Search

Elizabeth Mostofsky,1–3 Jillian A Dunn,3 Sonia Hernández-Díaz,3 Anna C Johansson,2,4 Murray A Mittleman1–4 1Cardiovascular Epidemiology Research Unit, Beth Israel Deaconess Medical Center, Boston, MA, USA; 2Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; 3Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 4Department of Medicine, Harvard Medical School, Boston, MA, USA Background: Rather than identifying exposures and outcomes for research solely based on interests of medical professionals, there is a need for research that answers questions that are important to patients, so that they may make treatment decisions based on evidence that reflect their individual preferences.Objective: To identify exposures and outcomes of interest that could be studied with electronic health record data from inpatient care.Design, setting, participants: Mixed-methods analysis of semi-structured interviews administered in 2017 to 76 patients and 26 physicians who receive or provide care at Beth Israel Deaconess Medical Center in Boston, MA.Measurements: After conducting detailed semi-structured interviews about topics of interest that can be studied using electronic health records of inpatient care, we used an inductive approach to identify themes about the health care experience.Results: Participants reported concerns about adverse effects of medication changes, drug interactions, and surgery and other invasive procedures. The outcomes of greatest concern to them were in-hospital deaths and hospital-acquired infections. Participants commented on the importance of clear communication and information transfers, the hospital environment, accurate skills and knowledge, and upholding patient dignity and respect.Conclusion: Engaging patients and physicians in the research development process provided insight to the exposures and outcomes they consider important. Our questions about exposures and outcomes of interest were restricted to topics that could be studied with electronic health record data from inpatient care, but using a similar approach to elicit feedback about the health care experience could be used to glean insight for other areas of future research. Keywords: patient-oriented methods, clinical, health communication

Background Some research has suggested a potential link between prenatal exposure to proton pump inhibitors (PPIs) or H2-receptor antagonists (H2RAs) and the development of childhood asthma. Aim To quantify the relative risk of asthma in children who experienced prenatal exposure to PPIs and/or H2RAs, adjusting for potential confounders. Methods In this observational cohort study (NCT01787435), women aged 18-45 years with completed pregnancies between January 1996 and December 2010 were identified from The Health Improvement Network in the United Kingdom, and were linked to infants. Hazard ratios (HRs) were estimated using Cox proportional hazard models. Results Our analysis identified 2371 prenatally exposed and 7745 unexposed infants. The incidence of asthma (per 1000 person-years) was 19.52 in the unexposed cohort, 23.88 in the PPI cohort and 32.16 in the H2RA cohort. After adjusting for maternal healthcare utilisation during the year before pregnancy, the HR for asthma in infants whose mothers received prescriptions at any time during pregnancy was 1.12 (95% confidence interval: 0.88-1.44) for PPIs and 1.43 (1.20-1.70) for H2RAs, when compared with unexposed infants. With further adjustment for maternal comorbidities and other medications, the HR for asthma was 1.03 (0.76-1.40) for PPIs and 1.32 (1.05-1.64) for H2RAs. Conclusions Our analysis showed no association between prenatal exposure to PPIs and asthma in childhood after adjusting for confounders. The association found for H2RAs may be explained largely by underlying environmental or genetic factors, as suggested by reductions in hazard ratio estimates following adjustment for maternal comorbidities. [ABSTRACT FROM AUTHOR]

Background: Prior studies have suggested an increased risk of oral clefts after exposure to amoxicillin in early pregnancy, but findings have been inconsistent.Methods: Among participants in the Slone Epidemiology Center Birth Defects Study from 1994 to 2008, we identified 877 infants with cleft lip with/without cleft palate and 471 with cleft palate alone. Controls included 6952 nonmalformed infants. Mothers were interviewed about demographic, reproductive and medical factors, and details of medication use. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) associated with use of amoxicillin in the first trimester using conditional logistic regression and adjusting for known risk factors for oral clefts, as well as for infections, fever, and concomitant treatments.Results: In the control group, 2.1% of women had used amoxicillin in the first trimester. Maternal use of amoxicillin was associated with an increased risk of cleft lip with/without cleft palate (adjusted OR = 2.0 [95% confidence interval = 1.0-4.1]), with an OR of 4.3 (1.4-13.0) for third-gestational-month use. Risks were not elevated for use of other penicillins or cephalosporins. For cleft palate, the OR for first-trimester amoxicillin was 1.0 (0.4-2.3) with an OR of 7.1 (1.4-36) for third-gestational month use.Conclusions: Amoxicillin use in early pregnancy may be associated with an increased risk of oral clefts. [ABSTRACT FROM AUTHOR]

