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.

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.

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.

Exposure to Gestational Diabetes Mellitus Prior to 26 Weeks Is Related to the Presence of Mediobasal Hypothalamic Gliosis in Children.

Intrauterine exposure to metabolic dysfunction leads to offspring metabolic dysfunction in human and rodent models, but underlying mechanisms are unclear. The mediobasal hypothalamus (MBH) is involved in energy homeostasis and weight regulation, and MBH gliosis is associated with obesity and insulin resistance. We tested the hypothesis that offspring exposed to gestational diabetes mellitus (GDM) in utero versus those unexposed would show evidence of MBH gliosis. Participants in the BrainChild Study (age 7-11 years with confirmed GDM exposure or no GDM exposure) underwent brain MRI to acquire T2-weighted images. By using the amygdala (AMY) and white matter (WM) as reference regions, MBH:AMY and MBH:WM T2 signal ratios were calculated as a radiologic measure of MBH gliosis. Linear regressions were used to examine associations between GDM exposure (GDM overall) and by timing of GDM exposure (≤26 weeks or >26 weeks) and MBH gliosis. Associations between prepregnancy BMI and child MBH gliosis were examined in secondary analyses. There were no differences in T2 signal ratios in children exposed versus not exposed to GDM overall, but children exposed to early GDM (≤26 weeks of gestation) had higher MBH:WM signal ratios than those not exposed (ß = 0.147; SE 0.06; P = 0.03), adjusting for child's age, sex, and BMI z score and maternal prepregnancy BMI, whereas no associations were seen for the control ratio (AMY:WM). Prepregnancy BMI was not associated with evidence of MBH gliosis. Early exposure to GDM was associated with radiologic evidence of MBH gliosis in children. These data provide mechanistic insight into brain pathways by which exposure to GDM may increase risk for metabolic dysfunction.

Ambient air pollution and COVID-19 incidence during four 2020-2021 case surges.

BACKGROUND: Air pollution exposure may make people more vulnerable to COVID-19 infection. However, previous studies in this area mostly focused on infection before May 2020 and long-term exposure. OBJECTIVE: To assess both long-term and short-term exposure to air pollution and COVID-19 incidence across four case surges from 03/1/2020 to 02/28/2021. METHODS: The cohort included 4.6 million members from a large integrated health care system in southern California with comprehensive electronic medical records (EMR). COVID-19 cases were identified from EMR. Incidence of COVID-19 was computed at the census tract-level among members. Prior 1-month and 1-year averaged air pollutant levels (PM2.5, NO2, and O3) at the census tract-level were estimated based on hourly and daily air quality data. Data analyses were conducted by each wave: 3/1/2020-5/31/2020, 6/1/202-9/30/2020, 10/1/2020-12/31/2020, and 1/1/2021-2/28/2021 and pooled across waves using meta-analysis. Generalized linear mixed effects models with Poisson distribution and spatial autocorrelation were used with adjustment for meteorological factors and census tract-level social and health characteristics. Results were expressed as relative risk (RR) per 1 standard deviation. RESULTS: The cohort included 446,440 COVID-19 cases covering 4609 census tracts. The pooled RRs (95% CI) of COVID-19 incidence associated with 1-year exposures to PM2.5, NO2, and O3 were 1.11 (1.04, 1.18) per 2.3 µg/m3,1.09 (1.02, 1.17) per 3.2 ppb, and 1.06 (1.00, 1.12) per 5.5 ppb respectively. The corresponding RRs (95% CI) associated with prior 1-month exposures were 1.11 (1.03, 1.20) per 5.2 µg/m3 for PM2.5, 1.09 (1.01, 1.17) per 6.0 ppb for NO2 and 0.96 (0.85, 1.08) per 12.0 ppb for O3. CONCLUSION: Long-term PM2.5 and NO2 exposures were associated with increased risk of COVID-19 incidence across all case surges before February 2021. Short-term PM2.5 and NO2 exposures were also associated. Our findings suggest that air pollution may play a role in increasing the risk of COVID-19 infection.

Asthma Disease Status, COPD, and COVID-19 Severity in a Large Multiethnic Population.

