Development and Validation of Algorithms to Estimate Live Birth Gestational Age in Medicaid Analytic eXtract Data.

BACKGROUND: While healthcare utilization data are useful for postmarketing surveillance of drug safety in pregnancy, the start of pregnancy and gestational age at birth are often incompletely recorded or missing. Our objective was to develop and validate a claims-based live birth gestational age algorithm. METHODS: Using the Medicaid Analytic eXtract (MAX) linked to birth certificates in three states, we developed four candidate algorithms based on: preterm codes; preterm or postterm codes; timing of prenatal care; and prediction models - using conventional regression and machine-learning approaches with a broad range of prespecified and empirically selected predictors. We assessed algorithm performance based on mean squared error (MSE) and proportion of pregnancies with estimated gestational age within 1 and 2 weeks of the gold standard, defined as the clinical or obstetric estimate of gestation on the birth certificate. We validated the best-performing algorithms against medical records in a nationwide sample. We quantified misclassification of select drug exposure scenarios due to estimated gestational age as positive predictive value (PPV), sensitivity, and specificity. RESULTS: Among 114,117 eligible pregnancies, the random forest model with all predictors emerged as the best performing algorithm: MSE 1.5; 84.8% within 1 week and 96.3% within 2 weeks, with similar performance in the nationwide validation cohort. For all exposure scenarios, PPVs were >93.8%, sensitivities >94.3%, and specificities >99.4%. CONCLUSIONS: We developed a highly accurate algorithm for estimating gestational age among live births in the nationwide MAX data, further supporting the value of these data for drug safety surveillance in pregnancy. See video abstract at, http://links.lww.com/EDE/B989 .

Validation of claims-based algorithms to identify non-live birth outcomes.

PURPOSE: Perinatal epidemiology studies using healthcare utilization databases are often restricted to live births, largely due to the lack of established algorithms to identify non-live births. The study objective was to develop and validate claims-based algorithms for the ascertainment of non-live births. METHODS: Using the Mass General Brigham Research Patient Data Registry 2000-2014, we assembled a cohort of women enrolled in Medicaid with a non-live birth. Based on ≥1 inpatient or ≥2 outpatient diagnosis/procedure codes, we identified and randomly sampled 100 potential stillbirth, spontaneous abortion, and termination cases each. For the secondary definitions, we excluded cases with codes for other pregnancy outcomes within ±5 days of the outcome of interest and relaxed the definitions for spontaneous abortion and termination by allowing cases with one outpatient diagnosis only. Cases were adjudicated based on medical chart review. We estimated the positive predictive value (PPV) for each outcome. RESULTS: The PPV was 71.0% (95% CI, 61.1-79.6) for stillbirth; 79.0% (69.7-86.5) for spontaneous abortion, and 93.0% (86.1-97.1) for termination. When excluding cases with adjacent codes for other pregnancy outcomes and further relaxing the definition, the PPV increased to 80.6% (69.5-88.9) for stillbirth, 86.6% (80.5-91.3) for spontaneous abortion and 94.9% (91.1-97.4) for termination. The PPV for the composite outcome using the relaxed definition was 94.4% (92.3-96.1). CONCLUSIONS: Our findings suggest non-live birth outcomes can be identified in a valid manner in epidemiological studies based on healthcare utilization databases.

Utility of fertility procedures and prenatal tests to estimate gestational age for live-births and stillbirths in electronic health plan databases.

PURPOSE: Current algorithms to evaluate gestational age (GA) during pregnancy rely on hospital coding at delivery and are not applicable to non-live births. We developed an algorithm using fertility procedures and fertility tests, without relying on delivery coding, to develop a novel GA algorithm in live-births and stillbirths. METHODS: Three pregnancy cohorts were identified from 16 health-plans in the Sentinel System: 1) hospital admissions for live-birth, 2) hospital admissions for stillbirth, and 3) medical chart-confirmed stillbirths. Fertility procedures and prenatal tests, recommended within specific GA windows were evaluated for inclusion in our GA algorithm. Our GA algorithm was developed against a validated delivery-based GA algorithm in live-births, implemented within a sample of chart-confirmed stillbirths, and compared to national estimates of GA at stillbirth. RESULTS: Our algorithm, including fertility procedures and 11 prenatal tests, assigned a GA at delivery to 97.9% of live-births and 92.6% of stillbirths. For live-births (n = 4 701 207), it estimated GA within 2 weeks of a reference delivery-based GA algorithm in 82.5% of pregnancies, with a mean difference of 3.7 days. In chart-confirmed stillbirths (n = 49), it estimated GA within 2 weeks of the clinically recorded GA at delivery for 80% of pregnancies, with a mean difference of 11.1 days. Implementation of the algorithm in a cohort of stillbirths (n = 40 484) had an increased percentage of deliveries after 36 weeks compared to national estimates. CONCLUSIONS: In a population of primarily commercially-insured pregnant women, fertility procedures and prenatal tests can estimate GA with sufficient sensitivity and accuracy for utility in pregnancy studies.

