Differences in mid-gestational and early postnatal neonatal cytokines and chemokines are associated with patterns of maternal autoantibodies in the context of autism.

Associations between maternal immune dysregulation (including autoimmunity and skewed cytokine/chemokine profiles) and offspring neurodevelopmental disorders such as autism have been reported. In maternal autoantibody-related autism, specific maternally derived autoantibodies can access the fetal compartment to target eight proteins critical for neurodevelopment. We examined the relationship between maternal autoantibodies to the eight maternal autoantibody-related autism proteins and cytokine/chemokine profiles in the second trimester of pregnancy in mothers of children later diagnosed with autism and their neonates' cytokine/chemokine profiles. Using banked maternal serum samples from 15 to 19 weeks of gestation from the Early Markers for Autism Study and corresponding banked newborn bloodspots, we identified three maternal/offspring groups based on maternal autoantibody status: (1) mothers with autoantibodies to one or more of the eight maternal autoantibody-related autismassociated proteins but not a maternal autoantibody-related autism-specific pattern, (2) mothers with a known maternal autoantibody-related autism pattern, and (3) mothers without autoantibodies to any of the eight maternal autoantibody-related autism proteins. Using a multiplex platform, we measured maternal second trimester and neonatal cytokine/chemokine levels. This combined analysis aimed to determine potential associations between maternal autoantibodies and the maternal and neonatal cytokine/chemokine profiles, each of which has been shown to have implications on offspring neurodevelopment independently.

Barriers to Healthcare for Latinx Autistic Children and Adolescents.

PURPOSE: To understand the ways in which autistic Latinx children experience disparities in diagnosis, healthcare, and receipt of specialty services. METHODS: 417 individuals who identified as Latinx caregivers of autistic children who were members of the same integrated healthcare system in Northern California were surveyed. Responses were analyzed using the child's insurance coverage (Government or Commercial) and caregiver's primary language (Spanish or English). RESULTS: Compared to the commercially-insured, government-insured participants accessed several services at a higher rate and were less likely to cite the high cost of co-pays as a barrier. CONCLUSION: There were no significant differences in service access by language status, but Spanish speakers were more likely to cite health literacy as a barrier to receiving care.

Maternal autoantibody profiles as biomarkers for ASD and ASD with co-occurring intellectual disability.

Maternal autoantibody-related ASD (MAR ASD) is a subtype of autism in which pathogenic maternal autoantibodies (IgG) cross the placenta, access the developing brain, and cause neurodevelopmental alterations and behaviors associated with autism in the exposed offspring. We previously reported maternal IgG response to eight proteins (CRMP1, CRMP2, GDA LDHA, LDHB, NSE, STIP1, and YBOX) and that reactivity to nine specific combinations of these proteins (MAR ASD patterns) was predictive of ASD risk. The aim of the current study was to validate the previously identified MAR ASD patterns (CRMP1 + GDA, CRMP1 + CRMP2, NSE + STIP1, CRMP2 + STIP1, LDHA + YBOX, LDHB + YBOX, GDA + YBOX, STIP1 + YBOX, and CRMP1 + STIP1) and their accuracy in predicting ASD risk in a prospective cohort employing maternal samples collected prior to parturition. We used prenatal plasma from mothers of autistic children with or without co-occurring intellectual disability (ASD = 540), intellectual disability without autism (ID = 184) and general population controls (GP = 420) collected by the Early Markers for Autism (EMA) study. We found reactivity to one or more of the nine previously identified MAR ASD patterns in 10% of the ASD group compared with 4% of the ID group and 1% of the GP controls (ASD vs GP: Odds Ratio (OR) = 7.81, 95% Confidence Interval (CI) 3.32 to 22.43; ASD vs ID: OR = 2.77, 95% CI (1.19-7.47)) demonstrating that the MAR ASD patterns are strongly associated with the ASD group and could be used to assess ASD risk prior to symptom onset. The pattern most strongly associated with ASD was CRMP1 + CRMP2 and increased the odds for an ASD diagnosis 16-fold (3.32 to >999.99). In addition, we found that several of these specific MAR ASD patterns were strongly associated with ASD with intellectual disability (ASD + ID) and others associated with ASD without ID (ASD-no ID). Prenatal screening for these MAR patterns may lead to earlier identification of ASD and facilitate access to the appropriate early intervention services based on each child's needs.

