Publications by authors named "Cathleen K Yoshida"

25 Publications

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

Mol Autism 2021 03 18;12(1):24. Epub 2021 Mar 18.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

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.
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http://dx.doi.org/10.1186/s13229-021-00429-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977191PMC
March 2021

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

Autism Res 2020 03 10;13(3):444-455. Epub 2019 Dec 10.

Kaiser Permanente Division of Research, Oakland, California.

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.
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http://dx.doi.org/10.1002/aur.2247DOI Listing
March 2020

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

Biol Psychiatry 2019 08 15;86(4):255-264. Epub 2019 May 15.

Division of Rheumatology, Allergy, and Clinical Immunology, Department of Internal Medicine, University of California, Davis, Davis, California; MIND Institute, University of California, Davis, Davis, California. Electronic address:

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.
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http://dx.doi.org/10.1016/j.biopsych.2019.04.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677631PMC
August 2019

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

Environ Health Perspect 2018 01 2;126(1):017001. Epub 2018 Jan 2.

Division of Research, Kaiser Permanente, Oakland, California, USA

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 (=553), ID without autism (=189), and general population (GP) controls (=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.
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http://dx.doi.org/10.1289/EHP1830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014693PMC
January 2018

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

Perm J 2017 ;21:16-009

Senior Research Scientist at the Division of Research in Oakland, CA.

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 χ 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.
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http://dx.doi.org/10.7812/TPP/16-009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424584PMC
March 2018

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

Environ Health Perspect 2017 03 23;125(3):474-480. Epub 2016 Aug 23.

Environmental Health Investigations Branch, California Department of Public Health, Richmond, California, USA.

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 ( = 545) meeting (DSM-IV-TR) criteria and ID ( = 181), as well as general population (GP) controls ( = 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 ´-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.
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http://dx.doi.org/10.1289/EHP277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5332182PMC
March 2017

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

J Autism Dev Disord 2015 Mar;45(3):719-30

Autism Research Program, Division of Research, Kaiser Permanente, 2000 Broadway, Oakland, CA, 94612, USA.

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]).
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http://dx.doi.org/10.1007/s10803-014-2227-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472909PMC
March 2015

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

Environ Res 2014 Aug 28;133:294-303. Epub 2014 Jun 28.

Division of Research, Kaiser Permanente, Oakland, CA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.envres.2014.04.034DOI Listing
August 2014

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

PLoS One 2013 24;8(10):e76978. Epub 2013 Oct 24.

Department of Psychiatry and Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076978PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811986PMC
August 2014

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

Obstet Gynecol 2011 Sep;118(3):583-591

From the Division of Research and the Department of Obstetrics and Gynecology, Kaiser Permanente of Northern California, Oakland, California; and the Departments of Epidemiology, Biostatistics, and Medicine, University of California, San Francisco, San Francisco, California.

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.
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http://dx.doi.org/10.1097/AOG.0b013e318229e6deDOI Listing
September 2011

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

Mol Autism 2011 Aug 2;2:13. Epub 2011 Aug 2.

Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Dr, Suite 6510, Davis, CA 95616, USA.

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.
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http://dx.doi.org/10.1186/2040-2392-2-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170586PMC
August 2011

Antidepressant use during pregnancy and childhood autism spectrum disorders.

Arch Gen Psychiatry 2011 Nov 4;68(11):1104-12. Epub 2011 Jul 4.

Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA.

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.
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http://dx.doi.org/10.1001/archgenpsychiatry.2011.73DOI Listing
November 2011

Antenatal ultrasound and risk of autism spectrum disorders.

J Autism Dev Disord 2010 Feb 1;40(2):238-45. Epub 2009 Sep 1.

Environmental Health Investigations Branch, California Department of Public Health, Richmond, CA 94804, USA.

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.
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http://dx.doi.org/10.1007/s10803-009-0859-4DOI Listing
February 2010

Brain-derived neurotrophic factor and autism: maternal and infant peripheral blood levels in the Early Markers for Autism (EMA) Study.

