Metabolomic insights into maternal and neonatal complications in type 1 diabetes pregnancies

Aims: Type 1 diabetes (T1D) in pregnancy is associated with suboptimal pregnancy outcomes, attributed to maternal hyperglycaemia and offspring hyperinsulinism (quantifiable by cord blood C-peptide). We assessed metabolomic patterns associated with risk factors (maternal hyperglycaemia, diet, BMI, weight gain) and perinatal complications (preeclampsia, large-for-gestational-age (LGA), neonatal hypoglycaemia, hyperinsulinism) in the Continuous Glucose Monitoring in women with Type 1 Diabetes in pregnancy trial (CONCEPTT). Methods: 174 CONCEPTT participants gave >1 non-fasting serum sample for the biorepository at 12wks (147 women), 24wks (167 women) and 34wks (160 women) with cord blood on 93 infants. Results from metabolite analysis (ultrahigh performance liquid chromatography – mass spectrometry; Metabolon, Germany) are presented as adjusted logistic/linear regression of maternal and cord blood metabolites, risk factors and perinatal complications using a modified Bonferroni limit of significance for dependent variables. Results: Maternal CGM time-above-range (but not BMI or excessive gestational weight gain) was associated with increased triglycerides in maternal blood and increased carnitines in cord blood. LGA, adiposity, neonatal hypoglycaemia, and offspring hyperinsulinism showed distinct metabolite profiles. LGA was associated with increased carnitines, steroid hormones and lipid metabolites, predominantly in the third trimester. However, neonatal hypoglycaemia and offspring hyperinsulinism were both associated with metabolite changes from the first trimester, featuring triglycerides or dietary phenols. Pre-eclampsia was associated with increased abundance of phosphatidylethanolamines, a membrane phospholipid, at 24wks. Conclusions/ interpretation: Altered lipid metabolism is a key pathophysiological feature of T1D pregnancy. New strategies for optimising maternal diet and insulin dosing from the first trimester are needed to improve pregnancy outcomes in T1D.This project was funded by Diabetes UK (PG 2017/2278). The CONCEPTT trial was funded by Juvenile Diabetes Research Foundation (JDRF) grants #17‐2011‐533, and grants under the JDRF Canadian Clinical Trial Network, a public‐private partnership including JDRF and FedDev Ontario and supported by JDRF #80‐2010‐585. Medtronic supplied the CGM sensors and CGM systems at reduced cost. The study sponsor/funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report. CLM is supported by the Diabetes UK Harry Keen Intermediate Clinical Fellowship (DUK-HKF 17/0005712), a BMA Foundation Award (Helen H Lawson Award) and the European Foundation for the Study of Diabetes – Novo Nordisk Foundation Future Leaders’ Award (NNF19SA058974). HRM conducts independent research supported by the National Institute for Health Research (Career Development Fellowship, CDF-2013-06-035), and is supported by Tommy’s charity. SF and AK acknowledge funding from the BBSRC (BB/M027252/1). DSF conducts independent research supported by the Canadian Institute for Health Research. This research was supported by the NIHR Cambridge BRC, the core biochemical assay laboratory (CBAL) and the core metabolomic and lipidomic laboratory (CMAL). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care