Background-Well characterized genes affecting warfarin metabolism (CYP2C9) and sensitivity (VKORC1) explain one-third of the variability in therapeutic dose before the International Normalized Ratio (INR) is measured.

IMPORTANCE Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown.OBJECTIVE To determine whether genotype-guided dosing improves the safety of warfarin initiation. DESIGN, SETTING, AND PATIENTSThe randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016.INTERVENTIONS Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment. MAIN OUTCOMES AND MEASURESThe primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty. RESULTS Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05-1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51-0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54-1.34), and there were no deaths.CONCLUSIONS AND RELEVANCE Among patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Further research is needed to determine the cost-effectiveness of personalized warfarin dosing.

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Maternal substance abuse during pregnancy is a growing problem with major public health and legal concerns. In utero substance exposure may adversely affect neonatal development; pregnancy outcome; and the long-term behavioral, cognitive, and developmental abilities of the child. Also, serious legal implications are associated with substance abuse during pregnancy, including charges of child abuse and neglect that may result in the removal of the neonate from parental care and loss of custodial rights. Timely detection of in utero drug exposure is necessary for early identification and effective management of exposed newborns. Accurate identification of drug-exposed newborns relies on maternal history; clinical presentation of the newborn; and laboratory testing of biological maternal matrices (ie, urine, blood, oral fluid, sweat, hair, and breast milk), neonatal matrices (ie, urine, meconium, hair, and umbilical cord blood and tissue), and/or matrices from both the mother and neonate (ie, placenta and amniotic fluid). Evaluation of biological matrices can account for in utero exposure at various stages of gestation and approximate the period (recent versus chronic use) of substance exposure. Each matrix has its own unique advantages and limitations in terms of ease of collection, the window of gestational exposure represented, and sensitivity for different parent drug analytes and metabolites, which must be carefully considered for accurate interpretation of results. Analytical approaches to sample preparation and analysis vary based on the complexity of these biological matrices. Immunoassays are routinely used for screening, and chromatographic separation coupled to mass spectrometry detection method is commonly used for definitive (confirmatory) testing. Some laboratories use a single technology for all testing. This review provides a discussion on approaches used to detect drug-exposed newborns, biological specimens that have been studied to identify and characterize drug exposures, example analytical methods for meconium and umbilical cord tissue as well as considerations surrounding the interpretation of results. A possible algorithm for testing is also proposed.