A profile and review of findings from the Early Markers for Autism study: unique contributions from a population-based case-control study in California.

BACKGROUND: The Early Markers for Autism (EMA) study is a population-based case-control study designed to learn more about early biologic processes involved in ASD. METHODS: Participants were drawn from Southern California births from 2000 to 2003 with archived prenatal and neonatal screening specimens. Across two phases, children with ASD (n = 629) and intellectual disability without ASD (ID, n = 230) were ascertained from the California Department of Developmental Services (DDS), with diagnoses confirmed according to DSM-IV-TR criteria based on expert clinical review of abstracted records. General population controls (GP, n = 599) were randomly sampled from birth certificate files and matched to ASD cases by sex, birth month and year after excluding individuals with DDS records. EMA has published over 20 papers examining immune markers, endogenous hormones, environmental chemicals, and genetic factors in association with ASD and ID. This review summarizes the results across these studies, as well as the EMA study design and future directions. RESULTS: EMA enabled several key contributions to the literature, including the examination of biomarker levels in biospecimens prospectively collected during critical windows of neurodevelopment. Key findings from EMA include demonstration of elevated cytokine and chemokine levels in maternal mid-pregnancy serum samples in association with ASD, as well as aberrations in other immune marker levels; suggestions of increased odds of ASD with prenatal exposure to certain endocrine disrupting chemicals, though not in mixture analyses; and demonstration of maternal and fetal genetic influence on prenatal chemical, and maternal and neonatal immune marker and vitamin D levels. We also observed an overall lack of association with ASD and measured maternal and neonatal vitamin D, mercury, and brain-derived neurotrophic factor (BDNF) levels. LIMITATIONS: Covariate and outcome data were limited to information in Vital Statistics and DDS records. As a study based in Southern California, generalizability for certain environmental exposures may be reduced. CONCLUSIONS: Results across EMA studies support the importance of the prenatal and neonatal periods in ASD etiology, and provide evidence for the role of the maternal immune response during pregnancy. Future directions for EMA, and the field of ASD in general, include interrogation of mechanistic pathways and examination of combined effects of exposures.

Neonatal Thyroid Stimulating Hormone and Subsequent Diagnosis of Autism Spectrum Disorders and Intellectual Disability.

Hypothyroid conditions in early life, if left untreated, are associated with adverse neurodevelopmental outcomes, including intellectual disability (ID). However, evidence addressing the role of neonatal thyroid hormone insufficiencies in the altered neurobiology underlying autism spectrum disorders (ASD), particularly among its subphenotypes, is limited. We conducted a population-based, case-control study among a sample of children born during 2000-2003 in Southern California. We examined neonatal thyroid-stimulating hormone (TSH) measured during routine newborn screening among children later diagnosed with ASD (n = 518) or ID (n = 145) and general population (GP) controls (n = 399). TSH was further analyzed in relation to ASD subgroups of intellectual ability and onset type (early-onset ASD vs. ASD with regression) ascertained by expert review of developmental services records. Odds ratios (ORs) of the differences in TSH between groups were obtained from multivariate logistic regression. We examined neonatal TSH as continuous (ln-transformed) and as quartiles. We found no association between continuous neonatal TSH levels and ASD (adj-OR: 1.00, 95% CI: 0.79-1.26) nor ID (adj-OR = 1.01, 95% CI: 0.73-1.40). Among ASD subphenotypes, we observed a suggestive inverse trend between ASD with regression and TSH, though the association only reached statistical significance in the highest TSH quartile (adj-OR: 0.50, 95% CI: 0.26-0.98). While there was little evidence that neonatal TSH is related to overall ASD risk, more work is needed to understand the influence of thyroid hormones on ASD subphenotypes. Autism Res 2020, 13: 444-455. © 2019 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Low levels of thyroid hormone at birth can negatively impact brain development. We studied whether newborn levels of thyroid stimulating hormone (TSH) were associated with autism spectrum disorder (ASD) and its subtypes in a sample of children born in California. Newborn TSH was not related to the overall risk of ASD or intellectual disability. However, the relationships of thyroid hormone levels at birth and specific subtypes of ASD, particularly ASD with developmental regression, may need more research.

