Accuracy of identifying pediatric acute bacterial sinusitis diagnoses in outpatient claims data.

PURPOSE: Acute bacterial sinusitis is among the most frequent outpatient infections in children and adolescents and is well suited to study in large healthcare utilization databases, but the validity of International Classification of Diseases, 10th Revision (ICD-10) codes together with antibiotic prescriptions to identify cases of acute bacterial sinusitis has not been established. We aimed to evaluate the validity of ICD-10 codes combined with antibiotic prescriptions to identify new diagnoses of acute bacterial sinusitis among pediatric patients evaluated in the outpatient setting. METHODS: Children and adolescents aged 17 years and younger with an outpatient diagnosis of acute sinusitis along with an antibiotic prescription from an ambulatory facility affiliated with the Mass General Brigham health system were identified via a clinical data warehouse. Patients were stratified by age (0-5 years, 6-11 years, and 12-17 years), and fifty cases per age group were randomly sampled. Medical records were independently reviewed by two pediatric infectious diseases physicians to assess for the documentation of a clinician-defined diagnosis of acute bacterial sinusitis. Positive predictive values (PPVs) and 95% confidence intervals (CIs) were calculated. RESULTS: 150 patients were included in the final cohort. Frontal, maxillary, and "unspecified" sinuses accounted for 88% of the diagnoses. The positive predictive value of the algorithm to identify clinician-defined diagnoses of acute bacterial sinusitis was 92% (95% CI 87%,95%). The PPVs were consistent across age strata. CONCLUSIONS: ICD-10 codes for acute sinusitis, when paired with a same-day antibiotic prescription, have a high positive predictive value among a cohort of pediatric patients, suggesting that they can be used to study new acute bacterial sinusitis diagnoses with claims.

Postpartum Opioid-Related Mortality in Patients With Public Insurance.

OBJECTIVE: To assess the incidence and risk factors for postpartum opioid overdose death and describe other causes of postpartum death in individuals with opioid use disorder (OUD). METHODS: We conducted a cohort study that used health care utilization data from the Medicaid Analytic eXtract linked to the National Death Index in the United States from 2006 to 2013. All pregnant individuals with live births or stillbirths and continuous enrollment for 3 months before delivery were eligible, including 4,972,061 deliveries. A subcohort of individuals with a documented history of OUD in the 3 months before delivery was identified. We estimated the cumulative incidence of death as occurring between delivery and 1 year postpartum among all individuals and individuals with OUD. Risk factors for opioid overdose death were assessed using odds ratios (ORs) and descriptive statistics, including demographics, health care utilization, obstetric conditions, comorbidities, and medications. RESULTS: The incidence of postpartum opioid overdose death per 100,000 deliveries was 5.4 (95% CI 4.5-6.4) among all individuals and 118 (95% CI 84-163) among individuals with OUD. Individuals with OUD had a sixfold higher incidence of all-cause postpartum death than all individuals. Common causes of death in individuals with OUD were other drug- and alcohol-related deaths (47/100,000), suicide (26/100,000), and other injuries, including accidents and falls (33/100,000). Risk factors strongly associated with postpartum opioid overdose death included mental health and other substance use disorders. Among patients with OUD, postpartum use of medication to treat OUD was associated with 60% lower odds of opioid overdose death (OR 0.4, 95% CI 0.1-0.9). CONCLUSION: Postpartum individuals with OUD have a high incidence of postpartum opioid overdose death and other preventable deaths, including nonopioid substance-related injuries, accidents, and suicide. Use of medications for OUD is strongly associated with lower opioid-related mortality.

Emulating a Target Trial of Interventions Initiated During Pregnancy with Healthcare Databases: The Example of COVID-19 Vaccination.

