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

Study Overview
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Brief Summary
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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?

Detailed Description
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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.

Official Title
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Fetal Metabolic Consequences of Late Preterm Steroid Exposure

Conditions
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Pregnancy Preterm, Neonatal Hypoglycemia, Hyperglycemia Drug Induced

Intervention / Treatment
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* Other: Maternal glycemic control


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Women will undergo regular maternal blood glucose screening and treatment of hyperglycemia following BMZ administration to achieve maternal glycemic control until delivery or hospital discharge, for a maximum of 5 days. | Other: Maternal glycemic control<br>* 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.<br>|
| No Intervention: Usual Care<br>Routine antenatal care will be performed without any maternal blood glucose screening nor treatment as is usual care at each of the study sites. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Umbilical Cord Blood C-peptide | C-peptide level (ng/mL) as measure of fetal hyperinsulinemia | At delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Umbilical Cord Blood Cortisol | Cortisol level (ug/mL) as measure of fetal immune suppression | At delivery | 
| Umbilical Insulin-Like Growth Factor 1 | Insulin-like growth factor 1 level (ng/mL) as a measure of in utero metabolic status | At delivery | 
| Umbilical Cord Blood Leptin | Leptin level (ng/mL) as measure of fetal adiposity | At delivery | 
| Neonatal Hypoglycemia | Number of neonates with capillary blood glucose < 40 mg/dL | After birth, up to 48 hours of life | 
| 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 | 
| Neonatal Glucose Nadir | Lowest neonatal capillary blood glucose (mg/dL) | After birth, during hospital admission, assessed up to 28 days | 
| 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 | 
| 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 | 
| 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 | 
| Neonatal Seizures | Number of neonates who had seizures | After birth, during hospital admission, assessed up to 28 days | 
| Neonatal Mortality | Number of neonates who died | After birth, during hospital admission, assessed up to 28 days | 
| 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 | 
| Maternal Insulin Treatment | Number of mothers who received insulin for treatment of hyperglycemia | For five days after first dose of betamethasone administration | 
| Maternal Hypoglycemia | Number of mothers with capillary blood glucose <60 mg/dL | For five days after first dose of betamethasone administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Betamethasone, Late preterm, Steroids