Maternal betamethasone for prevention of Respiratory Distress Syndrome in neonates: population pharmacokinetic and pharmacodynamic approach

 Pharmacol Ther. 2020 Nov;108(5):1026-1035. doi: 10.1002/cpt.1887. Epub 2020 Jun 4.


Despite antenatal corticosteroids therapy, Respiratory Distress Syndrome (RDS) is still a leading cause of neonatal morbidity and mortality in premature newborns. To date the relationship between in utero fetal drug exposure and occurrence of RDS remains poorly evaluated. This study aims to describe the pharmacokinetics of betamethasone in pregnant women and to evaluate the transplacental drug transfer and administration scheme for the prevention of RDS. Pregnant women more than 27 weeks’ gestation and who received at least a single dose of betamethasone for prevention of RDS were enrolled. Maternal, cord blood and amniotic fluid betamethasone time-courses were analyzed using the Monolix software. A total of 220 maternal blood, 56 cord blood and 26 amniotic fluid samples were described by a two-compartment model with two effect compartments linked by rate transfer constants. Apparent clearances and volumes of distribution parameters were allometrically scaled for a 70kg third trimester pregnant woman. The impact of a twin pregnancy was found to increase maternal clearance by 28%. Using a fetal-to-mother exposure ratio, the median [95%CI] transplacental transfer of betamethasone was estimated to 35% [0.11 – 0.67]. After adjustment for gestational age and twin pregnancy, RDS was found to be associated to the time spent in utero below quantifiable concentrations (i.e. < 1 ng/mL): OR [95%CI] of 1.10 [1.01 – 1.19] per day increase (p<0.05). Trying to take into account both efficacy and safety, we simulated different dosing schemes in order to maintain a maximum of fetuses above 1 ng/mL without exceeding the total standard dose.