BACKGROUND: Observational studies are often the only option to estimate effects of interventions during pregnancy. Causal inference from observational data can be conceptualized as an attempt to emulate a hypothetical pragmatic randomized trial: the target trial. OBJECTIVE: To provide a step-by-step description of how to use healthcare databases to estimate the effects of interventions initiated during pregnancy. As an example, we describe how to specify and emulate a target trial of COVID-19 vaccination during pregnancy, but the framework can be generally applied to point and sustained strategies involving both pharmacologic and non-pharmacologic interventions. METHODS: First, we specify the protocol of a target trial to evaluate the safety and effectiveness of vaccination during pregnancy. Second, we describe how to use observational data to emulate each component of the protocol of the target trial. We propose different target trials for different gestational periods because the outcomes of interest vary by gestational age at exposure. We identify challenges that affect (i) the target trial and thus its observational emulation (censoring and competing events), and (ii) mostly the observational emulation (confounding, immortal time, and measurement biases). CONCLUSION: Some biases may be unavoidable in observational emulations, but others are avoidable. For instance, immortal time bias can be avoided by aligning the start of follow-up with the gestational age at the time of the intervention, as we would do in the target trial. Explicitly emulating target trials at different gestational ages can help reduce bias and improve the interpretability of effect estimates for interventions during pregnancy.

Atomoxetine in Early Pregnancy and the Prevalence of Major Congenital Malformations: A Multinational Study.

Objective: Most research on safety of attention-deficit/hyperactivity disorder (ADHD) medications during pregnancy concerns central nervous system stimulants, while little is known about the safety of atomoxetine, a primary treatment alternative. We assessed the prevalence of major congenital malformations overall, and cardiac malformations and limb malformations specifically, after first-trimester exposure.Methods: In this cohort study, we included all approximately 2.4 million pregnancies ending in live births recorded in the population-based nationwide health registers of Denmark, Iceland, Norway, and Sweden (2003-2017) and approximately 1.8 million publicly insured pregnancies ending in live births recorded in the US Medicaid Analytic eXtract (MAX, 2001-2013) health care claims database. We compared the prevalence of major congenital malformations in the newborn among pregnancies exposed and unexposed to atomoxetine. For each country, we calculated prevalence ratios (PRs), crude and stratified by propensity scores (PSs). We pooled the country-specific PS strata to obtain a PR adjusted for potential confounding factors.Results: We identified 368 pregnancies exposed to atomoxetine during the first trimester in the 4 Nordic countries and 622 in the US. The pooled crude PR for any major congenital malformation was 1.18 (95% CI, 0.88-1.60), and the adjusted PR was 0.99 (95% CI, 0.74-1.34). For cardiac malformations, the adjusted PR was 1.34 (95% CI, 0.86-2.09). For limb malformations, the adjusted PR was 0.90 (95% CI, 0.38-2.16).Conclusions: After atomoxetine exposure in early pregnancy, we observed no increase in major congenital malformations overall and, although with some uncertainty due to sample size, no statistically increased risk estimates for cardiac malformations and limb malformations.

Association of In Utero Antipsychotic Medication Exposure With Risk of Congenital Malformations in Nordic Countries and the US.

Importance: Psychiatric disorders are common among female individuals of reproductive age. While antipsychotic medication use is increasing, the safety of such medications in pregnancy is an area with large evidence gaps. Objective: To evaluate the risk of first-trimester antipsychotic exposure with respect to congenital malformations, focusing on individual drugs and specific malformation subtypes. Design, Setting, and Participants: This cohort study used data from nationwide health registers from the 5 Nordic countries and the US and spanned 1996 to 2018. The Nordic cohort included all pregnancies resulting in singleton live-born infants, and the US cohort consisted of publicly insured mothers linked to their live-born infants nested in the nationwide Medicaid Analytic eXtract. Data were analyzed from November 2020 to April 2022. Exposures: One or more first-trimester dispensing of any atypical, any typical, and individual antipsychotic drugs. Main Outcomes and Measures: Any major congenital malformation and specific malformation subtypes previously suggested to be associated with antipsychotic exposure in utero: cardiovascular malformations, oral clefts, neural tube defects, hip dysplasia, limb reduction defects, anorectal atresia/stenosis, gastroschisis, hydrocephalus, other specific brain anomalies, and esophageal disorders. Propensity score stratification was used to control for potential confounders. Pooled adjusted estimates were calculated using indirect standardization. Results: A total of 6 455 324 unexposed mothers (mean maternal age range across countries: 24-31 years), 21 751 mothers exposed to atypical antipsychotic drugs (mean age range, 26-31 years), and 6371 mothers exposed to typical antipsychotic drugs (mean age range, 27-32 years) were included in the study cohort. Prevalence of any major malformation was 2.7% (95% CI, 2.7%-2.8%) in unexposed infants, 4.3% (95% CI, 4.1%-4.6%) in infants with atypical antipsychotic drug exposure, and 3.1% (95% CI, 2.7%-3.5%) in infants with typical antipsychotic drug exposure in utero. Among the most prevalent exposure-outcome combinations, adjusted relative risks (aRR) were generally close to the null. One exception was olanzapine exposure and oral cleft (aRR, 2.1 [95% CI, 1.1-4.3]); however, estimates varied across sensitivity analyses. Among moderately prevalent combinations, increased risks were observed for gastroschisis and other specific brain anomalies after atypical antipsychotic exposure (aRR, 1.5 [95% CI, 0.8-2.6] and 1.9 [95% CI, 1.1-3.0]) and for cardiac malformations after chlorprothixene exposure (aRR, 1.6 [95% CI, 1.0-2.7]). While the association direction was consistent across sensitivity analyses, confidence intervals were wide, prohibiting firm conclusions. Conclusions and Relevance: In this study, considering the evidence from primary and sensitivity analyses and inevitable statistical noise for very rare exposure-outcome combinations, in utero antipsychotic exposure generally was not meaningfully associated with an increased risk of malformations. The observed increased risks of oral clefts associated with olanzapine, gastroschisis, and other specific brain anomalies with atypical antipsychotics and cardiac malformations with chlorprothixene requires confirmation as evidence continues to accumulate.

