Cathleen K. Yoshida

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

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 Brocas area (RR, 2.5; 95% CI, 1.3–5.0), internal capsule (RR, 2.2; 95% CI, 1.1–4.4), Wernickes 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. Ann Neurol 2005

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

BackgroundImmune 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.MethodsUsing 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.ResultsElevated 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.ConclusionThe 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.

Maternal Mid-Pregnancy Autoantibodies to Fetal Brain Protein: The Early Markers for Autism Study

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.

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

Neonatal hyperbilirubinemia and risk of autism spectrum disorders.

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 ≥1 bilirubin test in the first 30 days of life. No case-control differences were observed for maximal bilirubin levels of ≥15 mg/dL (10.1% vs 12.1%), ≥20 mg/dL (2.1% vs 2.5%), 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 ≥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.

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

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.

Congenital anomalies associated with autism spectrum disorders.

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).

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

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.

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

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.

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

BackgroundBiologic 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.ObjectiveTo investigate levels of cytokines and chemokines in newborn blood specimens as possible early biologic markers for autism.MethodsWe 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.ResultsCytokines 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.ConclusionMeasurement 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.