Development and validation of claims-based algorithms for estimating gestational age of spontaneous abortion and termination.

To study the risk of spontaneous abortion (SAB) or termination using healthcare utilization databases, algorithms to estimate the gestational age (GA) are needed. Using Medicaid data, we developed a hierarchical algorithm to classify pregnancy outcomes. We identified the subset of potential SAB and termination cases, and abstracted the GA from linked electronic medical records (gold standard). We developed three approaches: (1) assign median GA for SAB and termination cases in the US; (2) draw a random GA from the population distributions; (3) estimate GA based on regression models. Algorithm performance was assessed based on the proportion of pregnancies with estimated GA within 1-4 weeks of the gold standard, the mean squared error (MSE) and the R-squared. Approach 1 and Approach 3 had similar performance, though approach 3 using random forest models with variables selected via the Boruta algorithm had better MSE and R-squared. For SAB, 58.0% of pregnancies were correctly classified within 2 weeks of the gold standard (MSE: 8.7, R-squared: 0.09). For termination, the proportions were 66.3% (MSE: 11.7; R-squared: 0.35). SABs and terminations can be studied in healthcare utilization data with careful implementation of validated algorithms though higher level of GA misclassification is expected compared to live births.

Development and Validation of an Algorithm to Predict Stillbirth Gestational Age in Medicaid Billing Records.

INTRODUCTION: With Medicaid covering half of US pregnancies, Medicaid Analytic eXtract (MAX) provides a valuable data source to enrich understanding about stillbirth etiologies. OBJECTIVE: We developed and validated a claims-based algorithm to predict GA at stillbirth. METHOD: We linked the stillbirths identified in MAX 1999-2013 to Florida Fetal Death Records (FDRs) to obtain clinical estimates of GA (N=825). We tested several algorithms including using a fixed median GA, median GA at the time of specific prenatal screening tests, and expanded versions considering additional predictors of stillbirth within including linear regression and random forest models. We estimated the proportion of pregnancies with differences of ± 1, 2, 3 and 4 weeks between the predicted and FDR GA and the model mean square error (MSE). We validated the selected algorithms in two external samples. RESULTS: The best performing algorithm was a random forest model (MSE of 12.67 weeks2) with 84% of GAs within ± 4 weeks. Assigning a fixed GA of 28 weeks resulted in an MSE of 60.21 weeks2 and proportions of GA within ± 4 weeks of 32%. We observed consistent results in the external samples. DISCUSSION: Our prediction algorithm for stillbirths can facilitate pregnancy research in the Medicaid population.

Hierarchical Clustering Analysis to Inform Classification of Congenital Malformations for Surveillance of Medication Safety in Pregnancy.

There is growing interest in the secondary use of healthcare data to evaluate medication safety in pregnancy. Tree-based scan statistics (TBSS) offer an innovative approach to help identify potential safety signals. TBSS utilize hierarchically organized outcomes, generally based on existing clinical coding systems that group outcomes by organ system. When assessing teratogenicity, such groupings often lack a sound embryologic basis given the etiologic heterogeneity of congenital malformations. The study objective was to enhance the grouping of congenital malformations to be used in scanning approaches through implementation of hierarchical clustering analysis (HCA) and to pilot test an HCA-enhanced TBSS approach for medication safety surveillance in pregnancy in two test cases using >4.2 million mother-child dyads from two US-nationwide databases. HCA identified (1) malformation combinations belonging to the same organ system already grouped in existing classifications, (2) known combinations across different organ systems not previously grouped, (3) unknown combinations not previously grouped, and (4) malformations seemingly standing on their own. Testing the approach with valproate and topiramate identified expected signals, and a signal for an HCA-cluster missed by traditional classification. Augmenting existing classifications with clusters identified through large data exploration may be promising when defining phenotypes for surveillance and causal inference studies.

Comparative Safety of In Utero Exposure to Buprenorphine Combined With Naloxone vs Buprenorphine Alone.