An Exploratory Examination of Neonatal Cytokines and Chemokines as Predictors of Autism Risk: The Early Markers for Autism Study.

BACKGROUND: The identification of an early biomarker for autism spectrum disorder (ASD) would improve the determination of risk, leading to earlier diagnosis and, potentially, earlier intervention and improved outcomes. METHODS: Data were generated from the Early Markers for Autism study, a population-based case-control study of prenatal and neonatal biomarkers of ASD. Newborn bloodspots of children with ASD (n = 370), children with developmental delay (n = 140), and general population (GP) controls (n = 378) were analyzed for 42 different immune markers using a Luminex multiplex platform. Comparisons of immune marker concentrations between groups were examined using logistic regression and partial least squares discriminant analysis. RESULTS: Children with ASD had significantly increased neonatal levels of interleukin-6 (IL-6) and IL-8 compared with GP controls. An increase in IL-8 was especially significant in the ASD group with early onset compared with the GP group, with an adjusted odds ratio of 1.97 (95% confidence interval, 1.39-2.83; p = .00014). In addition, children with ASD had significantly elevated levels of eotaxin-1, interferon-γ, and IL-12p70 relative to children with developmental delay. We observed no significant differences in levels of immune markers between the developmental delay and GP groups. CONCLUSIONS: Elevated levels of some inflammatory markers in newborn bloodspots indicated a higher degree of immune activation at birth in children who were subsequently diagnosed with ASD. The data from this exploratory study suggest that with further expansion, the development of neonatal bloodspot testing for cytokine/chemokine levels might lead to the identification of biomarkers that provide an accurate assessment of ASD risk at birth.

Prenatal Maternal Serum Concentrations of Per- and Polyfluoroalkyl Substances in Association with Autism Spectrum Disorder and Intellectual Disability.

BACKGROUND: Emerging work has examined neurodevelopmental outcomes following prenatal exposure to per- and polyfluoroalkyl substances (PFAS), but few studies have assessed associations with autism spectrum disorder (ASD). OBJECTIVES: Our objective was to estimate associations of maternal prenatal PFAS concentrations with ASD and intellectual disability (ID) in children. METHODS: Participants were from a population-based nested case-control study of children born from 2000 to 2003 in southern California, including children diagnosed with ASD (n=553), ID without autism (n=189), and general population (GP) controls (n=433). Concentrations of eight PFAS from stored maternal sera collected at 15-19 wk gestational age were quantified and compared among study groups. We used logistic regression to obtain adjusted odds ratios for the association between prenatal PFAS concentrations (parameterized continuously and as quartiles) and ASD versus GP controls, and separately for ID versus GP controls. RESULTS: Geometric mean concentrations of most PFAS were lower in ASD and ID groups relative to GP controls. ASD was not significantly associated with prenatal concentrations of most PFAS, though significant inverse associations were found for perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) [adjusted ORs for the highest vs. lowest quartiles 0.62 (95% CI: 0.41, 0.93) and 0.64 (95% CI: 0.43, 0.97), respectively]. Results for ID were similar. CONCLUSIONS: Results from this large case-control study with prospectively collected prenatal measurements do not support the hypothesis that prenatal exposure to PFAS is positively associated with ASD or ID. https://doi.org/10.1289/EHP1830.

Demographic and Clinical Characteristics Associated with Engagement in Behavioral Health Treatment Among Children with Autism Spectrum Disorders.

This study investigates demographic and clinical factors associated with initiation, continuation, and adherence to behavioral health treatment (BHT) among children with autism spectrum disorder. Among 293 insured children referred for applied behavior analysis (ABA) based BHT, 23% never initiated treatment. Among those initiating treatment, 31% discontinued treatment within 1 year of treatment initiation, and only 15% received 80% or more of recommended treatment hours. Younger age at referral to treatment, private health insurance, and receiving more than 10 h/week of BHT were associated with treatment engagement. Co-occurring psychiatric and medical conditions were related to treatment discontinuation among children 5 years or older. These findings suggest specific subgroups that may benefit from additional support with engaging in recommended behavioral health treatment.

A Survey of Parents with Children on the Autism Spectrum: Experience with Services and Treatments.

