Types of diabetes during pregnancy and risk of depression and anxiety in offspring from childhood to young adulthood.

AIMS: To assess maternal pre-existing type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes mellitus (GDM) during pregnancy and risk of depression and anxiety from childhood to young adulthood in offspring. MATERIALS AND METHODS: This birth cohort included singletons born during 1995-2015, followed using electronic medical records through 2020. Cox regression was used to estimate hazard ratio (HR) of depression or anxiety diagnosis during follow-up associated with in-utero exposure to maternal diabetes. RESULTS: Among 439 590 offspring, 29 891 (6.8%) had depression and 51 918 (11.8%) had anxiety. T1D, followed by T2D and GDM requiring antidiabetes medication were associated with risk of depression and anxiety in offspring. Compared with no diabetes during pregnancy, the adjusted HRs (95% confidence interval) of depression in offspring associated with T1D, T2D or GDM requiring medications were 1.44 (1.09-1.91), 1.30 (1.15-1.47) and 1.18 (1.11-1.26) respectively; conversely, HRs were 0.97 (0.82-1.15) for T2D and 0.99 (0.94-1.04) for GDM without medications. The associations with anxiety followed similar patterns. The significant associations were observed for offspring ages 5-12 and >12-18 years and attenuated for 18-25 years. CONCLUSION: These data suggest that the severity of diabetes (T1D vs. T2D requiring medications vs. GDM requiring medications) during pregnancy may increase the vulnerability of offspring for depression or anxiety.

Prenatal Exposure to Source-Specific Fine Particulate Matter and Autism Spectrum Disorder.

In this study, associations between prenatal exposure to fine particulate matter (PM2.5) from 9 sources and development of autism spectrum disorder (ASD) were assessed in a population-based retrospective pregnancy cohort in southern California. The cohort included 318,750 mother-child singleton pairs. ASD cases (N = 4559) were identified by ICD codes. Source-specific PM2.5 concentrations were estimated from a chemical transport model with a 4 × 4 km2 resolution and assigned to maternal pregnancy residential addresses. Cox proportional hazard models were used to estimate the hazard ratios (HR) of ASD development for each individual source. We also adjusted for total PM2.5 mass and in a separate model for all other sources simultaneously. Increased ASD risk was observed with on-road gasoline (HR [CI]: 1.18 [1.13, 1.24]), off-road gasoline (1.15 [1.12, 1.19]), off-road diesel (1.08 [1.05, 1.10]), food cooking (1.05 [1.02, 1.08]), aircraft (1.04 [1.01, 1.06]), and natural gas combustion (1.09 [1.06, 1.11]), each scaled to standard deviation increases in concentration. On-road gasoline and off-road gasoline were robust for other pollutant groups. PM2.5 emitted from different sources may have different impacts on ASD. The results also identify PM source mixtures for toxicological investigations that may provide evidence for future public health policies.

Associations of Autism Spectrum Disorder with PM2.5 Components: A Comparative Study Using Two Different Exposure Models.

This retrospective cohort study examined associations of autism spectrum disorder (ASD) with prenatal exposure to major fine particulate matter (PM2.5) components estimated using two independent exposure models. The cohort included 318 750 mother-child pairs with singleton deliveries in Kaiser Permanente Southern California hospitals from 2001 to 2014 and followed until age five. ASD cases during follow-up (N = 4559) were identified by ICD codes. Prenatal exposures to PM2.5, elemental (EC) and black carbon (BC), organic matter (OM), nitrate (NO3-), and sulfate (SO42-) were constructed using (i) a source-oriented chemical transport model and (ii) a hybrid model. Exposures were assigned to each maternal address during the entire pregnancy, first, second, and third trimester. In single-pollutant models, ASD was associated with pregnancy-average PM2.5, EC/BC, OM, and SO42- exposures from both exposure models, after adjustment for covariates. The direction of effect estimates was consistent for EC/BC and OM and least consistent for NO3-. EC/BC, OM, and SO42- were generally robust to adjustment for other components and for PM2.5. EC/BC and OM effect estimates were generally larger and more consistent in the first and second trimester and SO42- in the third trimester. Future PM2.5 composition health effect studies might consider using multiple exposure models and a weight of evidence approach when interpreting effect estimates.

Low Rate of Cancer Detection by Colonoscopy in Asymptomatic, Average-Risk Subjects with Negative Results From Fecal Immunochemical Tests.