Development and Validation of Algorithms to Estimate Live Birth Gestational Age in Medicaid Analytic eXtract Data.

BACKGROUND: While healthcare utilization data are useful for postmarketing surveillance of drug safety in pregnancy, the start of pregnancy and gestational age at birth are often incompletely recorded or missing. Our objective was to develop and validate a claims-based live birth gestational age algorithm. METHODS: Using the Medicaid Analytic eXtract (MAX) linked to birth certificates in three states, we developed four candidate algorithms based on: preterm codes; preterm or postterm codes; timing of prenatal care; and prediction models - using conventional regression and machine-learning approaches with a broad range of prespecified and empirically selected predictors. We assessed algorithm performance based on mean squared error (MSE) and proportion of pregnancies with estimated gestational age within 1 and 2 weeks of the gold standard, defined as the clinical or obstetric estimate of gestation on the birth certificate. We validated the best-performing algorithms against medical records in a nationwide sample. We quantified misclassification of select drug exposure scenarios due to estimated gestational age as positive predictive value (PPV), sensitivity, and specificity. RESULTS: Among 114,117 eligible pregnancies, the random forest model with all predictors emerged as the best performing algorithm: MSE 1.5; 84.8% within 1 week and 96.3% within 2 weeks, with similar performance in the nationwide validation cohort. For all exposure scenarios, PPVs were >93.8%, sensitivities >94.3%, and specificities >99.4%. CONCLUSIONS: We developed a highly accurate algorithm for estimating gestational age among live births in the nationwide MAX data, further supporting the value of these data for drug safety surveillance in pregnancy. See video abstract at, http://links.lww.com/EDE/B989 .

Validation of claims-based algorithms to identify non-live birth outcomes.

PURPOSE: Perinatal epidemiology studies using healthcare utilization databases are often restricted to live births, largely due to the lack of established algorithms to identify non-live births. The study objective was to develop and validate claims-based algorithms for the ascertainment of non-live births. METHODS: Using the Mass General Brigham Research Patient Data Registry 2000-2014, we assembled a cohort of women enrolled in Medicaid with a non-live birth. Based on ≥1 inpatient or ≥2 outpatient diagnosis/procedure codes, we identified and randomly sampled 100 potential stillbirth, spontaneous abortion, and termination cases each. For the secondary definitions, we excluded cases with codes for other pregnancy outcomes within ±5 days of the outcome of interest and relaxed the definitions for spontaneous abortion and termination by allowing cases with one outpatient diagnosis only. Cases were adjudicated based on medical chart review. We estimated the positive predictive value (PPV) for each outcome. RESULTS: The PPV was 71.0% (95% CI, 61.1-79.6) for stillbirth; 79.0% (69.7-86.5) for spontaneous abortion, and 93.0% (86.1-97.1) for termination. When excluding cases with adjacent codes for other pregnancy outcomes and further relaxing the definition, the PPV increased to 80.6% (69.5-88.9) for stillbirth, 86.6% (80.5-91.3) for spontaneous abortion and 94.9% (91.1-97.4) for termination. The PPV for the composite outcome using the relaxed definition was 94.4% (92.3-96.1). CONCLUSIONS: Our findings suggest non-live birth outcomes can be identified in a valid manner in epidemiological studies based on healthcare utilization databases.

