Mechanism of Neonatal Hypoglycemia After Late Preterm Steroids: Are Fetal Metabolic Effects Responsible?

Authors

Ashley N Battarbee
Grecio J Sandoval
Cynthia Gyamfi-Bannerman
Sean C Blackwell
Alan T N Tita
Uma M Reddy
Lucky Jain

Publication Date

8-1-2022

Journal

American Journal of Perinatology Reports

Abstract

OBJECTIVE:

Betamethasone administration in the late preterm period(340/7–365/7 weeks’ gestation) not only reduces neonatal respiratory morbidity but also increases neonatal hypoglycemia through an uncertain mechanism.¹ Based on data from pregnant individuals with diabetes, excessive amounts of maternal glucose can cross the placenta and cause fetal hyperinsulinemia, which can cause neonatal hypoglycemia at birth.² Given that betamethasone can also increase maternal glucose levels,³ our objective was to explore the potential mechanisms for late preterm steroid-induced neonatal hypoglycemia by measuring the fetal metabolic effects of antenatal late preterm betamethasone and assessing the relationship of the fetal metabolic effects with neonatal hypoglycemia.

STUDY DESIGN:

This was a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network Antenatal Late Preterm Steroids trial, a randomized trial of antenatal betamethasone vs placebo in participants with threatened late preterm birth (2010–2015).¹ Motherneonate dyads with stored umbilical cord blood plasma were included. Major congenital anomalies were excluded. C-peptide, insulin, leptin, and insulin-like growth factor binding protein 1 (IGFBP-1) were measured in the umbilical cord blood plasma and compared between the betamethasone and placebo groups. Multivariable generalized linear regression estimated the association between the betamethasone and biomarker levels. Subsequently, the associations between the fetal biomarkers and neonatal hypoglycemia (glucose<40 mg/dL)⁴ were investigated with multivariable logistic regression. This secondary analysis was approved by The University of North Carolina at Chapel Hill Institutional Review Board. All the tests were two-tailed, and statistical significance was defined as P<.05.

RESULTS:

Of 2,831 participants in the primary trial, 203 met the inclusion criteria for this analysis: 106 (52%) were exposed to betamethasone, and 97 (48%) were exposed to placebo. A total of 173 (85%) participants delivered preterm, and 23 (11%) had gestational diabetes mellitus. The baseline characteristics were similar between the groups (Supplemental Table 1). Overall, 61 (30%) neonates had hypoglycemia: 35 (33%) were exposed to betamethasone and 26 (27%) were exposed to a placebo. Betamethasone exposure was associated with higher levels of C-peptide, insulin, and leptin but not of IGFBP-1 (Figure). There was no effect modification by gestational diabetes, but there was effect modification by the duration of time from study drug administration to delivery, whereby the associations between betamethasone and C-peptide, insulin, and leptin were the strongest among participants who delivered between 12 to 24 hours after study drug administration (Supplemental Table 2). Fetal C-peptide and insulin levels of >90th percentile, were associated with higher odds of neonatal hypoglycemia (adjusted odds ratio 3.16, 95% confidence interval 1.08–9.24 and adjusted odds ratio 6.42, 95% confidence interval 2.11–19.60, respectively; Supplemental Table 3).

CONCLUSION:

Betamethasone given in the late preterm period is associated with fetal metabolic alterations such as hyperinsulinemia, and these alterations are associated with 3- to 6-fold higher odds of neonatal hypoglycemia. Although the results of this analysis warrant further validation, the mechanism of late preterm steroid-induced neonatal hypoglycemia may be similar to that observed in neonates born to pregnant people with diabetes mellitus. Further research targeting the fetal metabolic effects demonstrated here is needed to determine if the increased risk of neonatal hypoglycemia after late preterm steroids can be prevented.

Keywords

Female, Gestational Age, Humans, Hypoglycemia, Infant, Newborn, Infant, Newborn, Diseases, Pregnancy, Premature Birth, Prenatal Care, Steroids

Comments

PMID: 35364060