BACKGROUND & AIMS: Screening colonoscopies are of uncertain benefit for persons with negative results from a fecal immunochemical test (FIT). We investigated detection of CRC by colonoscopy in asymptomatic, average-risk, FIT-negative subjects. METHODS: We conducted a retrospective, population-based cohort study of 96,804 subjects with an initial negative result from a FIT at ages 50-75 years, from 2008 through 2014, who then underwent colonoscopy, using the Kaiser Permanente California databases. We identified participants diagnosed with CRC from January 1, 2008 through December 31, 2015 from a cancer registry. Subjects were followed until initial colonoscopy, health plan disenrollment, death, or December 31, 2015. We reviewed records from 400 randomly selected persons without CRC (controls) for risk features to estimate the proportion who underwent screening colonoscopy. We performed logistic regression to identify variables associated with CRC detection. RESULTS: Of 257 subjects with a diagnosis of CRC, 102 did not have a record of CRC risk factors; 86 of these patients (84.3%) had non-advanced-stage CRC (no regional node spread/distant metastases). Of the 400 controls, 299 (74.75%; 95% CI, 70.49%-79.01%) lacked CRC risk features, enabling estimation that 72,263 (mean age, 57.5 ± 7.0 y; 54.5% female) had undergone screening colonoscopy. CRC was detected in 1.4 per 1000 persons after 1 FIT, without association with increasing FITs (P = .97). CRC was detected in 1.3 per 1000 persons in 2 y or less after the last FIT and in 4.4 per 1000 persons more than 2 y after the last FIT (P < .001). When the last FIT was 2 y earlier or less, CRC increased from 0.7 per 1000 persons age 50-59 y to 3.1 per 1000 persons older than 70 y. Age and time from the last FIT were associated with CRC, with adjusted odds ratios of 1.08 (95% CI, 1.05-1.11) and 2.76 (95% CI, 1.28-5.95), respectively. CONCLUSIONS: In asymptomatic, average-risk persons with a negative result from a FIT, CRC is infrequent within 2 y after the last FIT (especially for persons younger than 60 y), usually non-advanced, and unrelated to the number of FITs performed.

Adjuvant Chemotherapy Does Not Improve Recurrence-Free Survival in Patients With Stage 2 or Stage 3 Rectal Cancer After Neoadjuvant Chemoradiotherapy and Total Mesorectal Excision.

BACKGROUND: Current guidelines for locally advanced stage 2/3 rectal cancer recommend neoadjuvant chemoradiotherapy followed by total mesorectal excision and adjuvant chemotherapy. The oncologic benefit of adjuvant chemotherapy has not been consistently demonstrated. OBJECTIVE: The purpose of this study was to evaluate disease recurrence and survival in patients with rectal cancer who received adjuvant chemotherapy after chemoradiotherapy and total mesorectal excision. DESIGN: This was a retrospective review of patients with stage 2/3 rectal cancer after chemoradiotherapy and surgery, based on receipt of adjuvant chemotherapy. SETTINGS: The study was conducted at the Kaiser Permanente Southern California system of 14 hospitals and associated clinics. PATIENTS: A total of 862 patients with stage 2/3 rectal cancer diagnosed and treated between January 1, 2005, and December 31, 2016, were included in this study. INTERVENTIONS: The study involved neoadjuvant chemoradiotherapy followed by total mesorectal excision with or without adjuvant chemotherapy. MAIN OUTCOME MEASURES: The primary end point was recurrence-free survival. RESULTS: A total of 348 stage 2 and 514 stage 3 patients were included; 660 patients (76.6%) underwent adjuvant chemotherapy. Mean patient follow-up after surgery was 63.0 months (range, 3-160). Multivariable analysis showed that yp stage (HR for yp stage 2 = 4.74; yp stage 3 = 8.83) and en bloc resection (HR = 1.76) were the only variables that significantly predicted disease recurrence. Neither pretreatment tumor stage nor receipt of adjuvant chemotherapy was significantly associated with recurrence-free survival. Log-rank testing failed to demonstrate significant recurrence-free survival improvement after receipt of adjuvant chemotherapy in any patient subgroup. LIMITATIONS: The study was limited by selection bias attributed to the nature of a retrospective study without patient randomization or predefined treatment protocol. CONCLUSIONS: In stage 2/3 rectal cancer treated with chemoradiotherapy and surgery, the addition of adjuvant chemotherapy was not associated with decreased recurrence-free survival in the entire cohort or in any subgroup, whereas tumor response to chemoradiotherapy is closely associated with disease recurrence. These findings have important consequences for treatment and surveillance decisions for patients with rectal cancer. Presurgical efforts that maximize tumor downstaging, such as total neoadjuvant therapy, may produce better oncologic outcomes than traditional adjuvant chemotherapy. See Video Abstract at http://links.lww.com/DCR/B134. LA QUIMIOTERAPIA ADYUVANTE NO MEJORA LA SOBREVIDA LIBRE DE RECURRENCIA EN PACIENTES CON CÁNCER DE RECTO ESTADÍOS II O III DESPUÉS DE RADIO-QUIMIOTERAPIA NEOADYUVANTE Y ESCISIÓN TOTAL DEL MESORRECTO: Las guías actuales para el tratamiento de cáncer rectal en estadio II-III localmente avanzado, recomiendan la radio-quimioterapia neoadyuvante con escisión total del mesorrecto seguidas de quimioterapia adyuvante. El beneficio oncológico de la quimioterapia adyuvante no ha sido demostrado de manera fehaciente.Evaluar la recurrencia y sobrevida a la enfermedad en pacientes con cáncer rectal que recibieron quimioterapia adyuvante después de radio-quimioterapia y escisión total del mesorrecto.Revisión retrospectiva de pacientes con cáncer rectal en estadios II-III después de radio-quimioterapia y cirugía, basada en la recepción de quimioterapia adyuvante.Sistema Permanente de Kaiser Sur-Californiano de 14 hospitales y clínicas asociadas.862 pacientes con cáncer rectal en estadio II-III diagnosticados y tratados entre el 1 de Enero 2005 y el 31 de Diciembre 2016.Radio-quimioterapia neoadyuvante seguida de escisión total del mesorrecto +/- quimioterapia adyuvante.El objetivo primario fue la sobrevida libre de recurrencia.Fueron incluidos 348 pacientes en estadio II y 514 en estadio III. 660 pacientes (76,6%) se sometieron a quimioterapia adyuvante. El seguimiento medio de cada paciente después de la cirugía fué de 63.0 meses (rango, 3-160). El análisis multivariable mostró que la etapa yp (Cociente de riesgo para estadío yp II = 4.74 y estadío yp III = 8.83) y la resección en bloque (Cociente de riesgo = 1.76) fueron las únicas variables que predijeron significativamente la recurrencia de la enfermedad. Ni el estadío tumoral previo al tratamiento ni la recepción de quimioterapia adyuvante se asociaron significativamente con la sobrevida libre de recurrencia. Las pruebas de rango logarítmico no pudieron demostrar una mejoría significativa de la sobrevida libre de recurrencia después de recibir quimioterapia adyuvante en cualquier subgrupo de pacientes.Sesgo de selección, debido al estudio retrospectivo sin aleatorización de los pacientes o protocolo de tratamiento predefinido.En casos de cáncer de recto estadíos II-III tratados con radio-quimioterapia y cirugía, la adición de quimioterapia adyuvante no se asoció con una disminución de la sobrevida libre de recurrencia en toda la cohorte o en ningún subgrupo, mientras que la respuesta tumoral a la radio-quimioterapia está estrechamente asociada con la recurrencia de la enfermedad. Estos hallazgos tienen consecuencias importantes en la decisión del tratamiento y la vigilancia en pacientes con cáncer de recto. Los esfuerzos pre-quirúrgicos que maximizan la reducción del tamaño del tumor, como la terapia neoadyuvante total, pueden producir mejores resultados oncológicos que la quimioterapia adyuvante tradicional. Consulte Video Resumen en http://links.lww.com/DCR/B134.

