Hyperglycemia Drug Induced, Neonatal Hypoglycemia, Pregnancy Preterm
Conditions
Keywords
Betamethasone, Late preterm, Steroids
Brief 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?
Detailed 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.
Interventions
OTHERMaternal 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.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Umbilical Cord Blood C-peptide | At delivery | C-peptide level (ng/mL) as measure of fetal hyperinsulinemia |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Umbilical Insulin-Like Growth Factor 1 | At delivery | Insulin-like growth factor 1 level (ng/mL) as a measure of in utero metabolic status |
| Umbilical Cord Blood Leptin | At delivery | Leptin level (ng/mL) as measure of fetal adiposity |
| Neonatal Hypoglycemia | After birth, up to 48 hours of life | Number of neonates with capillary blood glucose \< 40 mg/dL |
| Neonatal Hypoglycemia Treatment | After birth, during hospital admission, assessed up to 28 days | Number of neonates with hypoglycemia requiring treatment with dextrose gel or dextrose intravenous fluids |
| Neonatal Glucose Nadir | After birth, during hospital admission, assessed up to 28 days | Lowest neonatal capillary blood glucose (mg/dL) |
| Timing of Neonatal Blood Glucose Nadir | After birth, during hospital admission, assessed up to 28 days | Number of hours after birth when lowest neonatal capillary blood glucose was measured |
| Umbilical Cord Blood Cortisol | At delivery | Cortisol level (ug/mL) as measure of fetal immune suppression |
| Neonatal Intensive Care Unit Length of Stay | From neonatal intensive care unit admission to discharge, assessed up to 28 days | Number of days of neonatal intensive care unit stay |
| Neonatal Seizures | After birth, during hospital admission, assessed up to 28 days | Number of neonates who had seizures |
| Neonatal Mortality | After birth, during hospital admission, assessed up to 28 days | Number of neonates who died |
| Maternal Hyperglycemia | For five days after first dose of betamethasone administration | 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 |
| Maternal Insulin Treatment | For five days after first dose of betamethasone administration | Number of mothers who received insulin for treatment of hyperglycemia |
| Maternal Hypoglycemia | For five days after first dose of betamethasone administration | Number of mothers with capillary blood glucose \<60 mg/dL |
| Neonatal Intensive Care Unit Admission | Date of delivery to date of discharge from hospital, assessed up to 28 days | Number of neonates admitted to the neonatal intensive care unit for \> 24 hours |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intervention 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. | 43 |
| Usual Care Routine antenatal care will be performed without any maternal blood glucose screening nor treatment as is usual care at each of the study sites. | 42 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Usual Care | Total | Intervention |
|---|---|---|---|
| Age, Continuous | 28 years | 28 years | 27 years |
| Race/Ethnicity, Customized Hispanic | 7 Participants | 15 Participants | 8 Participants |
| Race/Ethnicity, Customized Non-Hispanic Black | 16 Participants | 33 Participants | 17 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 18 Participants | 35 Participants | 17 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment United States | 42 Participants | 85 Participants | 43 Participants |
| Sex: Female, Male Female | 42 Participants | 85 Participants | 43 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 42 | 0 / 43 | 0 / 42 |
| other Total, other adverse events | 11 / 44 | 7 / 42 | 30 / 43 | 35 / 42 |
| serious Total, serious adverse events | 0 / 44 | 0 / 42 | 0 / 43 | 0 / 42 |
Outcome results
Primary
Umbilical Cord Blood C-peptide
C-peptide level (ng/mL) as measure of fetal hyperinsulinemia
Time frame: At delivery
Population: Umbilical cord blood specimen only available for 70 neonates
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Umbilical Cord Blood C-peptide | 1.02 ng/mL |
| Neonates Born to Mothers Receiving Usual Care | Umbilical Cord Blood C-peptide | 1.09 ng/mL |
p-value: 0.97Wilcoxon (Mann-Whitney)
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
Time frame: For five days after first dose of betamethasone administration
Population: Only 39 participants in the intervention group had at least one capillary blood glucose measured
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Maternal Hyperglycemia | 32 Participants |
| Neonates Born to Mothers Receiving Usual Care | Maternal Hyperglycemia | 0 Participants |
Secondary
Maternal Hypoglycemia
Number of mothers with capillary blood glucose \<60 mg/dL
Time frame: For five days after first dose of betamethasone administration
Population: Only 39 mothers in the intervention group had at least one capillary blood glucose measured
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Maternal Hypoglycemia | 0 Participants |
Secondary
Maternal Insulin Treatment
