Benzodiazepine Use Early in Pregnancy and Risk for Congenital Malformations

Background: Existing data on malformations associated with benzodiazepine use in pregnancy are conflicting. Objective: To assess the risk for major congenital malformations from first-trimester exposure to benzodiazepines. Design: Population-based U.S. cohort study. Setting: Medicaid (2000–2018) and Merative MarketScan (2003–2020) databases. Participants: Pregnant persons enrolled from 90 days before pregnancy to 30 days after delivery, and their live-born infants enrolled for 90 days after birth. Measurements: Exposure was defined as at least 1 fill of a benzodiazepine in the first trimester. Primary outcomes were any major congenital malformation and organ-specific malformations previously associated with benzodiazepine exposure. The investigators estimated relative risks (RRs) comparing exposed versus unexposed pregnancies with propensity score fine stratification weights to control for confounders. An RR of 1.3 or higher was prespecified as clinically significant. Results: In total, 51 339 of 2 478 434 (2.1%) publicly insured and 27 779 of 1 750 721 (1.6%) commercially insured pregnancies had benzodiazepine exposure. The adjusted absolute risks for any malformation in exposed versus unexposed pregnancies were 4.0% versus 4.1% for Medicaid and 4.9% versus 4.8% for MarketScan. The pooled adjusted RR was 0.99 (95% CI, 0.96 to 1.03). Associations with organ-specific malformations were not consistently observed in sensitivity analyses, nor was a dose–response relationship observed. Analyses of different benzodiazepines yielded similar results. The risk for selected organ-specific malformations was increased in some analyses of coexposure to benzodiazepines and other psychoactive medications, but a consistent pattern did not emerge. Limitations: Potential nondifferential exposure and outcome misclassification; analyses restricted to malformations prevalent at birth. Conclusion: No substantial increase in the risk for malformations was consistently identified across data sources. Findings from coexposure analyses were inconsistent and warrant further study. Primary Funding Source: National Institute of Child Health and Human Development.

Reframing Social Drivers of Health in Patient Quality and Safety

A Retrospective Study Evaluating the Utilization of G2211

Telehealth Utilization and Health Conditions Addressed Among the U.S. Medicare Population

Neither Metformin nor Ursodeoxycholic Acid Effectively Treats Postacute Sequelae of COVID-19: A Randomized Clinical Trial: Annals of Internal Medicine: Vol 179, No 4

Background: There is no proven treatment to alleviate symptoms of postacute sequelae of SARS-CoV-2 infection (PASC), despite its substantial public health burden. Objective: To evaluate the efficacy of metformin and ursodeoxycholic acid (UDCA) in improving PASC symptoms in adults. Design: Double-blind, placebo-controlled, randomized clinical trial. (Clinical Research Information Service: KCT0009342) Setting: Two tertiary hospitals in South Korea, July 2024 to April 2025. Participants: Of 666 adults screened, 396 with a PASC index score of 12 or greater were randomly assigned. Intervention: Oral metformin (uptitrated to 1500 mg/d), UDCA (900 mg once daily), or double placebo for 14 days (1:1:1). Measurements: Proportion of participants achieving PASC recovery (index score <12) at 8 weeks. Results: Among 396 randomized participants (median age, 36 years [IQR, 28 to 49 years]; 72% women), 132 received metformin, 132 received UDCA, and 132 received placebo. The mean interval from SARS-CoV-2 infection was 9.8 months (SD, 7.5). The mean baseline PASC score was 19.3 (SD, 5.7). Recovery occurred in 63.6% (84 of 132) with metformin, 68.2% (90 of 132) with UDCA, and 68.2% (90 of 132) with placebo. Mean changes in PASC scores from baseline to week 8 were −10.05 (95% CI, −11.35 to −8.76) with metformin and −10.62 (CI, −11.79 to −9.45) with UDCA, compared with −10.43 (CI, −11.69 to −9.18) with placebo. Limitation: Findings may not be generalizable to patients with more severe or persistent long COVID. Conclusion: A 2-week course of metformin or UDCA did not significantly improve recovery from PASC. Primary Funding Source: National Institute of Infectious Diseases, National Institute of Health, South Korea

Annals for Educators - November 2025

In older adults with impaired physical performance after MI, multidomain rehabilitation reduced CV death or CV hospitalization at 1 y

Clinical Impact Ratings GIM/FP/GP: 6 out of 7 Cardiology: 6 out of 7 Geriatrics: 6 out of 7

Continuing Glucagon-Like Peptide-1 Receptor Agonists Into the First Trimester of Pregnancy and Pregnancy Outcomes: A Target Trial Emulation Study Using Claims Information: Annals of Internal Medicine: Vol 179, No 7