Trends in Adolescent Depression Screening Outcomes Over the COVID-19 Pandemic at a Large, Integrated Health Care System in Southern California.

PURPOSE: Little is known about changes in depression screening outcomes among adolescents in primary healthcare across the COVID-19 pandemic. We describe trends in depression screening outcomes within a large integrated health care system in Southern California. METHODS: Retrospective electronic health record data from preventative healthcare visits of 11-12-year-olds and 13-17-year-olds screened for depression from March 1, 2017, to August 31, 2022, were extracted in 6-month blocks. The percentages of screens meeting "threshold depression" were reported overall, and by sex, race or ethnicity, and median household income quintiles. We used Poisson regression to estimate rate ratios of threshold depression in 3 winter blocks (September to February) comparing lockdown (2020), reopening (2021) to a pre-COVID (2019) period, and reopening relative to lockdown. Disparities in trends by sex, race, or ethnicity and household income were tested using interaction terms. RESULTS: Of 735,333 visits with complete screening (183,550 for 11-12-year-olds and 551,783 for 13-17-year-olds), 4.6%, 6.5%, and 7.4% of 11-12-year-olds had "threshold depression" during winter blocks of pre-COVID, lockdown and reopening, respectively. The corresponding rates were 5.8%, 8.5%, and 9.8% for 13-17-year-olds. The rates were higher during lockdown and reopening relative to pre-COVID and higher during reopening relative to lockdown for both age groups (all p-values <.001). Trends differed by sex in both age groups (p-values <.001) and by race or ethnicity (p = .001) in the 13-17-year age group. DISCUSSION: Californian adolescents demonstrated an increase in threshold depression since COVID lockdown starting March 2020 with further increase observed during reopening in September 2021. Future studies are needed to determine the long-term trends.

Preeclampsia Onset, Days to Delivery, and Autism Spectrum Disorders in Offspring: Clinical Birth Cohort Study.

BACKGROUND: Maternal preeclampsia is associated with a risk of autism spectrum disorders (ASD) in offspring. However, it is unknown whether the increased ASD risk associated with preeclampsia is due to preeclampsia onset or clinical management of preeclampsia after onset, as clinical expectant management of preeclampsia allows pregnant women with this complication to remain pregnant for potentially weeks depending on the onset and severity. Identifying the risk associated with preeclampsia onset and exposure provides evidence to support the care of high-risk pregnancies and reduce adverse effects on offspring. OBJECTIVE: This study aimed to fill the knowledge gap by assessing the ASD risk in children associated with the gestational age of preeclampsia onset and the number of days from preeclampsia onset to delivery. METHODS: This retrospective population-based clinical cohort study included 364,588 mother-child pairs of singleton births between 2001 and 2014 in a large integrated health care system in Southern California. Maternal social demographic and pregnancy health data, as well as ASD diagnosis in children by the age of 5 years, were extracted from electronic medical records. Cox regression models were used to assess hazard ratios (HRs) of ASD risk in children associated with gestational age of the first occurrence of preeclampsia and the number of days from first occurrence to delivery. RESULTS: Preeclampsia occurred in 16,205 (4.4%) out of 364,588 pregnancies; among the 16,205 pregnancies, 2727 (16.8%) first occurred at <34 weeks gestation, 4466 (27.6%) first occurred between 34 and 37 weeks, and 9012 (55.6%) first occurred at ≥37 weeks. Median days from preeclampsia onset to delivery were 4 (IQR 2,16) days, 1 (IQR 1,3) day, and 1 (IQR 0,1) day for those first occurring at <34, 34-37, and ≥37 weeks, respectively. Early preeclampsia onset was associated with greater ASD risk (P=.003); HRs were 1.62 (95% CI 1.33-1.98), 1.43 (95% CI 1.20-1.69), and 1.23 (95% CI 1.08-1.41), respectively, for onset at <34, 34-37, and ≥37 weeks, relative to the unexposed group. Within the preeclampsia group, the number of days from preeclampsia onset to delivery was not associated with ASD risk in children; the HR was 0.995 (95% CI 0.986-1.004) after adjusting for gestational age of preeclampsia onset. CONCLUSIONS: Preeclampsia during pregnancy was associated with ASD risk in children, and the risk was greater with earlier onset. However, the number of days from first preeclampsia onset to delivery was not associated with ASD risk in children. Our study suggests that ASD risk in children associated with preeclampsia is not increased by expectant management of preeclampsia in standard clinical practice. Our results emphasize the need to identify effective approaches to preventing the onset of preeclampsia, especially during early pregnancy. Further research is needed to confirm if this finding applies across different populations and clinical settings.

