IMPORTANCE: The frequency of antipsychotic (AP) use during pregnancy has approximately doubled during the last decade. However, little is known about their safety for the developing fetus, and concerns have been raised about a potential association with congenital malformations.
OBJECTIVE: To examine the risk for congenital malformations overall and cardiac malformations associated with first-trimester exposure to APs.
DESIGN, SETTING, AND PARTICIPANTS: This nationwide sample of 1 360 101 pregnant women enrolled in Medicaid with a live-born infant constituted the pregnancy cohort nested in the Medicaid Analytic Extract database, which included data from January 1, 2000, to December 31, 2010. Participants were enrolled in Medicaid from 3 months before their last menstrual period through at least 1 month after delivery. Relative risks (RRs) were estimated using generalized linear models with fine stratification on the propensity score to control for the underlying psychiatric disorders and other potential confounders. Data were analyzed during 2015.
EXPOSURES: Use of APs during the first trimester, the etiologically relevant period for organogenesis.
MAIN OUTCOMES AND MEASURES: Major congenital malformations overall and cardiac malformations identified during the first 90 days after delivery.
RESULTS: Of the 1 341 715 pregnancies that met inclusion criteria (mean [SD] age of women, 24.02 [5.77] years), 9258 (0.69%) filled at least 1 prescription for an atypical AP and 733 (0.05%) filled at least 1 prescription for a typical AP during the first trimester. Overall, 32.7 (95% CI, 32.4-33.0) per 1000 births not exposed to APs were diagnosed with congenital malformations compared with 44.5 (95% CI, 40.5-48.9) per 1000 births exposed to atypical and 38.2 (95% CI, 26.6-54.7) per 1000 births exposed to typical APs. Unadjusted analyses suggested an increased risk for malformations overall for atypical APs (RR, 1.36; 95% CI, 1.24-1.50) but not for typical APs (RR, 1.17; 95% CI, 0.81-1.68). After confounding adjustment, the RR was reduced to 1.05 (95% CI, 0.96-1.16) for atypical APs and 0.90 (95% CI, 0.62-1.31) for typical APs. The findings for cardiac malformations were similar. For the individual agents examined, a small increased risk in overall malformations (RR, 1.26; 95% CI, 1.02-1.56) and cardiac malformations (RR, 1.26; 95% CI, 0.88-1.81) was found for risperidone that was independent of measured confounders.
CONCLUSIONS AND RELEVANCE: Evidence from this large study suggests that use of APs early in pregnancy generally does not meaningfully increase the risk for congenital malformations overall or cardiac malformations in particular. The small increase in the risk for malformations observed with risperidone requires additional study.
OBJECTIVE: To describe patterns and secular trends in the use of immunomodulatory agents in pregnant women with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS).
METHODS: We identified a cohort of women with SLE, RA, PsA, or AS enrolled in public (Medicaid, 2001-2010) or private (Optum Clinformatics, 2004-2012) health insurance, and we included women filling prescriptions for immunomodulatory agents (including steroids, nonbiologic disease-modifying agents, and biologic agents) in the 3-month period immediately prior to their pregnancies. The proportion of women continuing or discontinuing individual agents during pregnancy was reported. Annual prescription fill rates, estimated after accounting for patient characteristics and random variability from year to year in mixed-effects regression models, were used to conduct time trends analysis.
RESULTS: We included 2,645 women being treated with immunomodulatory agents prior to pregnancy. More women with PsA or AS stopped filling prescriptions for immunomodulatory agents during pregnancy (61%) than women with SLE (26%) or women with RA (34.5%). From the first to the third trimester, the proportions of women filling prescriptions for immunomodulatory agents decreased across all indications. Overall, steroids and hydroxychloroquine were the most frequently used agents in pregnancy (48.4% and 27.1%, respectively). The rates (reported per 100 deliveries in our cohort) for steroid prescription fills during pregnancy decreased significantly from 54.4 in 2001 to 42.4 in 2012, while rates for biologic agents increased from 5.1 in 2001 to 16.6 in 2012 (P < 0.001 for both trends).
