Fetal metabolic consequences of late preterm steroid exposure

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ABSTRACT There is a fundamental gap in understanding the adverse metabolic effects of antenatal late preterm steroids. In 2016, an important randomized clinical trial of 2831 late preterm pregnancies showed that antenatal betamethasone (BMZ) significantly reduced neonatal respiratory complications compared with placebo. Yet, those neonates exposed to BMZ in utero were more likely to have hypoglycemia at birth. This unexpected adverse outcome raised concern among obstetricians and neonatologists, as hypoglycemia is a known risk factor for neonatal seizures and neurodevelopmental impairment. This unintended neonatal hypoglycemia after antenatal late preterm steroids creates an important knowledge gap in clinical care that needs to be filled. Our long-term goal is to reduce late preterm neonatal morbidity. The objectives of this application are to measure umbilical cord C-peptide levels in women exposed and in women unexposed to BMZ in the late preterm period, and among those exposed, to implement and test a protocol to identify and treat BMZ-induced maternal hyperglycemia prior to delivery. Our central hypotheses are that 1) compared to unexposed fetuses, antenatal BMZ is associated with fetal hyperinsulinemia as measured by elevated umbilical cord C-peptide level and 2) identification and treatment of maternal hyperglycemia following BMZ lowers fetal insulin level. The rationale for the proposed research is that steroid-induced maternal hyperglycemia leads to fetal hyperinsulinemia, causing hypoglycemia in neonates who are delivered during this period. Thus, fetal hyperinsulinemia and neonatal hypoglycemia observed after exposure to BMZ in utero can be prevented by achieving maternal euglycemia prior to delivery. These hypotheses will be tested by pursuing the following specific aims: 1) Measure the association between late preterm BMZ exposure and fetal metabolic and hormone levels; and 2) Test the effect of screening for and treatment of BMZ-induced maternal hyperglycemia on fetal metabolic and hormone levels. The approach is innovative because it departs from usual care in which non-diabetic women are not screened nor treated for hyperglycemia after treatment with antenatal BMZ. The proposed research is significant because it is expected to advance and expand understanding of the in utero metabolic and hormonal changes associated with antenatal BMZ exposure and test an intervention to prevent these consequences. Ultimately such knowledge has the potential to inform larger, multicenter studies to prevent neonatal hypoglycemia and change clinical practice for treatment of women with threatened late preterm delivery.