Objective
Betamethasone administration in the late preterm period (34 0/7–36 5/7 weeks’ gestation) not only reduces neonatal respiratory morbidity but also increases neonatal hypoglycemia through an uncertain mechanism. 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. Given that betamethasone can also increase maternal glucose levels, 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). Mother-neonate 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) 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.
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.
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.
| Characteristics | Antenatal betamethasone (n=106) | Placebo (n=97) | P -value |
|---|---|---|---|
| Maternal body mass index (kg/m 2 ) | 31.9 (28.3–37.9) | 31.5 (27.1–36.6) | .54 |
| Total pregnancy weight gain (kg) | 10.9 (6.8–15.0) | 12.7 (8.6–16.0) | .09 |
| Maternal age (y) | 28.5 (24.0–34.0) | 27.0 (22.0–33.0) | .10 |
| Race or ethnicity | .65 | ||
| Non-Hispanic Black | 30 (28.3) | 22 (22.7) | |
| Non-Hispanic White | 39 (36.8) | 37 (38.1) | |
| Hispanic | 36 (34.0) | 38 (39.2) | |
| Other | 1 (0.9) | 0 | |
| Nulliparous | 40 (37.7) | 42 (43.3) | .42 |
| Cigarette use during pregnancy | 19 (17.9) | 11 (11.3) | .19 |
| Alcohol use during pregnancy | 2 (1.9) | 2 (2.1) | 1.00 |
| Hypertensive disorder during pregnancy | .32 | ||
| None | 65 (61.3) | 61 (62.9) | |
| Gestational hypertension | 10 (9.4) | 6 (6.2) | |
| Preeclampsia without severe features | 10 (9.4) | 16 (16.5) | |
| Preeclampsia with severe features | 21 (19.8) | 14 (14.4) | |
| Gestational diabetes mellitus | 12 (11.3) | 11 (11.3) | 1.00 |
| Chronic hypertension | 12 (11.3) | 14 (14.4) | .51 |
| Asthma requiring medical therapy | 7 (6.6) | 11 (11.3) | .24 |
| Thyroid disorder | .72 | ||
| None | 100 (94.3) | 92 (94.8) | |
| Hypothyroidism | 4 (3.8) | 2 (2.1) | |
| Hyperthyroidism | 2 (1.9) | 3 (3.1) | |
| Gestational age at randomization (wk) | 35.6 (34.7–36.1) | 35.4 (34.9–36.3) | .83 |
| Time from randomization to delivery (h) | 27.7 (15.7–61.9) | 31.9 (14.6–96.2) | .43 |
| Number of doses received | .70 | ||
| 1 dose | 42 (39.6) | 41 (42.3) | |
| 2 doses | 64 (60.4) | 56 (57.7) | |
| Reason for anticipated late preterm birth | .73 | ||
| Preterm labor with intact membranes | 33 (31.1) | 32 (33.0) | |
| PPROM | 25 (23.6) | 19 (19.6) | |
| Hypertensive disorder of pregnancy | 30 (28.3) | 29 (29.9) | |
| Fetal growth restriction | 1 (0.9) | 2 (2.1) | |
| Oligohydramnios | 2 (1.9) | 0 | |
| Other | 15 (14.2) | 15 (15.5) | |
| Time from membrane rupture to delivery (h) | 5.1 (1.2–15.8) | 5.7 (0.5–11.9) | .46 |
| Clinical chorioamnionitis | 1 (0.9) | 4 (4.1) | .20 |
| Intrapartum antibiotics | 12 (11.3) | 8 (8.2) | .46 |
| Type of labor | .83 | ||
| No labor, cesarean delivery | 11 (10.4) | 10 (10.3) | |
| Spontaneous | 22 (20.8) | 24 (24.7) | |
| Spontaneous, augmented | 21 (19.8) | 15 (15.5) | |
| Induced | 52 (49.1) | 48 (49.5) | |
| Time from labor onset to delivery (h) a | 14.3 (6.4–19.2) | 12.7 (8.1–19.6) | .89 |
| Gestational age at delivery (wk) | 35.9 (35.1–36.7) | 36.1 (35.1–36.7) | .23 |
| Birthweight (g) | 2759 (2230–2840) | 2553 (2350–3024) | .20 |
| Small-for-gestational-age | 22 (20.8) | 17 (17.5) | .56 |
| Male sex | 65 (61.3) | 60 (61.9) | .94 |
| Time from delivery to first feeding (h) | 2.1 (1.0–7.4) | 2.5 (1.1–11.8) | .50 |
| Breastfeeding | 74 (69.8) | 72 (74.2) | .48 |
| Minor congenital malformations b | 2 (1.9) | 3 (3.1) | .67 |
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