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.
Supplementary Material
FIGURE. Association of betamethasone and fetal metabolic biomarkers compared to placebo.
Adjusted for maternal body mass index, gestational diabetes mellitus, number of hours from study drug exposure to delivery, and hospital as a random effect. Number of unquantifiable values: C-peptide (n=1), insulin (n=1), and IGFBP-1 (n=68).
CI, confidence interval; IGFBP-1, insulin-like growth factor binding protein 1.
Battarbee. Mechanism of neonatal hypoglycemia after late preterm steroids. Am J Obstet Gynecol 2022.
ACKNOWLEDGMENTS
The authors thank Felecia Ortiz, RN, BSN and Sabine Bousleiman, RNC, MSN, MPH, for protocol development and coordination between clinical research centers and Kathleen Jablonski, PhD for protocol and data management. The authors also thank Ronald Wapner, MD; Elizabeth A. Thom, PhD; Carol Blaisdell, MD; and Catherine Spong, MD, for protocol development and oversight.
This study was supported by grants (HL098554 and HL098354) from the National Heart, Lung, and Blood Institute; grants (HD21410, HD27915, HD27917, HD27869, HD34116, HD34208, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, HD53097, HD53118, HD68268, HD68258, HD68282, and U10 HD36801) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development; and by grant (UL1 TR000040) from the National Center for Advancing Translational Sciences, National Institutes of Health. A.N.B. was supported by grant K23HD103875 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The comments and views expressed in this article are those of the authors and do not necessarily represent the views of the National Institutes of Health. The funding sources did not have any role in the study design, data analysis and interpretation of data, writing of the manuscript, or the decision of the place of submission.
APPENDIX
In addition to the authors, other members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network are as follows:
The University of North Carolina at Chapel Hill, Chapel Hill, NC: K. Clark, J. Thorp, S. Timlin, R. Bass, K. Dorman, S. Brody (WakeMed Health & Hospitals), J. Warren (Mission Health System)
Columbia University, New York, NY: S. Bousleiman, R. Wapner, M. DiVito, M. Talucci, L. Plante (Drexel University), C. Tocci (Drexel University), M. Hoffman (Christiana Care Health Systems), S. Lynch (Christiana Care Health Systems), A. Ranzini (St. Peter’s University Hospital), M. Lake (St. Peter’s University Hospital), J. Smulian (Lehigh Valley Health Network), D. Skupski (New York Hospital Queens)
The University of Texas Health Science Center at Houston-Children’s Memorial Hermann Hospital, Houston, TX: F. Ortiz, B. Sibai, M. Hutchinson, P. Givens, and L. Garcia (LBJ General Hospital)
The University of Alabama at Birmingham, Birmingham, AL: S. Harris, J. Biggio, A. Todd, L. Merin, G. Adams, M. Tew, J. Grant
The University of Texas Medical Branch, Galveston, TX: A. Salazar, G. Saade, L. McCoy, B. Aguillon, M. Wilson, J. Sikes, G. Hankins, G. Olson, H. Harirah
Brown University, Providence, RI: D. Allard, D. Rouse, L. Beati, B. Wallin, J. Rousseau, B. Hughes
The Ohio State University, Columbus, OH: F. Johnson, J. Iams, M. Prasad, D. McKenna, R. Ozug, T. Dible, K. Snow, K. Fennig, S. Webster, M. Donohue
The University of Utah Health Sciences Center, Salt Lake City, UT: K. Hill, E. Clark, A. Sowles, S. Timothy, P. Reed (deceased; Intermountain Healthcare), M. Varner
MetroHealth Medical Center-Case Western Reserve University, Cleveland, OH: M. Duchon, E. Chien, W. Dalton, C. Milluzzi, L. Wolfe, K. Kushner, B. Mercer
Northwestern University, Chicago, IL: G. Mallett, W. Grobman, A. Peaceman, L.Stein, M. Dinsmoor (NorthShore University Health System), K. Paychek (NorthShore University HealthSystem)
University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO: K. Hale, R. Gibbs, M. Hoffman, J.C. Carey, H. Galan, K. Heyborne, T. Metz, A. Rosenberg
Duke University, Durham, NC: T. Bishop, G. Swamy, A. Murtha, R. Heine, C. Grotegut, L. Brancazio
Stanford University, Stanford, CA: K. Kushniruk, M. Norton, Y. El-Sayed, D. Lyell, A. Sit, C. Willson, A. Monk, E. Kogut, R. Knapp
The University of Texas Southwestern Medical Center, Dallas, TX: L. Moseley, B. Casey, J. Price, M. Santillan, J. Gerald A. Sias, K. Gonzales
University of Pittsburgh, Pittsburgh, PA: H. Simhan, S. Caritis, H. Birkland, P. Cotroneo
Oregon Health & Science University, Portland, OR: L. Pereira, J. Tolosa, C. McEvoy, M. Rincon, J. Snyder
Wayne State University, Detroit, MI: N. Hauff, Y. Sorokin
The George Washington University Biostatistics Center, Washington, D.C.: E. Thom, V. Momirova, G. Heinrich, T. Billingsley, T. Spangler
National Heart, Lung, and Blood Institute, Bethesda, MD: C. Blaisdell
Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD: C. Spong, S. Tolivaisa
MFMU Network Steering Committee Chair (Medical University of South Carolina, Charleston, SC): J. P. VanDorsten, MD.
Footnotes
The authors report no conflict of interest.
This study was conducted on behalf of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
Additional members of this network have been listed in the Appendix.
This study was presented in the oral plenary session at the 40th annual meeting of the Society for Maternal-Fetal Medicine, Grapevine, TX, Feb 3–8, 2020.
Contributor Information
Ashley N. Battarbee, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, 1700 6th Ave. South, Rm 10270, Birmingham, AL 35233.
Grecio J. Sandoval, The Biostatistics Center, The George Washington University, Washington, DC.
Cynthia Gyamfi-Bannerman, Department of Obstetrics and Gynecology, Columbia University, New York, NY.
Sean C. Blackwell, Department of Obstetrics and Gynecology, The University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital, Houston, TX.
Alan T. N. Tita, Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, Birmingham, AL.
Uma M. Reddy, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.
Lucky Jain, Department of Obstetrics and Gynecology, Emory University, Atlanta, GA.
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