Internal validation of gestational age estimation algorithms in healthcare databases using pregnancies conceived with fertility procedures.

Fertility procedures recorded in healthcare databases can be used to estimate the start of pregnancy, which can serve as a reference standard to validate gestational age estimates based on International Classification of Diseases (ICD) codes. In a cohort of 17,398 pregnancies conceived by fertility procedures in MarketScan (2011-2020), we estimated gestational age at the end of pregnancy using algorithms based on (1) days since fertility procedure (the reference); (2) ICD-9/ICD-10 (before/after October 2015) codes indicating gestational length recorded at the end of pregnancy (method A); and (3) ICD-10 enhanced with Z3A codes denoting specific gestation weeks recorded at prenatal visits (method B). We calculated the proportion of pregnancies with an estimated gestational age within 14 days of the reference. Method A accuracy was similar for ICD-9 and ICD-10 codes. After 2015, method B was more accurate than method A: For term births, within-14-day-agreements were 90.8% for method A and 98.7% for method B. Corresponding estimates were 70.1% and 95.6% for preterm births; 35.3% and 92.6% for stillbirths; 54.3% and 64.2% for spontaneous abortions; and 16.7% and 84.6% for elective terminations. ICD-10-based algorithms that incorporate Z3A codes improve the accuracy of gestational age estimation in healthcare databases, especially for preterm and non-live births.

Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure.

BACKGROUND: Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use. METHODS: We identified a population-based cohort of pregnant women and their children within two health care utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control. RESULTS: The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score-adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine. CONCLUSIONS: The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate. (Funded by the National Institute of Mental Health.).

Accounting for Twins and Other Multiple Births in Perinatal Studies Conducted Using Healthcare Administration Data.

The analysis of perinatal studies is complicated by twins and other multiple births even when they are not the exposure, outcome, or a confounder of interest. Common approaches to handling multiples in studies of infant outcomes include restriction to singletons, counting outcomes at the pregnancy-level (i.e., by counting if at least one twin experienced a binary outcome), or infant-level analysis including all infants and, typically, accounting for clustering of outcomes by using generalised estimating equations or mixed effects models. Several healthcare administration databases only support restriction to singletons or pregnancy-level approaches. For example, in MarketScan insurance claims data, diagnoses in twins are often assigned to a single infant identifier, thereby preventing ascertainment of infant-level outcomes among multiples. Different approaches correspond to different causal questions, produce different estimands, and often rely on different assumptions. We demonstrate the differences that can arise from these different approaches using Monte Carlo simulations, algebraic formulas, and an applied example. Furthermore, we provide guidance on the handling of multiples in perinatal studies when using healthcare administration data.

First Trimester Use of Buprenorphine or Methadone and the Risk of Congenital Malformations.