Background: Estrogen plus progestin therapy increases the risk for coronary heart disease (CHD) in postmenopausal women. However, this increased risk might be limited to the first years of use and to women who start therapy late in menopause.Objective: To estimate the effect of continuous estrogen plus progestin therapy on CHD risk over time and stratified by years since menopause.Design: Women's Health Initiative randomized, double-blinded, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00000611)Setting: 40 U.S. clinical centers.Patients: 16 608 postmenopausal women with an intact uterus at baseline from 1993 to 1998.Intervention: Conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo.Measurements: Adherence-adjusted hazard ratios and CHD-free survival curves estimated through inverse probability weighting.Results: Compared with no use of hormone therapy, the hazard ratio for continuous use of estrogen plus progestin therapy was 2.36 (95% CI, 1.55 to 3.62) for the first 2 years and 1.69 (CI, 0.98 to 2.89) for the first 8 years. For women within 10 years after menopause, the hazard ratios were 1.29 (CI, 0.52 to 3.18) for the first 2 years and 0.64 (CI, 0.21 to 1.99) for the first 8 years, and the CHD-free survival curves for continuous use and no use of estrogen plus progestin crossed at about 6 years (CI, 2 years to 10 years).Limitation: The analysis may not have fully adjusted for joint determinants of adherence and CHD risk. Sample sizes for some subgroup analyses were small.Conclusion: No suggestion of a decreased risk for CHD was found within the first 2 years of estrogen plus progestin use, including in women who initiated therapy within 10 years after menopause. A possible cardioprotective effect in these women who initiated therapy closer to menopause became apparent only after 6 years of use.Primary Funding Source: National Heart, Lung, and Blood Institute. [ABSTRACT FROM AUTHOR]

Background: Widespread human exposure to phthalates, some of which are developmental and reproductive toxicants in experimental animals, raises concerns about potential human health risks. Underappreciated sources of exposure include phthalates in the polymers coating some oral medications. Objective: The objective of this study was to evaluate whether users of phthalate-containing medications have higher urinary concentrations of phthalate metabolites than do nonusers. Methods: We used publically available files from the National Health and Nutrition Examination Survey for the years 1999DS2004. For certain survey periods, participants were asked to recall use of prescription medication during the past 30 days, and for a subsample of individuals, the urinary concentrations of phthalate metabolites were measured. We a priori identified medications potentially containing phthalates as inactive ingredients and then compared the mean urinary concentration of phthalate metabolites between users and nonusers of those medications. Results: Of the 7,999 persons with information on urinary phthalate concentrations, 6 reported using mesalamine formulations, some of which may include dibutyl phthalate (DBP) ; the mean urinary concentration of monobutyl phthalate, the main DBP metabolite, among these mesalamine users was 50 times higher than the mean for nonusers (2,257 µg/L vs. 46 µg/L ; p < 0.0001) . Users of didanosine, omeprazole, and theophylline products, some of which may contain diethyl phthalate (DEP) , had mean urinary concentrations of monoethyl phthalate, the main DEP metabolite, significantly higher than the mean for nonusers. Conclusion: Select medications might be a source of high exposure to some phthalates, one of which, DBP, shows adverse developmental and reproductive effects in laboratory animals. These results raise concern about potential human health risks, specifically among vulnerable segments of the general population and particularly pregnant women and children. [ABSTRACT FROM AUTHOR]

