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Objective: To assess whether women with a genetic predisposition to medical conditions known to increase pre‐eclampsia risk have an increased risk of pre‐eclampsia in pregnancy. Design: Case–control study. Setting and population: Pre‐eclampsia cases (n = 498) and controls (n = 1864) in women of European ancestry from five US sites genotyped on a cardiovascular gene‐centric array. Methods: Significant single‐nucleotide polymorphisms (SNPs) from 21 traits in seven disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal and thrombophilia) with published genome‐wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous scaled genetic instrument with pre‐eclampsia. Odds of pre‐eclampsia were compared across quartiles of the genetic instrument and evaluated for significance. Main outcome measures: Genetic predisposition to medical conditions and relationship with pre‐eclampsia. Results: An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of pre‐eclampsia (DBP, overall OR 1.11, 95% CI 1.01–1.21, P = 0.025; BMI, OR 1.10, 95% CI 1.00–1.20, P = 0.042), whereas alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89, 95% CI 0.82–0.97, P = 0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early‐onset pre‐eclampsia cases (at <34 weeks of gestation, OR 1.30, 95% CI 1.08–1.56, P = 0.005). For other traits, there was no evidence of an association. Conclusions: These results suggest that the underlying genetic architecture of pre‐eclampsia may be shared with other disorders, specifically hypertension and obesity. A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre‐eclampsia. A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre‐eclampsia. [ABSTRACT FROM AUTHOR]

BACKGROUND: : Subarachnoid hemorrhage (SAH) in pregnancy occurs because of a variety of etiologies, which range from ruptured aneurysms to benign venous bleeding. The more malignant etiologies represent an important cause of maternal morbidity and mortality. We sought to investigate the epidemiology and mechanisms of pregnancy-related SAH. METHODS: : Using the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality, we extracted pregnancy-related admissions for women ages 15-44 from 1995-2008 and identified admissions complicated by SAH. Logistic regression identified independent predictors of SAH. Outcomes and risk factors were then compared with age-matched, nonpregnant women with SAH. We also analyzed our institution's experience with pregnancy-related SAH. RESULTS: : There were 639 cases (5.8 per 100,000 deliveries) of pregnancy-related SAH in the cohort during the study period; SAH was associated with 4.1% of all pregnancy-related in-hospital deaths. More than half of the SAH cases occurred postpartum. Advancing age, African-American race, Hispanic ethnicity, hypertensive disorders, coagulopathy, tobacco, drug or alcohol abuse, intracranial venous thrombosis, sickle cell disease, and hypercoagulability were independent risk factors for pregnancy-related SAH. Compared with SAH in nonpregnant controls, pregnancy-related SAH had lower clipping/coiling rates (12.7% vs. 44.5%, P < 0.001). We identified 12 cases of pregnancy-related SAH in our hospital, the majority of which presented postpartum and with severe headache. CONCLUSION: : SAH during pregnancy results from a range of etiologies, and is less likely to be because of a cerebral aneurysm than SAH occurring in the nonpregnant patient. Peripartum SAH frequently occurs in the setting of hypertensive disorders. [ABSTRACT FROM AUTHOR]

BACKGROUND: : Maternal morbidity and mortality are increased in the United States compared with that of other developed countries. The objective of this investigation is to determine the extent to which it is possible to predict which patients will experience near-miss morbidity or mortality. METHODS: : The authors defined near-miss morbidity as end-organ injury associated with length of stay greater than the 99 percentile or discharge to a second medical facility, and identified all cases of near-miss morbidity or death from admissions for delivery in the 2003-2006 Nationwide Inpatient Sample. Logistic regression was used to examine the effect of maternal characteristics on rates of near-miss morbidity/mortality. RESULTS: : Approximately 1.3 per 1,000 hospitalizations for delivery was complicated by near-miss morbidity/mortality as defined in this study (95% CI 1.3-1.4). Most of these events (58.3%) occurred in 11.8% of the delivering population-in those women with important medical comorbidities or obstetric complications identified before admission for delivery. The highest rates were noted among women with pulmonary hypertension (98.0 cases per 1,000 deliveries), malignancy (23.4 per 1,000), and systemic lupus erythematosus (21.1 per 1,000). CONCLUSIONS: : Risk for near-miss morbidity or mortality is substantially increased among an identifiable subset of pregnant women. To the extent that antepartum multidisciplinary coordination and high-quality intrapartum care improve delivery outcomes for women with significant antepartum medical and obstetric disease, then public health investments to reduce the national burden of delivery-related near-miss morbidity and mortality will have the greatest effect by focusing resources on identifying and serving these high-risk groups. [ABSTRACT FROM AUTHOR]

