Prenatal and Newborn Immunoglobulin Levels from Mother-Child Pairs and Risk of Autism Spectrum Disorders.

BACKGROUND: An etiological role for immune factors operating during early brain development in children with autism spectrum disorders (ASD) has not yet been established. A major obstacle has been the lack of early biologic specimens that can be linked to later diagnosis. In a prior study, we found lower risk of ASD associated with higher levels of maternally-derived total IgG and Toxoplasmosis gondii (Toxo) IgG in newborn blood spot specimens from children later diagnosed with ASD compared to population controls. METHODS: We obtained maternal mid-gestational serum specimens and newborn screening blood spots from the California Genetics Disease Screening Program (GDSP) for linked mother-baby pairs for 84 children with ASD and 49 children with developmental delay but not ASD (DD) identified from California Department of Developmental Services records and for 159 population controls sampled from birth certificates.Immunoglobulin levels in maternal and newborn specimens were measured by solid phase immunoassays and analyzed in logistic regression models for total IgG, total IgM, and Toxo IgG, and, for maternal specimens only, Toxo IgM. Correlations between maternal and newborn ranked values were evaluated. RESULTS: In both maternal and newborn specimens, we found significantly lower risk of ASD associated with higher levels of Toxo IgG. In addition, point estimates for all comparisons were < 1.0 suggesting an overall pattern of lower immunoglobulin levels associated with higher ASD risk but most did not reach statistical significance. We did not find differences in maternal or newborn specimens comparing children with DD to controls. DISCUSSION: These results are consistent with evidence from our prior study and other published reports indicating that immune factors during early neurodevelopment may be etiologically relevant to ASD. Lowered immunoglobulin levels may represent suboptimal function of the maternal immune system or reduced maternal exposure to common infectious agents. CONCLUSION: Patterns seen in these selected immunoglobulins may provide clues to mechanisms of early abnormalities in neurodevelopment contributing to ASD. We recommend further study of immunoglobulin profiles in larger samples of linked mother-baby pairs to evaluate possible etiologic relevance.

Maternal Infection During Pregnancy and Autism Spectrum Disorders.

We conducted a nested case-control study including 407 cases and 2,075 frequency matched controls to investigate the association between maternal infections during pregnancy and risk of autism spectrum disorders (ASD). Cases, controls, and maternal infections were ascertained from Kaiser Permanente Northern California clinical databases. No overall association between diagnoses of any maternal infection during pregnancy and ASD was observed [adjusted odds ratio (ORadj) = 1.15, 95 % confidence interval (CI) 0.92-1.43]. However, women with infections diagnosed during a hospital admission (ORadj = 1.48, 95 % CI 1.07-2.04), particularly bacterial infections (ORadj = 1.58, 95 % CI 1.06-2.37), were at increased risk of delivering a child with ASD. Multiple infections during pregnancy were associated with ASD (ORadj = 1.36, 95 % CI 1.05-1.78).

Prenatal and neonatal peripheral blood mercury levels and autism spectrum disorders.

BACKGROUND: Prenatal and early-life exposures to mercury have been hypothesized to be associated with increased risk of autism spectrum disorders (ASDs). OBJECTIVES: This study investigated the association between ASDs and levels of total mercury measured in maternal serum from mid-pregnancy and infant blood shortly after birth. METHODS: The study sample was drawn from the Early Markers for Autism (EMA) Study. Three groups of children who were born in Orange County, CA in 2000-2001 were identified: children with ASD (n=84), children with intellectual disability or developmental delay (DD) (n=49), and general population controls (GP) (n=159). Maternal serum specimens and newborn bloodspots were retrieved from the California Department of Public Health prenatal and newborn screening specimen archives. Blood mercury levels were measured in maternal serum samples using mass spectrometer and in infant bloodspots with a 213 nm laser. RESULTS: Maternal serum and infant blood mercury levels were significantly correlated among all study groups (all correlations >0.38, p<0.01). Adjusted logistic regression models showed no significant associations between ASD and log transformed mercury levels in maternal serum samples (ASD vs. GP: OR [95% CI]=0.96 [0.49-1.90]; ASD vs. DD: OR [95% CI]=2.56 [0.89-7.39]). Results for mercury levels in newborn blood samples were similar (ASD vs. GP: OR [95% CI]=1.18 [0.71-1.95]; ASD vs. DD: OR [95% CI]=1.96 [0.75-5.14]). CONCLUSIONS: Results indicate that levels of total mercury in serum collected from mothers during mid-pregnancy and from newborn bloodspots were not significantly associated with risk of ASD, though additional studies with greater sample size and covariate measurement are needed.

Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions.

OBJECTIVE: This study was designed to examine the pattern of familial recurrence of autism spectrum disorder (ASD) in terms of genetic and environmental contributions related to timing of birth. METHOD: The authors linked California Department of Developmental Services records with state birth certificates to identify all siblings and half siblings of individuals affected with ASD born between 1990 and 2003. A total of 6,616 full siblings, 644 maternal half siblings, and 299 paternal half siblings born after ASD index cases were used to calculate recurrence risks. Control families, identified through matching to cases, were included for comparison (a total of 29,384 siblings). RESULTS: The overall sibling recurrence risk was 10.1%, compared with a prevalence of 0.52% in siblings of controls. The recurrence risk in second-born children was higher (11.5%) than in later-born siblings (7.3%); a similar pattern was observed for maternal half siblings (6.5% for second-born compared with 3.0% for later-born siblings; 4.8% overall). The recurrence risk was significantly higher for siblings who immediately followed the index case in birth order compared with those later in birth order. The recurrence risk for paternal half siblings (2.3%) was half the overall recurrence risk for maternal half siblings but was similar to that for later-born maternal half siblings. An exponential effect of short interbirth interval was observed, with the recurrence risk reaching 14.4% for an interbirth interval of 18 months or less, compared with 6.8% for an interval of 4 years or more. An identical phenomenon was observed in maternal half siblings. CONCLUSIONS: The results support genetic susceptibility in the familial recurrence of ASD along with factors related to timing of birth.

Neonatal cytokines and chemokines and risk of Autism Spectrum Disorder: the Early Markers for Autism (EMA) study: a case-control study.

BACKGROUND: Biologic markers of infection and inflammation have been associated with Autism Spectrum Disorders (ASD) but prior studies have largely relied on specimens taken after clinical diagnosis. Research on potential biologic markers early in neurodevelopment is required to evaluate possible causal pathways and screening profiles. OBJECTIVE: To investigate levels of cytokines and chemokines in newborn blood specimens as possible early biologic markers for autism. METHODS: We conducted a population-based case-control study nested within the cohort of infants born from July 2000 to September 2001 to women who participated in the prenatal screening program in Orange County, California, USA. The study population included children ascertained from the California Department of Developmental Services with Autism Spectrum Disorder (ASD, n = 84), or developmental delay but not ASD (DD, n = 49), and general population controls randomly sampled from the birth certificate files and frequency matched to ASD cases on sex, birth month and birth year (GP, n = 159). Cytokine and chemokine concentrations were measured in archived neonatal blood specimens collected for routine newborn screening. RESULTS: Cytokines were not detected in the vast majority of newborn samples regardless of case or control status. However, the chemokine monocyte chemotactic protein-1 (MCP-1) was elevated and the chemokine Regulated upon Activation Normal T-Cell Expressed and Secreted (RANTES) was decreased in ASD cases compared to GP controls. The chemokines macrophage inflammatory protein-1alpha (MIP-1α) and RANTES were decreased in children with DD compared to GP controls. CONCLUSION: Measurement of immune system function in the first few days of life may aid in the early identification of abnormal neurodevelopment and shed light on the biologic mechanisms underlying normal neurodevelopment.

Evidence of reproductive stoppage in families with autism spectrum disorder: a large, population-based cohort study.

