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.

Temporal variation in the effectiveness of biologics in asthma: Effect modification by changing patient characteristics.

BACKGROUND: The underlying population of patients selected for each respiratory monoclonal antibody might change as other biologics are approved. OBJECTIVE: To evaluate effect modification by calendar time of the effectiveness of each respiratory biologics in asthma. METHODS: The Effectiveness of Respiratory biologics in Asthma (ERA) is a retrospective cohort of severe asthma patients from the Mass General Brigham clinics between January 2013 and September 2023. Periods were pre-specified as the anti-IgE (2013-2015), anti-IL5 (2016-2018), anti-IL4/13 (2019-2021) or anti-alarmin (2022-2023) era. We evaluated each biologic's effect on asthma-related exacerbations comparing the one-year period before and after therapy initiation using Poisson regression and Cox regression for time-to-first exacerbation. RESULTS: Of 647 biologic-naïve patients, 165 initiated omalizumab, 235 anti-IL5, 227 dupilumab, and 20 tezepelumab. Omalizumab's effectiveness improved as more biologics were approved: incidence rate ratio (IRR) 1.16 [0.94-1.43] anti-IgE era vs. 0.54 [0.37-0.80] anti-IL4/13-alarmin era. Omalizumab patients in the anti-IL4/13-alarmin era had lower blood eosinophil counts and less chronic rhinosinusitis with nasal polyps (CRSwNP). For anti-IL5s, effectiveness peaked in the anti-IL4/13 era (IRR 0.52 [0.42-0.64]) when patients had higher BMI and less concomitant CRSwNP. Dupilumab was most effective in the anti-IL4/13 era (IRR 0.60 [0.50-0.72]). There were fewer current smokers in dupilumab patients in the anti-IL4/13 era. Results were similar in time-to-event analyses and in sensitivity analyses accounting for the COVID-19 pandemic. CONCLUSION: There are temporal variations in the effectiveness of biologics partly explained by the shift in the underlying population, particularly for omalizumab. Though having more choices was associated with better patient selection for omalizumab, this was inconsistent for other biologics.

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.

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.

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.

Removing the FDA's Boxed Hepatotoxicity Warning and Liver Function Testing Requirement for Ambrisentan.

Importance: Endothelin receptor antagonists are first-line therapy for pulmonary arterial hypertension (PAH). The first 2 agents approved in the class, bosentan and ambrisentan, initially carried boxed warnings for hepatotoxicity and required monthly liver function tests (LFTs) as part of a risk evaluation and mitigation strategy (REMS); however, in 2011, as further safety data emerged on ambrisentan, the boxed hepatotoxicity warning and LFT requirements were removed. Objective: To analyze changes in the use of and LFT monitoring for ambrisentan and bosentan after changes to the ambrisentan labeling and REMS. Design, Setting, and Participants: This serial cross-sectional study used data from 3 longitudinal health care insurance claims databases-Medicaid, Optum's deidentified Clinformatics Data Mart, and Merative Marketscan-to perform an interrupted time series analysis of prescription fills and LFTs for patients taking ambrisentan and bosentan. Participants were patients filling prescriptions for ambrisentan and bosentan from July 1, 2007, to December 31, 2018. Data analysis was performed from April 2021 to August 2023. Exposure: Removal of the boxed warning for hepatotoxicity and the REMS LFT monitoring requirements on ambrisentan in March 2011. Main Outcomes and Measures: The primary outcomes were use of ambrisentan (ie, individuals with at least 1 dispensing per 1 000 000 individuals enrolled in the 3 datasets) vs bosentan and LFT monitoring (ie, proportion of initiators with at least 1 ordered test) before initiation and before the first refill. Results: A total of 10 261 patients received a prescription for ambrisentan during the study period (7442 women [72.5%]; mean [SD] age, 52.6 [17.6] years), and 11 159 patients received a prescription for bosentan (7931 women [71.1%]; mean [SD] age, 47.7 [23.7] years). Removal of the ambrisentan boxed hepatotoxicity warning and LFT monitoring requirement was associated with an immediate increase in the use of ambrisentan (1.50 patients per million enrollees; 95% CI, 1.08 to 1.92 patients per million enrollees) but no significant change in the use of bosentan. There were reductions in recorded LFTs before drug initiation (13.1% absolute decrease; 95% CI, -18.2% to -8.0%) and before the first refill (26.4% absolute decrease; 95% CI, -34.4% to -18.5%) of ambrisentan but not bosentan. Conclusions and Relevance: In this serial cross-sectional study of ambrisentan, labeling changes and removal of the REMS-related LFT requirement were associated with shifts in prescribing and testing behavior for ambrisentan but not bosentan. Further clinician education may be needed to maximize the benefits of REMS programs and labeling warnings designed to ensure the safe administration of high-risk medications.

