Date Published: September 19, 2019
Publisher: Public Library of Science
Author(s): Augusto F. Schmidt, Matthew W. Kemp, Mark Milad, Lisa A. Miller, James P. Bridges, Michael W. Clarke, Paranthaman S. Kannan, Alan H. Jobe, Umberto Simeoni.
Antenatal corticosteroids (ACS) are standard of care for women at risk of preterm delivery, although choice of drug, dose or route have not been systematically evaluated. Further, ACS are infrequently used in low resource environments where most of the mortality from prematurity occurs. We report proof of principle experiments to test betamethasone-phosphate (Beta-P) or dexamethasone-phosphate (Dex-P) given orally in comparison to the clinical treatment with the intramuscular combination drug beta-phosphate plus beta-acetate in a Rhesus Macaque model. First, we performed pharmacokinetic studies in non-pregnant monkeys to compare blood levels of the steroids using oral dosing with Beta-P, Dex-P and an effective maternal intramuscular dose of the beta-acetate component of the clinical treatment. We then evaluated maternal and fetal blood steroid levels with limited fetal sampling under ultrasound guidance in pregnant macaques. We found that oral Beta is more slowly cleared from plasma than oral Dex. The blood levels of both drugs were lower in maternal plasma of pregnant than in non-pregnant macaques. Using the pharmacokinetic data, we treated groups of 6–8 pregnant monkeys with oral Beta-P, oral Dex-P, or the maternal intramuscular clinical treatment and saline controls and measured pressure-volume curves to assess corticosteroid effects on lung maturation at 5d. Oral Beta-P improved the pressure-volume curves similarly to the clinical treatment. Oral Dex-P gave more variable and nonsignificant responses. We then compared gene expression in the fetal lung, liver and hippocampus between oral Beta-P and the clinical treatment by RNA-sequencing. The transcriptomes were largely similar with small gene expression differences in the lung and liver, and no differences in the hippocampus between the groups. As proof of principle, ACS therapy can be effective using inexpensive and widely available oral drugs. Clinical dosing strategies must carefully consider the pharmacokinetics of oral Beta-P or Dex-P to minimize fetal exposure while achieving the desired treatment responses.
Although Standard of Care for women at risk of preterm delivery in high income countries [1, 2], antenatal corticosteroids (ACS) are inconsistently used in low resource environments despite endorsement of the World Health Organization . ACS were considered to be the number one intervention to decrease mortality from prematurity in low resource environments in a 2015 World Health Organization report . A recent analysis emphasizes that ACS alone may have only a modest impact on mortality without other improvements in diagnostic, obstetric and newborn care . And there are potential risks of ACS in low resource environments such as hypoglycemia that may be unrecognized an untreated . The largest trial in low resource environments demonstrated no benefit for low birth weight infants and increased perinatal mortality for all treated pregnancies . A general concern about ACS is that the choice of drug and treatment schedule has not been optimized despite indications that current dosing strategies may expose the fetus to higher doses of these potent corticosteroids than is necessary for the desired maturational effects [8, 9]. The accepted ACS treatments are maternal Intramuscular with either a 1 to 1 mixture of betamethasone phosphate and betamethasone acetate (Beta-P + Beta-Ac) given as two 12 mg doses 24 hour apart or four doses maternal intramuscular of 6 mg dexamethasone phosphate (Dex-P) given at 12 hour intervals [4, 10]. We demonstrated that a single dose of Beta-Ac alone that exposed the fetus to low Beta levels was equivalent to the clinical treatment for lung maturational responses in fetal sheep and monkeys [11, 12]. Maternal infusions of Beta-P to achieve low constant fetal exposures to Beta also cause lung maturation in fetal sheep . However, Beta-Ac is not available as a single component drug and maternal infusions are impractical, particularly in low resource environments. As corticosteroid toxicity is proportionate to dose even for short-term exposures , our long-term goal is to develop a lower dose and presumably safer treatment option for ACS. We recently reported that oral corticosteroids were effective for ACS in a sheep model . We have extended these observations to the non-human primate by evaluating the pharmacokinetics and lung maturational effects of oral Dex-P and Beta-P as inexpensive and readily available alternatives for ACS. The study also includes mRNA sequencing of fetal lung, hippocampus and liver to evaluate both lung and systemic effects of oral dosing of ACS. These primate studies are essential proof of concept observations that can help justify randomized controlled trials of new ACS treatment options for worldwide use.
The standard of care for ACS is by repeated maternal intramuscular injections, using several fluorinated corticosteroid preparations that cross the placenta to the fetus [10, 25]. However, the pharmacokinetics to establish optimal drug choice, dose and treatment were never evaluated . Other routes of treatment have been reported but have been minimally studied . Fetal intramuscular steroids were considered for human use to selectively target the fetus, but fetal intramuscular corticosteroids were not as effective as maternal ACS in sheep models . Intravascular ACS using Dex-P also has been reported but will cause very high maternal plasma corticosteroid levels. There are no experimental reports of oral ACS in animals, and the clinical experience with oral ACS is limited to one trial and case reports. Egerman and colleagues reported in 1997 the pharmacokinetics of 6 mg intramuscular Dex-P and 8 mg PO Dex-P in third trimester pregnant women . Peak plasma levels for maternal oral Dex were about 65% of intramuscular levels with peak concentrations at 30 min. for intramuscular and 2 hr. for PO treatments. Plasma half-life values and bioactivity were similar. They then reported a clinical trial in 1998 for women at risk for preterm delivery to receive 4 doses of 6 mg Beta-P intramuscular or 4 doses of 8 mg Beta-P PO, repeated at 12 hr. intervals . This study was stopped at 39% enrollment for more neonatal sepsis and intraventricular hemorrhage in the oral treatment group. There was no explanation for the increase in adverse outcomes with the oral treatment, but the adverse outcomes were lower than expected in the intramuscular treated patients. This trial is a cautionary note indicating that careful monitoring is essential for future trials with oral ACS.