INTRODUCTION:: Multiple studies have used administrative datasets to examine the epidemiology of sepsis in general, but the entity of postoperative sepsis has been studied less intensively. Therefore, we undertook an analysis of the epidemiology of postoperative sepsis using the Nationwide Inpatient Sample, the largest in-patient dataset available in the United States. METHODS:: Elective admissions of patients aged 18 yr or older with a length of stay more than 3 days for any 1 of the 20 most common elective operative procedures were extracted from the dataset for the years 1997-2006. Postoperative sepsis was defined using the appropriate International Classification of Diseases, Ninth Revision, Clinical Modification codes; severe sepsis was defined as sepsis along with organ dysfunction. Logistic regression was used to assess the significance of temporal trends after adjusting for relevant demographic characteristics, operative procedure, and comorbid conditions. RESULTS:: We identified 2,039,776 admissions for analysis. The rate of severe sepsis increased from 0.3% in 1997 to 0.9% in 2006. This trend persisted after adjusting for relevant covariables-the adjusted odds ratio of severe sepsis per year increase in the study period was 1.12 (95% CI, 1.11-1.13; P < 0.001). The in-hospital mortality rate for patients with severe postoperative sepsis declined from 44.4% in 1997 to 34.0% in 2006; this trend also persisted after adjustment for relevant covariables-the adjusted odds ratio per year was 0.94 (95% CI, 0.93-0.95; P < 0.001). CONCLUSION:: During the 10-yr period that we studied, there was a marked increase in the rate of severe postoperative sepsis but a concomitant decrease in the in-hospital mortality rate in severe sepsis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Perioperative acute ischemic stroke (AIS) is a recognized complication of noncardiac, nonvascular surgery, but few data are available regarding incidence and effect on outcome. This study examines the epidemiology of perioperative AIS in three common surgeries: hemicolectomy, total hip replacement, and lobectomy/segmental lung resection. METHODS: Discharges for patients aged 18 yr or older who underwent any of the surgical procedures listed above were extracted from the Nationwide Inpatient Sample, an administrative database that contains 20% of all discharges from non-Federal hospitals each year, for years 2000 to 2004. Using appropriate International Classification of Diseases, 9th revision, Clinical Modification codes, patients with perioperative AIS were identified, as were comorbid conditions that may be risk factors for perioperative AIS. Multivariate logistic regression was performed to identify independent predictors of perioperative AIS and to ascertain the effect of AIS on outcome. RESULTS: A total of 0.7% of 131,067 hemicolectomy patients, 0.2% of 201,235 total hip replacement patients, and 0.6% of 39,339 lobectomy/segmental lung resection patients developed perioperative AIS. For patients older than 65 yr, AIS rose to 1.0% for hemicolectomy, 0.3% for hip replacement, and 0.8% for pulmonary resection. Multivariate logistic regression analysis revealed renal disease (odds ratio, 3.0), atrial fibrillation (odds ratio, 2.0), history of stroke (odds ratio, 1.6), and cardiac valvular disease (odds ratio, 1.5) to be the most significant risk factors for perioperative AIS. CONCLUSIONS: Perioperative AIS is an important source of morbidity and mortality associated with noncardiac, nonvascular surgery, particularly in elderly patients and patients with atrial fibrillation, valvular disease, renal disease, or previous stroke. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The objective of the study was to examine the trends in the rate of peripartum hysterectomy and the contribution of changes in maternal characteristics to these trends. STUDY DESIGN: This was a cross-sectional study of peripartum hysterectomy identified from hospitalizations for delivery recorded in the 1994-2007 Nationwide Inpatient Sample. RESULTS: The overall rate of peripartum hysterectomy increased by 15% during the study period. The rate of hysterectomy for abnormal placentation increased by 1.2-fold; adjustment for previous cesarean delivery explained nearly all of this increase. The rate of hysterectomy for uterine atony following repeat cesarean delivery increased nearly 4-fold, following primary cesarean delivery approximately 2.5-fold, and following vaginal delivery about 1.5-fold. This fast growing trend in peripartum hysterectomy secondary to uterine atony was also largely explained by increasing rates of primary and repeat cesareans. CONCLUSION: Rates of peripartum hysterectomy increased substantially in the United States from 1994 to 2007; much of this increase was due to rising rates of cesarean delivery. [ABSTRACT FROM AUTHOR]