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.

Tramadol use in U.S. Adults With Commercial Health Insurance, 2005-2021.

INTRODUCTION: Tramadol has been associated with chronic opioid use and emergency room (ER) visits. However, little is known about trends in prescription tramadol use in the U.S. METHODS: Optum's de-identified Clinformatics® Data Mart Database was used to assess trends in monthly incident and prevalent tramadol use from 2005 to 2021, stratified by sex and age (18-64 vs. ≥65 years). State-specific trends following scheduling of tramadol as Class IV controlled substance in August 2014 were analyzed with random effects regression models. Demographics, comorbidities, initiation setting, dose, and co-dispensing with other opioids and central nervous system (CNS) agents were assessed in people initiating tramadol, stratified by age and initiation year (2005-2010, 2011-2015, 2016-2021). Analyses were performed in 2023 and 2024. RESULTS: During 2005-2021, the mean percentage using tramadol in a given month was 0.88% of younger females, 0.55% of younger males, 1.97% of older females, and 1.14% of older males; 5,729,652 initiations were identified. Since 2014, estimated relative yearly decrease was 4% (95% CI 3%; 5%) in use and 5% (95% CI 4%; 5%) in initiation, with variation across states. Primary care percentage of tramadol initiations declined from 49.2% in 2005-2010 to 37.2% in 2016-2021. During 2016-2021, co-dispensing with other CNS agents occurred in 37.8% of younger and 32.1% of older adults initiating tramadol. CONCLUSIONS: Tramadol use was higher in females and older adults, exhibited heterogeneous trends across states, and shifted from primary care to ER and specialist settings over time. Co-dispensing with other CNS agents was common and warrants further monitoring.

Chronic Hypertension During Pregnancy: Prevalence and Treatment in the United States, 2008-2021.

BACKGROUND: Treatment of chronic hypertension during pregnancy has been shown to reduce the risk of adverse perinatal outcomes. In this study, we examined the prevalence and treatment of chronic hypertension during pregnancy and assessed changes in these outcomes following the release of the updated 2017 hypertension guidelines of the American College of Cardiology and American Heart Association. METHODS: We analyzed the MerativeTM Marketscan® Research Database of United States commercial insurance claims from 2007 to 2021. We assessed the prevalence of chronic hypertension during pregnancy and oral antihypertensive medication use over time. We then performed interrupted time series analyses to evaluate changes in these outcomes. RESULTS: The prevalence of chronic hypertension steadily increased from 1.8% to 3.7% among 1 900 196 pregnancies between 2008 and 2021. Antihypertensive medication use among pregnant individuals with chronic hypertension was relatively stable (57%-60%) over the study period. The proportion of pregnant individuals with chronic hypertension treated with methyldopa or hydrochlorothiazide decreased (from 29% to 2% and from 11% to 5%, respectively), while the proportion treated with labetalol or nifedipine increased (from 19% to 42% and from 9% to 17%, respectively). The prevalence or treatment of chronic hypertension during pregnancy did not change following the 2017 American College of Cardiology and American Heart Association hypertension guidelines. CONCLUSIONS: The prevalence of chronic hypertension during pregnancy doubled between 2008 and 2021 in a nationwide cohort of individuals with commercial insurance. Labetalol replaced methyldopa as the most commonly used antihypertensive during pregnancy. However, only about 60% of individuals with chronic hypertension in pregnancy were treated with antihypertensive medications.