Importance: Use of buprenorphine or methadone to treat opioid use disorder is recommended in pregnancy; however, their teratogenic potential is largely unknown. Objective: To compare the risk of congenital malformations following in utero exposure to buprenorphine vs methadone. Design, Setting, and Participants: This population-based cohort study used health care utilization data from publicly insured Medicaid beneficiaries in the US from 2000 to 2018. A total of 13 360 pregnancies with enrollment from 90 days prior to pregnancy start through 1 month after delivery and first trimester use of buprenorphine or methadone were included and linked to infants. Data were analyzed from July to December 2022. Exposure: A pharmacy dispensing of buprenorphine or a code for administration of methadone in the first trimester. Main Outcomes and Measures: Primary outcomes included major malformations overall and malformations previously associated with opioids (any cardiac malformations, ventricular septal defect, secundum atrial septal defect/nonprematurity-related patent foramen ovale, neural tube defects, clubfoot, and oral clefts). Secondary outcomes included other organ system-specific malformations. Risk differences and risk ratios (RRs) were estimated comparing buprenorphine with methadone, adjusting for confounders with propensity score overlap weights. Results: The cohort included 9514 pregnancies with first-trimester buprenorphine exposure (mean [SD] maternal age, 28.4 [4.6] years) and 3846 with methadone exposure (mean [SD] maternal age, 28.8 [4.7] years). The risk of malformations overall was 50.9 (95% CI, 46.5-55.3) per 1000 pregnancies for buprenorphine and 60.6 (95% CI, 53.0-68.1) per 1000 pregnancies for methadone. After confounding adjustment, buprenorphine was associated with a lower risk of malformations compared with methadone (RR, 0.82; 95% CI, 0.69-0.97). Risk was lower with buprenorphine for cardiac malformations (RR, 0.63; 95% CI, 0.47-0.85), including both ventricular septal defect (RR, 0.62; 95% CI, 0.39-0.98) and secundum atrial septal defect/nonprematurity-related patent foramen ovale (RR, 0.54; 95% CI, 0.30-0.97), oral clefts (RR, 0.65; 95% CI, 0.35-1.19), and clubfoot (RR, 0.55; 95% CI, 0.32-0.94). Results for neural tube defects were uncertain given low event counts. In secondary analyses, buprenorphine was associated with a decreased risk of central nervous system, urinary, and limb malformations but a greater risk of gastrointestinal malformations compared with methadone. These findings were consistent in sensitivity and bias analyses. Conclusions and Relevance: In this cohort study, the risk of most malformations previously associated with opioid exposure was lower in buprenorphine-exposed infants compared with methadone-exposed infants, independent of measured confounders. Malformation risk is one factor that informs the individualized patient decision regarding medications for opioid use disorder in pregnancy.

Comparative Risk of Major Congenital Malformations With Antiseizure Medication Combinations vs Valproate Monotherapy in Pregnancy.

BACKGROUND AND OBJECTIVES: Valproate should be avoided in pregnancy, but it is the most effective drug for generalized epilepsies. Alternative treatment may require combinations of other drugs. Our objectives were to describe first trimester use of antiseizure medication (ASM) combinations that are relevant alternatives to valproate and determine whether specific combinations were associated with a lower risk of major congenital malformations (MCM) compared with valproate monotherapy. METHODS: We conducted a population-based cohort study using linked national registers from Denmark, Finland, Iceland, Norway, and Sweden and administrative health care data from the United States and New South Wales, Australia. We described first trimester use of ASM combinations among pregnant people with epilepsy from 2000 to 2020. We compared the risk of MCM after first trimester exposure to ASM combinations vs valproate monotherapy and low-dose valproate plus lamotrigine or levetiracetam vs high-dose valproate (≥1,000 mg/d). We used log-binomial regression with propensity score weights to calculate adjusted risk ratios (aRRs) and 95% CIs for each dataset. Results were pooled using fixed-effects meta-analysis. RESULTS: Among 50,905 pregnancies in people with epilepsy identified from 7.8 million total pregnancies, 788 used lamotrigine and levetiracetam, 291 used lamotrigine and topiramate, 208 used levetiracetam and topiramate, 80 used lamotrigine and zonisamide, and 91 used levetiracetam and zonisamide. After excluding pregnancies with use of other ASMs, known teratogens, or a child diagnosed with MCM of infectious or genetic cause, we compared 587 exposed to lamotrigine-levetiracetam duotherapy and 186 exposed to lamotrigine-topiramate duotherapy with 1959 exposed to valproate monotherapy. Pooled aRRs were 0.41 (95% CI 0.24-0.69) and 1.26 (0.71-2.23), respectively. Duotherapy combinations containing low-dose valproate were infrequent, and comparisons with high-dose valproate monotherapy were inconclusive but suggested a lower risk for combination therapy. Other combinations were too rare for comparative safety analyses. DISCUSSION: Lamotrigine-levetiracetam duotherapy in first trimester was associated with a 60% lower risk of MCM than valproate monotherapy, while lamotrigine-topiramate was not associated with a reduced risk. Duotherapy with lamotrigine and levetiracetam may be favored to treat epilepsy in people with childbearing potential compared with valproate regarding MCM, but whether this combination is as effective as valproate remains to be determined. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in people with epilepsy treated in the first trimester of pregnancy, the risk of major congenital malformations is lower with lamotrigine-levetiracetam duotherapy than with valproate alone, but similar with lamotrigine-topiramate.

