Can Sibling Sex Ratios Be Used as a Valid Test for the Prenatal Androgen Hypothesis of Autism Spectrum Disorders?

Sibling sex ratios have been applied as an indirect test of a hypothesized association between prenatal testosterone levels and risk for autism, a developmental disorder disproportionately affecting males. Differences in sibling sex ratios between those with and without autism would provide evidence of a shared risk factor for autism and offspring sex. Conclusions related to prenatal testosterone, however, require additional assumptions. Here, we used directed acyclic graphs (DAGs) to clarify the elements required for a valid test of the hypothesis that sibling sex ratios differ between children with and without autism. We then conducted such a test using a large, population-based sample of children

Cohort effects explain the increase in autism diagnosis among children born from 1992 to 2003 in California

The incidence and prevalence of autism have dramatically increased over the last 20 years. Decomposition of autism incidence rates into age, period and cohort effects disentangle underlying domains of causal factors linked to time trends. We estimate an age-period-cohort effect model for autism diagnostic incidence overall and by level of functioning

Prenatal Vitamin D Levels in Maternal Sera and Offspring Specific Learning Disorders

Recent evidence has suggested potential harmful effects of vitamin D deficiency during pregnancy on offspring brain development, for example, elevated risks for neuropsychiatric disorders. Findings on general cognition and academic achievement are mixed, and no studies have examined the effect of prenatal 25-hydroxyvitamin D (25(OH)D) levels on diagnosed specific learning disorders, which was the aim of this study. We examined a nested case–control sample from the source cohort of all singleton-born children in Finland between 1996 and 1997 (n = 115,730). A total of 1607 cases with specific learning disorders (mean age at diagnosis: 9.9 years) and 1607 matched controls were identified from Finnish nationwide registers. Maternal 25(OH)D levels were analyzed from serum samples collected during the first trimester of pregnancy and stored in a national biobank. Conditional logistic regression was used to test the association between maternal 25(OH)D and offspring specific learning disorders. There were no significant associations between maternal 25(OH)D levels and specific learning disorders when vitamin D was examined as a log-transformed continuous variable (adjusted OR 0.98, 95% CI 0.82–1.18, p = 0.84) or as a categorical variable (25(OH)D 50 nmol/L), nor when it was divided into quintiles (adjusted OR for the lowest quintile 1.00, 95% CI 0.78–1.28, p = 0.99 compared to the highest quintile). This study found no association between low maternal 25(OH)D in early pregnancy and offspring specific learning disorders

Prenatal Vitamin D Levels in Maternal Sera and Offspring Specific Learning Disorders

Recent evidence has suggested potential harmful effects of vitamin D deficiency during pregnancy on offspring brain development, for example, elevated risks for neuropsychiatric disorders. Findings on general cognition and academic achievement are mixed, and no studies have examined the effect of prenatal 25-hydroxyvitamin D (25(OH)D) levels on diagnosed specific learning disorders, which was the aim of this study. We examined a nested case–control sample from the source cohort of all singleton-born children in Finland between 1996 and 1997 (n = 115,730). A total of 1607 cases with specific learning disorders (mean age at diagnosis: 9.9 years) and 1607 matched controls were identified from Finnish nationwide registers. Maternal 25(OH)D levels were analyzed from serum samples collected during the first trimester of pregnancy and stored in a national biobank. Conditional logistic regression was used to test the association between maternal 25(OH)D and offspring specific learning disorders. There were no significant associations between maternal 25(OH)D levels and specific learning disorders when vitamin D was examined as a log-transformed continuous variable (adjusted OR 0.98, 95% CI 0.82–1.18, p = 0.84) or as a categorical variable (25(OH)D 50 nmol/L), nor when it was divided into quintiles (adjusted OR for the lowest quintile 1.00, 95% CI 0.78–1.28, p = 0.99 compared to the highest quintile). This study found no association between low maternal 25(OH)D in early pregnancy and offspring specific learning disorders

Attention-deficit/hyperactivity disorder and risk for psychiatric and neurodevelopmental disorders in siblings