Low birth weight (LBW) infants have lower infant mortality in groups in which LBW is most frequent. For example, in 1991, US infants born to smokers had higher risks of both LBW and infant mortality than infants born to nonsmokers. However, among LBW infants, infant mortality was lower for infants born to smokers (relative rate = 0.79). There are competing theories regarding this so-called 'paradox.' One is that maternal smoking is beneficial for LBW infants. The authors use causal diagrams to show that, even in the absence of any beneficial effect of smoking, an inverse association due to stratification on birth weight can be found. This variable is affected by the exposure of interest and shares common causes with the outcome. That is, LBW infants born to smokers may have a lower risk of mortality than other LBW infants whose LBW is due to causes associated with high mortality (e.g., birth defects). Under realistic causal diagrams, adjustment for birth weight is unwarranted when the analytical goal is to estimate overall effects of prenatal variables on infant mortality. Even for estimating direct effects of prenatal variables, adjustment for birth weight may be invalid when there is an unmeasured common cause of LBW and mortality. An appropriate justification for conditioning on birth weight requires specifying 1) the causal question motivating this analytical approach and 2) the assumptions regarding the proposed underlying biologic mechanisms. [ABSTRACT FROM AUTHOR]

Context: The 1992 peace settlement that ended the civil war in El Salvador included land redistribution and other provisions designed to improve the socioeconomic status of ex-combatants and vulnerable civilians.Objective: To describe associations between postwar social and economic assistance programs, especially land reform, and current child health status as reflected by nutrition in a population of resettled rural refugees.Design: A population-based cross-sectional survey of child nutritional status and principal elements of the reconstruction process.Setting: A single rural municipality in northern El Salvador.Participants: A representative sample of 761 children younger than 5 years, living in 27 villages.Main Outcome Measure: Prevalence of stunting (low height for age) in children younger than 5 years.Results: Prevalence of stunting was 32.4%. Stunting was significantly more prevalent among children whose families cultivated less land (odds ratio [OR] for stunting per additional hectare of redistributed land cultivated, 0.64; 95% confidence interval [CI], 0.44-0.93). Less than half of newly transferred land was being cultivated by its owners. Most of the children (84.7%) lived in families cultivating 2 hectares or less of redistributed land. Stunting was also more prevalent among children whose households lacked piped water (adjusted OR, 2.72; 95% CI, 1.87-3.96) vs those who had had piped water since before the cease-fire.Conclusions: Malnutrition, particularly stunting, persisted at high levels and was strongly associated with delay in full cultivation of redistributed land and in provision of water. [ABSTRACT FROM AUTHOR]

Abstract Background To balance the cardiovascular benefits from low-dose aspirin against the gastrointestinal harm caused, studies have considered the coronary heart disease risk for each individual but not their gastrointestinal risk profile. We characterized the gastrointestinal risk profile of low-dose aspirin users in real clinical practice, and estimated the excess risk of upper gastrointestinal complications attributable to aspirin among patients with different gastrointestinal risk profiles. Methods To characterize aspirin users in terms of major gastrointestinal risk factors (i.e., advanced age, male sex, prior ulcer history and use of non-steroidal anti-inflammatory drugs), we used The General Practice Research Database in the United Kingdom and the Base de Datos para la Investigación Farmacoepidemiológica en Atención Primaria in Spain. To estimate the baseline risk of upper gastrointestinal complications according to major gastrointestinal risk factors and the excess risk attributable to aspirin within levels of these factors, we used previously published meta-analyses on both absolute and relative risks of upper gastrointestinal complications. Results Over 60% of aspirin users are above 60 years of age, 4 to 6% have a recent history of peptic ulcers and over 13% use other non-steroidal anti-inflammatory drugs. The estimated average excess risk of upper gastrointestinal complications attributable to aspirin is around 5 extra cases per 1,000 aspirin users per year. However, the excess risk varies in parallel to the underlying gastrointestinal risk and might be above 10 extra cases per 1,000 person-years in over 10% of aspirin users. Conclusion In addition to the cardiovascular risk, the underlying gastrointestinal risk factors have to be considered when balancing harms and benefits of aspirin use for an individual patient. The gastrointestinal harms may offset the cardiovascular benefits in certain groups of patients where the gastrointestinal risk is high and the cardiovascular risk is low.