Prescription Stimulant Use During Pregnancy and Risk of Neurodevelopmental Disorders in Children.

Importance: Use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy is increasing in the US. Whether exposure to these medications in utero impacts the risk of neurodevelopmental disorders in children is uncertain. Objective: To evaluate the association of childhood neurodevelopmental disorders with in utero exposure to stimulant medications for ADHD. Design, Setting, and Participants: This cohort study included health care utilization data from publicly insured (Medicaid data from 2000 to 2018) and commercially insured (MarketScan Commercial Claims Database data from 2003 to 2020) pregnant individuals aged 12 to 55 years in the US with enrollment from 3 months prior to pregnancy through 1 month after delivery, linked to children. Children were monitored from birth until outcome diagnosis, disenrollment, death, or end of the study (December 2018 for Medicaid and December 2020 for MarketScan). Exposures: Dispensing of amphetamine/dextroamphetamine or methylphenidate in the second half of pregnancy. Main Outcomes and Measures: Autism spectrum disorder, ADHD, and a composite of any neurodevelopmental disorder were defined using validated algorithms. Hazard ratios were estimated comparing amphetamine/dextroamphetamine and methylphenidate to no exposure. Results: The publicly insured cohort included 2 496 771 stimulant-unexposed, 4693 amphetamine/dextroamphetamine-exposed, and 786 methylphenidate-exposed pregnancies with a mean (SD) age of 25.2 (6.0) years. The commercially insured cohort included 1 773 501 stimulant-unexposed, 2372 amphetamine/dextroamphetamine-exposed, and 337 methylphenidate-exposed pregnancies with a mean (SD) age of 31.6 (4.6) years. In unadjusted analyses, amphetamine/dextroamphetamine and methylphenidate exposure were associated with a 2- to 3-fold increased risk of the neurodevelopmental outcomes considered. After adjustment for measured confounders, amphetamine/dextroamphetamine exposure was not associated with any outcome (autism spectrum disorder: hazard ratio [HR], 0.80; 95% CI, 0.56-1.14]; ADHD: HR, 1.07; 95% CI, 0.89-1.28; any neurodevelopmental disorder: HR, 0.91; 95% CI, 0.81-1.28). Methylphenidate exposure was associated with an increased risk of ADHD (HR, 1.43; 95% CI, 1.12-1.82]) but not other outcomes after adjustment (autism spectrum disorder: HR, 1.06; 95% CI, 0.62-1.81; any neurodevelopmental disorder: HR, 1.15; 95% CI, 0.97-1.36). The association between methylphenidate and ADHD did not persist in sensitivity analyses with stricter control for confounding by maternal ADHD. Conclusions and Relevance: The findings in this study suggest that amphetamine/dextroamphetamine and methylphenidate exposure in utero are not likely to meaningfully increase the risk of childhood neurodevelopmental disorders.

Safety of GLP-1 Receptor Agonists and Other Second-Line Antidiabetics in Early Pregnancy.

