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.

Fig. 1. Sketch of fetal blood levels estimated from cord blood.

These curves represent predicted fetal plasma after maternal treatments with the 3 mg betamethasone phosphate (Beta P) plus 3 mg betamethasone acetate (Beta Ac) mixture given 24 h apart (red curve), 3 mg dexamethasone phosphate (Dex P) given every 12 h (orange curve), and 3 mg Beta Ac component (blue curve) based on measurements in a sheep model with the characteristics of drug levels that we will discuss. The light gray area on the figure is our estimate of a good target for fetal plasma levels for lung maturation. Issues for dosing are: 1. The range for minimal dose for fetal lung response. 2. Need for high peak exposure. 3. Nature of exposure—duration and continuous for a durable response. Redrawn from Ballard and Ballard.

Fig. 2. Pharmacokinetic and pharmacodynamics studies of corticosteroids in nonpregnant, reproductive age women.

a Pharmacokinetic measurements of betamethasone phosphate (Beta Phos—6 mg) given orally or IM, dexamethasone (Dex Phos—6 mg) given orally or IM dose, or 6 mg of the 1:1 mixture of Beta Phos (3 mg) plus Beta Acetate (Beta Ac, 3 mg) given IM to healthy Indian women with blood measurements over 96 h and after 9 days from the initial dose (redrawn from ref. ). Beta from the Beta P plus Beta Ac had a slow clearance with blood levels measurable 9 days after the initial dose and with no further apparent clearance between 9 and 13 days from the Beta Ac component. b Effects of ACS on plasma glucose. A single dose of 6 mg dexamethasone P or the 1:1 mixture of 3 mg Beta P + 3 mg of Beta Ac increased post-prandial blood glucose. All PO and IM treatments had comparable effects on blood sugar (redrawn from ref. ). c Effects of single ACS doses on cortisol. A single dose of 6 mg dexamethasone P or the 1:1 mixture of 3 mg Beta P + 3 mg of Beta Ac suppressed cortisol, but the Beta P plus Beta Ac treated group had longer suppression of cortisol to more than 4 days (redrawn from ref. ).

Fig. 3. Testing for minimal ACS dose for fetal lung maturation in sheep.

a Maternal and fetal plasma levels of betamethasone for treatments with 0.125 mg/kg Beta Ac maternal IM. Area under the curve (AUC_0–24 h) is 443 ng/ml h for Beta in the ewe and 56 ng/ml h in the fetus. The fetal levels stay above 1 ng/ml for 24 h. Redrawn from ref. b Maternal and fetal drug levels after 0.125 mg/kg Beta P. AUC_0–24 in ewes were 557 and 79 ng/ml h in fetus. Redrawn from ref. The fetal levels remain above 1 ng/ml for only 8 h despite the very high plasma levels in the ewes. c Pressure–volume curves after preterm delivery and ventilation measured 2 days after a single treatment, showing similar improvements of the low-dose Beta Ac and the clinical dosing. d The composite gas exchange variable, Ventilation Efficiency Index (VEI) which incorporates tidal volume/kg, peak ventilation pressure, PaCO₂, and ventilation rate for the clinical dosing and Beta Ac component alone showing similar improvements of the VEI with low-dose Beta Ac and the clinical dosing. Redrawn from ref. . *Different than control p < 0.05.

Fig. 4. Minimal dose and durability in sheep.

a Constant betamethasone infusions in pregnant ewes to target fetal plasma levels of 20 (maternal infusions of Beta P loading dose 0.28 ng/kg then 0.48 ng/kg/12 h), 10 (loading dose of 0.14 ng/kg + 0.24 ng/kg over 12 h), or 2 ng/ml (loading dose of 0.028 ng Beta P + 0.048 ng/kg/12 h infusion), with documentation of fetal levels of Beta for 24 h. b Evaluation of lung performance by measuring VEI after infusion to the three target levels. c Additional data for fetuses infused with Beta P to achieve a fetal exposure of 1 ng/ml for 36 h. There was no durable effect at 4 or 7 days. The clinical treatment requires two doses for durability in sheep. Redrawn from ref. d Ewes were treated with one or two doses of IM 0.25 mg/kg Beta P plus Beta Ac. The lambs were delivered at intervals from treatment of 1–10 days a single dose improved preterm lung function at 1 day but not 7 days. The two-dose treatments had efficacy to 7 days with residual effects at 10 days.

Fig. 5. Minimal corticosteroid dose for lung maturation in monkeys.

a PK data for 0.125 mg/kg Beta Ac maternal IM or 0.15 mg/kg oral Dex P from nonpregnant monkeys. Redrawn from ref. b Fetal monkeys at about 30 days gestational age were treated with maternal Beta Ac given IM 0.125 mg/kg and 5 days later were delivered for measurement of static pressure–volume curves (redrawn from ref. ). c Sat phosphotidylcholine in alveolar wash was also used as a maturation marker which increased with the low-dose Beta Ac treatment. d PK data for 0.125 mg/kg Beta Ac maternal IM or 0.15 mg/kg oral Dex P from monkey fetuses. The curves have only three data points because samples from fetuses were collected with ultrasound-guided chordocentesis. The low dose of 0.125 mg/kg yielded fetal plasma levels of about 1 ng/ml for 24 h. equivalent to the much higher exposure with clinical dose (redrawn from ref. ). e, f Fetal monkeys at about 30 days gestational age were treated with maternal oral Beta P or Dex P and 5 days later were delivered for measurement of static pressure–volume curves. Redrawn from refs. ^, *Different from control (p < 0.05).

Fig. 6. Lung and hippocampus RNA-sequencing after treatment with ACS, studied 5 h after the ACS dose or saline control (n = 3 animals/group).

a Gene set enrichment analysis for biological processes associated with differentially regulated genes in the fetal lung 5 h after treatment with Beta Ac evaluated 5 days after treatment. a ACS treatment induced cellular differentiation and surfactant-related processes as well as apoptosis while suppressing immune response and lung developmental pathways. b Biological processes altered associated with differentially regulated genes in the fetal hippocampus for 5 h after 0.125 mg/kg Beta Ac +  Beta P resulted in suppression of genes associated with neuronal cell differentiation and neurogenesis. All redrawn from ref.