Background: Probands with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for several psychiatric and neurodevelopmental disorders. The risk of these disorders among the siblings of probands has not been thoroughly assessed in a population-based cohort.Methods: Every child born in Finland in 1991–2005 and diagnosed with ADHD in 1995–2011 were identified from national registers. Each case was matched with four controls on sex, place, and date of birth. The full siblings of the cases and controls were born in 1981–2007 and diagnosed in 1981–2013. In total, 7369 cases with 12 565 siblings and 23 181 controls with 42 753 siblings were included in the analyses conducted using generalized estimating equations.Results: 44.2% of the cases and 22.2% of the controls had at least one sibling diagnosed with any psychiatric or neurodevelopmental disorder (risk ratio, RR = 2.1; 95% CI 2.0–2.2). The strongest associations were demonstrated for childhood-onset disorders including ADHD (RR = 5.7; 95% CI 5.1–6.3), conduct and oppositional disorders (RR = 4.0; 95% CI 3.5–4.5), autism spectrum disorders (RR = 3.9; 95% CI 3.3–4.6), other emotional and social interaction disorders (RR = 2.7; 95% CI 2.4–3.1), learning and coordination disorders (RR = 2.6; 95% CI 2.4–2.8), and intellectual disability (RR = 2.4; 95% CI 2.0–2.8). Also, bipolar disorder, unipolar mood disorders, schizophrenia spectrum disorders, other neurotic and personality disorders, substance abuse disorders, and anxiety disorders occurred at increased frequency among the siblings of cases.Conclusions: The results offer potential utility for early identification of neurodevelopmental and psychiatric disorders in at-risk siblings of ADHD probands and also argue for more studies on common etiologies.</p

Prenatal Cotinine Levels and ADHD Among Offspring

OBJECTIVES: An association between maternal smoking during pregnancy and offspring attention-deficit/hyperactivity disorder (ADHD) has been shown across several studies based on self-reports. No previous studies have investigated the association of nicotine exposure measured by cotinine levels during pregnancy and offspring ADHD. METHODS: In this population-based study, 1079 patients born between 1998 and 1999 and diagnosed with ADHD according to the International Classification of Diseases and 1079 matched controls were identified from Finnish nationwide registers. Maternal cotinine levels were measured by using quantitative immunoassays from maternal serum specimens collected during the first and second trimesters of pregnancy and archived in the national biobank. RESULTS: There was a significant association between increasing log-transformed maternal cotinine levels and offspring ADHD. The odds ratio was 1.09 (95% confidence interval [CI] 1.06-1.12) when adjusting for maternal socioeconomic status, maternal age, maternal psychopathology, paternal age, paternal psychopathology, and child's birth weight for gestational age. In the categorical analyses with cotinine levels in 3 groups, heavy nicotine exposure (cotinine level >50 ng/mL) was associated with offspring ADHD, with an odds ratio of 2.21 (95% CI 1.63-2.99) in the adjusted analyses. Analyses by deciles of cotinine levels revealed that the adjusted odds for offspring ADHD in the highest decile was 3.34 (95% CI 2.02-5.52). CONCLUSIONS: The study reveals an association with and a dose-response relationship between nicotine exposure during pregnancy and offspring ADHD. Future studies incorporating maternal smoking and environmental, genetic, and epigenetic factors are warranted.Peer reviewe

Maternal Vitamin D Levels and the Risk of Offspring Attention-Deficit/Hyperactivity Disorder

Objective: Recent evidence has highlighted the importance of vitamin D in the development of the central nervous system. Some studies have shown an association between maternal vitamin D deficiency during pregnancy and offspring attention-deficit/hyperactivity disorder (ADHD) symptoms based on parent or teacher ratings. There are no previous studies on early pregnancy 25-hydroxyvitamin D [25(OH)D] levels and the risk of diagnosed offspring ADHD. Our aim was to examine maternal 25(OH)D levels in early pregnancy and offspring ADHD. Method: In this nationwide population-based case-control study, 1,067 ADHD cases (born between 1998 and 1999 and diagnosed according to the International Classification of Diseases) and 1,067 matched controls were identified from Finnish registers. Maternal 25(OH)D levels were measured using quantitative immunoassay from maternal sera, collected during the first trimester and archived in the national biobank. Conditional logistic regression was used to examine the association between maternal 25(OH)D and offspring ADHD. Results: There was a significant association between decreasing log-transformed maternal 25(OH)D levels and offspring ADHD both in the unadjusted analyses (odds ratio 1.65; 95% CI 1.33-2.05; p <.001) and in the analyses adjusting for maternal socioeconomic status and age (odds ratio 1.45; 95% CI 1.15-1.81; p = .002). Analyses by quintiles of maternal 25(OH)D levels in the lowest versus highest quintile revealed an adjusted odds ratio for offspring ADHD of 1.53 (95% CI 1.11-2.12; p = .010). Conclusion: This study demonstrated an association between low maternal 25(OH)D during pregnancy and an elevated risk for offspring ADHD. If replicated in independent samples, this finding may have significant public health implications.Peer reviewe