Buprenorphine versus Methadone for Opioid Use Disorder in Pregnancy.

BACKGROUND: Opioid agonist therapy is strongly recommended for pregnant persons with opioid use disorder. Buprenorphine may be associated with more favorable neonatal and maternal outcomes than methadone, but existing data are limited. METHODS: We conducted a cohort study involving pregnant persons who were enrolled in public insurance programs in the United States during the period from 2000 through 2018 in which we examined outcomes among those who received buprenorphine as compared with those who received methadone. Exposure to the two medications was assessed in early pregnancy (through gestational week 19), late pregnancy (gestational week 20 through the day before delivery), and the 30 days before delivery. Risk ratios for neonatal and maternal outcomes were adjusted for confounders with the use of propensity-score overlap weights. RESULTS: The data source for the study consisted of 2,548,372 pregnancies that ended in live births. In early pregnancy, 10,704 pregnant persons were exposed to buprenorphine and 4387 to methadone. In late pregnancy, 11,272 were exposed to buprenorphine and 5056 to methadone (9976 and 4597, respectively, in the 30 days before delivery). Neonatal abstinence syndrome occurred in 52.0% of the infants who were exposed to buprenorphine in the 30 days before delivery as compared with 69.2% of those exposed to methadone (adjusted relative risk, 0.73; 95% confidence interval [CI], 0.71 to 0.75). Preterm birth occurred in 14.4% of infants exposed to buprenorphine in early pregnancy and in 24.9% of those exposed to methadone (adjusted relative risk, 0.58; 95% CI, 0.53 to 0.62); small size for gestational age in 12.1% and 15.3%, respectively (adjusted relative risk, 0.72; 95% CI, 0.66 to 0.80); and low birth weight in 8.3% and 14.9% (adjusted relative risk, 0.56; 95% CI, 0.50 to 0.63). Delivery by cesarean section occurred in 33.6% of pregnant persons exposed to buprenorphine in early pregnancy and 33.1% of those exposed to methadone (adjusted relative risk, 1.02; 95% CI, 0.97 to 1.08), and severe maternal complications developed in 3.3% and 3.5%, respectively (adjusted relative risk, 0.91; 95% CI, 0.74 to 1.13). Results of exposure in late pregnancy were consistent with results of exposure in early pregnancy. CONCLUSIONS: The use of buprenorphine in pregnancy was associated with a lower risk of adverse neonatal outcomes than methadone use; however, the risk of adverse maternal outcomes was similar among persons who received buprenorphine and those who received methadone. (Funded by the National Institute on Drug Abuse.).

Association between SARS-CoV-2 infection during pregnancy and postpartum depressive and anxiety symptoms: finding from the International Registry of Coronavirus Exposure in Pregnancy (IRCEP) study.

While there has been concern over the perinatal mental health implications of the COVID-19 outbreak, evidence on the risk of postpartum depression and anxiety following SARS-CoV-2 infection is limited. We studied this question using the International Registry of Coronavirus Exposure in Pregnancy, which included both a prospective and retrospective cohort. Study participants were required to have been tested for SARS-CoV-2 between the date of last menstrual period and delivery. The exposure of interest was SARS-CoV-2 infection during pregnancy, as well as COVID-19 severity (severe, moderate, mild, and asymptomatic). The outcome was postpartum depression and anxiety symptoms, assessed by the 4-item Patient Health Questionnaire. The final analytic cohort consisted of 3819 participants (COVID-19 positive: 771; COVID-19 negative: 3048). After adjusting for confounding by socio-demographics, prior obstetric and maternal health comorbidities, mothers with severe COVID-19 had an increased risk of depressive (aRR: 1.72; 95%CI: 1.18-2.52) and anxiety (aRR: 1.40; 0.98-2.00) symptoms. The strength of the association was attenuated for women with moderate COVID-19 (aRR = 1.12; 0.86-1.44 for depressive symptoms; aRR = 1.18; 0.96-1.44 for anxiety symptoms). No increased risk was observed for mild or asymptomatic illness. The findings can inform targeted interventions to minimize the risk of adverse COVID-19-related mental health outcomes for pregnant women.