CONCLUSION: Steroids and hydroxychloroquine remain the most widely prescribed treatment options in pregnancy, but the use of biologic agents is becoming increasingly common.
OBJECTIVE: To systematically compare the risk of adverse events (AEs) for 13 targeted immunomodulators (TIMs) indicated for ankylosing spondylitis (AS), inflammatory bowel diseases, juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis (PsA), or rheumatoid arthritis (RA).
METHODS: We searched electronic databases through July 2015 to retrieve randomized controlled trials (RCTs) and observational studies comparing AEs between 2 or more TIMs head-to-head. We reported on the following outcomes: number of AEs, discontinuation due to AEs, serious AEs, mortality, serious infections, tuberculosis, herpes zoster, and malignancies. We qualitatively synthesized the literature and conducted random-effects meta-analyses if 3 or more studies provided data for an outcome.
RESULTS: Ten head-to-head RCTs and 51 observational studies were included in this systematic review. A majority of the studies (70%) were conducted in RA patients. Risk of treatment discontinuation due to AEs was higher with infliximab than with adalimumab or etanercept in RA, PsA, and AS. A higher risk for serious infections was noted with infliximab than with abatacept, adalimumab, or etanercept in RA. Risk for treatment discontinuation due to AEs, serious infections, and tuberculosis was lower with etanercept than with adalimumab in RA. Limited evidence suggested no comparative differences in risk for mortality, malignancies, and herpes zoster for adalimumab, etanercept, and infliximab in RA.
CONCLUSION: Important differences were noted in the safety profile of TIMs in RA, generally favoring abatacept, adalimumab, and etanercept over infliximab. Head-to-head comparative evidence for other TIMs and non-RA populations was insufficient to draw conclusions for most of the safety outcomes.
PURPOSE: This study examined the accuracy of claims-based algorithms to identify smoking against self-reported smoking data.
METHODS: Medicare patients enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study were identified. For each patient, self-reported smoking status was extracted from Women's Hospital Rheumatoid Arthritis Sequential Study and the date of this measurement was defined as the index-date. Two algorithms identified smoking in Medicare claims: (i) only using diagnoses and procedure codes and (ii) using anti-smoking prescriptions in addition to diagnoses and procedure codes. Both algorithms were implemented: first, only using 365-days pre-index claims and then using all available pre-index claims. Considering self-reported smoking status as the gold standard, we calculated specificity, sensitivity, positive predictive value, negative predictive value (NPV), and area under the curve (AUC).
RESULTS: A total of 128 patients were included in this study, of which 48% reported smoking. The algorithm only using diagnosis and procedure codes had the lowest sensitivity (9.8%, 95%CI 2.4%-17.3%), NPV (54.9%, 95%CI 46.1%-63.9%), and AUC (0.55, 95%CI 0.51-0.59) when applied in the period of 365 days pre-index. Incorporating pharmacy claims and using all available pre-index information improved the sensitivity (27.9%, 95%CI 16.6%-39.1%), NPV (60.4%, 95%CI 51.3%-69.5%), and AUC (0.64, 95%CI 0.58-0.70). The specificity and positive predictive value was 100% for all the algorithms tested.
CONCLUSION: Claims-based algorithms can identify smokers with limited sensitivity but very high specificity. In the absence of other reliable means, use of a claims-based algorithm to identify smoking could be cautiously considered in observational studies.
BACKGROUND AND OBJECTIVES: β blockers are widely used in the treatment of hypertensive disorders during pregnancy. These medications cross the placenta and may cause physiologic changes in neonates exposed in utero. We sought to define the risks of neonatal hypoglycemia and bradycardia associated with maternal exposure to β blockers at the time of delivery in a large, nationwide cohort of Medicaid beneficiaries.
METHODS: We used a cohort of 2 292 116 completed pregnancies linked to liveborn infants of Medicaid-enrolled women from 2003 to 2007. We examined the risks of neonatal hypoglycemia and neonatal bradycardia associated with maternal exposure to β blockers at the time of delivery. Propensity score matching was used to control for potential confounders including maternal demographics, obstetric and medical conditions, and exposure to other medications.