IMPORTANCE: Few studies have examined the curtailment of reproduction (ie, stoppage) after the diagnosis of a child with autism spectrum disorder (ASD). OBJECTIVE: To examine stoppage in a large, population-based cohort of families in which a child has received a diagnosis of ASD. DESIGN, SETTING, AND PARTICIPANTS: Individuals with ASD born from January 1, 1990, through December 31, 2003, were identified in the California Department of Developmental Services records, which were then linked to state birth certificates to identify full sibs and half-sibs and to obtain information on birth order and demographics. A total of 19,710 case families in which the first birth occurred within the study period was identified. These families included 39,361 individuals (sibs and half-sibs). Control individuals were randomly sampled from birth certificates and matched 2:1 to cases by sex, birth year, and maternal age, self-reported race/ethnicity, and county of birth after removal of children receiving services from the California Department of Developmental Services. Using similar linkage methods as for case families, 36,215 pure control families (including 75,724 total individuals) were identified that had no individuals with an ASD diagnosis. EXPOSURES: History of affected children. MAIN OUTCOMES AND MEASURES: Stoppage was investigated by comparing the reproductive behaviors of parents after the birth of a child with ASD vs an unaffected child using a survival analysis framework for time to next birth and adjusting for demographic variables. RESULTS: For the first few years after the birth of a child with ASD, the parents' reproductive behavior was similar to that of control parents. However, birth rates differed in subsequent years; overall, families whose first child had ASD had a second child at a rate of 0.668 (95% CI, 0.635-0.701) that of control families, adjusted for birth year, birth weight, maternal age, and self-reported maternal race/ethnicity. Results were similar when a later-born child was the first affected child in the family. Reproductive curtailment was slightly stronger among women who changed partners (relative rate for second-born children, 0.553 [95% CI, 0.498-0.614]). CONCLUSIONS AND RELEVANCE: These results provide the first quantitative assessment and convincing statistical evidence of reproductive stoppage related to ASD. These findings have implications for recurrence risk estimation and genetic counseling.

Prenatal and perinatal risk factors in a twin study of autism spectrum disorders.

INTRODUCTION: Multiple studies associate prenatal and perinatal complications with increased risks for autism spectrum disorders (ASDs). The objectives of this study were to utilize a twin study design to 1) Investigate whether shared gestational and perinatal factors increase concordance for ASDs in twins, 2) Determine whether individual neonatal factors are associated with the presence of ASDs in twins, and 3) Explore whether associated factors may influence males and females differently. METHODS: Data from medical records and parent response questionnaires from 194 twin pairs, in which at least one twin had an ASD, were analyzed. RESULTS: Shared factors including parental age, prenatal use of medications, uterine bleeding, and prematurity did not increase concordance risks for ASDs in twins. Among the individual factors, respiratory distress demonstrated the strongest association with increased risk for ASDs in the group as a whole (OR 2.11, 95% CI 1.27-3.51). Furthermore, respiratory distress (OR 2.29, 95% CI 1.12-4.67) and other markers of hypoxia (OR 1.99, 95% CI 1.04-3.80) were associated with increased risks for ASDs in males, while jaundice was associated with an increased risk for ASDs in females (OR 2.94, 95% CI 1.28-6.74). CONCLUSIONS: Perinatal factors associated with respiratory distress and other markers of hypoxia appear to increase risk for autism in a subgroup of twins. Future studies examining potential gender differences and additional prenatal, perinatal and postnatal environmental factors are required for elucidating the etiology of ASDs and suggesting new methods for treatment and prevention.

Autism and developmental screening in a public, primary care setting primarily serving Hispanics: challenges and results.

