Euglycemia After Antenatal Late Preterm Steroids, the E-ALPS Study

Neonatal Hypoglycemia Clinical Trial

— E-ALPS  

Official title:

Fetal Metabolic Consequences of Late Preterm Steroid Exposure

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03076775
• Other study ID #: 18-1970
• Secondary ID: 1R03HD096188-01
• Status: Completed
• Phase: N/A
• Start date: June 8, 2017
• Est. completion date: November 19, 2021

Study information

• Verified date: December 2021
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Annually in the U.S 300,000 neonates are born late preterm, defined as 34 weeks 0 days - 36 weeks 6 days. The Antenatal Late Preterm Steroids (ALPS) Trial demonstrated that maternal treatment with betamethasone in the late preterm period significantly reduces neonatal respiratory complications, but also increases neonatal hypoglycemia, compared to placebo.

This research study will attempt to answer the following primary question: Does a management protocol aimed at maintaining maternal euglycemia after ALPS decrease fetal hyperinsulinemia, compared to usual antepartum care?

Description:

Euglycemia after Antenatal Late Preterm Steroids, the E-ALPS Study:

There is a fundamental gap in understanding the adverse metabolic effects of antenatal late preterm steroids (ALPS). In 2016, an important randomized clinical trial of 2827 late preterm pregnancies showed that antenatal betamethasone (BMZ) significantly reduced neonatal respiratory complications compared with placebo. However, those neonates exposed to BMZ were also more likely to have hypoglycemia at birth. This unexpected adverse outcome raised concern among both obstetricians and neonatologists and remains an important knowledge gap to be filled. The rationale for the proposed research is that steroid-induced maternal hyperglycemia leads to transient fetal hyperinsulinemia, which causes hypoglycemia in neonates that are delivered during this time-period. Thus, the fetal metabolic consequences and subsequent neonatal hypoglycemia observed after exposure to BMZ in utero can be prevented by achieving maternal euglycemia prior to delivery.

This protocol describes a randomized clinical trial to evaluate whether screening for and treatment of steroid-induced hyperglycemia in non-diabetic women treated with BMZ in the late preterm period can decrease the rate of fetal hyperinsulinemia, thus reducing neonatal hypoglycemia and improving short-term neonatal outcomes.

This study was formerly approved as Institutional Review Board #16-3200.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 86
• Est. completion date: November 19, 2021
• Est. primary completion date: February 18, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

• Singleton gestation with no known major fetal anomalies

• Gestational age at randomization between 34 weeks 0 days and 36 weeks 5 days

• Receiving antenatal betamethasone due to high probability of delivery in late preterm period

Exclusion Criteria:

• Pre-gestational or gestational diabetes mellitus

• Maternal contraindication to insulin

• Planned outpatient treatment with antenatal betamethasone

• Participation in clinical trial that could affect primary outcome or participation in this trial in a previous pregnancy

Related Conditions & MeSH terms

• Hyperglycemia
• Hyperglycemia Drug Induced
• Hypoglycemia
• Neonatal Hypoglycemia
• Pregnancy Preterm
• Premature Birth

Intervention

Other:
• Maternal glycemic control
Maternal capillary blood glucose testing will be performed according to oral intake status: every 2 hours if not eating (NPO) or fasting and 1-hour postprandial if eating regular meals. Hyperglycemia, defined based on the American Diabetes Association and the American College of Obstetricians and Gynecologists recommendations as well as current practice at study sites, will be treated according to study guidelines based on oral intake status: insulin infusion if NPO and subcutaneous insulin if eating regular meals.

Locations

Country	Name	City	State
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	University of North Carolina - Chapel Hill	Chapel Hill	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Country where clinical trial is conducted

United States, 

References & Publications (16)

ACOG Committee on Practice Bulletins. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 60, March 2005. Pregestational diabetes mellitus. Obstet Gynecol. 2005 Mar;105(3):675-85. — View Citation

American College of Obstetricians and Gynecologists' Committee on Obstetric Practice; Society for Maternal- Fetal Medicine. Committee Opinion No.677: Antenatal Corticosteroid Therapy for Fetal Maturation. Obstet Gynecol. 2016 Oct;128(4):e187-94. doi: 10.1097/AOG.0000000000001715. — View Citation

American Diabetes Association. Standards of medical care in diabetes - 2016. Diabetes Care. 2016; 39(suppl1):S1-S106.

Consortium on Safe Labor, Hibbard JU, Wilkins I, Sun L, Gregory K, Haberman S, Hoffman M, Kominiarek MA, Reddy U, Bailit J, Branch DW, Burkman R, Gonzalez Quintero VH, Hatjis CG, Landy H, Ramirez M, VanVeldhuisen P, Troendle J, Zhang J. Respiratory morbidity in late preterm births. JAMA. 2010 Jul 28;304(4):419-25. doi: 10.1001/jama.2010.1015. — View Citation

Gilbert WM, Nesbitt TS, Danielsen B. The cost of prematurity: quantification by gestational age and birth weight. Obstet Gynecol. 2003 Sep;102(3):488-92. — View Citation

Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita AT, Reddy UM, Saade GR, Rouse DJ, McKenna DS, Clark EA, Thorp JM Jr, Chien EK, Peaceman AM, Gibbs RS, Swamy GK, Norton ME, Casey BM, Caritis SN, Tolosa JE, Sorokin Y, VanDorsten JP, Jain L; NICHD Maternal-Fetal Medicine Units Network. Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. N Engl J Med. 2016 Apr 7;374(14):1311-20. doi: 10.1056/NEJMoa1516783. Epub 2016 Feb 4. — View Citation