RESULTS: There were 10 585 (0.5%) pregnancies exposed to β blockers at the time of delivery. The risk of neonatal hypoglycemia was 4.3% in the β blocker-exposed neonates versus 1.2% in the unexposed; the risk of neonatal bradycardia was 1.6% in the exposed versus 0.5% in the unexposed. After controlling for confounders, risk remained elevated for both neonatal hypoglycemia and bradycardia among exposed pregnancies versus unexposed (adjusted odds ratio, 1.68, 95% confidence interval, 1.50-1.89 and adjusted odds ratio, 1.29, 95% confidence interval, 1.07-1.55, respectively).
CONCLUSION: Our findings suggest that neonates born to mothers exposed to β blockers in late pregnancy, including labetalol, are at elevated risk for neonatal hypoglycemia and bradycardia.
In a case-control study, matching on a disease risk score (DRS), which includes many confounders, should theoretically result in greater precision than matching on only a few confounders; however, this has not been investigated. We simulated 1,000 hypothetical cohorts with a binary exposure, a time-to-event outcome, and 13 covariates. Each cohort comprised 2 subcohorts of 10,000 patients each: a historical subcohort and a concurrent subcohort. DRS were estimated in the historical subcohorts and applied to the concurrent subcohorts. Nested case-control studies were conducted in the concurrent subcohorts using incidence density sampling with 2 strategies-matching on age and sex, with adjustment for additional confounders, and matching on DRS-followed by conditional logistic regression for 9 outcome-exposure incidence scenarios. In all scenarios, DRS matching yielded lower average standard errors and mean squared errors than did matching on age and sex. In 6 scenarios, DRS matching also resulted in greater empirical power. DRS matching resulted in less relative bias than did matching on age and sex at lower outcome incidences but more relative bias at higher incidences. Post-hoc analysis revealed that the effect of DRS model misspecification might be more pronounced at higher outcome incidences, resulting in higher relative bias. These results suggest that DRS matching might increase the statistical efficiency of case-control studies, particularly when the outcome is rare.
OBJECTIVE: To compare the risk of incident hypertension between initiators of tumor necrosis factor (TNF)-α inhibitors and initiators of nonbiologic disease modifying antirheumatic drugs (hereafter referred to as nonbiologics) in rheumatoid arthritis patients taking methotrexate monotherapy.
METHODS: We conducted a cohort study using insurance claims data (2001-2012) from the US. We identified initiators of use of either TNF-α inhibitors or nonbiologics. Subsequent exposure to these agents was measured monthly in a time-varying manner. The outcome of interest was incident hypertension, defined by a diagnosis and a prescription for an antihypertensive drug. Marginal structural models estimated hazard ratios (HRs) adjusted for both baseline and time-varying confounders. To validate the primary analysis, we designed a verification analysis to evaluate a known association between leflunomide (a nonbiologic disease modifying agent) and hypertension.
RESULTS: We identified 4,822 initiations of TNF-α inhibitor use and 2,400 of nonbiologic use. Crude incidence rates of hypertension per 1,000 person-years of follow-up were 36 (95% CI [confidence interval]: 32, 41) for the TNF-α inhibitor group and 42 (95% CI: 34, 51) for the nonbiologics group. The crude HR of TNF-α inhibitors versus nonbiologics for the risk of incident hypertension was 0.85 (95% CI: 0.67, 1.1). After adjusting for both baseline and time-varying covariates using marginal structural models, the HR was 0.95 (95% CI: 0.74, 1.2). In the verification analysis, the adjusted HR of incident hypertension was 2.3 (95% CI: 1.7, 3.0) in leflunomide initiators compared with methotrexate initiators.
CONCLUSION: Treatment with TNF-α inhibitors was not associated with a reduced risk of incident hypertension compared with nonbiologics in rheumatoid arthritis patients.See Video Abstract at http://links.lww.com/EDE/B36.