We implemented screening of children 16-30 months of age (n = 1,760) from a typically under-served, primarily Hispanic, population, at routine pediatric appointments using the modified checklist for autism in toddlers (M-CHAT) and Ages and Stages Questionnaire. Screen positive rates of 26 and 39%, respectively, were higher than previous reports. Hispanics were more likely to score M-CHAT positive than non-Hispanics (adjusted OR 1.7, 95% CI 1.2-2.4), as were those screened in Spanish. About 30% of screen-positive children were referred for further assessment, but only half were seen. Thus screening in this population is feasible, but may require additional resources. Attention to the cultural applicability of screening instruments, as well as to explaining the results or need for additional services to parents, is critical to serve the growing Hispanic population.

Adaptation of the "ten questions" to screen for autism and other neurodevelopmental disorders in Uganda.

Neurodevelopmental disorders are recognized to be relatively common in developing countries but little data exist for planning effective prevention and intervention strategies. In particular, data on autism spectrum disorders are lacking. For application in Uganda, we developed a 23-question screener (23Q) that includes the Ten Questions screener and additional questions on autism spectrum disorder behaviors. We then conducted household screening of 1169 children, 2-9 years of age, followed by clinical assessment of children who screened positive and a sample of those who screened negative to evaluate the validity of the screener. We found that 320 children (27% of the total) screened positive and 68 children received a clinical diagnosis of one or more moderate to severe neurodevelopmental disorders (autism spectrum disorder; cerebral palsy; epilepsy; cognitive, speech and language, hearing, or vision impairment), including 8 children with autism spectrum disorders. Prevalence and validity of the screener were evaluated under different statistical assumptions. Sensitivity of the 23Q ranged from 0.55 to 0.80 and prevalence for ≥1 neurodevelopmental disorders from 7.7/100 children to 12.8/100 children depending on which assumptions were used. The combination of screening positive on both autism spectrum disorders and Ten Questions items was modestly successful in identifying a subgroup of children at especially high risk of autism spectrum disorders. We recommend that autism spectrum disorders and related behavioral disorders be included in studies of neurodevelopmental disorders in low-resource settings to obtain essential data for planning local and global public health responses.

Use of birth certificates to examine maternal occupational exposures and autism spectrum disorders in offspring.

The continuing rise in the prevalence of autism spectrum disorders has led to heightened interest in the role of nongenetic factors, including exogenous exposures, but little research has been conducted. To explore a possible role in autism etiology, we used data available from our prior studies to examine potential occupational exposures, as these may occur at higher levels than environmental exposures. Parental occupation was obtained from birth certificates for 284 children with autism and 659 controls, born in 1994 in the San Francisco Bay Area. Self-reported occupation and industry were coded into eight exposure/chemical groups based on potential neurotoxicity or reprotoxicity by a board-certified physician in occupational medicine and an industrial hygienist blinded to case-control status. Mothers of autistic children were twice as likely to work in occupations considered exposed (14.4%) as mothers of controls (7.2%) (adjusted odds ratio [AOR] 2.3 [95% confidence interval {CI} 1.3-4.2]). The exposure categories of the greatest frequency among case mothers were exhaust and combustion products (AOR = 12.0 [95% CI 1.4-104.6]) and disinfectants (AOR = 4.0 [95% CI 1.4-12.0]). Paternal occupational exposure was not associated with autism, potentially consistent with a direct in-utero exposure effect. There are several limitations of this hypothesis-generating study, including lack of detail on workplace and job duties, leading to possible misclassification and low proportion exposed. However, this misclassification would not be biased by case-control status and is unlikely to explain the associations we did find, suggesting that further research on exogenous exposures may yield useful etiologic clues.

Head circumferences in twins with and without Autism Spectrum Disorders.

To determine the genetic relationship between head circumference (HC) and Autism Spectrum Disorders (ASDs). Twin pairs with at least one twin with an ASD were assessed. HCs in affected and unaffected individuals were compared, as were HC correlations in monozygotic and dizygotic pairs. 404 subjects, ages 4-18, were included. 20 % of males and 27 % of females with an ASD had macrocephaly. Unaffected co-twins showed similar rates (16 % of males and 22 % of females). Statistical analysis revealed no significant difference in HCs between affected and unaffected twins. Twins with ASDs and unaffected co-twins have similar HCs and increased rates of macrocephaly. Correlations demonstrated partial inheritance of HCs. Thus, macrocephaly may represent an endophenotype in ASDs.

