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着根本性的差距。 2016年，一项针对2831例晚期早孕的重要随机临床试验显示，产前 与安慰剂相比，倍他米松(BMZ)显著减少了新生儿呼吸道并发症。然而， 那些在宫内暴露于BMZ的新生儿在出生时更有可能出现低血糖。这是出乎意料的 不良后果引起产科医生和新生儿专家的关注，因为低血糖是一种已知的风险 导致新生儿癫痫发作和神经发育障碍的因素。这一意外的新生儿低血糖后 产前晚期早产类固醇在临床护理方面造成了一个重要的知识缺口，需要填补。我们的 长期目标是减少晚期早产儿发病率。此应用程序的目标是 检测晚期接触BMZ和未接触BMZ的女性脐带血C肽水平 早产期，以及在暴露的人中，实施和测试一项协议，以识别和治疗BMZ诱导的 产妇临产前高血糖。我们的中心假设是：1)与未暴露的胎儿相比， 脐血C肽升高与胎儿高胰岛素血症的关系 2)识别和治疗BMZ后的母体高血糖可降低胎儿胰岛素水平。这个 提出这项研究的理由是，类固醇诱导的母体高血糖会导致胎儿 高胰岛素血症，在此期间出生的新生儿会出现低血糖。因此，胎儿 宫内接触BMZ后出现的高胰岛素血症和新生儿低血糖可以通过以下方法预防 在分娩前实现母体正常血糖。这些假说将通过以下方式进行检验 具体目标：1)测量晚期早产BMZ暴露与胎儿代谢和 激素水平；以及2)检测筛查和治疗BMZ所致母体高血糖的效果 对胎儿新陈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接受BMZ治疗后，不会因高血糖而接受筛查或治疗。这个 拟议的研究具有重要意义，因为它有望促进和扩大对宫内发育的理解 与产前接触BMZ相关的代谢和激素变化并测试预防措施 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 预防新生儿低血糖改变治疗先兆晚期妇女的临床实践 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.