Paternal Use of Metformin During the Sperm Development Period Preceding Conception and Risk for Major Congenital Malformations in Newborns.

BACKGROUND: Metformin is the most used oral antidiabetic medication. Despite its established safety profile, it has known antiandrogenic and epigenetic modifying effects. This raised concerns about possible adverse developmental effects caused by genomic alterations related to paternal use of metformin during the spermatogenesis period preceding conception. OBJECTIVE: To assess the potential adverse intergenerational effect of metformin by examining the association between paternal metformin use during spermatogenesis and major congenital malformations (MCMs) in newborns. DESIGN: Nationally representative cohort study. SETTING: A large Israeli health fund. PARTICIPANTS: 383 851 live births linked to fathers and mothers that occurred in 1999 to 2020. MEASUREMENTS: MCMs and parental cardiometabolic conditions were ascertained using clinical diagnoses, medication dispensing information, and laboratory test results. The effect of metformin use on MCMs was estimated using general estimating equations, accounting for concurrent use of other antidiabetic medications and parental cardiometabolic morbidity. RESULTS: Compared with unexposed fathers, the prevalence of cardiometabolic morbidity was substantially higher among fathers who used metformin during spermatogenesis, and their spouses. Whereas the crude odds ratio (OR) for paternal metformin exposure in all formulations and MCMs was 1.28 (95% CI, 1.01 to 1.64), the adjusted OR was 1.00 (CI, 0.76 to 1.31). Within specific treatment regimens, the adjusted OR was 0.86 (CI, 0.60 to 1.23) for metformin in monotherapy and 1.36 (CI, 1.00 to 1.85) for metformin in polytherapy, a treatment that was more common in patients with more poorly controlled diabetes. LIMITATION: Laboratory test results for hemoglobin A1c to assess underlying diabetes severity were available only for a subset of the cohort. CONCLUSION: Paternal use of metformin in monotherapy does not increase the risk for MCMs. Association for metformin in polytherapy could potentially be explained by worse underlying parental cardiometabolic risk profile. PRIMARY FUNDING SOURCE: None.

Metformin Use in the First Trimester of Pregnancy and Risk for Nonlive Birth and Congenital Malformations: Emulating a Target Trial Using Real-World Data.

BACKGROUND: Metformin is a first-line pharmacotherapy for type 2 diabetes, but there is limited evidence about its safety in early pregnancy. OBJECTIVE: To evaluate the teratogenicity of metformin use in the first trimester of pregnancy. DESIGN: In an observational cohort of pregnant women with pregestational type 2 diabetes receiving metformin monotherapy before the last menstrual period (LMP), a target trial with 2 treatment strategies was emulated: insulin monotherapy (discontinue metformin treatment and initiate insulin within 90 days of LMP) or insulin plus metformin (continue metformin and initiate insulin within 90 days of LMP). SETTING: U.S. Medicaid health care administration database (2000 to 2018). PARTICIPANTS: 12 489 pregnant women who met the eligibility criteria. MEASUREMENTS: The risk and risk ratio of nonlive births, live births with congenital malformations, and congenital malformations among live births were estimated using standardization to adjust for covariates. RESULTS: A total of 850 women were in the insulin monotherapy group and 1557 in the insulin plus metformin group. The estimated risk for nonlive birth was 32.7% under insulin monotherapy (reference) and 34.3% under insulin plus metformin (risk ratio, 1.02 [95% CI, 1.01 to 1.04]). The estimated risk for live birth with congenital malformations was 8.0% (CI, 5.7% to 10.2%) under insulin monotherapy and 5.7% (CI, 4.5% to 7.3%) under insulin plus metformin (risk ratio, 0.72 [CI, 0.51 to 1.09]). LIMITATION: Possible residual confounding by glycemic control and body mass index. CONCLUSION: Compared with switching to insulin monotherapy, continuing metformin and adding insulin in early pregnancy resulted in little to no increased risk for nonlive birth among women receiving metformin before pregnancy. Under conventional statistical criteria, anything between a 49% decrease and a 9% increase in risk for congenital malformations was highly compatible with our data. PRIMARY FUNDING SOURCE: National Institutes of Health.