Association of Antidepressant Use During Pregnancy With Risk of Neurodevelopmental Disorders in Children.

Importance: Antidepressant use during pregnancy has been associated with neurodevelopmental disorders in children in some studies. However, results may be explained by uncontrolled confounding by parental mental health status, genetics, and environmental factors. Objective: To evaluate the association between antidepressant use in pregnancy and neurodevelopmental outcomes in children. Design, Setting, and Participants: This cohort study of health care utilization data was separated into cohorts of publicly and privately insured pregnant individuals and their children nested in the Medicaid Analytic eXtract (MAX; 2000-2014) and the IBM MarketScan Research Database (MarketScan; 2003-2015). A total of 1.93 million pregnancies in MAX and 1.25 million pregnancies in MarketScan were recorded. Children were followed from birth until outcome diagnosis, disenrollment, death, or end of study (maximum 14 years). Analyses were conducted between August 2020 and July 2021. Exposures: Dispensing of antidepressant medication from gestational week 19 until delivery, the period of synaptogenesis. Main Outcomes and Measures: Neurodevelopmental disorders in children defined using validated algorithms. Early pregnancy exposure was considered in sensitivity analyses, and approaches to confounding adjustment included propensity score fine stratification, discontinuers comparison, and sibling analyses. Results: Among the individuals included in the analysis, there were 145 702 antidepressant-exposed and 3 032 745 unexposed pregnancies; the mean (SD) age among the antidepressant exposed and unexposed was 26.2 (5.7) and 24.3 (5.8) years in MAX and 32.7 (4.6) and 31.9 (4.6) years in MarketScan, respectively; and in MAX, which collected information on race and ethnicity, 72.4% of the antidepressant-exposed and 37.1% of the unexposed individuals were White. Crude results suggested up to a doubling in risk of neurodevelopmental outcomes associated with antidepressant exposure; however, no association was observed in the most fully adjusted analyses. When comparing antidepressant-exposed and unexposed siblings, hazard ratios were 0.97 (95% CI, 0.88-1.06) for any neurodevelopmental disorder, 0.86 (95% CI, 0.60-1.23) for autism spectrum disorder, 0.94 (95% CI, 0.81-1.08) for attention-deficit/hyperactivity disorder, 0.77 (95% CI, 0.42-1.39) for specific learning disorders, 1.01 (95% CI, 0.88-1.16) for developmental speech/language disorder, 0.79 (95% CI, 0.54-1.17) for developmental coordination disorder, 1.00 (95% CI, 0.45-2.22) for intellectual disability, and 0.95 (95% CI, 0.80-1.12) for behavioral disorders. Results were generally consistent for antidepressant classes and drugs and across exposure windows. Conclusions and Relevance: The results of this cohort study suggest that antidepressant use in pregnancy itself does not increase the risk of neurodevelopmental disorders in children. However, given strong crude associations, antidepressant exposure in pregnancy may be an important marker for the need of early screening and intervention.

Characteristics of Prescription Opioid Analgesics in Pregnancy and Risk of Neonatal Opioid Withdrawal Syndrome in Newborns.