Autism Res 2008 Apr;1(2):130-7

Division of Research, Kaiser Permanente Northern California, Oakland, California 94612, USA.

To investigate levels of brain-derived neurotrophic factor (BDNF) in mid-pregnancy and neonatal blood specimens as early biologic markers for autism, 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, CA. Cases (n=84) were all children receiving services for autism at the Regional Center of Orange County. Two comparison groups from the same study population were included: children with mental retardation or developmental delay (n=49) receiving services at the same regional center, and children not receiving services for developmental disabilities, randomly sampled from the California birth certificate files (n=159), and frequency matched to autism cases on sex, birth year, and birth month. BDNF concentrations were measured in archived mid-pregnancy and neonatal blood specimens drawn during routine prenatal and newborn screening using a highly sensitive bead-based assay (Luminex, Biosource Human BDNF Antibody Bead Kit, Invitrogen-Biosource, Carlsbad, CA). The concentration of BDNF in maternal mid-pregnancy and neonatal specimens was similar across all three study groups. These data do not support previous findings of an association between BDNF and autism and suggest that the concentration of BDNF during critical periods of early neurodevelopment is not likely to be a useful biomarker for autism susceptibility.
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http://dx.doi.org/10.1002/aur.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613010PMC
April 2008

Maternal mid-pregnancy autoantibodies to fetal brain protein: the early markers for autism study.

Biol Psychiatry 2008 Oct 20;64(7):583-8. Epub 2008 Jun 20.

Division of Research, Kaiser Permanente Northern California, Oakland, California 94612, USA.

Background: Immune dysfunction has been associated with autism, yet whether maternal immune status during pregnancy plays a causal role remains to be clarified.

Methods: We conducted a population-based case-control study nested within the cohort of infants born July 2000-September 2001 to women who participated in the prenatal screening program in Orange County, California. Cases (AU; n = 84) were children receiving services for autism at the Regional Center of Orange County. Two control groups were included: children with mental retardation or developmental delay (MR; n = 49) receiving services at the same regional center; and children not receiving services for developmental disabilities, randomly sampled from the California birth certificate files (GP; n = 160). Maternal autoantibody reactivity to fetal brain protein was measured by Western blot in archived mid-pregnancy blood specimens drawn during routine prenatal screening. Presence of specific bands and band patterns were compared between the three study groups.

Results: The pattern of maternal mid-gestation antibody reactivity to human fetal brain protein varied by study group and by autism onset type, although most differences did not reach statistical significance. Reactivity to a band at 39 kDa was more common among mothers of children with autism (7%) compared with mothers of MR (0%; p = .09) and GP control subjects (2%; p = .07), and simultaneous reactivity to bands at 39 kDa and 73 kDa was found only in mothers of children with early onset autism (n = 3).

Conclusions: Our findings indicate that further studies of prenatal immune markers might be a productive area for etiologic and biologic marker discovery for autism.
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http://dx.doi.org/10.1016/j.biopsych.2008.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574992PMC
October 2008

Maternal Rh D status, anti-D immune globulin exposure during pregnancy, and risk of autism spectrum disorders.

Am J Obstet Gynecol 2008 Sep 13;199(3):234.e1-6. Epub 2008 Jun 13.

Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA.

Objective: The objective of the study was to investigate the association between maternal Rh D status, prenatal exposure to anti-D immune globulin, and the risk of autism in the offspring.

Study Design: Case-control study among children born from 1995 to 1999 at Kaiser Permanente Northern California hospitals. Cases (n = 400) were children with an autism diagnosis; controls (n = 410) were children without autism, randomly sampled and frequency matched to cases on sex, birth year, and birth hospital. Maternal Rh D status and anti-D immune globulin exposure were ascertained from prenatal medical records.

