Transplacental Therapeutic Drug Monitoring in Pregnant Women with Fetal Tachyarrhythmia Using HPLC-MS/MS

Abstract

Fetal arrhythmia develops in 0.1–5% of pregnancies and may cause fetal heart failure and fetal hydrops, thus increasing fetal, neonatal, and infant mortality. The timely initiation of transplacental antiarrhythmic therapy (ART) promotes the conversion of fetal tachycardia to sinus rhythm and the regression of the concomitant non-immune fetal hydrops. The optimal treatment regimen search for the fetus with tachyarrhythmia is still of high value. Polymorphisms of these genes determines the individual features of the drug pharmacokinetics. The aim of this study was to study the pharmacokinetics of transplacental anti-arrhythmic drugs in the fetal therapy of arrhythmias using HPLC-MS/MS, as well as to assess the effect of the multidrug-resistance gene ABCB1 3435C > T polymorphism on the efficacy and maternal/fetal complications of digoxin treatment. The predisposition to a decrease in the bioavailability of the digoxin in patients with a homozygous variant of the CC polymorphism showed a probable association with the development of ART side effects. A pronounced decrease in heart rate in women with the 3435TT allele of the ABCB1 gene was found. The homozygous TT variant in the fetus showed a probable association with an earlier response to ART and rhythm disruptions on the digoxin dosage reduction. high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) methods for digoxin and sotalol therapeutic drug monitoring in blood plasma, amniotic fluid, and urine were developed. The digoxin and sotalol concentrations were determined in the plasma blood, urine, and amniotic fluid of 30 pregnant women at four time points (from the beginning of the transplacental antiarrhythmic therapy to delivery) and the plasma cord blood of 30 newborns. A high degree of correlation between the level of digoxin and sotalol in maternal and cord blood was found. The ratio of digoxin and sotalol in cord blood to maternal blood was 0.35 (0.27 and 0.46) and 1.0 (0.97 and 1.07), accordingly. The digoxin concentration in the blood of the fetus at the moment of the first rhythm recovery episode, 0.58 (0.46, 0.8) ng/mL, was below the therapeutic interval. This confirms the almost complete transplacental transfer of sotalol and the significant limitation in the case of digoxin. Previously, ABCB1/P-glycoprotein had been shown to limit fetal exposure to drugs. Further studies (including multicenter ones) to clarify the genetic features of the transplacental pharmacokinetics of antiarrhythmic drugs are needed.