Maternal obesity and diabetes during pregnancy and early autism screening score at well-child visits in standard clinical practice.

LAY ABSTRACT: Early intervention and treatment can help reduce disability in children diagnosed with autism spectrum disorder. Screening for autism spectrum disorder in young children identifies those at increased likelihood of diagnosis who may need further support. Previous research has reported that exposure to maternal obesity and diabetes during pregnancy is associated with higher likelihood of autism spectrum disorder diagnosis in children. However, little is known about whether these maternal conditions are associated with how very young children score on autism spectrum disorder screening tools. This study examined associations between exposure to maternal obesity and diabetes during pregnancy and offspring scores on the Quantitative Checklist for Autism in Toddlers, an autism spectrum disorder screening questionnaire administered between 18-24 months at well-child visits. A higher score on the Quantitative Checklist for Autism in Toddlers suggests a higher likelihood of autism spectrum disorder; children with scores 3 or greater are referred to developmental pediatricians for evaluation. Our study found that children of mothers with obesity or diabetes during pregnancy had higher scores than children whose mothers did not have these conditions. Associations with maternal obesity and gestational diabetes diagnosed at or before 26 weeks of pregnancy were also present in children who did not have later autism spectrum disorder diagnoses, suggesting that exposure to these conditions during early pregnancy may be associated with a broad range of social and behavioral abilities. Identifying associations between maternal health conditions and early Quantitative Checklist for Autism in Toddlers screening scores could influence future screening and provision of support for children of mothers with these conditions.

Neighborhood Disadvantage and Autism Spectrum Disorder in a Population With Health Insurance.

Importance: Family socioeconomic status has been associated with autism spectrum disorder (ASD) diagnoses. Less is known regarding the role of neighborhood disadvantage in the United States, particularly when children have similar access to health insurance. Objective: To evaluate the association between neighborhood disadvantage and the diagnosis of ASD and potential effect modification by maternal and child demographic characteristics. Design, Setting, and Participants: This cohort study examined a retrospective birth cohort from Kaiser Permanente Southern California (KPSC), an integrated health care system. Children born in 2001 to 2014 at KPSC were followed up through KPSC membership records. Electronic medical records were used to obtain an ASD diagnosis up to December 31, 2019, or the last follow-up. Data were analyzed from February 2022 to September 2023. Exposure: Socioeconomic disadvantage at the neighborhood level, an index derived from 7 US census tract characteristics using principal component analysis. Main Outcomes and Measures: Clinical ASD diagnosis based on electronic medical records. Associations between neighborhood disadvantage and ASD diagnosis were determined by hazard ratios (HRs) from Cox regression models adjusted for birth year, child sex, maternal age at delivery, parity, severe prepregnancy health conditions, maternal race and ethnicity, and maternal education. Effect modification by maternal race and ethnicity, maternal education, and child sex was assessed. Results: Among 318 372 mothers with singleton deliveries during the study period, 6357 children had ASD diagnoses during follow-up; their median age at diagnosis was 3.53 years (IQR, 2.57-5.34 years). Neighborhood disadvantage was associated with a higher likelihood of ASD diagnosis (HR, 1.07; 95% CI, 1.02-1.11, per IQR = 2.70 increase). Children of mothers from minoritized racial and ethnic groups (African American or Black, Asian or Pacific Islander, Hispanic or Latinx groups) had increased likelihood of ASD diagnosis compared with children of White mothers. There was an interaction between maternal race and ethnicity and neighborhood disadvantage (difference in log-likelihood = 21.88; P < .001 for interaction under χ24); neighborhood disadvantage was only associated with ASD among children of White mothers (HR, 1.17; 95% CI, 1.09-1.26, per IQR = 2.00 increase). Maternal education and child sex did not significantly modify the neighborhood-ASD association. Conclusions and Relevance: In this study, children residing in more disadvantaged neighborhoods at birth had higher likelihood of ASD diagnosis among a population with health insurance. Future research is warranted to investigate the mechanisms behind the neighborhood-related disparities in ASD diagnosis, alongside efforts to provide resources for early intervention and family support in communities with a higher likelihood of ASD.

Decomposing the variance: The unique and shared associations of fine and ultrafine particulate matter exposed during pregnancy with child autism spectrum disorder.