INTRODUCTION: Autism spectrum disorders (ASD) are lifelong neurodevelopmental disorders, and little is known about how parents address the health and psychosocial consequences of ASD. Few studies have examined use of various treatments and services in a large, diverse sample of children with ASD and their families. OBJECTIVE: This paper presents methods to create an autism research resource across multiple large health delivery systems and describes services and treatments used by children with ASD and their families. METHODS: Four study sites conducted a Web survey of parents of children and adolescents with ASD who were members of Kaiser Permanente. We tabulated data distributions of survey responses and calculated χ2 statistics for differences between responders and nonresponders. RESULTS: The children of the 1155 respondents were racially and ethnically diverse (55% white, 6% black, 5% Asian, 9% multiracial, 24% Hispanic) and representative of the total population invited to participate with respect to child sex (83% male), child age (57% < 10 years), and ASD diagnosis (64% autistic disorder). The most frequently used services and treatments were Individualized Education Programs (85%), family physician visits (78%), and occupational and speech therapy (55% and 60%, respectively). Home-based programs frequently included implementation of social skills training (44%) and behavior management (42%). Prescription medication use was high (48%). Caregivers reported disruption of personal and family routines because of problem behaviors. CONCLUSION: These survey data help to elucidate parents' experiences with health services for their children with ASD and serve as a potential resource for future research.

Polychlorinated Biphenyl and Organochlorine Pesticide Concentrations in Maternal Mid-Pregnancy Serum Samples: Association with Autism Spectrum Disorder and Intellectual Disability.

BACKGROUND: Polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) are neurodevelopmental toxicants, but few studies have examined associations with autism spectrum disorder (ASD). OBJECTIVES: We aimed to determine whether prenatal exposure to PCBs and OCPs influences offspring risk of ASD and intellectual disability without autism (ID). METHODS: We conducted a population-based case-control study among Southern California births, including children with ASD (n = 545) meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV-TR) criteria and ID (n = 181), as well as general population (GP) controls (n = 418). Concentrations of 11 PCB congeners and 2 OCPs measured in banked second-trimester serum samples were compared between the diagnostic groups. Logistic regression was used to calculate crude and adjusted odds ratios (AOR) for associations with ASD, and separately for ID, compared with GP controls, by quartiles of analyte concentrations in primary analyses. RESULTS: Geometric mean levels of several PCB congeners were higher in the ASD group than in the ID and GP groups. ASD risk was elevated for a number of PCB congeners, particularly for the highest vs. lowest quartile of PCB138/158 (AOR = 1.79; 95% CI: 1.10, 2.71) and PCB153 (AOR = 1.82; 95% CI: 1.10, 3.02), and for highest deciles of other congeners in secondary analyses. PCB138/158 was also associated with increased ID (AOR = 2.41; 95% CI: 1.18, 4.91), though no trend was suggested. OCPs were not associated with increased risk of ASD in primary analyses, whereas nonmonotonic increases in risk of ID were found with p,p´-DDE. CONCLUSIONS: Our results suggest higher levels of some organochlorine compounds during pregnancy are associated with ASD and ID. Citation: Lyall K, Croen LA, Sjödin A, Yoshida CK, Zerbo O, Kharrazi M, Windham GC. 2017. Polychlorinated biphenyl and organochlorine pesticide concentrations in maternal mid-pregnancy serum samples: association with autism spectrum disorder and intellectual disability. Environ Health Perspect 125:474-480; http://dx.doi.org/10.1289/EHP277.

Association Between Influenza Infection and Vaccination During Pregnancy and Risk of Autism Spectrum Disorder.