BACKGROUND: Current studies of asthma history on coronavirus disease 2019 (COVID-19) outcomes are limited and lack consideration of disease status. OBJECTIVE: To conduct a population-based study to assess asthma disease status and chronic obstructive pulmonary disease (COPD) in relation to COVID-19 severity. METHODS: Patients diagnosed with COVID-19 (n = 61,338) in a large, diverse integrated health care system were identified. Asthma/COPD history, medication use, and covariates were extracted from electronic medical records. Asthma patients were categorized into those with and without clinical visits for asthma 12 or fewer months prior to COVID-19 diagnosis and labeled as active and inactive asthma, respectively. Primary outcomes included COVID-19-related hospitalizations, intensive respiratory support (IRS), and intensive care unit admissions within 30 days, and mortality within 60 days after COVID-19 diagnosis. Logistic and Cox regression were used to relate COVID-19 outcomes to asthma/COPD history. RESULTS: The cohort was 53.9% female and 66% Hispanic and had a mean age of 43.9 years. Patients with active asthma had increased odds of hospitalization, IRS, and intensive care unit admission (odds ratio 1.47-1.66; P < .05) compared with patients without asthma or COPD. No increased risks were observed for patients with inactive asthma. Chronic obstructive pulmonary disease was associated with increased risks of hospitalization, IRS, and mortality (odds ratio and hazard ratio 1.27-1.67; P < .05). Among active asthma patients, those using asthma medications had greater than 25% lower odds for COVID-19 outcomes than those without medication. CONCLUSIONS: Patients with asthma who required clinical care 12 or fewer months prior to COVID-19 or individuals with COPD history are at increased risk for severe COVID-19 outcomes. Proper medication treatment for asthma may lower this risk.

Types of diabetes during pregnancy and longitudinal BMI in offspring from birth to age 10 years.

OBJECTIVE: To examine longitudinal BMI trajectory from birth to age 10 years in a clinical cohort after exposure to maternal pre-existing type 1 (T1D), type 2 (T2D), gestational diabetes managed with or without anti-diabetes medication, and no diabetes during pregnancy. METHODS: Data included 218 227 singleton children born in 2008-2015 from a population-based integrated healthcare system; 537 exposed to maternal T1D, 7836 to T2D, 6982 to medicated GDM and 12 576 to unmedicated GDM. Differences in BMI over time among groups were assessed by non-linear mixed-effects models adjusting for covariates. RESULTS: Children's BMI was significantly lower 6-months after birth for all diabetes exposed groups compared to no diabetes. Beginning at approximately age 2.5 years, BMI was significantly higher for T1D, T2D and medicated GDM groups compared to the no diabetes group. At age 3, the growth pattern started separating with highest BMI in T1D and T2D groups, followed by medicated GDM, unmedicated GDM, and the no diabetes groups. By age 7, BMI was significantly higher for the unmedicated GDM group compared to the no diabetes group. Adjusted BMI was generally comparable between T1D and T2D groups for all ages. Starting at age 5, T1D, T2D and medicated GDM groups had BMI greater than one SD over the BMI in the no diabetes group. CONCLUSION: In a clinical cohort with standard diabetes management approaches, a hierarchical BMI growth pattern exists in offspring exposed to different types of diabetes during pregnancy after adjusting for important covariates, starting as early as age 3 years.

Intrapartum Antibiotic Exposure and Body Mass Index in Children.

BACKGROUND: Intrapartum antibiotic prophylaxis (IAP) reduces a newborn's risk of group B streptococcal infection (GBS) but may lead to an increased childhood body mass index (BMI). METHODS: This was a retrospective cohort study of infants (n = 223 431) born 2007-2015 in an integrated healthcare system. For vaginal delivery, we compared children exposed to GBS-IAP and to any other type or duration of intrapartum antibiotics to no antibiotic exposure. For cesarean delivery, we compared children exposed to GBS-IAP to those exposed to all other intrapartum antibiotics, including surgical prophylaxis. BMI over 5 years was compared using nonlinear multivariate models with B-spline functions, stratified by delivery mode and adjusted for demographics, maternal factors, breastfeeding, and childhood antibiotic exposure. RESULTS: In vaginal deliveries, GBS-IAP was associated with higher BMI from 0.5 to 5.0 years of age compared to no antibiotics (P < .0001 for all time points, ΔBMI at age 5 years 0.12 kg/m2, 95% confidence interval [CI]: .07-.16 kg/m2). Other antibiotics were associated with higher BMI from 0.3 to 5.0 years of age. In cesarean deliveries, GBS-IAP was associated with increased BMI from 0.7 years to 5.0 years of age (P < .05 for 0.7-0.8 years, P < .0001 for all other time points) compared to other antibiotics (ΔBMI at age 5 years 0.24 kg/m2, 95% CI: .14-.34 kg/m2). Breastfeeding did not modify these associations. CONCLUSIONS: GBS-IAP was associated with a small but sustained increase in BMI starting at very early age. This association highlights the need to better understand the effects of perinatal antibiotic exposure on childhood health.