Importance: Increasing use of second-line noninsulin antidiabetic medication (ADM) in pregnant individuals with type 2 diabetes (T2D) may result in fetal exposure, but their teratogenic risk is unknown. Objective: To evaluate periconceptional use of second-line noninsulin ADMs and whether it is associated with increased risk of major congenital malformations (MCMs) in the infant. Design, Setting, and Participants: This observational population-based cohort study used data from 4 Nordic countries (2009-2020), the US MarketScan Database (2012-2021), and the Israeli Maccabi Health Services database (2009-2020). Pregnant women with T2D were identified and their live-born infants were followed until up to 1 year after birth. Exposure: Periconceptional exposure was defined as 1 or more prescription fill of sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, or insulin (active comparator) from 90 days before pregnancy to end of first trimester. Main Outcomes and Measures: Relative risks (RRs) and 95% CIs for MCMs were estimated using log-binomial regression models, adjusting for key confounders in each cohort and meta-analyzed. Results: Periconceptional exposure to second-line noninsulin ADMs differed between countries (32, 295, and 73 per 100 000 pregnancies in the Nordics, US, and Israel, respectively), and increased over the study period, especially in the US. The standardized prevalence of MCMs was 3.7% in all infants (n = 3 514 865), 5.3% in the infants born to women with T2D (n = 51 826), and among infants exposed to sulfonylureas was 9.7% (n = 1362); DPP-4 inhibitors, 6.1% (n = 687); GLP-1 receptor agonists, 8.3% (n = 938); SGLT2 inhibitors, 7.0% (n = 335); and insulin, 7.8% (n = 5078). Compared with insulin, adjusted RRs for MCMs were 1.18 (95% CI, 0.94-1.48), 0.83 (95% CI, 0.64-1.06), 0.95 (95% CI, 0.72-1.26), and 0.98 (95% CI, 0.65-1.46) for infants exposed to sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors, respectively. Conclusions and Relevance: Use of second-line noninsulin ADMs is rapidly increasing for treatment of T2D and other indications, resulting in an increasing number of exposed pregnancies. Although some estimates were imprecise, results did not indicate a large increased risk of MCMs above the risk conferred by maternal T2D requiring second-line treatment. Although reassuring, confirmation from other studies is needed, and continuous monitoring will provide more precise estimates as data accumulate.

Prescription medication use during pregnancy in the United States from 2011 to 2020: trends and safety evidence.

BACKGROUND: Medication use during pregnancy has increased in the United States despite the lack of safety data for many medications. OBJECTIVE: This study aimed to inform research priorities by examining trends in medication use during pregnancy and identifying gaps in safety information on the most commonly prescribed medications. STUDY DESIGN: We identified population-based cohorts of commercially (MarketScan 2011-2020) and publicly (Medicaid Analytic eXtract/Transformed Medicaid Statistical Information System Analytic Files 2011-2018) insured pregnancies ending in live birth from 2 health care utilization databases. Medication use was based on filled prescriptions between the date of last menstrual period through delivery, as well as the period before the last menstrual period and during specific trimesters. We also included a cross-sectional representative sample of pregnancies ascertained by the National Health and Nutrition Examination Survey (2011-2020), with information on prescription medication use during the preceding month obtained through maternal interviews. Teratogen Information System was used to classify the available evidence on teratogenic risk. RESULTS: Among over 3 million pregnancies, the medications most commonly dispensed at any time during pregnancy were analgesics, antibiotics, and antiemetics. The top medications were ondansetron (16.8%), amoxicillin (13.5%), and azithromycin (12.4%) in MarketScan, nitrofurantoin (22.2%), acetaminophen (21.3%; mostly as part of acetaminophen-hydrocodone products), and ondansetron (19.5%) in Medicaid Analytic eXtract/Transformed Medicaid Statistical Information System Analytic Files, and levothyroxine (5.0%), sertraline (2.9%), and insulin (2.9%) in the National Health and Nutrition Examination Survey group. The most commonly dispensed suspected teratogens during the first trimester were antithyroid medications. The use of antidiabetic and psychotropic medications has continued to increase in the United States during the last decade, opioid dispensation has decreased by half, and antibiotics and antiemetics continue to be common. For one-quarter of medications, there is insufficient evidence available to characterize their safety profile in pregnancy. CONCLUSION: There is a need for more drug research in pregnant patients. Future research should focus on anti-infectives with high utilization and limited level of evidence on safety for use during pregnancy. Although lack of evidence is not evidence of safety concerns, it does not indicate risk either. In many instances, the benefits outweigh the risks when these medications are used clinically, and some of the medications with no proven safety may be necessary to treat patients.