Is infertility associated with childhood autism?

Concerns persist about a possible link between infertility and risk of autism spectrum disorders (ASD). Interpretation of existing studies is limited by racial/ethnic homogeneity of study populations and other factors. Using a case-control design, we evaluated infertility history and treatment documented in medical records of members of Kaiser Permanente Northern California. Among singletons (349 cases, 1,847 controls), we found no evidence to support an increase in risk of ASD associated with infertility. Among multiple births (21 cases, 54 controls), we found an increased risk associated with infertility history and with infertility evaluations and treatment around the time of index pregnancy conception; however, small sample size and lack of detailed data on treatments preclude firm interpretation of results for multiple births.

Are thyroid hormone concentrations at birth associated with subsequent autism diagnosis?

Thyroid hormones substantially influence central nervous system development during gestation. We hypothesized that perturbations of early thyroid profiles may contribute to the development of autism spectrum disorders (ASD). Thyroid pathways could provide a mechanism by which environmental factors that affect the thyroid system may impact autism occurrence or phenotypic expression. We investigated whether thyroxine (T4) levels at birth are associated with subsequent ASD, using two existing California study groups in multivariate analysis. One study group included children born in the San Francisco Bay Area in 1994, with cases identified through the California Department of Developmental Services (DDS) and/or the Kaiser Permanente Medical Care Program of Northern California (244 cases, 266 controls); the other included children born in California in 1995, with cases identified through DDS (310 cases, 518 controls). Matched controls were selected from birth certificate records. This exploratory analysis suggested that infants with very low T4 (<3rd percentile) may have higher ASD risk, although results reached statistical significance only for the 1995 study group (1995: OR = 2.74 (95% CI 1.30-5.75; 1994: OR = 1.71 (95% CI 0.57-5.19). A variety of alternate analyses were conducted with available data, without further resolution of the difference between the two study groups. The results of our study indicate that further studies are warranted to investigate whether thyroid hormone perturbations play a role in the development of ASD by evaluating additional potential confounders and genotype or phenotype in larger studies.

Antidepressant use during pregnancy and childhood autism spectrum disorders.

CONTEXT: The prevalence of autism spectrum disorders (ASDs) has increased over recent years. Use of antidepressant medications during pregnancy also shows a secular increase in recent decades, prompting concerns that prenatal exposure may contribute to increased risk of ASD. OBJECTIVE: To systematically evaluate whether prenatal exposure to antidepressant medications is associated with increased risk of ASD. DESIGN: Population-based case-control study. Medical records were used to ascertain case children and control children and to derive prospectively recorded information on mothers' use of antidepressant medications, mental health history of mothers, and demographic and medical covariates. SETTING: The Kaiser Permanente Medical Care Program in Northern California. PARTICIPANTS: A total of 298 case children with ASD (and their mothers) and 1507 randomly selected control children (and their mothers) drawn from the membership of the Kaiser Permanente Medical Care Program in Northern California. MAIN OUTCOME MEASURES: ASDs. RESULTS: Prenatal exposure to antidepressant medications was reported for 20 case children (6.7%) and 50 control children (3.3%). In adjusted logistic regression models, we found a 2-fold increased risk of ASD associated with treatment with selective serotonin reuptake inhibitors by the mother during the year before delivery (adjusted odds ratio, 2.2 [95% confidence interval, 1.2-4.3]), with the strongest effect associated with treatment during the first trimester (adjusted odds ratio, 3.8 [95% confidence interval, 1.8-7.8]). No increase in risk was found for mothers with a history of mental health treatment in the absence of prenatal exposure to selective serotonin reuptake inhibitors. CONCLUSION: Although the number of children exposed prenatally to selective serotonin reuptake inhibitors in this population was low, results suggest that exposure, especially during the first trimester, may modestly increase the risk of ASD. The potential risk associated with exposure must be balanced with the risk to the mother or fetus of untreated mental health disorders. Further studies are needed to replicate and extend these findings.