Validation of an ICD-10-based algorithm to identify stillbirth in the Sentinel System.

PURPOSE: To develop and validate an International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM)-based algorithm to identify cases of stillbirth using electronic healthcare data. METHODS: We conducted a retrospective study using claims data from three Data Partners (healthcare systems and insurers) in the Sentinel Distributed Database. Algorithms were developed using ICD-10-CM diagnosis codes to identify potential stillbirths among females aged 12-55 years between July 2016 and June 2018. A random sample of medical charts (N = 169) was identified for chart abstraction and adjudication. Two physician adjudicators reviewed potential cases to determine whether a stillbirth event was definite/probable, the date of the event, and the gestational age at delivery. Positive predictive values (PPVs) were calculated for the algorithms. Among confirmed cases, agreement between the claims data and medical charts was determined for the outcome date and gestational age at stillbirth. RESULTS: Of the 110 potential cases identified, adjudicators determined that 54 were stillbirth events. Criteria for the algorithm with the highest PPV (82.5%; 95% CI, 70.9%-91.0%) included the presence of a diagnosis code indicating gestational age ≥20 weeks and occurrence of either >1 stillbirth-related code or no other pregnancy outcome code (i.e., livebirth, spontaneous abortion, induced abortion) recorded on the index date. We found ≥90% agreement within 7 days between the claims data and medical charts for both the outcome date and gestational age at stillbirth. CONCLUSIONS: Our results suggest that electronic healthcare data may be useful for signal detection of medical product exposures potentially associated with stillbirth.

Overall and cause-specific mortality in the Sentinel system: A power analysis.

PURPOSE: Mortality data within the Sentinel Death Tables remain generally uncharacterized. Assessment of mortality data within Sentinel will help inform its utility for medical product safety studies. METHODS: To determine if Sentinel contains sufficient all-cause and cause-specific mortality events to power postmarketing safety studies. We calculated crude rates of all-cause mortality and suicide and proportional mortality from suicide from 2004 to 2012 in seven Sentinel data partners. Results were stratified by data partner, sex, age group, and calendar year and compared with national estimates from Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research. We performed sample size estimations for all-cause mortality and 10 leading causes of death. RESULTS: We observed 479 694 deaths, including 5811 suicides, during 68 million person-years of follow-up. Pooled mean death and suicide rates in the data partners were 710 and 8.6 per 100 000 person-years, respectively (vs 810 and 11.8 nationally). The mean proportional mortality from suicide among the data partners was 1.2%, compared with 1.5% nationally. National trends of decreasing overall mortality and increasing proportional mortality for suicide were reflected within Sentinel. We estimated that detecting hazard ratios of 1.25 and 3 would require 16 442 and 460 exposed patients, respectively, for overall mortality, and 1.3 million and 37 411, respectively, for suicide. CONCLUSIONS: This was the first study to investigate mortality data in the Sentinel death tables. We found that all-cause mortality appeared well powered for use as a safety outcome and cause-specific mortality outcomes may be adequately powered in certain circumstances. Further investigation into the quality of the Sentinel death data is needed.

Antiemetic use among pregnant women in the United States: the escalating use of ondansetron.