Jolley JA, Rajan PV, Petersen R, Fong A, Wing DA. Effect of antenatal betamethasone on blood glucose levels in women with and without diabetes. Diabetes Res Clin Pract. 2016 Aug;118:98-104. doi: 10.1016/j.diabres.2016.06.005. Epub 2016 Jun 17. — View Citation

Kühl C, Andersen GE, Hertel J, Mølsted-Pedersen L. Metabolic events in infants of diabetic mothers during first 24 hours after birth. I. Changes in plasma glucose, insulin and glucagon. Acta Paediatr Scand. 1982 Jan;71(1):19-25. — View Citation

Langen ES, Kuperstock JL, Sung JF, Taslimi M, Byrne J, El-Sayed YY. Maternal glucose response to betamethasone administration. Am J Perinatol. 2015 Feb;30(2):143-8. doi: 10.1055/s-0034-1376387. Epub 2014 Jun 10. — View Citation

Martin JA, Hamilton BE, Osterman MJ, Driscoll AK, Mathews TJ. Births: Final Data for 2015. Natl Vital Stat Rep. 2017 Jan;66(1):1. — View Citation

McIntire DD, Leveno KJ. Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstet Gynecol. 2008 Jan;111(1):35-41. doi: 10.1097/01.AOG.0000297311.33046.73. — View Citation

Obenshain SS, Adam PA, King KC, Teramo K, Raivio KO, Räihä N, Schwartz R. Human fetal insulin response to sustained maternal hyperglycemia. N Engl J Med. 1970 Sep 10;283(11):566-70. — View Citation

Refuerzo JS, Garg A, Rech B, Ramin SM, Vidaeff A, Blackwell SC. Continuous glucose monitoring in diabetic women following antenatal corticosteroid therapy: a pilot study. Am J Perinatol. 2012 May;29(5):335-8. doi: 10.1055/s-0031-1295642. Epub 2011 Nov 17. — View Citation

Shelton SD, Boggess KA, Smith T, Herbert WN. Effect of betamethasone on maternal glucose. J Matern Fetal Neonatal Med. 2002 Sep;12(3):191-5. — View Citation

Sifianou P, Thanou V, Karga H. Metabolic and hormonal effects of antenatal betamethasone after 35 weeks of gestation. J Pediatr Pharmacol Ther. 2015 Mar-Apr;20(2):138-43. doi: 10.5863/1551-6776-20.2.138. — View Citation

Society for Maternal-Fetal Medicine (SMFM) Publications Committee. Implementation of the use of antenatal corticosteroids in the late preterm birth period in women at risk for preterm delivery. Am J Obstet Gynecol. 2016 Aug;215(2):B13-5. doi: 10.1016/j.ajog.2016.03.013. Epub 2016 Mar 15. Review. Erratum in: Am J Obstet Gynecol. 2017 Feb;216(2):180. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Umbilical Cord Blood C-peptide	C-peptide level (ng/mL) as measure of fetal hyperinsulinemia	At delivery
Secondary	Umbilical Cord Blood Cortisol	Cortisol level (ug/mL) as measure of fetal immune suppression	At delivery
Secondary	Umbilical Insulin-Like Growth Factor 1	Insulin-like growth factor 1 level (ng/mL) as a measure of in utero metabolic status	At delivery
Secondary	Umbilical Cord Blood Leptin	Leptin level (ng/mL) as measure of fetal adiposity	At delivery
Secondary	Neonatal Hypoglycemia	Number of neonates with capillary blood glucose < 40 mg/dL	After birth, up to 48 hours of life
Secondary	Neonatal Hypoglycemia Treatment	Number of neonates with hypoglycemia requiring treatment with dextrose gel or dextrose intravenous fluids	After birth, during hospital admission, assessed up to 28 days
Secondary	Neonatal Glucose Nadir	Lowest neonatal capillary blood glucose (mg/dL)	After birth, during hospital admission, assessed up to 28 days
Secondary	Timing of Neonatal Blood Glucose Nadir	Number of hours after birth when lowest neonatal capillary blood glucose was measured	After birth, during hospital admission, assessed up to 28 days
Secondary	Neonatal Intensive Care Unit Admission	Number of neonates admitted to the neonatal intensive care unit for > 24 hours	Date of delivery to date of discharge from hospital, assessed up to 28 days
Secondary	Neonatal Intensive Care Unit Length of Stay	Number of days of neonatal intensive care unit stay	From neonatal intensive care unit admission to discharge, assessed up to 28 days
Secondary	Neonatal Seizures	Number of neonates who had seizures	After birth, during hospital admission, assessed up to 28 days
Secondary	Neonatal Mortality	Number of neonates who died	After birth, during hospital admission, assessed up to 28 days
Secondary	Maternal Hyperglycemia	Number of mothers with intrapartum capillary blood glucose >110 mg/dL, fasting capillary blood glucose >95 mg/dL, or 1-hour postprandial capillary blood glucose >140 mg/dL	For five days after first dose of betamethasone administration
Secondary	Maternal Insulin Treatment	Number of mothers who received insulin for treatment of hyperglycemia	For five days after first dose of betamethasone administration
Secondary	Maternal Hypoglycemia	Number of mothers with capillary blood glucose <60 mg/dL	For five days after first dose of betamethasone administration