The association of short-term increases in ambient PM2.5 and temperature exposures with stillbirth: racial/ethnic disparities among Medicaid recipients.

Racial/ethnic disparities in the association between short-term (e.g. days, weeks) ambient fine particulate matter (PM2.5) and temperature exposures and stillbirth in the US have been understudied. A time-stratified, case-crossover design using a distributed lag non-linear model (0 to 6-day lag) estimated stillbirth odds due to short-term increases in average daily PM2.5 and temperature exposures among 118,632 Medicaid recipients from 2000-2014. Disparities by maternal race/ethnicity (Black, White, Hispanic, Asian, American Indian) and zip-code level socioeconomic status (SES) were assessed. In the temperature-adjusted model, a 10 µg/m3 increase in PM2.5 concentration was marginally associated with increased stillbirth odds at lag 1 (0.68% 95%CI:[-0.04,1.40]) and lag 2 (0.52% 95%CI:[-0.03,1.06]), but not lag 0-6 (2.80% 95%CI:[-0.81,6.45]). An association between daily PM2.5 concentrations and stillbirth odds was found among Black individuals at the cumulative lag (0-6 days: 9.26% 95%CI:[3.12,15.77]), but not among other races/ethnicities. A stronger association between PM2.5 concentrations and stillbirth odds existed among Black individuals living in zip codes with the lowest median household income (lag0-6:14.13% 95%CI:[4.64,25.79]). Short-term temperature increases were not associated with stillbirth risk among any race/ethnicity. Black Medicaid enrollees, and especially those living in lower SES areas, may be more vulnerable to stillbirth due to short-term increases in PM2.5 exposure.

Trends in Use and Evidence of Adherence to Risk Evaluation and Mitigation Strategy Pregnancy Testing Requirements for Thalidomide, Lenalidomide, and Pomalidomide in the USA, 2000-2020.

INTRODUCTION: Lenalidomide, pomalidomide, and thalidomide are effective treatments for multiple myeloma but are teratogenic. To mitigate this risk, the US Food and Drug Administration (FDA) required risk evaluation and mitigation strategy (REMS) programs for these drugs, which include pregnancy testing among women of childbearing potential-twice before initiation, weekly in the first month on treatment, and every 2-4 weeks thereafter. OBJECTIVE: We evaluated dispensing trends of lenalidomide, pomalidomide, and thalidomide and assessed adherence to REMS pregnancy testing requirements among at-risk patients taking these drugs. METHODS: Using three US health insurance claims databases (Optum Clinformatics® [2004-2020], Merative Marketscan [2003-2019], and Medicaid [2000-2018]), we assessed monthly use of the drugs, patient characteristics and treatment persistence among drug initiators, and claims-based evidence for adherence to pregnancy testing requirements among initiators with child-bearing potential. RESULTS: Lenalidomide was the most prescribed agent following its approval in 2006 and through the end of the study period. A total of 48,311 lenalidomide (mean age = 59 years [standard deviation (SD) = 16]), 17,550 thalidomide (mean age = 65 years [SD = 12]), and 6560 pomalidomide initiators (mean age = 65 years [SD = 11]) were identified; 45% of initiators of each drug were women. Among initiators under follow-up on day 90, 70% were still on therapy. Initiators of childbearing potential comprised 3% (N = 1,920) of all initiators; among this cohort, 12% had evidence in claims data of two pregnancy tests before initiation, and 9% with at least 33 days of follow-up of four tests during the first month of treatment. By contrast, 52% who received a refill had claims-based evidence of a pregnancy test within 7 days of dispensing. CONCLUSION: Although most patients who initiated lenalidomide, pomalidomide, and thalidomide were not of child-bearing potential, further investigation into actual non-adherence to pregnancy testing is needed.