PURPOSE: To examine ondansetron use in pregnancy in the context of other antiemetic use among a large insured United States population of women delivering live births. METHODS: We assessed ondansetron and other antiemetic use among pregnant women delivering live births between 2001 and 2015 in 15 data partners contributing data to the Mini-Sentinel Distributed Database. We identified live birth pregnancies using a validated algorithm, and all forms of ondansetron and other available antiemetics were identified using National Drug Codes or procedure codes. We assessed the prevalence of antiemetic use by trimester, calendar year, and formulation. RESULTS: In over 2.3 million pregnancies, the prevalence of ondansetron, promethazine, metoclopramide, or doxylamine/pyridoxine use anytime in pregnancy was 15.2, 10.3, 4.0, and 0.4%, respectively. Ondansetron use increased from <1% of pregnancies in 2001 to 22.2% in 2014, with much of the increase attributable to oral ondansetron beginning in 2006. Promethazine and metoclopramide use increased modestly between 2001 (13.8%, 3.2%) and 2006 (16.0%, 6.0%) but decreased annually through 2014 (8.0%, 3.2%). Doxylamine/pyridoxine, approved for management of nausea and vomiting in pregnancy in 2013, was used in 1.8% of pregnancies in 2014. For all antiemetics, use was highest in the first trimester. CONCLUSIONS: We observed a marked increase in ondansetron use by study year, prescribed to nearly one-quarter of insured pregnant women in 2014, occurring in conjunction with decreased use of promethazine and metoclopramide. Given the widespread use of ondansetron in pregnancy, data establishing product efficacy and methodologically rigorous evaluation of post-marketing safety are needed. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Development of a mother-child database for drug exposure and adverse event detection in the Military Health System.

PURPOSE: The aim of this study was to develop a mother-child linked database consisting of all eligible active duty military personnel, retirees, and their dependents in order to conduct medication-related analyses to improve the safety and quality of care in the Military Health System (MHS). METHODS: Eligible women of reproductive age with at least one pregnancy-related encounter between January 2005 and December 2013 receiving care in the MHS were included in the study population. Building on previously published algorithms, we used pregnancy-related diagnostic and procedure codes, parameterized temporal constraints, and data elements unique to the MHS to identify pregnancies ending in live births, stillbirth, spontaneous abortion, or ectopic pregnancy. Pregnancies ending in live births were matched to presumptive offspring using birth dates and family-based sponsorship identification. Antidepressant and antiepileptic use during pregnancy was evaluated using electronic pharmacy data. RESULTS: Algorithms identified 755,232 women who experienced 1,099,648 complete pregnancies with both pregnancy care encounter and pregnancy outcome. Of the 924,320 live birth pregnancies, 827,753 (90.0%) were matched to offspring. Algorithms also identified 5,663 stillbirths, 11,358 ectopic pregnancies, and 169,665 spontaneous abortions. Among the matched singleton live birth pregnancies, 7.1% of mothers were dispensed an antidepressant at any point during pregnancy, usually a selective serotonin reuptake inhibitor, (75.3%), whereas 1.3% of mothers were dispensed an antiepileptic drug.

Acetaminophen overdose in the Military Health System.

PURPOSE: We report the annual trend, distribution, and determinants of acetaminophen overdose using data from the Military Health System. We also assess the proportion of individuals with an acetaminophen overdose who received a prescription for any acetaminophen-containing medication prior to their event. METHODS: Diagnostic International Classification of Diseases, 9th revision (ICD-9) codes from inpatient medical encounters were used to identify patients with acetaminophen overdose. We used Poisson regression to estimate adjusted prevalence ratios (aPRs) for associations between selected socio-demographic characteristics and acetaminophen overdose. Pharmacy records for individuals with an acetaminophen overdose were obtained to evaluate the proportion who received a prescription for any acetaminophen-containing medication prior to their overdose. RESULTS: Annual age-adjusted and sex-adjusted prevalence of acetaminophen overdose increased by 38.5% from 2004 to 2008. Acetaminophen overdose was significantly more common in female subjects than in male subjects (aPR = 3.24, 95%CI = 2.97-3.55). Individuals aged 15-17 and 18-24 also were significantly more likely to have an overdose compared with those aged 45-64 (aPR = 6.06, 95%CI = 5.25-7.00 and aPR = 4.58, 95%CI = 4.01-5.23, respectively). Among active duty service members, acetaminophen overdose was six times more common in junior enlisted service members than in officers (aPR = 6.06, 95%CI = 3.90-9.40). The proportion of individuals with an inpatient overdose who had any prescription for an acetaminophen-containing medication in the 365, 30, and 7 days before the overdose was 53.3%, 23.7%, and 16.3%, respectively. CONCLUSIONS: Identification of at-risk populations will aid the military in ongoing efforts to decrease medication misuse. Findings suggest a potential need for improved labeling of over-the-counter medications and medication safety education efforts for unintentional acetaminophen overdose and continued efforts to identify individuals at risk for intentional overdose. Published 2012. This article is a US Government work and is in the public domain in the USA.