Increased Risk of ADHD at Short and Long Interpregnancy Intervals in a National Birth Cohort

BackgroundShort or long interpregnancy interval (IPI) may adversely impact conditions for foetal development. Whether attention deficit hyperactivity disorder (ADHD) is related to IPI has been largely unexplored.ObjectivesTo examine the association between IPI and ADHD in a large, population‐based Finnish study.MethodsAll children born in Finland between 1991 and 2005 and diagnosed with ADHD (ICD‐9 314x or ICD‐10 F90.x) from 1995 to 2011 were identified using data from linked national registers. Each subject with ADHD was matched to 4 controls based on sex, date of birth, and place of birth. A total of 9564 subjects with ADHD and 34,479 matched controls were included in analyses. IPI was calculated as the time interval between sibling birth dates minus the gestational age of the second sibling. The association between IPI and ADHD was determined using conditional logistic regression and adjusted for potential confounders.ResultsRelative to births with an IPI of 24 to 59 months, those with the shortest IPI (ConclusionsThe risk of ADHD is higher among children born following short or long IPIs although further studies are needed to explain this association.</p

Proband and Familial Autoimmune Diseases Are Associated With Proband Diagnosis of Autism Spectrum Disorders

Objective: There is evidence that parental autoimmune diseases (ADs) are associated with autism spectrum disorders (ASD) in offspring. The association between offspring ASD and ADs diagnosed in siblings and probands remains less clear. We examined whether proband and familial diagnoses of ADs were associated with increased odds of ASD in probands.Method: The study is based on a nested case-control design that used data from a large national birth cohort (N = 1.2 million) in Finland. There were 4,600 cases of ASD and controls matched 1:4 on date of birth, sex, and residence. Data were accessed from national medical, birth, and central registries.Results: Probands had a statistically significant increase in odds of ASD when they (adjusted odds ratio [OR] = 1.2), their mother (adjusted OR = 1.1), or their sibling (adjusted OR = 1.2) were diagnosed with an AD. With regard to specific ADs, we found a statistically significant increase in odds of ASD in probands diagnosed with autoimmune thyroiditis (adjusted OR = 2.7). Further analyses considering ADs by body system yielded a statistically significant increase in odds of ASD in probands with ADs associated with the central/peripheral nervous (adjusted OR = 4.8) and skin/mucous membrane (adjusted OR = 1.3) systems. Probands of mothers diagnosed with ear/eye (adjusted OR = 1.6) or respiratory (adjusted OR = 1.4) ADs, or siblings diagnosed with skin/mucous membrane ADs (adjusted OR = 1.3) also had increased odds of ASD.Conclusion: The findings suggest that there may be common pathogenic, developmental mechanisms related to autoimmunity that are associated with the etiology of ASD.</p

The risk of childhood autism among second-generation migrants in Finland: a case–control study

Background: Studying second-generation immigrants can help in identifying genetic or environmental risk factors for childhood autism. Most previous studies have focused on maternal region of birth and showed inconsistent results. No previous study has been conducted in Finland. Methods: The study was a nested case–control study based on a national birth cohort. Children born in 1987–2005 and diagnosed with childhood autism by the year 2007 were identified from the Finnish Hospital Discharge Register. Controls were selected from the Finnish Medical Birth Register. Information on maternal and paternal country of birth and mother tongue was collected from the Finnish Central Population Register. There were 1132 cases and 4515 matched controls. The statistical test used was conditional logistic regression analysis. Results: Compared with children with two Finnish parents, the risk of childhood autism was increased for those whose parents are both immigrants (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI] 1.2–2.7) and for those with only an immigrant mother (aOR 1.8, 95% CI 1.2–2.7), but not for those with only an immigrant father. The risk was increased for those with a mother born in the former Soviet Union or Yugoslavia and for those with a mother or a father born in Asia. Specific parental countries of birth associated with an increased risk were the former Soviet Union, the former Yugoslavia and Vietnam. Conclusions: In Finland, children who are born to immigrant mothers with or without an immigrant partner, have an increased risk of childhood autism. The risk varies with immigrant parents’ region of birth. The findings may help in identifying possible risk factors, which can be examined in future studies