TNF-α inhibitor use during pregnancy and the risk of preeclampsia: population-based cohort study.

BACKGROUND: Although the clinical importance of preeclampsia is widely recognized, few treatment options are available for prevention. TNF-α inhibitors have been hypothesized to potentially prevent the disease. We aimed to examine whether exposure to TNF-α inhibitors during pregnancy reduces the risk of preeclampsia. METHODS: We conducted a population-based pregnancy cohort study using nationwide samples of publicly (Medicaid data, 2000-2018) and commercially (MarketScan Research Database, 2003-2020) insured pregnant women linked to their liveborn infants. Exposure was ascertained based on a filled prescription or administration code for TNF-α inhibitors during the first and second trimester of pregnancy. The outcomes included early-onset preeclampsia, late-onset preeclampsia, and small-for-gestational age. For baseline confounding adjustment, we leveraged propensity score overlap weights to estimate risk ratios (RR). RESULTS: Among 4 315 658 pregnancies in the Medicaid and the MarketScan cohort, 2736 (0.063%) were exposed to TNF-α inhibitors during the first trimester and 1712 (0.040%) during the second trimester. After adjustment, the risk of early-onset preeclampsia was not decreased among mothers exposed during the first trimester compared with unexposed women with treatment indications [RR pooled : 1.25, 95% confidence interval (CI) 0.93-1.67]. Similarly, the risk of late-onset preeclampsia was not decreased among mothers exposed during the second trimester compared with unexposed women (RR pooled : 0.99, 95% CI 0.81-1.22). CONCLUSION: Contrary to the hypothesis, exposure to TNF-α inhibitors during pregnancy did not appear to be associated with a reduced risk of early-onset or late-onset preeclampsia. These findings do not support consideration of the use of TNF-α inhibitors for the prevention of preeclampsia.

Association between gender-affirming hormone therapy and measures of glucose metabolism: A longitudinal study.

CONTEXT: The long-term effect of gender-affirming hormone therapy (GAHT) on glucose metabolism is an area of priority in transgender health research. OBJECTIVES: To evaluate the relation between GAHT and changes in fasting blood glucose (FG) and glycosylated hemoglobin (HbA1c) in transmasculine (TM) and transfeminine (TF) persons relative to the corresponding temporal changes in presumably cisgender persons (i.e. without any evidence of TGD status). DESIGN: Retrospective cohort study. SETTING: Three large integrated health systems. PARTICIPANTS: 2,425 TF and 2,127 TM persons compared with 33,995 cisgender males (CM) and 38,913 cisgender females (CF) enrolled in the same health plans. OUTCOMES/MEASURES: Temporal changes in FG and HbA1c levels examined using linear mixed models with main results expressed as ratios-of-ratios. RESULTS: The pre- versus post-GAHT ratios-of-ratio (95% confidence interval) estimates adjusted for age, race/ethnicity, study site, and body mass index in the model comparing TF and CM groups were 1.05 (1.01, 1.09) for FG and 1.03 (0.99, 1.06) for HbA1c. By contrast, the corresponding results in the models contrasting TM and cisgender cohort members were in the 0.99-1.00 range. The ratio-of-ratios comparing post-GAHT changes among transgender and cisgender persons were close to the null and without a discernable pattern. CONCLUSION: Though the within-transgender cohort data suggest an increase in the levels of FG and HbA1c following feminizing GAHT initiation, these changes were no longer evident when compared with the corresponding changes in cisgender referents. Based on these results, clinically important effects of GAHT on routine laboratory markers of glucose metabolism appear unlikely.

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.).