Number of mothers who received insulin for treatment of hyperglycemia
Time frame: For five days after first dose of betamethasone administration
Population: Only 39 mothers in the intervention group had at least one capillary blood glucose measured
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Maternal Insulin Treatment | 22 Participants |
Secondary
Neonatal Glucose Nadir
Lowest neonatal capillary blood glucose (mg/dL)
Time frame: After birth, during hospital admission, assessed up to 28 days
Population: Glucose only available on 82 neonates
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Neonatal Glucose Nadir | 42.3 mg/dL | Standard Deviation 2.9 |
| Neonates Born to Mothers Receiving Usual Care | Neonatal Glucose Nadir | 42.2 mg/dL | Standard Deviation 2.2 |
p-value: 0.97t-test, 2 sided
Secondary
Neonatal Hypoglycemia
Number of neonates with capillary blood glucose \< 40 mg/dL
Time frame: After birth, up to 48 hours of life
Population: Glucose only available for 82 neonates
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Neonatal Hypoglycemia | 20 Participants |
| Neonates Born to Mothers Receiving Usual Care | Neonatal Hypoglycemia | 21 Participants |
p-value: 0.83Chi-squared
Secondary
Neonatal Hypoglycemia Treatment
Number of neonates with hypoglycemia requiring treatment with dextrose gel or dextrose intravenous fluids
Time frame: After birth, during hospital admission, assessed up to 28 days
Population: Glucose only available for 82 neonates
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Neonatal Hypoglycemia Treatment | 9 Participants |
| Neonates Born to Mothers Receiving Usual Care | Neonatal Hypoglycemia Treatment | 8 Participants |
p-value: 0.79Chi-squared
Secondary
Neonatal Intensive Care Unit Admission
Number of neonates admitted to the neonatal intensive care unit for \> 24 hours
Time frame: Date of delivery to date of discharge from hospital, assessed up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Neonatal Intensive Care Unit Admission | 15 Participants |
| Neonates Born to Mothers Receiving Usual Care | Neonatal Intensive Care Unit Admission | 21 Participants |
p-value: 0.16Chi-squared
Secondary
Neonatal Intensive Care Unit Length of Stay
Number of days of neonatal intensive care unit stay
Time frame: From neonatal intensive care unit admission to discharge, assessed up to 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Neonatal Intensive Care Unit Length of Stay | 6 days |
| Neonates Born to Mothers Receiving Usual Care | Neonatal Intensive Care Unit Length of Stay | 7 days |
p-value: 0.59Wilcoxon (Mann-Whitney)
Secondary
Neonatal Mortality
Number of neonates who died
Time frame: After birth, during hospital admission, assessed up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Neonatal Mortality | 0 Participants |
| Neonates Born to Mothers Receiving Usual Care | Neonatal Mortality | 0 Participants |
Secondary
Neonatal Seizures
Number of neonates who had seizures
Time frame: After birth, during hospital admission, assessed up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Neonatal Seizures | 0 Participants |
| Neonates Born to Mothers Receiving Usual Care | Neonatal Seizures | 0 Participants |
Secondary
Timing of Neonatal Blood Glucose Nadir
Number of hours after birth when lowest neonatal capillary blood glucose was measured
Time frame: After birth, during hospital admission, assessed up to 28 days
Population: Glucose only available on 82 neonates
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Timing of Neonatal Blood Glucose Nadir | 1.7 hours |
| Neonates Born to Mothers Receiving Usual Care | Timing of Neonatal Blood Glucose Nadir | 1.7 hours |
p-value: 0.44Wilcoxon (Mann-Whitney)
Secondary
Umbilical Cord Blood Cortisol
Cortisol level (ug/mL) as measure of fetal immune suppression
Time frame: At delivery
Population: Umbilical cord blood specimen only available for 70 neonates
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Umbilical Cord Blood Cortisol | 2.0 ug/mL |
| Neonates Born to Mothers Receiving Usual Care | Umbilical Cord Blood Cortisol | 2.5 ug/mL |
p-value: 0.24Wilcoxon (Mann-Whitney)
Secondary
Umbilical Cord Blood Leptin
Leptin level (ng/mL) as measure of fetal adiposity
Time frame: At delivery
Population: Umbilical cord blood specimen only available for 71 neonates
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Umbilical Cord Blood Leptin | 7.5 ng/mL |
| Neonates Born to Mothers Receiving Usual Care | Umbilical Cord Blood Leptin | 5.6 ng/mL |
p-value: 0.55Wilcoxon (Mann-Whitney)
Secondary
Umbilical Insulin-Like Growth Factor 1
Insulin-like growth factor 1 level (ng/mL) as a measure of in utero metabolic status
Time frame: At delivery
Population: Umbilical cord blood specimen only available for 71 neonates
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neonates Born to Mothers Receiving Intervention | Umbilical Insulin-Like Growth Factor 1 | 78 ng/mL |
| Neonates Born to Mothers Receiving Usual Care | Umbilical Insulin-Like Growth Factor 1 | 58 ng/mL |
p-value: 0.15Wilcoxon (Mann-Whitney)