Importance: Buprenorphine combined with naloxone is commonly used to treat opioid use disorders outside of pregnancy. In pregnancy, buprenorphine alone is generally recommended because of limited perinatal safety data on the combination product. Objective: To compare perinatal outcomes following prenatal exposure to buprenorphine with naloxone vs buprenorphine alone. Design, Settings, and Participants: Population-based cohort study using health care utilization data from Medicaid-insured beneficiaries in the US from 2000 to 2018. The cohort was restricted to pregnant individuals linked to their liveborn infants, with maternal Medicaid enrollment from 3 months before pregnancy to 1 month after delivery and infant enrollment for the first 3 months after birth, unless they died sooner. Exposure: Use of buprenorphine with naloxone vs buprenorphine alone during the first trimester based on outpatient dispensings. Main Outcomes and Measures: Outcomes included major congenital malformations, low birth weight, neonatal abstinence syndrome, neonatal intensive care unit admission, preterm birth, respiratory symptoms, small for gestational age, cesarean delivery, and maternal morbidity. Confounder-adjusted risk ratios were calculated using propensity score overlap weights. Results: This study identified 3369 pregnant individuals exposed to buprenorphine with naloxone during the first trimester (mean [SD] age, 28.8 [4.6] years) and 5326 exposed to buprenorphine alone or who switched from the combination to buprenorphine alone by the end of the first trimester (mean [SD] age, 28.3 [4.5] years). When comparing buprenorphine combined with naloxone with buprenorphine alone, a lower risk for neonatal abstinence syndrome (absolute risk, 37.4% vs 55.8%; weighted relative risk, 0.77 [95% CI, 0.70-0.84]) and a modestly lower risk for neonatal intensive care unit admission (absolute risk, 30.6% vs 34.9%; weighted relative risk, 0.91 [95% CI, 0.85-0.98]) and small for gestational age (absolute risk, 10.0% vs 12.4%; weighted relative risk, 0.86 [95% CI, 0.75-0.98]) was observed. For maternal morbidity, the comparative rates were 2.6% vs 2.9%, respectively, and the weighted relative risk was 0.90 (95% CI, 0.68-1.19). No differences were observed with respect to major congenital malformations overall, low birth weight, preterm birth, respiratory symptoms, or cesarean delivery. Results were consistent across sensitivity analyses. Conclusions and Relevance: There were similar and, in some instances, more favorable neonatal and maternal outcomes for pregnancies exposed to buprenorphine combined with naloxone compared with buprenorphine alone. For the outcomes assessed, compared with buprenorphine alone, buprenorphine with naloxone during pregnancy appears to be a safe treatment option. This supports the view that both formulations are reasonable options for the treatment of opioid use disorder in pregnancy, affirming flexibility in collaborative treatment decision-making.

Patterns of paternal medication dispensation around the time of conception.

BACKGROUND: Past research on the safety of prenatal exposure to medications has focused on maternal use during gestation, with limited research into the potential effects of paternal use during the spermatogenic period preceding conception. Knowing the most common medications used by fathers around the time of conception can inform research priorities in this field. OBJECTIVES: To identify the most common medications dispensed to fathers in the preconception period. METHODS: Within the MarketScan research database of commercially insured individuals in the United States from 2011 to 2020, we identified pregnancies, estimated the date of conception, linked each pregnancy to the father using family enrolment information and required minimum enrolment period and prescription benefits. Then, we described the use of prescription medications by the father during the 90 days before conception based on pharmacy dispensation claims. RESULTS: Of 4,437,550 pregnancies, 51.6% were linked with a father. Among the 1,413,762 pregnancies connected with a father that also met the inclusion criteria, the most common classes of medications dispensed were psychotropics (8.66%), antibiotics (7.21%), and analgesics (6.82%). The most frequently dispensed medications were amoxicillin (3.75%), azithromycin (3.15%), fluticasone (2.70%) and acetaminophen/hydrocodone (2.70%). Some fathers filled prescriptions for medications associated with foetal embryopathy when used by the mother, including mycophenolate (0.04%), methotrexate (0.03%) and isotretinoin (0.02%). CONCLUSIONS: More than a third of fathers filled at least one prescription medication in the preconception period, and several of them are known to be embryotoxic, emphasizing the necessity for further investigation into the potential teratogenicity of paternal exposure.