Importance: Prescription opioids are often used during pregnancy even though they are associated with neonatal opioid withdrawal syndrome (NOWS). Most studies of adverse outcomes of opioid use for pain have assessed only the class-wide outcome despite the pharmacodynamic and pharmacokinetic heterogeneity across opioid medications. Objective: To compare the risk of NOWS across common types of opioids when prescribed as monotherapy during the last 3 months of pregnancy. Design, Setting, and Participants: This cohort study analyzed administrative claims data of Medicaid-insured mothers and newborns in 46 states and Washington DC from January 1, 2000, through December 31, 2014. Participants were mothers with 2 or more dispensed opioid prescriptions within 90 days before delivery and their eligible live-born neonates. Data were analyzed from February 2020 to March 2021. Exposure: Different types of opioid medications were compared by agonist strength (strong vs weak) and half-life (medium vs short and long vs short) of the opioid active ingredient. Main Outcomes and Measures: The primary outcome was NOWS, which was identified using an International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code in the 30 days after delivery. Relative risks (RRs) were adjusted for an exposure propensity score, including demographic characteristics, comorbidities, other medication use, and opioid treatment characteristics (including morphine milligram equivalents), using fine stratification. Results: The cohort comprised 48 202 opioid-exposed pregnancies with live newborns. A total of 1069 neonates (2.2%) had NOWS and 559 (1.2%) had severe NOWS. Opioid exposure during pregnancy included 16 202 pregnancies exposed to codeine, 4540 to oxycodone, 1244 to tramadol, 260 to methadone (dispensed for pain), 90 to hydromorphone, and 63 to morphine compared with 25 710 exposed to hydrocodone. Demographic characteristics varied across opioids, with tramadol, oxycodone, methadone, hydromorphone, and morphine being more commonly dispensed at older maternal age (≥35 years). Compared with hydrocodone, codeine had a lower adjusted RR of NOWS (0.57; 95% CI, 0.46-0.70), with a similar adjusted RR for tramadol (RR, 1.06; 95% CI, 0.73-1.56), and 2- to 3-fold higher adjusted RRs for oxycodone (1.87; 95% CI, 1.66-2.11), morphine (2.84; 95% CI, 1.30-6.22), methadone (3.02; 95% CI, 2.45-3.73), and hydromorphone (2.03; 95% CI, 1.09-3.78). Strong agonists were associated with a higher risk of NOWS than weak agonists (RR, 1.97; 95% CI, 1.78-2.17), and long half-life opioids were associated with an increased risk compared with short half-life products (RR, 1.33; 95% CI, 1.12-1.56). Findings were consistent across sensitivity and subgroup analyses. Conclusions and Relevance: Results of this study show higher risk of NOWS and severe NOWS among neonates with in utero exposure to strong agonists and long half-life prescription opioids. Information on the opioid-specific risk of NOWS may help prescribers select opioids for pain management in late stages of pregnancy.

Association of Antipsychotic Drug Exposure in Pregnancy With Risk of Neurodevelopmental Disorders: A National Birth Cohort Study.

Importance: Although antipsychotic drugs cross the placenta and animal data suggest potential neurotoxic effects, information regarding human neurodevelopmental teratogenicity is limited. Objective: To evaluate whether children prenatally exposed to antipsychotic medication are at an increased risk of neurodevelopmental disorders (NDD). Design, Settings, and Participants: This birth cohort study used data from the Medicaid Analytic eXtract (MAX, 2000-2014) and the IBM Health MarketScan Research Database (MarketScan, 2003-2015) for a nationwide sample of publicly (MAX) and privately (MarketScan) insured mother-child dyads with up to 14 years of follow-up. The MAX cohort consisted of 2 034 883 children who were not prenatally exposed and 9551 who were prenatally exposed to antipsychotic medications; the MarketScan consisted of 1 306 408 and 1221 children, respectively. Hazard ratios were estimated through Cox proportional hazards regression, using propensity score overlap weights for confounding control. Estimates from both cohorts were combined through meta-analysis. Exposures: At least 1 dispensing of a medication during the second half of pregnancy (period of synaptogenesis), assessed for any antipsychotic drug, at the class level (atypical and typical), and for the most commonly used drugs (aripiprazole, olanzapine, quetiapine, risperidone, and haloperidol). Main Outcomes and Measures: Autism spectrum disorder, attention-deficit/hyperactivity disorder, learning disability, speech or language disorder, developmental coordination disorder, intellectual disability, and behavioral disorder, identified using validated algorithms, and the composite outcome of any NDD. Data were analyzed from April 2020 to January 2022. Results: The MAX cohort consisted of 2 034 883 unexposed pregnancies and 9551 pregnancies with 1 or more antipsychotic drug dispensings among women with a mean (SD) age of 26.8 (6.1) years, 204 (2.1%) of whom identified as Asian/Pacific Islander, 2720 (28.5%) as Black, 500 (5.2%) as Hispanic/Latino, and 5356 (56.1%) as White. The MarketScan cohort consisted of 1 306 408 unexposed and 1221 exposed pregnancies among women with a mean (SD) age of 33.1 (5.0) years; race and ethnicity data were not available. Although the unadjusted results were consistent with an approximate 2-fold increased risk for most exposure-outcome contrasts, risks were no longer meaningfully increased after adjustment (eg, pooled unadjusted vs adjusted hazard ratios [95% CI] for any NDD after any antipsychotic exposure: 1.91 [1.79-2.03] vs 1.08 [1.01-1.17]), with the possible exception of aripiprazole (1.36 [1.14-1.63]). Results were consistent across sensitivity analyses. Conclusions and Relevance: The findings of this birth cohort study suggest that the increased risk of NDD seen in children born to women who took antipsychotic drugs late in pregnancy seems to be explained by maternal characteristics and is not causally related with prenatal antipsychotic exposure. This finding highlights the importance of closely monitoring the neurodevelopment of the offspring of women with mental illness to ensure early intervention and support. The potential signal for aripiprazole requires replication in other data before causality can be assumed.