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.

Seafood, fatty acid biosynthesis genes, and multiple sclerosis susceptibility.

BACKGROUND: The role of omega-3 fatty acid in multiple sclerosis (MS) susceptibility is unclear. OBJECTIVE: To determine whether fish/seafood intake or genetic factors that regulate omega-3 fatty acids levels are associated with MS risk. METHODS: We examined the association of fish and shrimp consumption and 13 tag single nucleotide polymorphisms (SNPs) in FADS1, FADS2, and ELOV2 with risk of MS in 1153 individuals from the MS Sunshine Study, a case-control study of incident MS or clinically isolated syndrome (CIS), recruited from Kaiser Permanente Southern California. RESULTS: Consuming fish/seafood at least once a week or at least once a month with regular fish oil use was associated with 44% reduced odds of MS/CIS (adjusted OR = 0.56; 95% CI = 0.41-0.76; p = 0.0002) compared with consuming fish/seafood less than once a month and no fish oil supplementation. Two FADS2 SNPs (rs174611 and rs174618) were independently associated with a lower risk of MS (adjusted ORs = 0.74, 0.79, p = 0.0056, 0.0090, respectively). Association of FADS2 SNPs with MS risk was confirmed in an independent dataset. CONCLUSION: These findings suggest that omega-3 fatty acid intake may be an important modifiable risk factor for MS. This is consistent with the other known health benefits of fish consumption and complementary genetic studies supporting a key role for omega-3 regulation.

Maternal Gestational Diabetes and Type 2 Diabetes During Pregnancy and Risk of Childhood Asthma in Offspring.

OBJECTIVE: To examine maternal preexisting type 2 diabetes (T2D) and gestational diabetes mellitus (GDM) on risk of childhood asthma. STUDY DESIGN: This retrospective birth cohort study included 97 554 singletons born in 2007-2011 within hospitals from a single integrated healthcare system. Children were prospectively followed from age 5 until December 31, 2017, using electronic medical records. Relative risks of childhood asthma associated with maternal diabetes in utero were estimated by hazard ratios using Cox regression adjusting for potential confounders. RESULTS: There were 3119 children (3.2%) who were exposed to preexisting T2D and 9836 (10.1%) to GDM. Among mothers with GDM, 3380 (34.4%) were dispensed antidiabetic medication during pregnancy. During a median of 7.6 years (IQR, 6.3-9.0 years) after birth, 15 125 children (15.5%) were diagnosed with asthma after age 5. Maternal diabetes interacted with maternal asthma history to affect child's asthma risk (P = .05). Among children without maternal asthma (n = 89 487), the adjusted hazard ratios for childhood asthma were 1.21 (95% CI, 1.08-1.36; P < .001) for exposure to T2D, 1.12 (95% CI, 1.01-1.25; P = .04) for GDM requiring antidiabetic medications, and 1.01 (95% CI, 0.93-1.10; P = .82) for GDM not requiring medications compared with no diabetes during pregnancy. The corresponding hazard ratios were 1.53 (95% CI, 1.19-1.96; P < .001), 1.11 (95% CI, 0.65-1.46; P = .44), and 0.84 (95% CI, 0.66-1.08; P = .17) among children without maternal asthma (n = 8067). Gestational age at GDM diagnosis was not associated with childhood asthma (P = .27). CONCLUSIONS: The risk of childhood asthma was predominately observed for exposure to preexisting T2D, small for GDM requiring medication, and not increased for GDM not requiring medication during pregnancy, compared with no diabetes during pregnancy.

Children Exposed to Maternal Obesity or Gestational Diabetes Mellitus During Early Fetal Development Have Hypothalamic Alterations That Predict Future Weight Gain.