Background: Glucagon-like peptide-1 receptor agonist (GLP-1RA) use has increased among women of reproductive age, but limited data exist on safety in pregnancy. Objective: To estimate the risk for nonlive birth, abnormal fetal growth, and major congenital malformation (MCM) with GLP-1RA dispensing in early pregnancy. Design: In an observational cohort of pregnant women aged 16 to 55 years with a GLP-1RA dispensation in the 90 days before the last menstrual period (LMP), a target trial with 2 treatment strategies was emulated: continuation of dispensing into the first trimester (≥1 further dispensation), or noncontinuation. Setting: Merative MarketScan U.S. insurance claims data (2011 to 2024). Participants: 3572 pregnancies (41.1% [n = 1467] among women with type 2 diabetes). Measurements: Risk for nonlive birth was estimated using a weighted Kaplan–Meier estimator. Among live-birth pregnancies linked to infants, the weighted prevalence of MCM, small for gestational age (SGA), and large for gestational age (LGA) was estimated. Results: The weighted risk for nonlive birth was 29.7% with continuation and 27.1% with noncontinuation (adjusted risk ratio, 1.09 [95% CI, 0.98 to 1.23]). Among 2529 live-birth pregnancies, 1443 (57.1%) received at least 1 GLP-1RA dispensation after LMP and 1499 (829 continuers) were linked to an infant. Weighted prevalence ratios for continuation versus noncontinuation were 1.29 (CI, 0.82 to 2.06) for SGA, 1.08 (CI, 0.84 to 1.40) for LGA, and 1.21 (CI, 0.83 to 1.82) for MCM. Limitation: Potential residual confounding by prior glycemic control. Conclusion: Risks for nonlive birth, SGA, LGA, and MCM were not definitively higher with continuation of GLP-1RAs into early pregnancy. However, estimates for MCM and SGA were imprecise and were compatible with both no increased risk and clinically relevant differences in risk. Primary Funding Source: National Institutes of Health.

Patient-Centered Prescription Opioid Tapering Methods: A Randomized Clinical Trial: Annals of Internal Medicine: Vol 179, No 9

Background: Evidence is needed on tapering long-term prescription opioids in outpatient settings. Objective: To determine and compare the effectiveness of 3 opioid tapering and pain control strategies (July 2018 to November 2023). Design: Randomized controlled trial. (ClinicalTrials.gov: NCT03445988) Setting: 11 U.S. sites. Participants: Adults with pain for at least 6 months receiving a morphine equivalent daily dose (MEDD) of 10 or higher for at least 3 months without moderate or severe opioid use disorder. Intervention: Patient-centered opioid tapering with close monitoring and electronic supports was administered as taper only, taper plus cognitive behavioral therapy for chronic pain (pain-CBT), or taper plus a chronic pain self-management program (CPSMP). Measurements: Taper success (primary outcome) was either an MEDD decrease of at least 50% with no increased pain or no MEDD increase with decreased pain intensity. Results: A total of 562 participants were randomly assigned (191 taper only, 203 taper plus pain-CBT, 168 taper plus CPSMP). The taper success rate was 50.9% (95% CI, 42.9% to 58.9%) for taper only, 48.6% (CI, 41.0% to 56.2%) for taper plus pain-CBT, and 44.5% (CI, 36.0% to 53.3%) for taper plus CPSMP. Tapering with pain-CBT or CPSMP provided no benefit in taper success over taper only (taper plus pain-CBT vs. taper only, −2.4 percentage points [CI, −11.9 to 7.2 percentage points]; taper plus CPSMP vs. taper only, −5.2 percentage points [CI, −15.3 to 4.8 percentage points]). Study-related adverse event risk (including opioid withdrawal symptoms) was highest in the taper only group (126 of 191 [66%]) compared with taper plus pain-CBT (109 of 203 [54%]) and taper plus CPSMP (108 of 168 [64%]). Limitation: Challenges related to COVID-19 reduced the sample size and made treatment groups imbalanced; low behavioral treatment attendance and losses to follow-up could have limited effectiveness. Conclusion: Adding CBT or self-management to patient-centered opioid tapering did not improve taper success at 12 months, although CBT may reduce adverse effects (including opioid withdrawal symptoms). Primary Funding Source: Patient-Centered Outcomes Research Institute.

Addressing Primary Care Needs in People Living With Sickle Cell Disease: A Narrative Review: Annals of Internal Medicine: Vol 179, No 3

Adults with sickle cell disease (SCD) are living longer due to advances in care but face a growing burden of chronic comorbid conditions that fall within the scope of primary care. However, primary care providers often lack structured guidance because literature on managing these conditions in the context of SCD is limited. This article outlines clinical approaches to hypertension, diabetes, obesity, chronic constipation, reproductive health, cognitive impairments, depression, and anxiety in people living with SCD. The authors highlight relevant epidemiology, screening recommendations, and treatment considerations that differ from those in the general population. Primary care providers play a crucial role in delivering comprehensive and preventive care to people living with SCD. Specific management of common chronic conditions in this population is necessary to reduce morbidity and improve quality of life.