IMPORTANCE: Maternal infections and fever during pregnancy are associated with increased risk for autism spectrum disorders (ASDs). To our knowledge, no study has investigated the association between influenza vaccination during pregnancy and ASD. OBJECTIVE: To investigate the association between influenza infection and vaccination during pregnancy and ASD risk. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included 196 929 children born at Kaiser Permanente Northern California from January 1, 2000 to December 31, 2010, at a gestational age of at least 24 weeks. EXPOSURES: Data on maternal influenza infection and vaccination from conception date to delivery date, obtained from Kaiser Permanente Northern California inpatient and outpatient databases. Influenza infection was defined by the International Classification of Diseases, Ninth Revision, Clinical Modification codes or positive influenza laboratory test results. MAIN OUTCOMES AND MEASURES: Clinical diagnoses of ASDs identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes 299.0, 299.8, or 299.9 recorded in Kaiser Permanente Northern California electronic medical records on at least 2 occasions any time from birth through June 2015. RESULTS: Within this cohort of 196 929 children, influenza was diagnosed in 1400 (0.7%) mothers and 45 231 (23%) received an influenza vaccination during pregnancy. The mean (SD) ages of vaccinated and unvaccinated women were 31.6 (5.2) and 30.4 (5.6) years, respectively. A total number of 3101 (1.6%) children were diagnosed with ASD. After adjusting for covariates, we found that maternal influenza infection (adjusted hazard ratio, 1.04; 95% CI, 0.68-1.58) or influenza vaccination (adjusted hazard ratio, 1.10; 95% CI, 1.00-1.21) anytime during pregnancy was not associated with increased ASD risk. In trimester-specific analyses, first-trimester influenza vaccination was the only period associated with increased ASD risk (adjusted hazard ratio, 1.20; 95% CI, 1.04-1.39). However, this association could be due to chance (P = 0.1) if Bonferroni corrected for the multiplicity of hypotheses tested (n = 8). Maternal influenza vaccination in the second or third trimester was not associated with increased ASD risk. CONCLUSIONS AND RELEVANCE: There was no association between maternal influenza infection anytime during pregnancy and increased ASD risk. There was a suggestion of increased ASD risk among children whose mothers received an influenza vaccination in their first trimester, but the association was not statistically significant after adjusting for multiple comparisons, indicating that the finding could be due to chance. These findings do not call for changes in vaccine policy or practice, but do suggest the need for additional studies on maternal influenza vaccination and autism.

Interpregnancy Interval and Risk of Autism Spectrum Disorders.

OBJECTIVE: To determine whether subsequent births after short and long interpregnancy intervals (IPIs) are associated with risk of autism spectrum disorder (ASD). METHOD: We assessed the association between IPI and ASD risk in a cohort of 45 261 children born at Kaiser Permanente Northern California (KPNC) between 2000 and 2009. Children with ASD were identified from International Classification of Diseases, Revision 9 diagnostic codes 299.0, 299.8, and 299.9 recorded in KPNC electronic medical records. IPI was defined as the time from the birth of the first child to the conception of the second child. Survival analysis and logistic regression models were used to evaluate the association between IPI and risk of ASD in second-born children. RESULTS: Children born after an IPI of <12 months or ≥72 months had a 2- to 3-fold increased ASD risk compared with children born after an interval of 36 to 47 months. Respective adjusted hazard ratios (95% confidence intervals) were as follows: <6 months, 3.0 (1.9-4.7); 6 to 8 months, 2.1 (1.4-3.3); 9 to 11 months, 1.9 (1.3-2.1); 12 to 23 months, 1.5 (1.1-2.1); and ≥72 months, 2.4 (1.5-3.7). The results are not explained by maternal BMI or change in BMI between pregnancies or by parental age, maternal antidepressant medication use, or unfavorable events occurring during the first or second pregnancy. CONCLUSIONS: Children born after interpregnancy intervals <2 years or >6 years may be at increased risk of ASD. The mechanism explaining this association is unknown, and more research is needed.

Prenatal and neonatal thyroid stimulating hormone levels and autism spectrum disorders.

Thyroid hormones are critical for normal brain development. This study examined autism spectrum disorders (ASD) and thyroid stimulating hormone (TSH) levels measured in mid-pregnancy maternal serum and infant blood after birth. Three groups of children born in Orange County, CA in 2000-2001 were identified: ASD (n = 78), developmental delay (n = 45), and general population controls (GP) (n = 149). Samples were retrieved from prenatal and newborn screening specimen archives. Adjusted logistic regression models showed inverse associations between ASD and log transformed TSH levels in maternal serum samples (ASD vs. GP: OR [95 % CI] 0.33 [0.12-0.91], Early Onset ASD vs. GP: 0.31 [0.10-0.98]). Results for thyroid levels in newborn blood samples were similar though not significant (ASD vs. GP: 0.61 [0.18-2.04]).

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.

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.

A genome-wide survey of transgenerational genetic effects in autism.