Results: No case-control differences were observed for maternal Rh negative status (11.5% vs 10.0%, P = .5) or prenatal anti-D immune globulin exposure (10.0% vs. 9.3%, P = .7). Risk of autism remained unassociated with maternal Rh status or prenatal exposure to anti-D immune globulins after adjustment for covariates.

Conclusion: These data support previous findings that prenatal exposure to thimerosal-containing anti-D immune globulins does not increase the risk of autism.
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http://dx.doi.org/10.1016/j.ajog.2008.04.044DOI Listing
September 2008

Infection in the first 2 years of life and autism spectrum disorders.

Pediatrics 2007 Jan;119(1):e61-9

Division of Research, Kaiser Permanente, Oakland, California, USA.

Objective: The purpose of this work was to investigate the association between infections in the first 2 years and subsequent diagnosis of autism spectrum disorders.

Methods: We conducted a case-control study among children born at Kaiser Permanente Northern California from 1995 to 1999. Case subjects (n = 403) were children with an autism diagnosis recorded in Kaiser Permanente databases. Control subjects (n = 2100) were randomly sampled from the remaining children without autism and frequency matched to case subjects on gender, birth year, and birth hospital. Information on infections and covariates were obtained from Kaiser Permanente and birth certificate databases.

Results: Overall, infection diagnoses in the first 2 years of life were recorded slightly less often for children with autism than control children (95.0% vs 97.5%). Among specific diagnoses, upper respiratory infections were significantly less frequently diagnosed and genitourinary infections more frequently diagnosed in children with autism. In the first 30 days of life, the frequency of having an infection was slightly higher among children with autism (22.6% vs 18.7%).

Conclusions: Children with subsequent diagnoses of autism do not have more overall infections in the first 2 years of life than children without autism. Data suggest that children with autism may have modestly elevated rates of infection in the first 30 days and that, during the first 2 years, children with autism may be at higher risk for certain types of infections and lower risk for others. Additional studies that explore the associations between prenatal and early childhood infections and autism may help clarify the role of infection and the immune system in the etiology of autism spectrum disorder.
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http://dx.doi.org/10.1542/peds.2006-1788DOI Listing
January 2007

Neuroimaging abnormalities in infants with congenital hemiparesis.

Pediatr Neurol 2006 Sep;35(3):191-6

Department of Neurology, University of California, San Francisco, California 94143-0137, USA.

Clinical and neuroimaging characteristics of congenital hemiparesis were examined in a retrospective cohort study nested within 199,176 births within the Kaiser Permanente Medical Care Program, 1997-2002. Infants with a physician diagnosis of paresis or cerebral palsy were electronically identified, and charts were reviewed to confirm congenital hemiparesis. A neuroradiologist reviewed available head MRI and CT scans. Of 96 infants with congenital hemiparesis (population prevalence 4.8 per 10,000), 81% received either a head magnetic resonance imaging (n = 55) or head computed tomography only (n = 23). Perinatal arterial infarction was the most common (30%) neuroimaging finding in term infants. Infants with right-sided hemiparesis (relative risk 4.6, 95% confidence interval 1.4-14.4) or moderate to severe weakness (relative risk 4.4, 95% confidence interval 1.1-17.7) were more likely to have had a perinatal arterial infarction. Periventricular white matter lesions predominated in preterm infants (71%). Brain malformations observed in 14 (18%) patients included polymicrogyria, heterotopia, and schizencephaly. The 14 infants (18%) with a normal head imaging study were more likely to outgrow all signs of hemiparesis by age 3 than were infants with an abnormal brain image (29% vs 0%, P < 0.001). Neuroimaging studies provide useful diagnostic and prognostic information in infants with congenital hemiparesis.
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http://dx.doi.org/10.1016/j.pediatrneurol.2006.03.002DOI Listing
September 2006

Congenital anomalies associated with autism spectrum disorders.

Dev Med Child Neurol 2006 Jun;48(6):500-7

California Department of Health Services, Genetic Disease Branch, Sequoia Foundation, Richmond, USA.