Pain management in pregnant and postpartum people with an opioid-use disorder (OUD) requires a balance between risks associated with opioid tolerance, including withdrawal or return to opioid use, considerations around social needs of the maternal-infant dyad, and the provision of adequate pain relief for the birth episode that is often characterized as the worst pain a person will experience in their lifetime. This multidisciplinary consensus statement between the Society for Obstetric Anesthesia and Perinatology (SOAP), Society for Maternal-Fetal Medicine (SMFM), and American Society of Regional Anesthesia and Pain Medicine (ASRA) provides a framework for pain management in obstetric patients with OUD. The purpose of this consensus statement is to provide practical and evidence-based recommendations and is targeted to health care providers in obstetrics and anesthesiology. The statement is focused on prenatal optimization of pain management, labor analgesia, and postvaginal delivery pain management, and postcesarean delivery pain management. Topics include a discussion of nonpharmacologic and pharmacologic options for pain management, medication management for OUD (eg, buprenorphine, methadone), considerations regarding urine drug testing, and other social aspects of care for maternal-infant dyads, as well as a review of current practices. The authors provide evidence-based recommendations to optimize pain management while reducing risks and complications associated with OUD in the peripartum period. Ultimately, this multidisciplinary consensus statement provides practical and concise clinical guidance to optimize pain management for people with OUD in the context of pregnancy to improve maternal and perinatal outcomes., Competing Interests: Conflicts of Interest, Funding: Please see DISCLOSURES at the end of this article., (Copyright © 2024 International Anesthesia Research Society.)

Competing Interests: Funding Support and Author Disclosures This study was funded by grant R01 HS027623 from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. Dr Bykov was also supported by National Institute of Health grant K01AG068365. Dr Bea was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant No. RS-2023-00273553). Dr Bykov has been a consultant for Alosa Health, unrelated to the study. Dr Huybrechts has been an investigator on grants to Brigham and Women’s Hospital from Takeda and UCB for unrelated work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To evaluate the comparative efficacy of two of the most commonly used second-line uterotonics-methylergonovine maleate and carboprost tromethamine., Methods: We conducted a double-blind randomized trial at two large academic perinatal centers in patients undergoing nonemergency cesarean delivery with uterine atony refractory to oxytocin, as diagnosed by the operating obstetrician. The intervention included administration of a single dose of intramuscular methylergonovine or carboprost intraoperatively at diagnosis. The primary outcome, uterine tone on a 0-10 numeric rating scale 10 minutes after study drug administration, was rated by operating obstetricians blinded to the drug administered. Secondary outcomes included uterine tone score at 5 minutes, administration of additional uterotonic agents, other interventions for uterine atony or hemorrhage, quantitative blood loss, urine output, postpartum change in serum hematocrit, transfusion, length of hospital stay, adverse drug or transfusion reactions, and postpartum hemorrhage complications. A sample size of 50 participants per group was planned to detect a 1-point difference (with estimated within-group SD of 1.5) in the mean primary outcome with 80% power at a two-sided α level of 0.05 while accounting for potential protocol violations., Results: A total of 1,040 participants were enrolled, with 100 randomized to receive one of the study interventions. Mean±SD 10-minute uterine tone scores were 7.3±1.7 after methylergonovine and 7.6±2.1 after carboprost, with an adjusted difference in means of -0.1 (95% CI, -0.8 to 0.6, P=.76). Additional second-line uterotonics were required in 30.0% of the methylergonovine arm and 34.0% in the carboprost arm (adjusted odds ratio 0.72, 95% CI, 0.27-1.89, P=.505), and geometric mean quantitative blood loss was 756 mL (95% CI, 636-898) and 708 mL (95% CI, 619-810) (adjusted ratio of geometric means 1.06, 95% CI, 0.86-1.31, P=.588), respectively. No differences were detected in the occurrence of other interventions for uterine atony or postpartum hemorrhage., Conclusion: No difference was detected in uterine tone scores 10 minutes after administration of either methylergonovine or carboprost for refractory uterine atony, indicating that either agent is acceptable., Clinical Trial Registration: ClinicalTrials.gov, NCT03584854., Competing Interests: Financial Disclosure: Naida M. Cole reports money was paid to her institution from the Foundation for Anesthesia Education Research through a Mentored Research Training grant. She received UpToDate royalties. Daniela A. Carusi received payment from Wolters Kluwer. Michaela K. Farber served on the advisory boards for Octapharma, HemoSonics, and Flat Medical. Paloma Toledo received speaker fees from Pacira for a SOAP-sponsored talk on a TAP blocks, unrelated to this article. The other authors did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