OBJECTIVE: Exposure in utero to maternal obesity or gestational diabetes mellitus (GDM) is linked to a high risk for obesity in offspring. Animal studies suggest that these exposures disrupt the development of the hypothalamus, a brain region that regulates body weight, predisposing offspring to develop obesity. This study tested the hypothesis in humans that in utero exposure to maternal obesity and/or GDM is associated with alterations in the hypothalamic response to glucose and the altered hypothalamic response would predict greater increases in child adiposity 1 year later. RESEARCH DESIGN AND METHODS: Participants were 91 children aged 7-11 years with and without in utero exposure to GDM. Maternal prepregnancy BMI and GDM exposures were determined from electronic medical records. Arterial spin labeling MRI was used to determine the child's hypothalamic blood flow response to oral glucose. Anthropometric measures were acquired in all children at their initial visit and again 1 year later in a subset of 44 children. RESULTS: Children exposed to GDM diagnosed at ≤26 weeks' gestation had increased hypothalamic blood flow (a marker of hypothalamic activation) in response to glucose when compared with unexposed children, and results remained after adjustments for child age, sex, BMI, and maternal prepregnancy BMI. Maternal prepregnancy BMI was positively associated with the child's hypothalamic response to glucose. Greater hypothalamic response to glucose predicted greater increases in child's BMI 1 year later. CONCLUSIONS: Increased glucose-linked hypothalamic activation during childhood represents a possible mechanism by which exposure to maternal metabolic disorders during fetal development increases future risk for obesity.

Attention-Deficit Hyperactivity Disorder Risk: Interaction Between Parental Age and Maternal History of Attention-Deficit Hyperactivity Disorder.

OBJECTIVE: To assess the interaction between maternal attention-deficit/hyperactivity disorder (ADHD) history and young parental age on child's ADHD risk. METHODS: The study included 321,272 singleton children born between 1995 and 2012 from hospitals within a single integrated health care organization. The children were prospectively followed up through electronic medical record systems from birth until the first date of the following: date of clinical diagnosis of ADHD, last date of continuous health plan membership, death due to any cause, or December 31, 2017. Risks of ADHD associated with a maternal history of ADHD before pregnancy and young parental age were assessed by using Cox regression adjusting for potential confounders. RESULTS: The children were followed up for a median (interquartile range) of 8.9 (6.2, 13.6) years from birth. Among them, 5.1% had ADHD diagnosis, 1.8% had a maternal history of ADHD before the pregnancy, and 4.4% had mothers <20 years and 2.3% had fathers <20 years at date of birth. The hazard ratio (HR) of ADHD in children associated with parental age <20 years varied by maternal history of ADHD (p < 0.005 for both multiplicative and additive interactions). For children without a maternal history of ADHD, the HR associated with at least 1 parent <20 years was 1.14 (95% confidence interval 1.04-1.24). However, for children with a maternal history of ADHD, the HR associated with at least 1 parent <20 years was 1.92 (95% confidence interval 1.31-2.82). CONCLUSION: High ADHD risk in offspring associated with young parenthood was predominantly observed among children with a maternal history of ADHD.

Breastfeeding Persistence at 6 Months: Trends and Disparities from 2008 to 2015.

OBJECTIVE: To assess trends and disparities in breastfeeding by maternal characteristics (race and ethnicity, age at delivery, obesity, parity, and level of education) and the relative importance among these for breastfeeding at 6 months. STUDY DESIGN: This retrospective birth cohort study included 195 861 live singleton children born at 32-42 weeks of gestation from 2008 to 2015 within a single integrated healthcare system. All children had healthcare coverage during the first year of life. Maternal characteristics and breastfeeding status at 6 months of age were extracted from electronic medical records. Trends over time of any breastfeeding ≥6 months were evaluated for the 5 maternal characteristics. Robust Poisson regression models were used to estimate breastfeeding rate differences associated with each of the 5 characteristics. The relative importance among them associated with breastfeeding ≥6 months was assessed by comparing model quasi-likelihood information criteria. RESULTS: Rates of breastfeeding ≥6 months significantly increased overall and among groups defined by the maternal characteristics. However, there was little improvement over time in closing disparities associated with maternal race and ethnicity, age at delivery, prepregnancy obesity status, and level of education. Education level contributed to the greatest disparity in breastfeeding ≥6 months. Maternal age was the second factor, followed by prepregnancy obesity and maternal race and ethnicity. CONCLUSIONS: Breastfeeding outreach programs focusing on women with less than a college education, women <25 years old, and women from non-Hispanic black or Hispanic race and ethnicity may help to reduce disparities and improve breastfeeding persistence rates within integrated healthcare systems.