Genetic heritability and shared environmental factors among twin pairs with autism.

CONTEXT: Autism is considered the most heritable of neurodevelopmental disorders, mainly because of the large difference in concordance rates between monozygotic and dizygotic twins. OBJECTIVE: To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment. DESIGN, SETTING, AND PARTICIPANTS: Twin pairs with at least 1 twin with an autism spectrum disorder (ASD) born between 1987 and 2004 were identified through the California Department of Developmental Services. MAIN OUTCOME MEASURES: Structured diagnostic assessments (Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule) were completed on 192 twin pairs. Concordance rates were calculated and parametric models were fitted for 2 definitions, 1 narrow (strict autism) and 1 broad (ASD). RESULTS: For strict autism, probandwise concordance for male twins was 0.58 for 40 monozygotic pairs (95% confidence interval [CI], 0.42-0.74) and 0.21 for 31 dizygotic pairs (95% CI, 0.09-0.43); for female twins, the concordance was 0.60 for 7 monozygotic pairs (95% CI, 0.28-0.90) and 0.27 for 10 dizygotic pairs (95% CI, 0.09-0.69). For ASD, the probandwise concordance for male twins was 0.77 for 45 monozygotic pairs (95% CI, 0.65-0.86) and 0.31 for 45 dizygotic pairs (95% CI, 0.16-0.46); for female twins, the concordance was 0.50 for 9 monozygotic pairs (95% CI, 0.16-0.84) and 0.36 for 13 dizygotic pairs (95% CI, 0.11-0.60). A large proportion of the variance in liability can be explained by shared environmental factors (55%; 95% CI, 9%-81% for autism and 58%; 95% CI, 30%-80% for ASD) in addition to moderate genetic heritability (37%; 95% CI, 8%-84% for autism and 38%; 95% CI, 14%-67% for ASD). CONCLUSION: Susceptibility to ASD has moderate genetic heritability and a substantial shared twin environmental component.

Birth prevalence of autism spectrum disorders in the San Francisco Bay area by demographic and ascertainment source characteristics.

Using standardized methods for multi-source surveillance, we calculated the prevalence of autism spectrum disorders (ASD) among children born in a racially diverse region in 1994 or 1996 as 4.7/1000 live births. Children with ASD before age 9 were identified through chart abstraction at health-related sources; three-quarters were being served by the state-wide Department of Developmental Services. In adjusted models, we found a male:female ratio of 6:1, a doubling of ASD prevalence among children of older mothers (40+), and lower prevalence with lower paternal education. Children of Black or Hispanic mothers had lower prevalence than those of White, non-Hispanic mothers, but these differences were attenuated after adjustment. Prevalence in children of Asian mothers was similar to Whites. Potential under-counting is discussed.

Neonatally measured immunoglobulins and risk of autism.

Previous studies indicate that prenatal exposure to infections is a possible pathway through which autism spectrum disorders (ASD) could be initiated. We investigated whether immunoglobulin levels in archived specimens obtained from newborns subsequently diagnosed with ASD are different from levels in newborn specimens from controls. Children with ASD born in six California counties in 1994 were ascertained through records of the California Department of Developmental Services (DDS) and Kaiser Permanente; controls were randomly selected using birth certificates. Archived newborn blood specimens were obtained from the California Genetic Disease Screening Program (GDSP) for N = 213 cases and N = 265 controls and assayed to determine levels of total IgG, antigen-specific IgG to selected common pathogens, total IgM, total IgA, and C-reactive protein (CRP). We did not find measurable levels of total IgM or IgA in any neonate and measurable CRP was present in only a few. No antigen-specific IgG antibodies were elevated in cases compared to controls and total IgG levels were lower. In adjusted models, a 10-unit increase in total IgG yielded an OR = 0.72 (95% CI 0.56, 0.91); a significantly decreasing trend in risk of ASD was observed across increasing exposure quartiles of total IgG (P = 0.01). The finding of lower IgG in cases may indicate maternal immune dysfunction during gestation and/or impaired transplacental transfer of immunoglobulins. Further investigation of IgG levels in newborns and the mechanisms by which they might be associated with ASD are warranted.