Neurodevelopmental Disorders Among Publicly or Privately Insured Children in the United States.

IMPORTANCE: Neurodevelopmental disorders are associated with poor health and social outcomes. Population-based data on incidence, age at diagnosis, and demographic variations are essential to identify modifiable risk factors and inform the planning of services and interventions. OBJECTIVES: To assess the incidence and timing of diagnosis of neurodevelopmental disorders during childhood in the US and to evaluate differences by population characteristics. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used nationwide data on birth cohorts nested in the 2000-2014 Medicaid Analytic eXtract and the 2003-2015 IBM MarketScan Research Database on 2 070 541 publicly and 1 309 900 privately insured children enrolled at birth. Data were analyzed between May 1, 2020, and June 30, 2021. MAIN OUTCOMES AND MEASURES: Neurodevelopmental disorders, autism spectrum disorders, attention-deficit/hyperactivity disorder, learning disabilities, speech or language disorders, developmental coordination disorders, intellectual disabilities, and behavioral disorders were identified based on validated algorithms. Kaplan-Meier analyses were used to estimate the incidence and timing of diagnosis, stratified by child's sex, birth year, maternal age at delivery, and race and ethnicity. RESULTS: The cohorts comprised 2 070 541 publicly insured children (1 045 426 boys [50.5%]) and 1 309 900 privately insured children (667 607 boys [51.0%]) enrolled at birth. By 8 years of age, 23.9% of publicly insured children and 11.0% of privately insured children received a diagnosis of 1 or more neurodevelopmental disorders (autism spectrum disorder, 1.6% and 1.3%; attention-deficit/hyperactivity disorder, 14.5% and 5.8%; learning disability, 1.2% and 0.6%; speech or language disorder, 8.4% and 4.5%; developmental coordination disorder, 0.9% and 0.7%; intellectual disability, 0.7% and 0.1%; and behavioral disorder, 8.4% and 1.5%). Risks were substantially higher among boys (incidence of ≥1 neurodevelopmental disorder by age 8 years for boys vs girls: 30.7% vs 16.7% among publicly insured children and 15.0% vs 6.7% among privately insured children) and White children (30.2% vs 9.1% among Asian children, 23.0% among Black children, 15.4% among Hispanic children, and 22.7% among children of unknown race or ethnicity; information on race and ethnicity was available only for publicly insured children). The association of maternal age and birth year with incidence of neurodevelopmental disorders varied by outcome. Except for attention-deficit/hyperactivity disorder, the diagnosis tended to be established somewhat earlier for privately insured children. The association of race and ethnicity with age at diagnosis varied by outcome. Co-occurring neurodevelopmental disorders were common, especially among children with autism spectrum disorder and intellectual disability (>70% had ≥1 other disorder). CONCLUSIONS AND RELEVANCE: In this population-based cohort study, a relatively high incidence of and co-occurrence of neurodevelopmental disorders as well as the disparity in incidence and timing of diagnosis by insurance type and race and ethnicity were found. These findings represent important public health concerns and underscore the need for timely and accessible developmental assessments and educational services to help reduce the burden of these disorders.

Trajectories of Prescription Opioid Utilization During Pregnancy Among Prepregnancy Chronic Users and Risk of Neonatal Opioid Withdrawal Syndrome.