Changes in Induced Medical and Procedural Abortion Rates in a Commercially Insured Population, 2018 to 2022 : An Interrupted Time-Series Analysis.

BACKGROUND: During the COVID-19 pandemic, access to in-person care was limited, and regulations requiring in-person dispensing of mifepristone for medical abortions were relaxed. The effect of the pandemic and accompanying regulatory changes on abortion use is unknown. OBJECTIVE: To estimate changes in the incidence rate of induced medical and procedural abortions. DESIGN: Serial cross-sectional study with interrupted time-series analyses. SETTING: Commercially insured persons in the United States. PARTICIPANTS: Reproductive-aged women. INTERVENTION: Onset of the COVID-19 pandemic in March 2020 and subsequent regulatory changes affecting the in-person dispensing requirement for mifepristone. MEASUREMENTS: Monthly age-adjusted incidence rates of medical and procedural abortions were measured among women aged 15 to 44 years from January 2018 to June 2022. Medical abortions were classified as in-person or telehealth. Linear segmented time-series regression was used to calculate changes in abortion rates after March 2020. RESULTS: In January 2018, the estimated age-adjusted monthly incidence rate of abortions was 151 per million women (95% CI, 142 to 161 per million women), with equal rates of medical and procedural abortions. After March 2020, there was an immediate 14% decrease in the monthly incidence rate of abortions (21 per million women [CI, 7 to 35 per million women]; P = 0.004), driven by a 31% decline in procedural abortions (22 per million women [CI, 16 to 28 per million women]; P < 0.001). Fewer than 4% of medical abortions each month were administered via telehealth. LIMITATION: Only abortions reimbursed by commercial insurance were measured. CONCLUSION: The incidence rate of procedural abortions declined during the COVID-19 pandemic, and this lower rate persisted after other elective procedures rebounded to prepandemic rates. Despite removal of the in-person dispensing requirement for mifepristone, the use of telehealth for insurance-covered medical abortions remained rare. Amid increasing state restrictions, commercial insurers have the opportunity to increase access to abortion care, particularly via telehealth. PRIMARY FUNDING SOURCE: Health Resources and Services Administration.

A prospective cohort study of preconception COVID-19 vaccination and miscarriage.