Use of oral contraceptives in pregnancy and major structural birth defects in offspring.

BACKGROUND: Oral contraceptives (OCs) are the most commonly used reversible contraceptive method among US women. Although the majority of previous studies have reported no association between OC use during pregnancy and birth defects, some studies have reported increased occurrence of neural tube defects, limb reduction defects, and urinary tract anomalies. METHODS: We assessed OC use among mothers who participated in the multisite, case-control, National Birth Defects Prevention Study. Mothers of 9986 infants with 32 types of birth defects and 4000 infants without birth defects were included. RESULTS: Maternal OC use during the first 3 months of pregnancy was associated with an increased odds ratio for 2 of 32 birth defects: hypoplastic left heart syndrome (adjusted odds ratio = 2.3 [95% confidence interval = 1.3-4.3) and gastroschisis (1.8 [1.3-2.7]). CONCLUSION: Previous reports of associations between OC use and specific types of anomalies were not corroborated. Given that associations were assessed for 32 types of birth defects, our findings of 2 increased associations between OC use and gastroschisis and hypoplastic left heart syndrome should be interpreted as hypotheses until they can be evaluated further. Overall, our findings are consistent with the majority of previous studies that found women who use OCs during early pregnancy have no increased risk for most types of major congenital malformations.

Antipsychotic Use and Stroke: A Retrospective Comparative Study in a Non-Elderly Population.

OBJECTIVE: To evaluate stroke risk among users of typical antipsychotics compared to users of atypical antipsychotics in a non-elderly and non-demented US population. METHODS: New users of antipsychotics aged 18-64 years without dementia were identified via electronic health care data from 13 health plans participating in the Sentinel System from January 2001 to September 2015. The risk of hospitalized stroke events, identified via ICD-9-CM diagnostic criteria, was compared between typical and atypical antipsychotic users using 1:1 matching on propensity score. Adjusted hazard ratios (HRs) and 95% CIs during the entire follow-up period and during 1- to 15-day and 16- to 90-day risk windows were estimated. The risk associated with haloperidol use was estimated separately. RESULTS: A total of 45,495 typical antipsychotic users were matched 1:1 to atypical antipsychotic users. While unmatched HRs suggest an increased stroke risk among typical antipsychotic users compared to atypical antipsychotic users, no increased risk was observed after matching during the entire follow-up period (HR = 0.87; 95% CI, 0.54-1.41), the 1- to 15-day risk window (HR = 1.16; 95% CI, 0.41-3.32), or the 16- to 90-day risk window (HR = 0.52; 95% CI, 0.20-1.36). The adjusted HR for haloperidol was 1.31 (95% CI, 0.54-3.21). CONCLUSION: These findings were not suggestive of an increased stroke risk in typical antipsychotic users compared to atypical antipsychotic users in a non-elderly and non-demented population.

A systematic review of validated suicide outcome classification in observational studies.

BACKGROUND: Suicidal outcomes, including ideation, attempt, and completed suicide, are an important drug safety issue, though few epidemiological studies address the accuracy of suicidal outcome ascertainment. Our primary objective was to evaluate validated methods for suicidal outcome classification in electronic health care database studies. METHODS: We performed a systematic review of PubMed and EMBASE to identify studies that validated methods for suicidal outcome classification published 1 January 1990 to 15 March 2016. Abstracts and full texts were screened by two reviewers using prespecified criteria. Sensitivity, specificity, and predictive value for suicidal outcomes were extracted by two reviewers. Methods followed PRISMA-P guidelines, PROSPERO Protocol: 2016: CRD42016042794. RESULTS: We identified 2202 citations, of which 34 validated the accuracy of measuring suicidal outcomes using International Classification of Diseases (ICD) codes or algorithms, chart review or vital records. ICD E-codes (E950-9) for suicide attempt had 2-19% sensitivity, and 83-100% positive predictive value (PPV). ICD algorithms that included events with 'uncertain' intent had 4-70% PPV. The three best-performing algorithms had 74-92% PPV, with improved sensitivity compared with E-codes. Read code algorithms had 14-68% sensitivity and 0-56% PPV. Studies estimated 19-80% sensitivity for chart review, and 41-97% sensitivity and 100% PPV for vital records. CONCLUSIONS: Pharmacoepidemiological studies measuring suicidal outcomes often use methodologies with poor sensitivity or predictive value or both, which may result in underestimation of associations between drugs and suicidal behaviour. Studies should validate outcomes or use a previously validated algorithm with high PPV and acceptable sensitivity in an appropriate population and data source.