Antenatal ultrasound and risk of autism spectrum disorders.

We evaluated antenatal ultrasound (U/S) exposure as a risk factor for autism spectrum disorders (ASD), comparing affected singleton children and control children born 1995-1999 and enrolled in the Kaiser Permanente health care system. Among children with ASD (n = 362) and controls (n = 393), 13% had no antenatal exposure to U/S examinations; case-control differences in number of exposures during the entire gestation or by trimester were small and not statistically significant. In analyses adjusted for covariates, cases were generally similar to controls with regard to the number of U/S scans throughout gestation and during each trimester. This study indicates that antenatal U/S is unlikely to increase the risk of ASD, although studies examining ASD subgroups remain to be conducted.

Interleukin-6 genotype and risk for cerebral palsy in term and near-term infants.

OBJECTIVE: Chorioamnionitis is associated with increased risk for cerebral palsy (CP) in term infants. A functional polymorphism in the interleukin-6 (IL-6) gene has been implicated in newborn brain injury. We studied whether the IL-6 -174 G/C polymorphism confers increased risk for CP in term infants. METHODS: This population-based case-control study included 334,333 live-born infants born at >or=36 weeks gestation within Kaiser Permanente Medical Care Program from 1991 to 2002. Case patients (n = 250) were identified from electronic records and confirmed by chart review, and comprised all infants with spastic or dyskinetic CP not caused by developmental abnormalities who had a neonatal blood specimen available for study. Control patients (n = 305) were randomly selected from the study population. RESULTS: Compared with genotype GG, the less common CC genotype was associated with increased risk for overall CP (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.5-4.6), quadriparetic CP (OR, 4.1; 95% CI, 1.8-9.3), and hemiparetic CP (OR, 2.7; 95% CI, 1.3-5.7), after controlling for race. The C allele conferred increased risk for CP in both recessive and additive genetic models. In multivariate analysis controlling for race, independent risk factors for CP included CC genotype compared with GG (OR, 2.4; 95% CI, 1.3-4.4), clinical chorioamnionitis (OR, 4.6; 95% CI, 2.1-10.4), maternal age >or= 35 (OR, 2.6; 95% CI, 1.6-4.1), and male sex (OR, 1.6; 95% CI, 1.1-2.4). INTERPRETATION: Our data suggest that a functional polymorphism in the IL-6 gene is a risk factor for CP among term and near-term infants.

Risk of autism and increasing maternal and paternal age in a large north American population.

Previous studies are inconsistent regarding whether there are independent effects of maternal and paternal age on the risk of autism. Different biologic mechanisms are suggested by maternal and paternal age effects. The study population included all California singletons born in 1989-2002 (n = 7,550,026). Children with autism (n = 23,311) were identified through the California Department of Developmental Services and compared with the remainder of the study population, with parental ages and covariates obtained from birth certificates. Adjusted odds ratios and 95% confidence intervals were used to evaluate the risk of autism associated with increasing maternal and paternal age. In adjusted models that included age of the other parent and demographic covariates, a 10-year increase in maternal age was associated with a 38% increase in the odds ratio for autism (odds ratio = 1.38, 95% confidence interval: 1.32, 1.44), and a 10-year increase in paternal age was associated with a 22% increase (odds ratio = 1.22, 95% confidence interval: 1.18, 1.26). Maternal and paternal age effects were seen in subgroups defined by race/ethnicity and other covariates and were of greater magnitude among first-born compared with later-born children. Further studies are needed to help clarify the biologic mechanisms involved in the independent association of autism risk with increasing maternal and paternal age.