STUDY QUESTION: To what extent is preconception maternal or paternal coronavirus disease 2019 (COVID-19) vaccination associated with miscarriage incidence? SUMMARY ANSWER: COVID-19 vaccination in either partner at any time before conception is not associated with an increased rate of miscarriage. WHAT IS KNOWN ALREADY: Several observational studies have evaluated the safety of COVID-19 vaccination during pregnancy and found no association with miscarriage, though no study prospectively evaluated the risk of early miscarriage (gestational weeks [GW] <8) in relation to COVID-19 vaccination. Moreover, no study has evaluated the role of preconception vaccination in both male and female partners. STUDY DESIGN, SIZE, DURATION: An Internet-based, prospective preconception cohort study of couples residing in the USA and Canada. We analyzed data from 1815 female participants who conceived during December 2020-November 2022, including 1570 couples with data on male partner vaccination. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible female participants were aged 21-45 years and were trying to conceive without use of fertility treatment at enrollment. Female participants completed questionnaires at baseline, every 8 weeks until pregnancy, and during early and late pregnancy; they could also invite their male partners to complete a baseline questionnaire. We collected data on COVID-19 vaccination (brand and date of doses), history of SARS-CoV-2 infection (yes/no and date of positive test), potential confounders (demographic, reproductive, and lifestyle characteristics), and pregnancy status on all questionnaires. Vaccination status was categorized as never (0 doses before conception), ever (≥1 dose before conception), having a full primary sequence before conception, and completing the full primary sequence ≤3 months before conception. These categories were not mutually exclusive. Participants were followed up from their first positive pregnancy test until miscarriage or a censoring event (induced abortion, ectopic pregnancy, loss to follow-up, 20 weeks' gestation), whichever occurred first. We estimated incidence rate ratios (IRRs) for miscarriage and corresponding 95% CIs using Cox proportional hazards models with GW as the time scale. We used propensity score fine stratification weights to adjust for confounding. MAIN RESULTS AND THE ROLE OF CHANCE: Among 1815 eligible female participants, 75% had received at least one dose of a COVID-19 vaccine by the time of conception. Almost one-quarter of pregnancies resulted in miscarriage, and 75% of miscarriages occurred <8 weeks' gestation. The propensity score-weighted IRR comparing female participants who received at least one dose any time before conception versus those who had not been vaccinated was 0.85 (95% CI: 0.63, 1.14). COVID-19 vaccination was not associated with increased risk of either early miscarriage (GW: <8) or late miscarriage (GW: 8-19). There was no indication of an increased risk of miscarriage associated with male partner vaccination (IRR = 0.90; 95% CI: 0.56, 1.44). LIMITATIONS, REASONS FOR CAUTION: The present study relied on self-reported vaccination status and infection history. Thus, there may be some non-differential misclassification of exposure status. While misclassification of miscarriage is also possible, the preconception cohort design and high prevalence of home pregnancy testing in this cohort reduced the potential for under-ascertainment of miscarriage. As in all observational studies, residual or unmeasured confounding is possible. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to evaluate prospectively the relation between preconception COVID-19 vaccination in both partners and miscarriage, with more complete ascertainment of early miscarriages than earlier studies of vaccination. The findings are informative for individuals planning a pregnancy and their healthcare providers. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Health [R01-HD086742 (PI: L.A.W.); R01-HD105863S1 (PI: L.A.W. and M.L.E.)], the National Institute of Allergy and Infectious Diseases (R03-AI154544; PI: A.K.R.), and the National Science Foundation (NSF-1914792; PI: L.A.W.). The funders had no role in the study design, data collection, analysis and interpretation of data, writing of the report, or the decision to submit the paper for publication. L.A.W. is a fibroid consultant for AbbVie, Inc. She also receives in-kind donations from Swiss Precision Diagnostics (Clearblue home pregnancy tests) and Kindara.com (fertility apps). M.L.E. received consulting fees from Ro, Hannah, Dadi, VSeat, and Underdog, holds stock in Ro, Hannah, Dadi, and Underdog, is a past president of SSMR, and is a board member of SMRU. K.F.H. reports being an investigator on grants to her institution from UCB and Takeda, unrelated to this study. S.H.-D. reports being an investigator on grants to her institution from Takeda, unrelated to this study, and a methods consultant for UCB and Roche for unrelated drugs. The authors report no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: N/A.

Treatment Failure and Adverse Events After Amoxicillin-Clavulanate vs Amoxicillin for Pediatric Acute Sinusitis.

