Fetal metabolic consequences of late preterm steroid exposure

摘要 在了解产前晚期早产类固醇的不良代谢影响方面存在根本性的差距。 2016年，一项针对2831例晚期早产的重要随机临床试验显示， 与安慰剂相比，贝替尼（BMZ）显著降低新生儿呼吸系统并发症。然而， 子宫内暴露于BMZ的新生儿在出生时更容易发生低血糖。这个意外的 由于低血糖是一种已知的风险，因此不良结局引起了产科医生和妇产科医生的关注 新生儿癫痫发作和神经发育障碍的因素。这种意外的新生儿低血糖， 产前晚期早产类固醇在临床护理中造成了需要填补的重要知识空白。我们 长期目标是减少晚期早产新生儿发病率。本申请的目的是 测量脐带C-肽水平的妇女暴露和妇女未暴露于BMZ的晚期 早产期，并在那些暴露，实施和测试的协议，以确定和治疗BMZ引起的 分娩前母体高血糖。我们的中心假设是：1）与未暴露的胎儿相比， 产前BMZ与胎儿高胰岛素血症相关，通过脐带C肽升高测量 2）BMZ后母体高血糖的识别和治疗降低了胎儿胰岛素水平。的 这项研究的基本原理是类固醇诱导的母体高血糖导致胎儿 高胰岛素血症，导致在此期间分娩的新生儿低血糖。因此，胎儿 子宫内暴露于BMZ后观察到的高胰岛素血症和新生儿低血糖可通过以下方法预防： 在分娩前达到母体健康。这些假设将通过以下方式进行检验： 具体目标：1）测量晚期早产BMZ暴露与胎儿代谢之间的关联， 激素水平;和2）测试筛查和治疗BMZ诱导的母体高血糖症的效果 对胎儿代谢和激素水平的影响这种方法是创新的，因为它不同于通常的护理， 非糖尿病妇女在产前用BMZ治疗后不进行高血糖症筛查或治疗。的 拟议的研究是重要的，因为它有望推进和扩大对子宫内 与产前BMZ暴露相关的代谢和激素变化，并测试干预措施， 这些后果。最终，这些知识有可能为更大规模的多中心研究提供信息， 预防新生儿低血糖并改变临床实践，以治疗晚期先兆子痫妇女 早产

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.