Prevalence of infantile hypertrophic pyloric stenosis in Texas, 1999-2002.

BACKGROUND: The cause of infantile hypertrophic pyloric stenosis (IHPS) is poorly understood. This descriptive study of IHPS focuses on the effect of maternal nativity, maternal Hispanic ethnicity, subtypes of maternal Asian ethnicity, and the timing of the infant's surgery, that is, pyloromyotomy. METHODS: All cases of IHPS born in Texas from 1999 through 2002 were retrieved from the Texas Birth Defects Registry. Crude prevalence ratios and adjusted prevalence ratios (aPRs) were calculated using logistic regression. RESULTS: IHPS occurred predominantly in boys (aPR 4.21; 95% CI: 3.81, 4.65) compared with girls. Compared with Whites, there was a lower prevalence among Blacks (aPR 0.36; 95% CI: 0.30, 0.43), foreign-born Hispanics (aPR 0.61; 95% CI: 0.54, 0.69), Chinese (aPR 0.11; 95% CI: 0.01, 0.78), Vietnamese (aPR 0.17; 95% CI: 0.06, 0.46), Asian Indians (aPR 0.33; 95% CI: 0.15, 0.75), and Filipinos (aPR 0.22; 95% CI: 0.05, 0.91). In aggregate, foreign born Asians had a decreased risk of IHPS (aPR 0.20; 95% CI: 0.11, 0.37) compared to Whites. We observed no decrease in the risk of IHPS among US-born Asians (in aggregate) or US-born Hispanics. The strength of these risk factors did not vary according to the timing of the pyloromyotomy. CONCLUSIONS: This study confirmed previous findings that female infants and Black infants have a lower rate of IHPS. Large decreases in rates of IHPS were observed among foreign-born Hispanics and foreign-born Asians, but not among their US-born counterparts. These findings may be explained by differences in the frequency of behavioral risk factors for IHPS or differences in the frequency of ascertainment of mild cases of IHPS by ethnicity or nativity.

Risk comparison for prenatal use of analgesics and selected birth defects, National Birth Defects Prevention Study 1997-2011.

PURPOSE: To compare the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and/or opioids to the use of acetaminophen without NSAIDs or opioids with respect to associations with birth defects. METHODS: We used data from the National Birth Defects Prevention Study (1997-2011). Exposure was self-reported maternal analgesic use from the month before through the third month of pregnancy (periconceptional). Adjusted odds ratios (aORs) were calculated to examine associations with 16 birth defects. RESULTS: Compared to acetaminophen, mothers reporting NSAIDs were significantly more likely to have offspring with gastroschisis, hypospadias, cleft palate, cleft lip with cleft palate, cleft lip without cleft palate, anencephaly, spina bifida, hypoplastic left heart syndrome, pulmonary valve stenosis, and tetralogy of Fallot (aOR range, 1.2-1.6). Opioids were associated with tetralogy of Fallot, perimembranous ventricular septal defect, and ventricular septal defect with atrial septal defect (aOR range, 1.8-2.3), whereas use of both opioids and NSAIDs was associated with gastroschisis, cleft palate, spina bifida, hypoplastic left heart syndrome, and pulmonary valve stenosis (aOR range, 2.0-2.9). CONCLUSIONS: Compared to periconceptional use of acetaminophen, selected birth defects occurred more frequently among infants of women using NSAIDs and/or opioids. However, we could not definitely determine whether these risks relate to the drugs or to indications for treatment.

A cross-sectional evidence-based review of pharmaceutical promotional marketing brochures and their underlying studies: is what they tell us important and true?