While fine particulate matter (PM2.5) has been associated with autism spectrum disorder (ASD), few studies focused on ultrafine particles (PM0.1). Given that fine and ultrafine particles can be highly correlated due to shared emission sources, challenges remain to distinguish their health effects. In a retrospective cohort of 318,371 mother-child pairs (4549 ASD cases before age 5) in Southern California, pregnancy average PM2.5 and PM0.1 were estimated using a California-based chemical transport model and assigned to residential addresses. The correlation between PM2.5 and PM0.1 was 0.87. We applied a two-step variance decomposition approach: first, decomposing PM2.5 and PM0.1 into the shared and unique variances using ordinary least squares linear regression (OLS) and Deming regression considering errors in both exposures; then assessing associations between decomposed PM2.5 and PM0.1 and ASD using Cox proportional hazard models adjusted for covariates. Prenatal PM2.5 and PM0.1 each was associated with increased ASD risk. OLS decomposition showed that associations were driven mainly by their shared variance, not by their unique variance. Results from Deming regression considering assumptions of measurement errors were consistent with those from OLS. This decomposition approach has potential to disentangle health effects of correlated exposures, such as PM2.5 and PM0.1 from common emissions sources.

Association of Labor Epidural Analgesia, Oxytocin Exposure, and Risk of Autism Spectrum Disorders in Children.

Importance: Maternal labor epidural analgesia (LEA) and oxytocin use for labor and delivery have been reported to be associated with child autism spectrum disorders (ASD). However, it remains unclear whether these 2 common medications used during labor and delivery have synergistic associations with ASD risk in children. Objective: To assess the independent associations of LEA and oxytocin during labor and delivery with ASD, as well as outcome modification associated with the concurrent use of both interventions. Design, Setting, and Participants: Data for this cohort study included 205 994 singleton births with vaginal deliveries in a single integrated health care system in Southern California from calendar years 2008 to 2017. Children were followed up to December 31, 2021. Data on use of LEA and oxytocin, covariates, and ASD outcome in children were obtained from electronic medical records. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) adjusting for covariates. Exposures: Labor epidural analgesia and/or oxytocin use during labor and delivery. Main Outcomes and Measures: A child's clinical diagnosis of ASD during follow-up and at age of diagnosis. Results: Among the cohort, 153 880 children (74.7%) were exposed to maternal LEA and 117 808 children (57.2%) were exposed to oxytocin during labor and delivery. The population of children was approximately half boys and half girls. The median (IQR) age of the mothers was 30.8 (26.8-34.5) years for those not exposed to LEA, 30.0 (25.9-33.8) years for those exposed to LEA, 30.4 (26.5-34.1) years for those unexposed to oxytocin, and 30.0 (25.9-33.9) years for those exposed to oxytocin during labor and delivery. A total of 5146 children (2.5%) had ASD diagnosed during follow-up. Oxytocin exposure was higher among LEA-exposed (67.7%) than -unexposed (26.1%) children. The ASD risk associated with LEA was independent of oxytocin exposure (HR, 1.28; 95% CI, 1.18-1.38); however, the ASD risk associated with oxytocin was not significant after adjusting for LEA exposure (HR, 1.05; 95% CI, 0.99-1.12). A significant interaction of LEA and oxytocin on child ASD risk was found (P = .02 for interaction). Compared with no exposure, HRs were 1.20 (95% CI, 1.09-1.32) for LEA alone, 1.30 (95% CI, 1.20-1.42) for both LEA and oxytocin, and 0.90 (95% CI, 0.78-1.04) for oxytocin alone. Conclusions and Relevance: The findings of this cohort study suggest an association between maternal LEA and ASD risk in children, and the risk appeared to be further increased if oxytocin was also administered. Oxytocin exposure without LEA exposure was not associated with ASD risk in children. These findings must be interpreted with caution. Further studies are needed to replicate or refute the study results and examine biological plausibility.

Maternal obesity, diabetes, preeclampsia, and asthma during pregnancy and likelihood of autism spectrum disorder with gastrointestinal disturbances in offspring.

LAY ABSTRACT: Autism spectrum disorder is heterogeneous and often accompanied by co-occurring conditions. Previous studies have shown that maternal health conditions during pregnancy including obesity, diabetes, preeclampsia, and asthma were associated with increased likelihood of autism. However, little has been done examining the likelihood associated with autism with co-occurring conditions. This study assessed these maternal health conditions in relationship to autism and gastrointestinal disturbances, a common co-occurring condition in children diagnosed with autism. Data included 308,536 mother-child pairs from one integrated health care system with comprehensive electronic medical records. Among the study cohort, 5,131 (1.7%) children had a diagnosis of autism by age 5. Gastrointestinal disturbances were present in 35.4% of children diagnosed with autism and 25.1% of children without autism diagnoses. Our results showed that each of the four maternal health conditions during pregnancy was associated with increased likelihood of gastrointestinal disturbances, autism without gastrointestinal disturbances, and autism with gastrointestinal disturbances. For all four maternal health conditions, the association was greatest for likelihood of autism with gastrointestinal disturbances. Given that children diagnosed with autism are more likely to have gastrointestinal disturbances and over 80% of gastrointestinal disturbances in this cohort were diagnosed prior to autism diagnosis, this study suggests that there may be common biological pathways between autism and gastrointestinal disturbances impacted by these maternal exposures. Future studies are warranted to assess associations between different exposures and autism with other co-occurring conditions to increase our understanding of autism heterogeneity.

Prenatal exposure to tailpipe and non-tailpipe tracers of particulate matter pollution and autism spectrum disorders.