Informatics describes the study and use of processes for obtaining and utilizing data. In the clinical context, these data are then used to inform and educate providers to improve patient care. In the current digital age, informatic solutions can help clinicians to understand past or current quality issues (afferent tools), to benchmark personal performance against national averages (feedback tools), and to disseminate information to encourage best practice and quality care (efferent tools). There are countless examples of how these tools can be adapted for use in obstetric anesthesia, with evidence to support their implementation. This article thus aimed to summarize the many ways in which informatics can help clinicians to harness the power of data to improve quality and safety in obstetric anesthesia., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 International Anesthesia Research Society.)

Background: Prescribed opioid analgesics are frequently used to manage pain in pregnancy. However, the available literature regarding the teratogenic potential of opioid use during pregnancy has not been systematically summarised. This systematic review and meta-analysis aimed to assess the quality of the evidence on these potential risks and calculate a pooled estimate of risk for any opioid analgesic and individual opioids., Methods: We searched PubMed, Embase and CINAHL for published studies assessing the risk of major congenital malformations in infants following first-trimester exposure to opioid analgesics compared with a reference group, excluding studies examining opioid agonist therapy or illicit opioid use. We assessed the risk of bias using the Risk of Bias in Non-Randomised Studies of Intervention tool. We pooled adjusted risk estimates from studies rated at serious risk of bias or better in a random-effects meta-analysis., Results: Of 12 identified studies, 11 were at high risk of bias (eight serious; three critical). Relative to unexposed infants, those exposed to any opioid use during the first trimester of pregnancy were not at an increased risk of major congenital malformations overall (relative risk 1.04, 95%CI 0.98-1.11); cardiovascular malformations (relative risk 1.07, 95%CI 0.96-1.20); or central nervous system malformations (relative risk 1.06, 95%CI 0.92-1.21). Raised risk estimates were observed for gastrointestinal malformations (relative risk 1.40, 95%CI 0.38-5.16) and cleft palate (relative risk 1.57, 95%CI 0.48-5.13) following any opioid exposure and atrial septal defects (relative risk 1.20, 95%CI 1.05-1.36) following codeine exposure., Conclusions: Although the meta-analysis did not indicate substantial increased risk for most malformations examined, this risk remains uncertain due to the methodological limitations of the included studies. Healthcare professionals and pharmaceutical regulators should be aware of the issues related to the quality of research in this field., (© 2024 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

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., (© 2024 by the American Diabetes Association.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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 Merative TM 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., Competing Interests: K.F. Huybrechts reports being an investigator on grants to Brigham and Women’s Hospital from Takeda and UCB for unrelated work.

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., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2038.

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.

