Preterm Neonates and Antenatal Corticosteroid Therapy

One of the most pressing challenges facing preterm neonates (born before 37 weeks' gestation) is the transition to breathing room air. As such, perinatal care is significantly focused on improving preterm lung function. Takahashi T, Fee EL, Takahashi Y, et al. found in a study published in the American Journal of Obstetrics and Gynecology that Betamethasone phosphate reduces the efficacy of antenatal steroid therapy and is associated with lower birthweights when administered to pregnant sheep in combination with betamethasone acetate.

The introduction of antenatal corticosteroid (ACS) therapy has resulted in an improved prognosis for a large cross-section of preterm-born neonates. Today, ACS therapy is the standard of care for women at risk of imminent preterm delivery. The American College of Obstetricians and Gynecologists recommends the use of a single course of ACS for pregnant women between 24 to 33 weeks' gestation who are at risk of preterm labor within 7 days. Although ACS therapy has been used widely, and benefits demonstrated when given to the right women at the right time, concerns remain regarding an increased potential risk of adverse effects, including fetal growth restriction, neonatal hypoglycemia, and negative effects on the maternal and fetal hypothalamic-pituitary-adrenal (HPA) axis.

Although there is room for improvement in ACS treatment efficacy, reliability, and optimal patient selection, sizable geographic variation in the usage of ACS remains.

The study was undertaken with this objective in mind by Takahashi T, Fee EL, Takahashi Y, et al. They focused on the differential pharmacodynamics of betamethasone phosphate (Beta-P) and betamethasone acetate (Beta-Ac), which are commonly used in combination as an ACS therapy. These two agents have distinct pharmacokinetic profiles after intramuscular (IM) injection. Beta-P can be absorbed quickly after IM administration, which leads to high peak concentration and a short half-life. Beta-Ac slowly dissolves before diffusing into the vascular space. This signature enables Beta-Ac to have a far longer half-life, with a much lower maximum concentration and delayed peak concentration time.

Using an established sheep model of prematurity and postnatal ventilation of the preterm lamb, authors compared the pharmacodynamic effects of low-dosage treatment with betamethasone acetate only against a standard dosage of betamethasone phosphate and betamethasone acetate as recommended by the American College of Obstetricians and Gynecologists for women at risk of imminent preterm delivery between 24 0/7 and 35 6/7 weeks' gestation.

Ewes carrying a single fetus at 1221 days' gestation were randomized to receive either:

• Maternal intramuscular injections of sterile saline (the saline negative control group, n=12)
• 2 maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate + betamethasone acetate administered at 24-hour dosing intervals (the betamethasone phosphate + betamethasone acetate group, n=12)
• 2 maternal intramuscular injections of 0.125 mg/kg betamethasone acetate administered at 24-hour dosing intervals (the betamethasone acetate group, n=11)

The fetuses were surgically delivered 48 hours after treatment initiation and ventilated for 30 minutes to determine functional lung maturation. The fetuses were euthanized after ventilation, and the lungs were collected for analysis using quantitative polymerase chain reaction and Western blot assays. Fetal plasma adrenocorticotropic hormone levels were measured in the cord blood samples taken at delivery.

Primary Findings

• A single course (2 doses at 0.125 mg/kg) of Beta-Ac achieved more consistent functional maturation of the ovine preterm lung than the combined Beta-Ac + Beta-P in 2, 0.25 mg/kg doses.
• A single course of combined Beta-P and Beta-Ac resulted in higher maternal and fetal plasma betamethasone concentrations in association with a greater degree of fetal HPA axis suppression and statistically significant reductions in birthweight than Beta-Ac alone.

On the basis of these observations, it may be concluded that for deliveries occurring 48 hours after treatment initiation, the coadministration of Beta-P with Beta-Ac not only fails to additionally benefit fetal ovine lung maturation but may also suppress GR-driven maturational signaling in the lung, compared with that elicited by the sole administration of Beta-Ac at a lower total dosage.

Overall, both treated groups had improved lung maturation compared with the saline control group. Favorable arterial blood gas data (pH, PaO2, and PaCO2), ventilation data (dynamic compliance, Vt, and VEI) and static compliance (V40 and PV curves) data all demonstrate that both ACS regimens could mature the preterm lung structurally, leading to more efficient gas exchange. In addition, HR was significantly reduced in both treated groups, suggesting that both ACS therapies could stabilize the cardiovascular system, potentially by improving cardiac performance and reducing vascular permeability.

"We hypothesized that the high fetal betamethasone levels achieved by the Beta-P component of combined Beta-P and Beta-Ac therapy would be redundant in driving preterm lung maturation. The study results supported our hypothesis and strongly suggested that lower-dosage treatment with Beta-Ac, avoiding high maternal-fetal steroid exposures, is both safer and more effective than combined Beta-P and Beta-Ac therapy. These findings add further impetus to the undertaking of clinical trials to optimize the agent of choice and dosing regimen for ACS therapies."

Source: Takahashi T, Fee EL, Takahashi Y, et al. Betamethasone phosphate reduces the efficacy of antenatal steroid therapy and is associated with lower birthweights when administered to pregnant sheep in combination with betamethasone acetate. Am J Obstet Gynecol 2022;226:564.e1-14. https://doi.org/10.1016/j.ajog.2021.10.001