Effects of parental genotype or parent-offspring genetic interaction are well established in model organisms for a variety of traits. However, these transgenerational genetic models are rarely studied in humans. We have utilized an autism case-control study with 735 mother-child pairs to perform genome-wide screening for maternal genetic effects and maternal-offspring genetic interaction. We used simple models of single locus parent-child interaction and identified suggestive results (P<10(-4)) that cannot be explained by main effects, but no genome-wide significant signals. Some of these maternal and maternal-child associations were in or adjacent to autism candidate genes including: PCDH9, FOXP1, GABRB3, NRXN1, RELN, MACROD2, FHIT, RORA, CNTN4, CNTNAP2, FAM135B, LAMA1, NFIA, NLGN4X, RAPGEF4, and SDK1. We attempted validation of potential autism association under maternal-specific models using maternal-paternal comparison in family-based GWAS datasets. Our results suggest that further study of parental genetic effects and parent-child interaction in autism is warranted.

Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: A case-control study.

BACKGROUND: Immune anomalies have been documented in individuals with autism spectrum disorders (ASDs) and their family members. It is unknown whether the maternal immune profile during pregnancy is associated with the risk of bearing a child with ASD or other neurodevelopmental disorders. METHODS: Using Luminex technology, levels of 17 cytokines and chemokines were measured in banked serum collected from women at 15 to 19 weeks of gestation who gave birth to a child ultimately diagnosed with (1) ASD (n = 84), (2) a developmental delay (DD) but not autism (n = 49) or (3) no known developmental disability (general population (GP); n = 159). ASD and DD risk associated with maternal cytokine and chemokine levels was estimated by using multivariable logistic regression analysis. RESULTS: Elevated concentrations of IFN-γ, IL-4 and IL-5 in midgestation maternal serum were significantly associated with a 50% increased risk of ASD, regardless of ASD onset type and the presence of intellectual disability. By contrast, elevated concentrations of IL-2, IL-4 and IL-6 were significantly associated with an increased risk of DD without autism. CONCLUSION: The profile of elevated serum IFN-γ, IL-4 and IL-5 was more common in women who gave birth to a child subsequently diagnosed with ASD. An alternative profile of increased IL-2, IL-4 and IL-6 was more common for women who gave birth to a child subsequently diagnosed with DD without autism. Further investigation is needed to characterize the relationship between these divergent maternal immunological phenotypes and to evaluate their effect on neurodevelopment.

Epidemiology of peripartum cardiomyopathy: incidence, predictors, and outcomes.

OBJECTIVES: To estimate the incidence, describe the mortality, and identify independent predictors of peripartum cardiomyopathy, a very serious cardiovascular complication of pregnancy associated with maternal morbidity and mortality among otherwise healthy women without prior heart disease. METHODS: We identified all cases of diagnosed heart failure that occurred among women within 1 month before to 5 months after delivery of a liveborn neonate in Kaiser Permanente Northern California delivery hospitals between 1995 and 2004. Incident peripartum cardiomyopathy was confirmed from medical records documenting dilated cardiomyopathy with reduced left ventricular systolic function after excluding women with prior heart failure or valvular disease. Data sources included medical records, electronic clinical databases, and state birth and death files. RESULTS: Among 227,224 eligible women, we confirmed 110 recognized peripartum cardiomyopathy cases (incidence: 4.84 per 10,000 live births, 95% confidence interval 3.98-5.83). Independent predictors included maternal age of 25 years or older, non-Hispanic African American and Filipino groups, parity of 4 or greater, multiple gestation, severe anemia, pre-existing and pregnancy-related hypertensive disorders, and hemolysis, elevated liver enzymes, low platelets syndrome. Maternal death rate (per 1,000 person-years) was higher among cases (6.12) than noncases (0.23; P<.001). Neonates whose mothers developed peripartum cardiomyopathy experienced poorer clinical outcomes. CONCLUSION: Within a large, diverse northern California population, 1 of every 2,066 women delivering a liveborn neonate had recognized, confirmed peripartum cardiomyopathy, which was associated with higher maternal and neonatal death rates and worse neonatal outcomes. Several readily available patient characteristics can be used to identify women at risk for this severe pregnancy complication. LEVEL OF EVIDENCE: II.

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.