Little is known about the impact of dose, duration, and timing of prenatal prescription opioid exposure on the risk of neonatal opioid withdrawal syndrome (NOWS). Using a cohort of 18,869 prepregnancy chronic opioid users nested within the 2000-2014 Medicaid Analytic eXtract, we assessed average opioid dosage within biweekly gestational age intervals, created group-based trajectory models, and evaluated the association between trajectory groups and NOWS risk. Women were grouped into 6 distinct opioid use trajectories which, based on observed patterns, were categorized as 1) continuous very low-dose use, 2) continuous low-dose use, 3) initial moderate-dose use with a gradual decrease to very low-dose/no use, 4) initial high-dose use with a gradual decrease to very low-dose use, 5) continuous moderate-dose use, and 6) continuous high-dose use. Absolute risk of NOWS per 1,000 infants was 7.7 for group 1 (reference group), 28.8 for group 2 (relative risk (RR) = 3.7, 95% confidence interval (CI): 2.8, 5.0), 16.5 for group 3 (RR = 2.1, 95% CI: 1.5, 3.1), 64.9 for group 4 (RR = 8.4, 95% CI: 5.6, 12.6), 77.3 for group 5 (RR = 10.0, 95% CI: 7.5, 13.5), and 172.4 for group 6 (RR = 22.4, 95% CI: 16.1, 31.2). Trajectory models-which capture information on dose, duration, and timing of exposure-are useful for gaining insight into clinically relevant groupings to evaluate the risk of prenatal opioid exposure.

Risk of Overdose Associated With Co-prescription of Antipsychotics and Opioids: A Population-Based Cohort Study.

The US FDA issued a black-box warning against co-prescription of antipsychotic (AP) agents and opioids due to the risk of respiratory depression, but evidence on the comparative safety of sedating vs nonsedating APs is lacking. We classified APs as sedating (eg, quetiapine, olanzapine, and chlorpromazine) and nonsedating (eg, aripiprazole, haloperidol, and risperidone) based on their affinity to the histamine-1 neuroreceptor (Ki < or ≥20, respectively) and sought to compare the rate of overdose between patients using sedating vs nonsedating APs plus opioids. We constructed a population-based cohort nested in the IBM MarketScan database (2004-2017). Patients with concomitant use of sedating APs and prescription opioids ("exposed") were 1:1 matched to patients with concomitant use of nonsedating APs and prescription opioids ("referent") based on the propensity score (PS). The primary outcome was any hospitalization or emergency department visit due to an overdose within 30 days. The final cohort comprised 62 604 exposed and an equal number of PS-matched reference patients. Characteristics of matched exposed and reference patients were similar. There were 178 overdose events among the exposed (35.3 events per 1000 person-years [PY]) vs 133 among the reference group (26.4 events per 1000 PY), for an adjusted hazard ratio of 1.34 (95% CI: 1.07-1.68). This finding was consistent across sensitivity and subgroup analyses. Among patients receiving prescription opioids, concomitant use of sedating APs was associated with an increased risk of overdose compared with nonsedating APs. Caution is required when co-prescribing opioids and APs. If co-prescription is needed, choosing a nonsedating agent should be preferred whenever possible given the clinical context.

Mining Clinical Data for Novel Posttraumatic Stress Disorder Medications.

BACKGROUND: Despite the prevalence and negative impact of posttraumatic stress disorder (PTSD), there are few medications approved by the U.S. Food and Drug Administration for treatment, and approved medications do not work well enough. We leveraged large-scale electronic health record data to identify existing medications that may be repurposed as PTSD treatments. METHODS: We constructed a mechanistic tree of all Food and Drug Administration-approved medications and used the tree-based scan statistic to identify medications associated with greater than expected levels of clinically meaningful improvement in PTSD symptoms using electronic health record data from the U.S. Department of Veterans Affairs. Our cohort included patients with a diagnosis of PTSD who had repeated symptom measurements using the PTSD Checklist over a 20-year period (N = 168,941). We calculated observed numbers based on patients taking each drug or mechanistically related class of drugs and the expected numbers based on the tree as a whole. RESULTS: Medications typically used to treat PTSD, such as the Food and Drug Administration-approved agent sertraline, were associated with improvement in PTSD symptoms, but the effects were small. Several, but not all, direct-acting antivirals used in the treatment of hepatitis C virus demonstrated a strong association with PTSD improvement. The finding was robust to a sensitivity analysis excluding patients who received established PTSD treatments, including trauma-focused psychotherapy, concurrent with hepatitis treatment. CONCLUSIONS: Our exploratory approach both demonstrated findings that are consistent with what is known about pharmacotherapy for PTSD and uncovered a novel class of medications that may improve PTSD symptoms.