Use of Real-World Data and Machine Learning to Screen for Maternal and Paternal Characteristics Associated with Cardiac Malformations.

Effective prevention of cardiac malformations, a leading cause of infant morbidity, is constrained by limited understanding of etiology. The study objective was to screen for associations between maternal and paternal characteristics and cardiac malformations. We selected 720,381 pregnancies linked to live-born infants (n=9,076 cardiac malformations) in 2011-2021 MarketScan US insurance claims data. Odds ratios were estimated with clinical diagnostic and medication codes using logistic regression. Screening of 2,000 associations selected 81 associated codes at the 5% false discovery rate. Grouping of selected codes, using latent semantic analysis and the Apriori-SD algorithm, identified elevated risk with known risk factors, including maternal diabetes and chronic hypertension. Less recognized potential signals included maternal fingolimod or azathioprine use. Signals identified might be explained by confounding, measurement error, and selection bias and warrant further investigation. The screening methods employed identified known risk factors, suggesting potential utility for identifying novel risk factors for other pregnancy outcomes.

Perinatal Outcomes Associated With Metformin Use During Pregnancy in Women With Pregestational Type 2 Diabetes Mellitus.

OBJECTIVE: We emulated a modified randomized trial (Metformin in Women With Type 2 Diabetes in Pregnancy [MiTy]) to compare the perinatal outcomes in women continuing versus discontinuing metformin during pregnancy among those with type 2 diabetes treated with metformin plus insulin before pregnancy. RESEARCH DESIGN AND METHODS: This study used two health care claims databases (U.S., 2000-2020). Pregnant women age 18-45 years with type 2 diabetes who were treated with metformin plus insulin at conception were eligible. The primary outcome was a composite of preterm birth, birth injury, neonatal respiratory distress, neonatal hypoglycemia, and neonatal intensive care unit admission. Secondary outcomes included the components of the primary composite outcome, gestational hypertension, preeclampsia, maternal hypoglycemia, cesarean delivery, infants large for gestational age, infants small for gestational age (SGA), sepsis, and hyperbilirubinemia. We adjusted for potential baseline confounders, including demographic characteristics, comorbidities, and proxies for diabetes progression. RESULTS: Of 2,983 eligible patients, 72% discontinued use of metformin during pregnancy. The average age at conception was 32 years, and the prevalence of several comorbidities was higher among continuers. The risk of the composite outcome was 46% for continuers and 48% for discontinuers. The adjusted risk ratio was 0.92 (95% CI 0.81, 1.03). Risks were similar between treatments and consistent between databases for most secondary outcomes, except for SGA, which was elevated in continuers only in the commercially insured population. CONCLUSIONS: Our findings were consistent with those reported in the MiTy randomized trial. Continuing metformin during pregnancy was not associated with increased risk of a neonatal composite adverse outcome. However, a possible metformin-associated risk of SGA warrants further consideration.

Internal validation of gestational age estimation algorithms in health-care databases using pregnancies conceived through fertility procedures.

Fertility procedures recorded in health-care 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 codes. In a cohort of 17 398 US MarketScan pregnancies (2011-2020) in which conception was achieved via fertility procedures, we estimated gestational age at the end of pregnancy using algorithms based on (1) time (days) since the fertility procedure (the reference standard); (2) International Classification of Diseases, Ninth Revision (ICD-9)/International Classification of Diseases, Tenth Revision (ICD-10) (before/after October 2015) codes indicating gestational length recorded at the end of pregnancy (method A); and (3) ICD-10 end-of-pregnancy codes 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 falling within 14 days ($\pm$14 days) of the reference standard. 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 agreement was 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 health-care databases, especially for preterm births 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.).

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.

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.

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.

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.

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.

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.

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.

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 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.