Applying the pragmatic-explanatory continuum indicator summary to the implementation of a physical activity coaching trial in chronic obstructive pulmonary disease.

BACKGROUND: Observational studies show that physical inactivity is associated with worse outcomes in chronic obstructive pulmonary disease (COPD). Despite practice guidelines recommending regular physical activity (PA), there are no large-scale experimental studies to confirm that patients at high risk for COPD exacerbations can increase their PA and consequently, have improved outcomes. PURPOSE: The purpose of this case study is to describe the use of a widely accepted pragmatic trials framework for the design and implementation of a pragmatic clinical trial (PCT) of PA coaching for COPD in a real-world setting. METHOD: The aim of the trial was to determine the effectiveness of a 12-month PA coaching intervention (Walk On!) compared to standard care for 2,707 patients at high risk for COPD exacerbations from a large integrated health care system. The descriptions of our implementation experiences are anchored within the pragmatic-explanatory continuum indicator summary (PRECIS-2) framework. DISCUSSION: Facilitators of PCT implementation include early and ongoing engagement and support of multiple stakeholders including patients, health system leaders, administrators, physician champions, and frontline clinicians, an organizational/setting that prioritizes positive lifestyle behaviors, and a flexible intervention that allows for individualization. Pragmatic challenges include reliance on electronic data that are not complete or available in real-time for patient identification, timing of outreach may not synchronize with patients' readiness for change, and high turnover of clinical staff drawn from the existing workforce. DISCUSSION: PRECIS-2 is a useful guide for organizing decisions about study designs and implementation approaches to help diverse stakeholders recognize the compromises between internal and external validity with those decisions.

MS Sunshine Study: Sun Exposure But Not Vitamin D Is Associated with Multiple Sclerosis Risk in Blacks and Hispanics.

Multiple sclerosis (MS) incidence and serum 25-hydroxyvitamin D (25OHD) levels vary by race/ethnicity. We examined the consistency of beneficial effects of 25OHD and/or sun exposure for MS risk across multiple racial/ethnic groups. We recruited incident MS cases and controls (blacks 116 cases/131 controls; Hispanics 183/197; whites 247/267) from the membership of Kaiser Permanente Southern California into the MS Sunshine Study to simultaneously examine sun exposure and 25OHD, accounting for genetic ancestry and other factors. Higher lifetime ultraviolet radiation exposure (a rigorous measure of sun exposure) was associated with a lower risk of MS independent of serum 25OHD levels in blacks (adjusted OR = 0.53, 95% CI = 0.31-0.83; p = 0.007) and whites (OR = 0.68, 95% CI = 0.48-0.94; p = 0.020) with a similar magnitude of effect that did not reach statistical significance in Hispanics (OR = 0.66, 95% CI = 0.42-1.04; p = 0.071). Higher serum 25OHD levels were associated with a lower risk of MS only in whites. No association was found in Hispanics or blacks regardless of how 25OHD was modeled. Lifetime sun exposure appears to reduce the risk of MS regardless of race/ethnicity. In contrast, serum 25OHD levels are not associated with MS risk in blacks or Hispanics. Our findings challenge the biological plausibility of vitamin D deficiency as causal for MS and call into question the targeting of specific serum 25OHD levels to achieve health benefits, particularly in blacks and Hispanics.

Influence of Statins and Cholesterol on Mortality Among Patients With Pancreatic Cancer.

