Antenatal corticosteroids: a reappraisal of the drug formulation and dose

Abstract

We review the history of antenatal corticosteroid therapy (ACS) and present recent experimental data to demonstrate that this, one of the pillars of perinatal care, has been inadequately evaluated to minimize fetal exposure to these powerful medications. There have been concerns since 1972 that fetal exposures to ACS convey risk. However, this developmental modulator, with its multiple widespread biologic effects, has not been evaluated for drug choice, dose, or duration of treatment, despite over 30 randomized trials. The treatment used in the United States is two intramuscular doses of a mixture of 6 mg betamethasone phosphate (Beta P) and 6 mg betamethasone acetate (Beta Ac). To optimize outcomes with ACS, the goal should be to minimize fetal drug exposure. We have determined that the minimum exposure needed for fetal lung maturation in sheep, monkeys, and humans (based on published cord blood corticosteroid concentrations) is about 1 ng/ml for a 48-h continuous exposure, far lower than the concentration reached by the current dosing. Because the slowly released Beta Ac results in prolonged fetal exposure, a drug containing Beta Ac is not ideal for ACS use. Impact Using sheep and monkey models, we have defined the minimum corticosteroid exposure for a fetal lung maturation. These results should generate new clinical trials of antenatal corticosteroids (ACS) at much lower fetal exposures to ACS, possibly given orally, with fewer risks for the fetus.

Association of Co-Exposure of Antenatal Steroid and Prophylactic Indomethacin with Spontaneous Intestinal Perforation

“…In animal studies, it was observed that, the loss of nitric oxide synthase (NOS) in the intestinal smooth muscle via combined inhibition of the neuronal NOS by steroids and endothelial NOS by indomethacin leads to disturbed intestinal motility and increases vulnerability of the intestine to perforation. [30][31][32] Extensive work on the pharmacokinetics and pharmacodynamics of antenatal steroids containing betamethasone 33 identified that the betamethasone acetate component of the combination, widely used in developed countries, is released very slowly in circulation, especially when given intramuscularly, leading to prolonged maternal and fetal levels for at least 4-6 days. This may explain coexposure having a pronounced effect when exposure to antenatal steroid was recent.…”

Benefits of a Single Dose of Betamethasone in Imminent Preterm Labour

“…In animal models, betamethasone levels that are effective for lung maturation (1–4 ng/mL) have been detected in the umbilical cord at the time of prenatal administration. [ 20 ] Based on these models, it was determined that in pregnant women > 28 weeks, the intramuscular administration of 11.4 mg of betamethasone produces levels > 1 ng/mL in the umbilical cord from the first hour of administration and are maintained for up to 1.4 days. Levels below 1 ng/mL increase the risk of surfactant therapy [ 21 ].…”

A Comparative Study of the Respiratory Neonatal Outcomes Utilizing Dexamethasone Sodium Phosphate versus a Mixture of Betamethasone Dipropionate and Betamethasone Sodium Phosphate as an Antenatal Corticosteroid Therapy

“…The authors suggest that the long-acting betamethasone acetate is not ideal for an antenatal corticosteroid since it is associated with prolonged fetal exposure, carrying the risk of unwanted complications and side effects. 25 The dual acting formulation is designed to enhance its efficacy with the administration of single injection per day. This rationale is still questionable regarding its efficacy and safety.…”