Introduction
Antenatal corticosteroids administration to pregnant women at imminent risk of premature birth is strongly recommended in clinical practice worldwide.1,2 It reduces the relative risks for respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and systemic infections in the first 48 hours of life, which are common causes of morbidity and mortality in preterm newborns.3 Current data demonstrate that corticosteroids administration is most beneficial within one week of therapy. Based on the scientific evidence, the World Health Organization, the American College of Obstetricians and Gynecologists, the Royal College of Obstetricians and Gynaecologists, and the Society of Obstetricians and Gynaecologists of Canada, all recommend antenatal corticosteroids administration to women at risk for preterm delivery between 24–34 weeks of gestation.4–7
Preterm birth is the most common perinatal morbidity associated with twin pregnancies, present in 30 to 50% of cases regardless of chorionicity.8,9 Therefore, the current guidelines also recommend administration of antenatal corticosteroids to women with multiple pregnancy and threatened preterm delivery. However, it is uncertain whether the benefits of antenatal corticosteroids observed in singleton pregnancies are similar in twin pregnancies because of the small number of twin pregnancies included in the studies.10,11 Also, the efficacy of corticosteroids in promoting lung maturation in twins may be reduced because of the more remarkable maternal physiological changes in multiple pregnancies. These changes could affect the pharmacokinetics of many drugs, including half-life, volume of distribution, and clearance in singleton pregnancy differently from that in twin pregnancy.12–14Consequently, that efficacy of corticosteroids in inducing maturation could be reduced due to the lower plasma exposure of twin fetuses to these drugs.
Betamethasone (BET) has been more commonly used in studies evaluating the effect of antenatal corticosteroid therapy on neonatal outcomes. BET is formulated as a fast releasing BET phosphate ester prodrug or a dual-acting formulation containing BET phosphate plus BET acetate esters. Both esters are fast and extensively metabolized to the active glucocorticoid BET.15,16 As far as we know, there are no bioavailability data after intramuscular BET esters administration. Ke and Milad (2019) have assumed that 94% of BET elimination is dependent on CYP3A4 based on the BET renal clearance in healthy adults of approximately 0.49 L/ h.17 Considering that CYP3A is induced by 86-124% in late pregnancy compared to postpartum period,18 BET total clearance is probably enhanced in pregnancy according to studies in healthy adults and pregnant women.19–22,11,15,23 BET total clearance has also been reported to be increased in twin pregnancies compared to singleton ones.19 Although there are studies that have evaluated the BET pharmacokinetics in twin pregnancies, they are few, and none of them studied multiple pregnancies separated by chorionicity.
Therefore, the objectives of the present study were to describe and compare the BET pharmacokinetic parameters in singleton, dichorionic (DC) and monochorionic (MC) twin pregnancies in order to evaluate, in the future trials, the need for adjusted doses of BET according to the chorionicity of multiple pregnancies.