Background: Recent studies have suggested associations between statins and enhanced survival among patients with pancreatic ductal adenocarcinoma (PDAC). However, the relationship between statins, cholesterol, and survival remains unclear. Methods: We conducted a retrospective cohort study on 2142 PDAC patients in a regional integrated healthcare system from 2006 to 2014. Electronic pharmacy records were used to abstract information on the type, length, and dosage of statin exposures starting in the year prior to diagnosis. The cumulative and individual effects of simvastatin, lovastatin, atorvastatin, pravastatin, and rosuvastatin on mortality were assessed using Cox proportional hazards regression. Statins were evaluated as any use (pre- and postdiagnosis as a time-dependent variable) and baseline use (prediagnosis only). We also evaluated whether low-density lipoprotein (LDL) cholesterol, measured at various time windows prior to diagnosis, had an independent influence on survival. Additional analyses were performed to examine whether cholesterol mediated the relationship between statins and mortality. All models included age, race, stage, surgery, gemcitabine-based chemotherapy, and the Charlson comorbidity index as covariates. Results: Any (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.79 to 0.97) and baseline (HR = 0.88, 95% CI = 0.79 to 0.98) statin use were both associated with a decreased risk in mortality. When assessing individual statins, we found reduced mortality among simvastatin (HR = 0.87, 95% CI = 0.77 to 0.98) and atorvastatin (HR = 0.58, 95% CI = 0.46 to 0.72) users. Cholesterol was not associated with mortality and did not mediate any relationships between statins and survival. Conclusions: Statin use rather than cholesterol level was associated with lower mortality risk in patients with pancreatic cancer. Statins appear to improve survival through a lipid-independent mechanism.

Potential of risk-based population guidelines to reduce cardiovascular risk in a large integrated health system.

OBJECTIVES: We evaluated an alternative way to implement guidelines using an automated risk calculator and risk-based decision tool to calculate patients' risk of cardiovascular disease (CVD) and recommend therapies. We compared such an approach with traditional guidelines. STUDY DESIGN: A retrospective cohort study of 1,506,109 Kaiser Permanente Southern California members 35 years or older. METHODS: We estimated 3-year risks of fatal and nonfatal myocardial infarction and stroke using an independently developed risk calculator, then graphically compared risks with observed outcomes. We used the area under the receiver operating characteristics curve to assess discrimination, and the Hosmer-Lemeshow statistic to test fit. We compared the characteristics and outcomes of populations identified for medication therapy by the risk-based decision tool and traditional guidelines using bivariate statistics. RESULTS: A risk score was obtained in 72% (1,082,158) of members. The risk calculator was fairly good in discrimination: the area under the curve was 0.774 (95% CI, 0.770-0.779) for myocardial infarction and 0.805 (95% CI, 0.801-0.808) for stroke. Predictiveness and fit was good based on graphical analysis and Hosmer-Lemeshow P < .0001. The risk-based decision tool identified high-risk patients for treatment who were not identified by traditional guidelines (3.80% of all those identified for statins, 3.04% for antihypertensives), as well as low-risk patients who were identified by guidelines (3.80% for statins, 2.51% for antihypertensives). CONCLUSIONS: The risk calculator provided risk estimates in most patients and demonstrated fairly good discrimination and predictiveness. The risk-based decision tool identified high-risk patients for treatment not identified by traditional guidelines, as well as low-risk patients for whom treatment may be unnecessary.

Patient-centered physical activity coaching in COPD (Walk On!): A study protocol for a pragmatic randomized controlled trial.

BACKGROUND: Physical inactivity is significantly associated with more frequent hospitalizations and increased mortality in COPD even after adjusting for disease severity. While practice guidelines recommend regular physical activity for all patients with COPD, health systems are challenged in operationalizing an effective and sustainable approach to assist patients in being physically active. METHODS: A pragmatic randomized controlled trial design was used to determine the effectiveness of a 12-month home and community-based physical activity coaching intervention (Walk On!) compared to standard care for 1650 patients at high risk for COPD exacerbations from a large integrated health care system. Eligible patients with a COPD-related hospitalization, emergency department visit, or observational stay in the previous 12months were automatically identified from the electronic medical records (EMR) system and randomized to treatment arms. The Walk On! intervention included collaborative monitoring of step counts, semi-automated step goal recommendations, individualized reinforcement from a physical activity coach, and peer/family support. RESULTS: The primary composite outcome included all-cause hospitalizations, emergency department visits, observational stays, and death in the 12months following randomization. Secondary outcomes included COPD-related utilization, cardio-metabolic markers, physical activity, symptoms, and health-related quality of life. With the exception of patient reported outcomes, all utilization and clinical variables were automatically captured from the EMR. CONCLUSIONS: If successful, findings from this multi-stakeholder driven trial of a generalizable and scalable physical activity intervention, carefully designed with sufficient flexibility, intensity, and support for a large ethnically diverse sample could re-define the standard of care to effectively address physical inactivity in COPD.