OBJECTIVE: Persistent pulmonary hypertension of the newborn, a clinical syndrome that results from the failure of the normal fetal-to-neonatal circulatory transition, is associated with substantial infant mortality and morbidity. We performed a case-control study to determine possible antenatal and perinatal predictors of persistent pulmonary hypertension of the newborn. METHODS: Between 1998 and 2003, the Slone Epidemiology Center enrolled 377 mothers of infants with persistent pulmonary hypertension of the newborn and 836 mothers of matched control subjects. Within 6 months of delivery, study nurses interviewed participants regarding demographic, medical, and obstetric characteristics. RESULTS: Factors that were independently associated with an elevated risk for persistent pulmonary hypertension of the newborn were infant male gender and black or Asian maternal race compared with white race. High prepregnancy BMI (>27 vs <20) was also associated with persistent pulmonary hypertension of the newborn, as were diabetes and asthma. Compared with infants who were delivered vaginally, the risk for persistent pulmonary hypertension of the newborn was higher for those who were born by cesarean section. Compared with infants who were born within 37 to 41 gestational weeks, the risk was higher for those who were born between 34 and 37 completed weeks and for those born beyond 41 weeks. Compared with infants within the 10th and 90th percentiles of birth weight for gestational age distribution, the risk was higher for infants above the 90th percentile. CONCLUSIONS: Our findings suggest an increased risk for persistent pulmonary hypertension of the newborn associated with cesarean delivery; late preterm or postterm birth; being large for gestational age; and maternal black or Asian race, overweight, diabetes, and asthma. It remains unclear whether some of these factors are direct causes of persistent pulmonary hypertension of the newborn or simply share common causes with it; however, clinicians should be alert to the increased need for monitoring and intervention among pregnancies with these risk factors. [ABSTRACT FROM AUTHOR]

Background: Opioid agonist therapy is strongly recommended for pregnant persons with opioid use disorder. Buprenorphine may be associated with more favorable neonatal and maternal outcomes than methadone, but existing data are limited.Methods: We conducted a cohort study involving pregnant persons who were enrolled in public insurance programs in the United States during the period from 2000 through 2018 in which we examined outcomes among those who received buprenorphine as compared with those who received methadone. Exposure to the two medications was assessed in early pregnancy (through gestational week 19), late pregnancy (gestational week 20 through the day before delivery), and the 30 days before delivery. Risk ratios for neonatal and maternal outcomes were adjusted for confounders with the use of propensity-score overlap weights.Results: The data source for the study consisted of 2,548,372 pregnancies that ended in live births. In early pregnancy, 10,704 pregnant persons were exposed to buprenorphine and 4387 to methadone. In late pregnancy, 11,272 were exposed to buprenorphine and 5056 to methadone (9976 and 4597, respectively, in the 30 days before delivery). Neonatal abstinence syndrome occurred in 52.0% of the infants who were exposed to buprenorphine in the 30 days before delivery as compared with 69.2% of those exposed to methadone (adjusted relative risk, 0.73; 95% confidence interval [CI], 0.71 to 0.75). Preterm birth occurred in 14.4% of infants exposed to buprenorphine in early pregnancy and in 24.9% of those exposed to methadone (adjusted relative risk, 0.58; 95% CI, 0.53 to 0.62); small size for gestational age in 12.1% and 15.3%, respectively (adjusted relative risk, 0.72; 95% CI, 0.66 to 0.80); and low birth weight in 8.3% and 14.9% (adjusted relative risk, 0.56; 95% CI, 0.50 to 0.63). Delivery by cesarean section occurred in 33.6% of pregnant persons exposed to buprenorphine in early pregnancy and 33.1% of those exposed to methadone (adjusted relative risk, 1.02; 95% CI, 0.97 to 1.08), and severe maternal complications developed in 3.3% and 3.5%, respectively (adjusted relative risk, 0.91; 95% CI, 0.74 to 1.13). Results of exposure in late pregnancy were consistent with results of exposure in early pregnancy.Conclusions: The use of buprenorphine in pregnancy was associated with a lower risk of adverse neonatal outcomes than methadone use; however, the risk of adverse maternal outcomes was similar among persons who received buprenorphine and those who received methadone. (Funded by the National Institute on Drug Abuse.). [ABSTRACT FROM AUTHOR]