This study examined whether major congenital structural anomalies identified in infancy occurred more frequently in children later diagnosed with autism spectrum disorders (ASD; n=417; 341 males, 76 females) than in comparison children (n=2,067; 1,681 males, 386 females). Participants were sampled from infants born at Kaiser Permanente Northern California facilities between 1995 and 1999 who remained health plan members for at least 2 years (n=88,163). Comparison children were frequency-matched to children with ASD according to sex, birth year, and birth hospital. Congenital anomalies were diagnosed in 10.8% of children with ASD and 6.2% of comparison children (crude odds ratio [ORc] 1.8, 95% confidence interval [CI] 1.3-2.6). This association remained significant after adjustment for key maternal and infant covariates (adjusted OR [ORa] 1.7, 95% CI 1.1-2.4). Almost all organ-system anomaly categories were more prevalent in children with ASD, however only gastrointestinal anomalies were significantly associated with ASD in adjusted analyses (1.9 vs 0.4%, ORa 5.1, 95% CI 1.8-14.1).
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http://dx.doi.org/10.1017/S001216220600106XDOI Listing
June 2006

Predictors of outcome in perinatal arterial stroke: a population-based study.

Ann Neurol 2005 Aug;58(2):303-8

Department of Neurology, University of California, San Francisco, USA.

Some infants with perinatal arterial ischemic stroke (PAS) experience development of cerebral palsy (CP), epilepsy, and cognitive impairment, whereas others have a normal outcome. Previous prognostic studies rarely have included all diagnosed cases of PAS within a population. Among 199,176 infants born within Kaiser Permanente from 1997 to 2002, we electronically identified head imaging reports and physician diagnoses suggesting stroke. The diagnosis of PAS was confirmed by review of brain imaging and medical records. Presentation of PAS was considered delayed if symptoms were only noted after 28 days. Outcomes were determined by chart review. Of 40 infants with PAS, 36 were observed over 12 months. Abnormal outcomes included CP (58%), epilepsy (39%), language delay (25%), and behavioral abnormalities (22%). A delayed presentation was associated with increased risk for CP (relative risk [RR], 2.2; 95% confidence interval [CI], 1.2-4.2). Radiological predictors of CP included large stroke size (RR, 2.0; 95% CI, 1.2-3.2) and injury to Broca's area (RR, 2.5; 95% CI, 1.3-5.0), internal capsule (RR, 2.2; 95% CI, 1.1-4.4), Wernicke's area (RR, 2.0; 95% CI, 1.1-3.8), or basal ganglia (RR, 1.9; 95% CI, 1.1-3.3). Among infants with PAS, specific radiological findings and a lack of symptoms in the newborn period are associated with increased risk for CP.
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http://dx.doi.org/10.1002/ana.20557DOI Listing
August 2005

Maternal and infant characteristics associated with perinatal arterial stroke in the infant.

JAMA 2005 Feb;293(6):723-9

Department of Neurology, University of California, San Francisco, CA 94117, USA.

Context: Perinatal arterial ischemic stroke (PAS) is a common cause of hemiplegic cerebral palsy. Risk factors for this condition have not been clearly defined.

Objective: To determine maternal and infant characteristics associated with PAS.

Design, Setting, And Patients: Case-control study nested within the cohort of all 199,176 infants born from 1997 through 2002 in the Kaiser Permanente Medical Care Program, a managed care organization providing care for more than 3 million residents of northern California. Case patients were confirmed by review of brain imaging and medical records (n = 40). Three controls per case were randomly selected from the study population.

Main Outcome Measure: Association of maternal and infant complications with risk of PAS.

