups. Regarding twins, similar adjusted risks were observed for PTB and LBW between the TPT and all three control groups. Significantly more Caesarean sections were performed after IVF (27.3% for singletons) and ICSI (25.1% for singletons) with ejaculated sperm compared with the TPT group (16.4% for singletons). The total rate of congenital malformations in the TPT group was 7.7% and did not differ significantly from any of the control groups. However, singleton TPT boys showed an increased rate of cardiac malformations (3.6%) compared with singleton boys after IVF (1.4%; P = 0.04) and NC (1.1%; P = 0.02). Considering the level of male infertility as a continuum over the four groups, tests for variance in the rate of cardiac malformations in singleton boys, and undescended testicles for singleton as well as twin boys were each significantly increased from NC to IVF to ICSI to TPT (P < 0.001). The rate of hypospadias showed the same pattern, but the TPT group did not differ significantly compared with the control groups. LIMITATIONS, REASONS FOR CAUTION One of the limitations is that the TPT group could not be classified according to testicular or epididymal sperm, as these data were not available in the IVF register. Another limitation is that registry-based studies are encumbered with the risk of reporting or coding errors or missing data due to insufficient coding. However, the quality of data on congenital malformations in HDR has, in other studies, been validated and found acceptable for epidemiological research, and furthermore, recordings on study and control groups are performed similarly. WIDER IMPLICATIONS OF THE FINDINGS Accumulating data show that TPT treatment is equally safe as conventional ICSI and IVF treatment and as NC with regard to neonatal outcome including congenital malformation. STUDY FUNDING/POTENTIAL COMPETING INTERESTS This study is supported by Laboratory of Reproductive Biology, Scientific Unit, Horsens Hospital. No competing interests declared.