BACKGROUND: Traffic-related air pollution exposure is associated with increased risk of autism spectrum disorder (ASD). It is unknown whether carbonaceous material from vehicular tailpipe emissions or redox-active non-tailpipe metals, eg. from tire and brake wear, are responsible. We assessed ASD associations with fine particulate matter (PM2.5) tracers of tailpipe (elemental carbon [EC] and organic carbon [OC]) and non-tailpipe (copper [Cu]; iron [Fe] and manganese [Mn]) sources during pregnancy in a large cohort. METHODS: This retrospective cohort study included 318,750 children born in Kaiser Permanente Southern California (KPSC) hospitals during 2001-2014, followed until age 5. ASD cases were identified by ICD codes. Monthly estimates of PM2.5 and PM2.5 constituents EC, OC, Cu, Fe, and Mn with 4 km spatial resolution were obtained from a source-oriented chemical transport model. These exposures and NO2 were assigned to each maternal address during pregnancy, and associations with ASD were assessed using Cox regression models adjusted for covariates. PM constituent effect estimates were adjusted for PM2.5 and NO2 to assess independent effects. To distinguish ASD risk associated with non-tailpipe from tailpipe sources, the associations with Cu, Fe, and Mn were adjusted for EC and OC, and vice versa. RESULTS: There were 4559 children diagnosed with ASD. In single-pollutant models, increased ASD risk was associated with gestational exposures to tracers of both tailpipe and non-tailpipe emissions. The ASD hazard ratios (HRs) per inter-quartile increment of exposure) for EC, OC, Cu, Fe, and Mn were 1.11 (95% CI: 1.06-1.16), 1.09 (95% CI: 1.04-1.15), 1.09 (95% CI: 1.04-1.13), 1.14 (95% CI: 1.09-1.20), and 1.17 (95% CI: 1.12-1.22), respectively. Estimated effects of Cu, Fe, and Mn (reflecting non-tailpipe sources) were largely unchanged in two-pollutant models adjusting for PM2.5, NO2, EC or OC. In contrast, ASD associations with EC and OC were markedly attenuated by adjustment for non-tailpipe sources. CONCLUSION: Results suggest that non-tailpipe emissions may contribute to ASD. Implications are that reducing tailpipe emissions, especially from vehicles with internal combustion engines, may not eliminate ASD associations with traffic-related air pollution.

Maternal exposure to aircraft emitted ultrafine particles during pregnancy and likelihood of ASD in children.

BACKGROUND: There is increasing evidence for adverse health effects associated with aircraft-emitted particulate matter (PM) exposures, which are largely in the ultrafine (PM0.1) size fraction, but no previous study has examined neurodevelopmental outcomes. OBJECTIVE: To assess associations between maternal exposure to aircraft ultrafine particles (UFP) during pregnancy and offspring autism spectrum disorder (ASD) diagnosis. METHODS: This large, representative cohort study included 370,723 singletons born in a single healthcare system. Demographic data, maternal health information, and child's ASD diagnosis by age 5 were extracted from electronic medical records. Aircraft exposure estimates for PM0.1 were generated by the University of California Davis/California Institute of Technology Source Oriented Chemical Transport model. Cox proportional hazard models were used to assess associations between maternal exposure to aircraft PM0·1 in pregnancy and ASD diagnosis, controlling for covariates. RESULTS: Over the course of follow-up, 4,554 children (1.4 %) were diagnosed with ASD. Increased risk of ASD was associated with maternal exposure to aircraft PM0.1 [hazard ratio, HR: 1.02, (95 % confidence interval (CI): 1.01-1.03) per IQR = 0.02 µg/m3 increase during pregnancy. Associations were robust to adjustment for total PM0.1 and fine particulate matter (PM2.5), near-roadway air pollution, and other covariates. Noise adjustment modestly attenuated estimates of UFP effects, which remained statistically significant. DISCUSSION: The results strengthen the emerging evidence that maternal particulate matter exposure during pregnancy is associated with offspring ASD diagnosis and identify aircraft-derived PM0.1 as novel targets for further study and potential regulation.

Prenatal air pollution, maternal immune activation, and autism spectrum disorder.

BACKGROUND: Autism Spectrum Disorder (ASD) risk is highly heritable, with potential additional non-genetic factors, such as prenatal exposure to ambient particulate matter with aerodynamic diameter < 2.5 µm (PM2.5) and maternal immune activation (MIA) conditions. Because these exposures may share common biological effect pathways, we hypothesized that synergistic associations of prenatal air pollution and MIA-related conditions would increase ASD risk in children. OBJECTIVES: This study examined interactions between MIA-related conditions and prenatal PM2.5 or major PM2.5 components on ASD risk. METHODS: In a population-based pregnancy cohort of children born between 2001 and 2014 in Southern California, 318,751 mother-child pairs were followed through electronic medical records (EMR); 4,559 children were diagnosed with ASD before age 5. Four broad categories of MIA-related conditions were classified, including infection, hypertension, maternal asthma, and autoimmune conditions. Average exposures to PM2.5 and four PM2.5 components, black carbon (BC), organic matter (OM), nitrate (NO3-), and sulfate (SO42-), were estimated at maternal residential addresses during pregnancy. We estimated the ASD risk associated with MIA-related conditions, air pollution, and their interactions, using Cox regression models to adjust for covariates. RESULTS: ASD risk was associated with MIA-related conditions [infection (hazard ratio 1.11; 95% confidence interval 1.05-1.18), hypertension (1.30; 1.19-1.42), maternal asthma (1.22; 1.08-1.38), autoimmune disease (1.19; 1.09-1.30)], with higher pregnancy PM2.5 [1.07; 1.03-1.12 per interquartile (3.73 µg/m3) increase] and with all four PM2.5 components. However, there were no interactions of each category of MIA-related conditions with PM2.5 or its components on either multiplicative or additive scales. CONCLUSIONS: MIA-related conditions and pregnancy PM2.5 were independently associations with ASD risk. There were no statistically significant interactions of MIA conditions and prenatal PM2.5 exposure with ASD risk.