Results: The population prevalence of PAS was 20 per 100,000 live births. The majority (85%) of infants with PAS were delivered at term. The following prepartum and intrapartum factors were more common among case than control infants: primiparity (73% vs 44%, P = .002), fetal heart rate abnormality (46% vs 14%, P<.001), emergency cesarean delivery (35% vs 13%, P = .002), chorioamnionitis (27% vs 11%, P = .03), prolonged rupture of membranes (26% vs 7%, P = .002), prolonged second stage of labor (25% vs 4%, P<.001), vacuum extraction (24% vs 11%, P = .04), cord abnormality (22% vs 6%, P = .01), preeclampsia (19% vs 5%, P = .01), and oligohydramnios (14% vs 3%, P = .01). Risk factors independently associated with PAS on multivariate analysis were history of infertility (odds ratio [OR], 7.5; 95% confidence interval [CI], 1.3-45.0), preeclampsia (OR, 5.3; 95% CI, 1.3-22.0), prolonged rupture of membranes (OR, 3.8; 95% CI, 1.1-12.8), and chorioamnionitis (OR, 3.4; 95% CI, 1.1-10.5). The rate of PAS increased dramatically when multiple risk factors were present.

Conclusions: Perinatal arterial ischemic stroke in infants is associated with several independent maternal risk factors. How these complications, along with their potential effects on the placenta and fetus, may play a role in causing perinatal stroke deserves further study.
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http://dx.doi.org/10.1001/jama.293.6.723DOI Listing
February 2005

Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study.

Arch Pediatr Adolesc Med 2005 Feb;159(2):151-7

Division of Research, Kaiser Foundation Research Institute, Kaiser Permanente, Oakland, Calif. 94612, USA.

Objective: To investigate the association between physician-documented diagnoses of maternal autoimmune diseases, allergies, and asthma around the time of pregnancy and subsequent diagnoses of autism in children.

Design: A case-control study nested within a cohort of infants born between January 1995 and June 1999.

Setting: Northern California Kaiser Permanente Medical Care Program.

Participants: Cases (n = 420) were children with at least 1 diagnosis of an autism spectrum disorder (ASD) recorded in Kaiser Permanente outpatient clinical databases. Controls (n = 2100) were children without an ASD diagnosis who were frequency matched to cases on sex, birth year, and hospital of birth.

Main Outcome Measures: Frequencies of maternal immunologic disorders were compared between cases and controls with a chi2 statistic, and relative risks were estimated by crude and adjusted odds ratios and 95% confidence intervals using logistic regression.

Results: The final study population included 407 cases and 2095 controls. A similar proportion of case and control mothers had a diagnosis of any autoimmune disease in the 4-year period surrounding pregnancy (10.3% vs 8.2%, P = .15). After adjustment for maternal factors, only 1 autoimmune condition, psoriasis, was significantly associated with ASDs (adjusted odds ratio, 2.7; 95% confidence interval, 1.3-5.8). A greater than 2-fold elevated risk of ASD was observed for maternal asthma and allergy diagnoses recorded during the second trimester of pregnancy.

Conclusions: These findings suggest that maternal autoimmune disorders present in women around the time of pregnancy are unlikely to contribute significantly to autism risk. Further etiologic investigations are needed to confirm these results and should include objective documentation of diagnoses and consider a larger set of maternal immune-related conditions, including asthma and allergies.
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http://dx.doi.org/10.1001/archpedi.159.2.151DOI Listing
February 2005

Neonatal hyperbilirubinemia and risk of autism spectrum disorders.

Pediatrics 2005 Feb;115(2):e135-8

Kaiser Permanente, Division of Research, 2000 Broadway, Oakland, CA 94612, USA.

Objective: To investigate the association between neonatal hyperbilirubinemia and autism spectrum disorders (ASD).

Methods: We conducted a large case-control study nested within the cohort of singleton term infants born between 1995 and 1998 at a northern California Kaiser Permanente hospital. Case subjects (n = 338) were children with an ASD diagnosis recorded in Kaiser Permanente outpatient databases; control subjects (n = 1817) were children without an ASD diagnosis, who were randomly sampled and frequency-matched to case subjects according to gender, birth year, and birth hospital.

