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.