In utero exposure to near-roadway air pollution and autism spectrum disorder in children.

IMPORTANCE: Previous studies have reported associations between in utero exposure to regional air pollution and autism spectrum disorders (ASD). In utero exposure to components of near-roadway air pollution (NRAP) has been linked to adverse neurodevelopment in animal models, but few studies have investigated NRAP association with ASD risk. OBJECTIVE: To identify ASD risk associated with in utero exposure to NRAP in a large, representative birth cohort. DESIGN, SETTING, AND PARTICIPANTS: This retrospective pregnancy cohort study included 314,391 mother-child pairs of singletons born between 2001 and 2014 at Kaiser Permanente Southern California (KPSC) hospitals. Maternal and child data were extracted from KPSC electronic medical records. Children were followed until: clinical diagnosis of ASD, non-KPSC membership, death, or December 31, 2019, whichever came first. Exposure to the complex NRAP mixture during pregnancy was assessed using line-source dispersion models to estimate fresh vehicle emissions from freeway and non-freeway sources at maternal addresses during pregnancy. Vehicular traffic load exposure was characterized using advanced telematic models combining traditional traffic counts and travel-demand models with cell phone and vehicle GPS data. Cox proportional-hazard models estimated hazard ratios (HR) of ASD associated with near-roadway traffic load and dispersion-modeled NRAP during pregnancy, adjusted for covariates. Non-freeway NRAP was analyzed using quintile distribution due to nonlinear associations with ASD. EXPOSURES: Average NRAP and traffic load exposure during pregnancy at maternal residential addresses. MAIN OUTCOMES: Clinical diagnosis of ASD. RESULTS: A total of 6,291 children (5,114 boys, 1,177 girls) were diagnosed with ASD. The risk of ASD was associated with pregnancy-average exposure to total NRAP [HR(95% CI): 1.03(1.00,1.05) per 5 ppb increase in dispersion-modeled NOx] and to non-freeway NRAP [HR(95% CI) comparing the highest to the lowest quintile: 1.19(1.11, 1.27)]. Total NRAP had a stronger association in boys than in girls, but the association with non-freeway NRAP did not differ by sex. The association of freeway NRAP with ASD risk was not statistically significant. Non-freeway traffic load exposure demonstrated associations with ASD consistent with those of NRAP and ASD. CONCLUSIONS: In utero exposure to near-roadway air pollution, particularly from non-freeway sources, may increase ASD risk in children.

Treatment Course of Patients with Exudative Age-Related Macular Degeneration Using Ocular Hypotensives.

PURPOSE: To characterize the visual outcomes and the treatment course of patients with exudative age-related macular degeneration (AMD) based on ocular hypotensive use. DESIGN: A matched retrospective cohort study of patients enrolled in Kaiser Permanente Southern California health plan was conducted. Patients taking ocular hypotensives were identified using pharmacy dispensing data and were matched to controls to compare visual acuity, number of anti-VEGF injections, and conversation to secondary anti-VEGF agents in the first year of treatment. Subgroup analysis was performed based on the number of ocular hypotensive agents (0, 1, 2 or 3+ agents) and drug class (aqueous suppressants and prostaglandin analogs). RESULTS: A total of 234 patients patients were examined. Baseline and final visual acuity did not significantly differ between drop users and controls, including on subgroup analysis. The average number of anti-VEGF injections did not differ between drop users and controls (6.1 vs 6.2, p=0.97), nor did the percentage of patients who were switched to a second-line anti-VEGF agent (23.9% vs 17.9%, p=0.26). Subgroup analysis did not reveal significant differences in the number of anti-VEGF injections and the percentage of patients switched to secondary agents, with patients receiving 6 ±1 injections across regardless of the number or class of ocular hypotensive agents used. CONCLUSION: Patients with concurrent glaucoma and exudative AMD have similar visual outcomes and treatment courses compared to those not taking ocular hypotensives. Although aqueous suppressants have been suggested to prolong anti-VEGF residence time, patients using these agents did not demonstrate visual benefit or a reduced injection burden in this series.

Association Between Epidural Analgesia During Labor and Risk of Autism Spectrum Disorders in Offspring.