Purpose: To estimate the prevalence of undiagnosed pulmonary tuberculosis (PTB) and the sensitivity of bacilloscopy in the border region of Chiapas, Mexico.Methods: We actively sought individuals aged 15 years or more with chronic cough from the Border Region of Chiapas, Mexico in three settings: one regional hospital, seven Primary Care Centers (PCC), and 32 communities. Individuals (a total of 899) reporting chronic cough were asked to provide three samples of sputum for acid-fast smears and cultures. The quality of acid-fast smears was evaluated using culture as the gold standard.Results: We obtained sputum specimens from 590 of 899 individuals with chronic cough. A diagnosis of PTB was confirmed in 78. A conservative estimate of the overall prevalence of PTB at the population level was 151 per 100,000 (95% CI: 88 to 241). In the regional hospital, the estimated case detection rate was 66% (29/44). The proportion of candidates for PTB therapy that were actually on treatment was 50% (14/28) at the PCC and 11% (2/19) in the communities. The sensitivity of the bacilloscopy was about 90% in the hospital, and slightly lower than 50% in the PCC and the communities.Conclusion: Improved procedures for PTB detection are required in the studied area to adequately control the disease and to provide therapy to affected patients. [ABSTRACT FROM AUTHOR]

Background: Evidence on the association between antibiotic use and combined oral contraceptive (COC) failure is controversial. We examined the effect of concomitant antibiotic treatment on the risk of breakthrough pregnancy among COC users.Study Designs: We performed a case-crossover study of 1330 COC failure cases among 17,721 women from the Slone Epidemiology Center Birth Defects Study (1997-2008) and among 25,941 women from the National Birth Defects Prevention Study (NBDPS, 1997-2005). Self-matched odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by comparing antibiotic use between the 4 weeks before conception ("case period") and the 4-8 weeks before conception ("control period") using conditional logistic regression. A case-time-control analysis was conducted using nonusers of COCs with unplanned pregnancies as controls.Results: For the combined data, the self-matched OR was 1.08 (95% CI: 0.63-1.84) and the case-time-control OR was 1.12 (0.63-1.98) for antibiotics overall. The results did not appreciably differ when adjusted for characteristics that might vary between the case and control period. However, among COC failure cases from the NBDPS, allowing a 1-month gap between the case and control period resulted in a self-matched OR of 1.45 (0.85-2.50) and a case-time-control OR of 1.55 (0.86-2.79) for antibiotics overall.Conclusions: We did not find an association between concomitant antibiotic use and the risk of breakthrough pregnancy among COC users. However, due to limited power and potential carryover effects, findings from this study cannot rule out an elevated risk of COC failure among antibiotic users. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKI) have improved the outcome and life expectancy of patients with chronic myeloid leukemia (CML). Patients are diagnosed with CML at younger ages, and patients treated for CML may become pregnant or choose to breastfeed. The information available to date on the safety of TKIs during pregnancy and lactation and the optimal management of these patients is largely anecdotal, based on personal or small-group experience, and heterogeneous. A panel of interested parties was convened by U.S. Food and Drug Administration to analyze the current data and discuss possible solutions. Possible solutions include prospective data collection, in clinical trials and in routine clinical practice, a more uniform and specific data collection, and greater coordination among involved entities. As patients with cancer are living longer, frequently receiving therapies for extended periods of time (or for life), data on appropriate management of patients through different reproductive phases of life are needed. It is thus time to change our approach for how to study treatment of cancer (including CML) during pregnancy or breastfeeding to develop evidence-based guidelines for safe and effective patient care., (©2024 American Association for Cancer Research.)

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.)

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., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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.

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: 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., (© 2024 John Wiley & Sons Ltd.)

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: 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 A 1c 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., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-1405.

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.