Objective: To investigate the association between surgeon-anesthesiologist sex discordance and patient mortality after noncardiac surgery., Background: Evidence suggests different practice patterns exist among female and male physicians. However, the influence of physician sex on team-based practices in the operating room and subsequent patient outcomes remains unclear in the context of noncardiac surgery., Methods: We conducted a population-based, retrospective cohort study of adult Ontario residents who underwent index, inpatient noncardiac surgery between January 2007 and December 2017. The primary exposure was physician sex discordance (ie, the surgeon and anesthesiologist were of the opposite sex). The primary outcome was 1-year mortality. The association between physician sex discordance and patient outcomes was modeled using multivariable Cox proportional hazard regression with adjustment for relevant physician, patient, and hospital characteristics., Results: Of 541,209 patients, 158,084 (29.2%) were treated by sex-discordant physician teams. Physician sex discordance was associated with a lower rate of mortality at 1 year [5.2% vs. 5.7%; adjusted HR: 0.95 (0.91-0.99)]. Patients treated by teams composed of female surgeons and male anesthesiologists were more likely to be alive at 1 year than those treated by all-male physician teams [adjusted HR: 0.90 (0.81-0.99)]., Conclusions: Noncardiac surgery patients had a lower likelihood of 1-year mortality when treated by sex-discordant surgeon-anesthesiologist teams. The likelihood of mortality was further reduced if the surgeon was female. Further research is needed to explore the underlying mechanisms of these observations and design strategies to diversify operating room teams to optimize performance and patient outcomes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Clinical practice guidelines recommend drug testing patients who are receiving opioids chronically for pain or medication for a substance use disorder (SUD)-particularly opioid use disorder (OUD)-but practices vary due to a lack of consensus on testing frequency during follow-up. This study aimed to evaluate rates and costs of outpatient drug testing practices for patients receiving opioids for chronic pain or medication for an SUD., Methods: Using claims data from a large de-identified claims data warehouse, we conducted a retrospective cohort study of chronic opioid, buprenorphine, and naltrexone users between January 2015 and December 2019. We identified two cohorts-chronic opioid medication cohort (CO) and SUD-indicated medication cohort (SUD). We assessed drug testing rates during follow-up using procedure codes and costs using copayment, deductible, co-insurance, and out-of-pocket data., Results: Among 6,657,515 eligible claimants, 367,118 (5.5 %) received opioids chronically and 73,303 (1.1 %) received an SUD-indicated medication. The cumulative proportion of drug testing during follow-up was similar between cohorts (CO: 36 %; SUD: 35 %), but rate of testing was consistently twice as frequent for the SUD cohort. All cost variables for the first drug test were higher on average in the SUD cohort than the CO cohort except copay: deductible (SUD: $18.54; CO: $7.33); co-insurance (SUD: $10.36; CO: $2.53); out-of-pocket (SUD: $29.39; CO: $10.57); copay (CO: $0.71; SUD: $0.49) (all p < 0.001)., Conclusions: Overall proportion of drug testing was similar between cohorts, but testing frequency was at least double during follow-up in the SUD cohort. Most cost variables were higher in the SUD cohort. Whether the high cost of drug testing is a barrier to medication use or is associated with treatment discontinuation should be evaluated., Competing Interests: Declaration of competing interest REB and BTB serve as clinical consultants to Alosa Health for opioid use disorder and pain management-related work. HSC serves as clinical consultant to Alosa Health for opioid use disorder treatment. BTB is a co-investigator on grants to his institution from Eli Lilly, GSK, Pfizer, Pacira, and Baxalta. He is a consultant to Aetion, Inc. for unrelated work. ASK reports serving as an expert witness for the class of state plaintiffs in the multidistrict opiate litigation (2018–2019). TT declares no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Understanding factors that explain why some women experience greater postoperative pain and consume more opioids after cesarean delivery is crucial to building an evidence base for personalized prevention. Comprehensive psychosocial assessment with validated questionnaires in the preoperative period can be time-consuming. A three-item questionnaire has shown promise as a simpler tool to be integrated into clinical practice, but its brevity may limit the ability to explain heterogeneity in psychosocial pain modulators among individuals. This study compared the explanatory ability of three models: (1) the 3-item questionnaire, (2) a 58-item questionnaire (long) including validated questionnaires (e.g., Brief Pain Inventory, Patient Reported Outcome Measurement Information System [PROMIS]) plus the 3-item questionnaire, and (3) a novel 19-item questionnaire (brief) assessing several psychosocial factors plus the 3-item questionnaire. Additionally, this study explored the utility of adding a pragmatic quantitative sensory test to models., Methods: In this prospective, observational study, 545 women undergoing cesarean delivery completed questionnaires presurgery. Pain during local anesthetic skin wheal before spinal placement served as a pragmatic quantitative sensory test. Postoperatively, pain and opioid consumption were assessed. Linear regression analysis assessed model fit and the association of model items with pain and opioid consumption during the 48 h after surgery., Results: A modest amount of variability was explained by each of the three models for postoperative pain and opioid consumption. Both the brief and long questionnaire models performed better than the three-item questionnaire but were themselves statistically indistinguishable. Items that were independently associated with pain and opioid consumption included anticipated postsurgical pain medication requirement, surgical anxiety, poor sleep, pre-existing pain, and catastrophic thinking about pain. The quantitative sensory test was itself independently associated with pain across models but only modestly improved models for postoperative pain., Conclusions: The brief questionnaire may be more clinically feasible than longer validated questionnaires, while still performing better and integrating a more comprehensive psychosocial assessment than the three-item questionnaire., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