Importance: Acute sinusitis is one of the most common indications for antibiotic prescribing in children, with an estimated 4.9 million such prescriptions in the US annually. Consensus does not exist regarding the optimal empirical antibiotic. Objective: To compare amoxicillin-clavulanate vs amoxicillin for the treatment of acute sinusitis in outpatient children. Design, Setting, and Participants: Cohort study of children and adolescents aged 17 years or younger with a new outpatient diagnosis of acute sinusitis and a same-day new prescription dispensation of amoxicillin-clavulanate or amoxicillin in a nationwide health care utilization database. Propensity score matching was used to mitigate confounding. Exposure: A new prescription dispensation of amoxicillin-clavulanate or amoxicillin. Main Outcomes and Measures: Treatment failure, defined as an aggregate of a new antibiotic dispensation, emergency department or inpatient encounter for acute sinusitis, or inpatient encounter for a sinusitis complication, was assessed 1 to 14 days after cohort enrollment. Adverse events were evaluated, including gastrointestinal symptoms, hypersensitivity and skin reactions, acute kidney injury, and secondary infections. Results: The cohort included 320 141 patients. After propensity score matching, there were 198 942 patients (99 471 patients per group), including 100 340 (50.4%) who were female, 101 726 (51.1%) adolescents aged 12 to 17 years, 52 149 (26.2%) children aged 6 to 11 years, and 45 067 (22.7%) children aged 0 to 5 years. Treatment failure occurred in 1.7% overall; 0.01% had serious failure (an emergency department or inpatient encounter). There was no difference in the risk of treatment failure between the amoxicillin-clavulanate and amoxicillin groups (relative risk [RR], 0.98 [95% CI, 0.92-1.05]). The risk of gastrointestinal symptoms (RR, 1.15 [95% CI, 1.05-1.25]) and yeast infections (RR, 1.33 [95% CI, 1.16-1.54]) was higher with amoxicillin-clavulanate. After patients were stratified by age, the risk of treatment failure after amoxicillin-clavulanate was an RR of 0.98 (95% CI, 0.86-1.12) for ages 0 to 5 years; RR was 1.06 (95% CI, 0.92-1.21) for 6 to 11 years; and RR was 0.87 (95% CI, 0.79-0.95) for 12 to 17 years. The age-stratified risk of adverse events after amoxicillin-clavulanate was an RR of 1.23 (95% CI, 1.10-1.37) for ages 0 to 5 years; RR was 1.19 (95% CI, 1.04-1.35) for 6 to 11 years; and RR was 1.04 (95% CI, 0.95-1.14) for 12 to 17 years. Conclusions and Relevance: In children with acute sinusitis who were treated as outpatients, there was no difference in the risk of treatment failure between those who received amoxicillin-clavulanate compared with amoxicillin, but amoxicillin-clavulanate was associated with a higher risk of gastrointestinal symptoms and yeast infections. These findings may help inform decisions for empirical antibiotic selection in acute sinusitis.

Achieving comparability in glycemic control between antidiabetic treatment strategies in pregnancy when using real world data.

PURPOSE: Healthcare utilization databases often lack information on glycemic control, a key confounder when studying the safety of antidiabetic treatments, since patients with worse control are channeled to second-line agents, in particular insulin, versus first-line agents such as metformin. We evaluated whether adjustment for measured characteristics attains balance in glycemic control when comparing antidiabetic treatment strategies in pregnant women with pregestational type 2 diabetes (T2DM). METHODS: In a US insurance claims database, we identified 3360 women with T2DM pregnant between 2004 and 2015, of whom a subset of 996 had data on hemoglobin A1c (HbA1c ) levels. We selected insulin only as the comparator group and used propensity score (PS)-matching on comorbidities and proxies of diabetes severity, but not on HbA1c , to adjust for confounding. We used standardized differences (st.diff) to assess balance in claims-based covariates and mean HbA1c (% ± SD) in the subset. RESULTS: There were imbalances in claims-based covariates before PS-matching, with smaller differences when both treatment strategies included insulin. After PS-matching, balance was achieved in most claims-based covariates (st.diff <0.1). Mean HbA1c was similar before and after PS-matching when both treatments included insulin (e.g., 7.1 ± 1.5 vs. 7.7 ± 1.8 and 7.1 ± 1.5 vs. 7.5 ± 1.7, respectively, for metformin + insulin vs. insulin only). Differences in mean HbA1c remained after PS-matching when non-insulin treatments were compared to treatments including insulin (e.g., 6.3 ± 1.1 vs. 7.6 ± 1.7 for metformin only vs. insulin only). CONCLUSIONS: Balance in both claims-based characteristics and glycemic control was attained after restricting the population to women with T2DM and comparing treatment strategies indicated for patients with similar diabetes severity. When comparing treatment strategies with versus without insulin, differences in glycemic control persisted after PS-matching even when balance was attained for other measured characteristics.

Prevalence of Mental Health Diagnoses in Commercially Insured Children and Adolescents in the US Before and During the COVID-19 Pandemic.

This cross-sectional study examines trends in the prevalence of various mental health diagnoses in children and adolescents in the US, stratified by age and sex, before and during the COVID-19 pandemic.

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 50 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: A total of 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.