BACKGROUND: A major marketing technique used by pharmaceutical companies is direct-to-physician marketing. This form of marketing frequently employs promotional marketing brochures, based on clinical research, which may influence how a physician prescribes medicines. This study's objective was to investigate whether or not the information in promotional brochures presented to physicians by pharmaceutical representatives is accurate, consistent, and valid with respect to the actual studies upon which the promotional brochures are based. METHODS: Physicians in five clinics were asked to consecutively collect pharmaceutical promotional brochures and to send them all to a centralized location. The brochures for any class of medication were collected on a continuous basis until 20 distinct promotional brochures were received by a central location. Once the brochure was received, the corresponding original study was obtained. Two blinded reviewers performed an evidence-based review of the article, comparing data that was printed on the brochure to what was found in the original study. RESULTS: Among the 20 studies, 75% of the studies were found to be valid, 80% were funded by the pharmaceutical company, 60% of the studies and the corresponding brochures presented patient-oriented outcomes, and 40% were compared to another treatment regimen. Of the 19 brochures that presented the data as graphs, 4 brochures presented a relative risk reduction while only 1 brochure presented an absolute risk reduction. 15% of the promotional marketing brochures presented data that was different from what was in the original published study. CONCLUSION: Given the present findings, physicians should be cautious about drawing conclusions regarding a medication based on the marketing brochures provided by pharmaceutical companies.

Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System.

AIM: To determine the rate ratio of neuropsychiatric hospitalizations in new users of varenicline compared to new users of nicotine replacement therapy (NRT) patch in the Military Health System (MHS). DESIGN, SETTING AND PARTICIPANTS: Varenicline (n = 19,933) and NRT patch (n = 15,867) users who initiated therapy from 1 August 2006 to 31 August 2007 within the MHS were included in this retrospective cohort study. After matching according to propensity scores, 10,814 users remained in each cohort. The study population included those with and without a history of neuropsychiatric disease. MEASUREMENTS: Patients were followed for neuropsychiatric hospitalizations defined by primary neuropsychiatric discharge diagnosis using ICD-9 codes from in-patient administrative claims. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated after propensity score matching on exposure for socio-demographic factors, health-care utilization, comorbidities, medication history and neuropsychiatric history. FINDINGS: There was no increase in the rate of neuropsychiatric hospitalizations in patients treated with varenicline compared to NRT patch when followed for 30 days (propensity-score matched HR = 1.14, 95% CI: 0.56-2.34). Results were similar after 60 days of follow-up. CONCLUSIONS: There does not appear to be an increase in neuropsychiatric hospitalizations with varenicline compared with nicotine replacement therapy patch over 30 or 60 days after drug initiation.

Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer.

Androgen-deprivation therapy (ADT) is a common treatment for men with prostate cancer. Although ADT is effective at suppressing prostate-specific antigen (PSA), stabilizing disease, alleviating symptoms in advanced disease, and potentially prolonging survival, it is not without serious side effects. However, to the authors' knowledge, there is lack of a systematic review of its major adverse effects to date. The authors of this report systematically reviewed and quantitatively assessed the literature on skeletal and cardiac side effects associated with ADT in men with prostate cancer. The PubMed database was searched for relevant published articles from 1966 to May 2008, and 683 articles were reviewed systematically from an original 20 different Medical Subject Heading search combinations. The focus of the review was on bone-related and cardiovascular-related outcomes. When appropriate, results were pooled from articles on specific adverse outcomes, summary risk estimates were calculated, and tests of heterogeneity were performed. Fourteen articles were identified that met inclusion criteria from the original 683 studies. Men who underwent ADT for prostate cancer had a significantly increased risk of overall fracture of 23% (summary relative risk, 1.23; 95% confidence interval [95% CI], 1.10-1.38) compared with men who had prostate cancer but who did not undergo ADT. Furthermore, men who underwent ADT had a 17% increase in cardiovascular-related mortality compared with men who did not undergo with ADT (summary hazards ratio, 1.17; 95% CI, 1.07-1.29). Significant elevations in the risk of diabetes also were observed from 2 large studies. ADT was associated with an increased risk of skeletal fracture, incident diabetes, and cardiovascular-related mortality, although the absolute risk of these events was low. Preventive measures against these adverse effects and careful assessment of patient's baseline health status should be considered.