Results: Approximately 28% of case and control subjects received > or =1 bilirubin test in the first 30 days of life. No case-control differences were observed for maximal bilirubin levels of > or =15 mg/dL (10.1% vs 12.1%), > or =20 mg/dL (2.1% vs 2.5%), or > or =25 mg/dL (0.3% vs 0.2%). Compared with children whose maximal neonatal bilirubin levels were <15 mg/dL or not measured, children with any degree of bilirubin level elevation were not at increased risk of ASD, after adjustment for gender, birth facility, maternal age, maternal race/ethnicity, maternal education, and gestational age (for bilirubin levels of 15-19.9 mg/dL: odds ratio: 0.7; 95% confidence interval: 0.5-1.2; for bilirubin levels of 20-24.9 mg/dL: odds ratio: 0.7; 95% confidence interval: 0.3-1.6; for bilirubin levels of > or =25 mg/dL: odds ratio: 1.1; 95% confidence interval: 0.1-11.2).

Conclusion: These data suggest that neonatal hyperbilirubinemia is not a risk factor for ASD.
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http://dx.doi.org/10.1542/peds.2004-1870DOI Listing
February 2005

Richardson score predicts short-term adverse respiratory outcomes in newborns >/=34 weeks gestation.

J Pediatr 2004 Dec;145(6):754-60

Kaiser Permanente Medical Care Program, Division of Research, Perinatal Research Unit, Oakland, California, USA.

Objectives: To develop a model to predict which newborns >/=34 weeks gestation with respiratory distress will die or will require prolonged (>3 days) assisted ventilation.

Methods: Retrospective cohort study using data from Northern California newborns >/=34 weeks gestation who presented with respiratory distress. We split the cohort into derivation and validation datasets. Bivariate and multivariate data analyses were performed on the derivation dataset. After developing a simple score on the derivation dataset, we applied it to the original as well as to a second validation dataset from Massachusetts.

Results: Of 2276 babies who met our initial eligibility criteria, 203 (9.3%) had the primary study outcome (assisted ventilation >3 days or death). A simple score based on gestational age, the lowest PaO 2 /FIO 2 , a variable combining lowest pH and highest PaCO 2 , and the lowest mean arterial blood pressure had excellent performance, with a c-statistic of 0.85 in the derivation dataset, 0.80 in the validation dataset, and 0.80 in the secondary validation dataset.

Conclusions: A simple objective score based on routinely collected physiologic predictors can predict respiratory outcomes in infants >/=34 weeks gestation with respiratory distress.
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http://dx.doi.org/10.1016/j.jpeds.2004.08.051DOI Listing
December 2004

Reproductive health counseling at pregnancy testing: a pilot study.

Contraception 2003 Nov;68(5):377-83

Adolescent Medicine, The Permanente Medical Group, 3400 Delta Fair Boulevard, Antioch, CA, USA.

Objectives: To pilot brief reproductive health counseling for women obtaining pregnancy testing in a managed-care setting who did not desire pregnancy.

Methods: Women received counseling, access to contraception and a booster call at 2 weeks. Changes in contraceptive behavior were evaluated.

Results: Of 85 women who completed counseling, 58 (68%) completed follow-up. Participants reported that counseling was useful at baseline (94%) and follow-up (83%). The staff found the intervention important (100%) and implementation feasible (100%). Forty-one percent of participants improved their use of contraception (from no use or from less effective use to more effective use). Twenty-nine percent continued highly effective use and 9% recessed from highly effective use. Of 22 participants with risk of sexually transmitted disease, 3 (14%) began using condoms consistently, while 1 (5%) continued using condoms consistently.

Conclusions: Counseling at pregnancy testing was well accepted by the staff and participants. Observed behavioral changes suggest that this intervention may be effective in increasing effective use of contraception.
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http://dx.doi.org/10.1016/j.contraception.2003.08.002DOI Listing
November 2003
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