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.)., (Copyright © 2024 Massachusetts Medical Society.)

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.

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.

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.

Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest.

Objective: To evaluate whether prophylactic administration of 1 g of intravenous calcium chloride after cord clamping reduces blood loss from uterine atony during intrapartum cesarean delivery., Methods: This single-center, block-randomized, placebo-controlled, double-blind superiority trial compared the effects of 1 g intravenous calcium chloride with those of saline placebo control on blood loss at cesarean delivery. Parturients at 34 or more weeks of gestation requiring intrapartum cesarean delivery after oxytocin exposure in labor were enrolled. Calcium or saline placebo was infused over 10 minutes beginning 1 minute after umbilical cord clamping in addition to standard care with oxytocin. The primary outcome was quantitative blood loss, analyzed by inverse Gaussian regression. Planned subgroup analysis excluded nonatonic bleeding, such as hysterotomy extension, arterial bleeding, and occult placenta accreta. We planned to enroll 120 patients to show a 200-mL reduction in quantitative blood loss in planned subgroup analysis, assuming up to 40% incidence of nonatonic bleeding (80% power, α<0.05)., Results: From April 2022 through March 2023, 828 laboring parturients provided consent and 120 participants were enrolled. Median blood loss was 840 mL in patients allocated to calcium chloride (n=60) and 1,051 mL in patients allocated to placebo (n=60), which was not statistically different (mean reduction 211 mL, 95% CI -33 to 410). In the planned subgroup analysis (n=39 calcium and n=40 placebo), excluding cases of surgeon-documented nonatonic bleeding, calcium reduced quantitative blood loss by 356 mL (95% CI 159-515). Rates of reported side effects were similar between the two groups (38% calcium vs 42% placebo)., Conclusion: Prophylactic intravenous calcium chloride administered during intrapartum cesarean delivery after umbilical cord clamping did not significantly reduce blood loss in the primary analysis. However, in the planned subgroup analysis, calcium infusion significantly reduced blood loss by approximately 350 mL. These data suggest that this inexpensive and shelf-stable medication warrants future study as a novel treatment strategy to decrease postpartum hemorrhage, the leading global cause of maternal morbidity and mortality., Clinical Trial Registration: ClinicalTrials.gov , NCT05027048., Competing Interests: Financial Disclosure Deirdre Lyell reports financial relationships with National Institutes of Health (NIH), the Society for Maternal-Fetal Medicine (SMFM), and UC San Francisco. Lyell is a stock owner in ZenFlow, unrelated to this work, and a consultant for stock options for Bloomlife, also unrelated to this work. The other authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)