Importance: Although the safety of labor epidural analgesia (LEA) for neonates has been well documented, the long-term health effects of LEA on offspring remain to be investigated. Objective: To assess the association between maternal LEA exposure and risk of autism spectrum disorders (ASDs) in offspring. Design, Setting, and Participants: Data for this retrospective longitudinal birth cohort study were derived from electronic medical records from a population-based clinical birth cohort. A total of 147 895 singleton children delivered vaginally between January 1, 2008, and December 31, 2015, in a single integrated health care system were included. Children were followed up from the age of 1 year until the first date of the following occurrences: clinical diagnosis of ASD, last date of health plan enrollment, death, or the study end date of December 31, 2018. Exposures: Use and duration of LEA. Main Outcomes and Measures: The main outcome was clinical diagnosis of ASD. Cox proportional hazards regression analysis was used to estimate the hazard ratio (HR) of ASD associated with LEA exposure. Results: Among the cohort of 147 895 singleton children (74 425 boys [50.3%]; mean [SD] gestational age at delivery, 38.9 [1.5] weeks), 109 719 (74.2%) were exposed to maternal LEA. Fever during labor was observed in 13 055 mothers (11.9%) in the LEA group and 510 of 38 176 mothers (1.3%) in the non-LEA group. Autism spectrum disorders were diagnosed in 2039 children (1.9%) in the LEA group and 485 children (1.3%) in the non-LEA group. After adjusting for potential confounders, including birth year, medical center, maternal age at delivery, parity, race/ethnicity, educational level, household income, history of comorbidity, diabetes during pregnancy, smoking during pregnancy, preeclampsia or eclampsia, prepregnancy body mass index, gestational weight gain, gestational age at delivery, and birth weight, the HR associated with LEA vs non-LEA exposure was 1.37 (95% CI, 1.23-1.53). Relative to the unexposed group, the adjusted HR associated with LEA exposure of less than 4 hours was 1.33 (95% CI, 1.17-1.53), with LEA exposure of 4 to 8 hours was 1.35 (95% CI, 1.20-1.53), and with LEA exposure of more than 8 hours was 1.46 (95% CI, 1.27-1.69). Within the LEA group, there was a significant trend of ASD risk associated with increasing duration of LEA exposure after adjusting for covariates (HR for linear trend, 1.05 [95% CI, 1.01-1.09] per 4 hours). Adding fever to the model did not change the HR estimate associated with LEA exposure (adjusted HR for LEA vs non-LEA, 1.37 [95% CI, 1.22-1.53]). Conclusions and Relevance: This study suggests that maternal LEA may be associated with increased ASD risk in children. The risk appears to not be directly associated with epidural-related maternal fever.

Radical Prostatectomy and Pelvic Lymph Node Dissection in Kaiser Permanente Southern California: 15-Year Experience.

INTRODUCTION: Radical prostatectomy (RP) with pelvic lymph node dissection (PLND) is the standard treatment of high-risk prostate cancer. High-risk patients and those with lymph node metastasis (LNM) require further treatment. We review outcomes of RP+PLND in Kaiser Permanente Southern California (KPSC). METHODS: Patients who underwent RP+PLND in KPSC from January 1, 2001, to July 1, 2015 were included. Patient charts were retrospectively reviewed for demographic information and clinicopathologic data which were used to calculate positive surgical margin rate, LNM, adjuvant treatment, 5-year biochemical recurrence, and overall survival. Univariate and multivariate logistic regression analyses were used to identify factors associated with margin positivity. RESULTS: Patients (N = 1829) underwent RP+PLND (241 high-risk, 943 intermediate-risk, 645 low-risk). Positive margin rates were 17.8%, 14.8%, and 11.9% in the high, intermediate- and low-risk groups. Biochemical recurrence rates were 22% in high-risk and 12.1% in the low-risk category. Androgen deprivation use was 4.1% in the high-risk group and 0.9% in the low-risk group. Five-year overall survival was 92.5% in lymph node-positive patients and 94.9% in lymph node-negative patients (p = 0.8). On multivariate analysis, age (odds ratio [OR] = 1.02, p = 0.02), prebiopsy prostate-specific antigen (OR = 1.02, p < 0.001), and clinical T stage (OR = 1.49, p = 0.01) were associated with margin positivity. CONCLUSION: In KPSC, RP+PLND was performed in patients with low-, intermediate-, and high-risk prostate cancer. Age, prebiopsy prostate-specific antigen, and clinical stage were associated with positive surgical margins in patients with LNM. Recipients of RP+PLND with LNM and positive surgical margins required adjuvant treatment.

Differences in Health Care Utilization in the Year Before Suicide Death: A Population-Based Case-Control Study.

OBJECTIVE: To compare health care usage between suicide decedents and living controls in the year before suicide in a large representative US population. PATIENTS AND METHODS: Cases (n=1221) and controls (n=3663) belonged to an integrated health care system from January 1, 2009, through December 31, 2014. Cases and controls were matched for age and sex in a 1:3 ratio, with diagnostic and/or billing codes used to enumerate and classify health care visits in the year before the index suicide. Matched analysis via conditional logistic regression related odds of suicide to visit type. A generalized estimating equation model was used to compare timing and frequency of visits between cases and controls. RESULTS: In the year before death, cases had an increased odds of both inpatient hospitalizations and emergency department nonmental health visits (odds ratio [OR], 1.55; 95% CI, 1.27-1.88; P<.001 and OR, 1.42; 95% CI, 1.26-1.60; P<.001) but not outpatient nonmental health visits (OR, 1.00; 95% CI, 0.99-1.01; P=.63). Decedents increased health care utilization closer to suicide death and had significantly more health care visits than did controls 3 months before suicide (6 vs 2; P=.01) but not 9 to 12 months before suicide (4 vs 2; P=.07). At all time points, cases used more mental health care services than did controls. CONCLUSION: Compared with controls, suicide decedents had emergency department visits and more inpatient hospitalizations, both mental health and nonmental health related. As death approached, cases' frequency of health care usage increased. The only category in which cases and controls did not differ was in the frequency of outpatient nonmental health visits.