Background Preeclampsia complicates approximately 3% to 5% of pregnancies and remains a major cause of maternal and neonatal morbidity and mortality. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Pravastatin, a hydrophilic, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, has been shown in preclinical studies to reverse various pathophysiological pathways associated with preeclampsia, providing biological plausibility for its use for preeclampsia prevention. However, human trials are lacking. Objective As an initial step in evaluating the utility of pravastatin in preventing preeclampsia, and after consultation with the U.S. Food and Drug Administration, we undertook a pilot randomized controlled trial with the objective to determine pravastatin safety and pharmacokinetic parameters when used in pregnant women at high risk of preeclampsia. Study Design We conducted a pilot, multicenter, double-blind, placebo-controlled, randomized trial of women with singleton, non-anomalous pregnancies at high risk for preeclampsia. Women between 120/7 and 166/7 weeks gestation were assigned to daily pravastatin 10 mg or placebo orally until delivery. Primary outcomes were maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included rates of preeclampsia and preterm delivery, gestational age at delivery, birthweight, and maternal and cord blood lipid profile (Clinicaltrials.gov Identifier NCT01717586). Results Ten women assigned to pravastatin and ten to placebo completed the trial. There were no differences between the two groups in rates of study drug side effects, congenital anomalies, or other adverse or serious adverse events. There was no maternal, fetal, or neonatal death. Pravastatin renal clearance was significantly higher in pregnancy compared to postpartum. Four subjects in the placebo group developed preeclampsia compared to none in the pravastatin group. Although pravastatin reduced maternal cholesterol concentrations, umbilical cord cholesterol concentrations and infant birthweight were not different between the groups. The majority of umbilical cord and maternal pravastatin plasma concentrations at time of delivery were below the lower limit of quantification of the assay. Conclusions This study provides preliminary safety and pharmacokinetic data regarding the use of pravastatin for preventing preeclampsia in high-risk pregnant women. Although the data are preliminary, no identifiable safety risks were associated with pravastatin use in this cohort. This favorable risk-benefit analysis justifies using pravastatin in a larger clinical trial with dose escalation.

No abstract

Background Bupropion is used to treat depression during pregnancy. However, its usefulness as a smoking cessation aid for pregnant women is not fully known. Objective To evaluate the preliminary efficacy of bupropion sustained-release for smoking cessation during pregnancy. Study design We conducted a randomized, prospective, double-blind, placebo-controlled, pilot trial. Pregnant women who smoked daily received individualized behavior counseling and were randomly assigned to a 12-week, twice-a-day treatment with 150 mg bupropion sustained-release or placebo. The primary study objectives were to 1) determine whether bupropion sustained-release reduces nicotine withdrawal symptoms on the quit date and during treatment period compared to placebo; and 2) whether it increases 7-day point prevalence abstinence at the end of treatment period and at the end of pregnancy. Results Subjects in the bupropion (n = 30) and placebo (n = 35) groups were comparable in age, smoking history, number of daily smoked cigarettes, and nicotine dependence. After controlling for maternal age and race, bupropion sustained-release reduced cigarette cravings (1.5 ± 1.1 vs 2.1 ± 1.2, P = 0.02) and total nicotine withdrawal symptoms (3.8 ± 4.3 vs 5.4 ± 5.1, P = 0.028) during the treatment period. Administration of bupropion sustained-release reduced tobacco exposure, as determined by levels of carbon monoxide in exhaled air (7.4 ± 6.4 vs 9.1 ± 5.8, P = 0.053) and concentrations of cotinine in urine (348 ± 384 ng/mL vs 831 ± 727 ng/mL, P = 0.007), and increased overall abstinence rates during treatment (19% vs 2%, P = 0.003). However, there was no significant difference in 7-day point prevalence abstinence rates between the two groups at the end of medication treatment (17% vs 3%, P = 0.087) and at the end of pregnancy (10% vs 3%, P = 0.328). Conclusion Individual smoking cessation counseling along with the twice-daily use of 150 mg bupropion sustained-release increased smoking cessation rates and reduced cravings and total nicotine withdrawal symptoms during the treatment period. However, there was no significant difference in abstinence rates between groups at the end of medication treatment and at end of pregnancy, likely due to the small sample size. A larger study is needed to confirm these findings and to examine the potential benefit/ risk ratio of bupropion sustained-release for smoking cessation during pregnancy.

Bupropion sustained release is used to promote smoking cessation in males and nonpregnant females. However, its efficacy as a smoking cessation aid during pregnancy is not reported. The pregnancyassociated changes in maternal physiology may alter the pharmacokinetics and pharmacodynamics of bupropion and consequently its efficacy in pregnant smokers. Therefore, the aims of this study were to determine the steady-state pharmacokinetics of bupropion during pregnancy and the effect of functional genetic variants of CYP2B6 and CYP2C19 on bupropion pharmacokinetics in pregnant women. Plasma and urine concentrations of bupropion and its metabolites hydroxybupropion (OHBUP), threohydrobupropion, and erythrohydrobupropion were determined by liquid chromatography-mass spectrometry. Subjects were genotyped for five nonsynonymous single-nucleotide polymorphisms that result in seven CYP2B6 alleles, namely *2, *3, *4, *5, *6, *7, and *9, and for CYP2C19 variants *2, *3, and *17. The present study reports that the isoform-specific effect of pregnancy on bupropion-metabolizing enzymes along with the increase of renal elimination of the drug could collectively result in a slight decrease in exposure to bupropion in pregnancy. In contrast, pregnancy-induced increase in CYP2B6-catalyzed bupropion hydroxylation did not impact the plasma levels of OHBUP, probably due to a higher rate of OHBUP glucuronidation, and renal elimination associated with pregnancy. Therefore, exposure to OHBUP, a pharmacologically active metabolite of the bupropion, appears to be similar to that of the nonpregnant state. The predicted metabolic phenotypes of CYP2B6*6 and variant alleles of CYP2C19 in pregnancy are similar to those in the nonpregnant state.