Maternal diabetes in pregnancy increases the risk of pregnancy complications, including stillbirth, pre-eclampsia and pathological fetal growth, where as many as 50% of infants can be born large-for-gestational age (LGA).1–3 Pregnancies with infants that are LGA can result in preterm birth, shoulder dystocia and stillbirth, as well as an increased risk of developing cardiometabolic complications later in life.2
‘Adverse pregnancy outcomes, particularly increased rates of perinatal mortality and pathological fetal growth, are also a concern in type 2 diabetes, which is increasing in prevalence.’
Whilst much of the literature to date has focused on management of these conditions in women with gestational diabetes (GDM) or type 1 diabetes, a recent systematic review highlights that adverse pregnancy outcomes, particularly increased rates of perinatal mortality and pathological fetal growth, are also a concern in type 2 diabetes, which is increasing in prevalence.1 Measures to predict at-risk pregnancies and to reduce adverse outcomes in pregnancies complicated by maternal diabetes are paramount.4,5
USE OF DIABETES TECHNOLOGIES TO PREDICT AND IMPROVE OUTCOMES
Continuous glucose monitoring (CGM) technology, which provides detailed information on glycaemic control over the 24-hour day,2 can improve pregnancy outcomes6,7 and detect temporal changes in glucose profiles associated with LGA in pregnancies complicated by type 1 diabetes and GDM.2,8,9 This has proved particularly important in type 1 diabetes, where these findings have led to new clinical guidelines recommending that CGM is offered to all women with type 1 diabetes in pregnancy, to improve glycaemic control and reduce neonatal complications.10,11
More recently, another advancement in diabetes technology has led to further recommendations aimed at improving outcomes in pregnancies complicated by type 1 diabetes. The AiDAPT (Automated Insulin Delivery in Women with Pregnancy Complicated by Type 1 Diabetes) trial assessed ‘pregnancy-specific’ hybrid closed-loop therapy, which utilises real-time CGM measurements to automatically adjust insulin delivery from an insulin pump. It was found to improve maternal glycaemic control, including an increase in time spent within the pregnancy glucose target range, and a reduction in time in a hyperglycaemic state, without increasing periods of hypoglycaemia.12 This was associated with lower rates of LGA, reduced maternal weight gain and reduced burden for mothers. It has now been incorporated into NICE guidance and is being implemented nationally.13,14
‘Other alternative or complementary diagnostic and therapeutic strategies for improving outcomes in pregnancies complicated by maternal diabetes should also be considered.’
It is clear that diabetes technologies are important for both prediction and prevention of adverse outcomes in type 1 diabetes. However, this technology’s potential in other types of diabetes in pregnancy needs to be determined, particularly in GDM, where screening is currently only offered to women with risk factors, at 24–28 weeks of gestation. Ongoing clinical trials are currently being conducted to determine if early-pregnancy CGM metrics can be used to predict adverse outcomes in pregnancies at risk of GDM and in those complicated by type 2 diabetes in the MAGiC15 and PROTECT16 studies respectively. The results of these studies will provide important data to inform the management of GDM and type 2 diabetes.
In parallel, other alternative or complementary diagnostic and therapeutic strategies for improving outcomes in pregnancies complicated by maternal diabetes should also be considered. Recent advances in understanding the molecular mechanisms linking a diabetic maternal environment to fetal growth may aid in this.
MECHANISMS LINKING HYPERGLYCAEMIA TO ADVERSE PREGNANCY OUTCOMES
The placenta is essential for normal fetal growth. In pregnancies complicated by maternal diabetes, there are several alterations that occur, including changes to the placental vasculature, growth and ability to transfer nutrients, including glucose, to the fetus.17
Studies have investigated the impact of glucose on the placenta, but often these studies have utilised supraphysiological glucose concentrations. We have shown that subtle fluctuations in maternal glucose, that mimic in vivo levels detected by CGM in pregnancies complicated by GDM and LGA, directly impact the placental transcriptome (unpublished observations). Functional enrichment analysis suggests that these transcriptomic changes may affect placental lipid metabolism and vascular development, which may explain why subtle fluctuations in glucose impact fetal growth and other adverse outcomes, although further work is required to confirm this.
In addition to direct effects of glucose, it is also important to understand the impact of other components of a diabetic environment on the placenta. These include extracellular vesicles (EVs), small lipid-bound vesicles released by cells and tissues, which have been shown to change in both concentration and microRNA content in the maternal circulation in pregnancies complicated by gestational diabetes.17,18
‘Molecular studies are beginning to improve our understanding of the events linking a diabetic environment to altered fetal growth through actions on the placenta.’
Recently, work in our team has established that specific microRNAs contained within EVs are altered in pregnancies with GDM, prior to the onset of LGA.19 Thus, they may have the potential to serve as biomarkers for the prediction of adverse outcomes. Additionally, EVs have been shown to traffic to and enter distal tissues, including the placenta, where they influence events by delivering their functionally active cargo.17,20 Many microRNAs are altered in the placenta in GDM.17
The focus of our current work is examining whether these changes could be attributed to EV delivery of microRNAs from the maternal circulation, and if maternally derived EVs and their microRNA cargo contribute to LGA by impacting placental function.
IN SUMMARY
Maternal diabetes increases the risk of complications for both the mother and the fetus. We have described how advancements in diabetes technology have led to improvements in maternal glycaemic control and perinatal outcomes, particularly in pregnancies complicated by type 1 diabetes. However, with rates of diabetes in pregnancy rising, there is a clear need to develop further complementary therapeutic strategies. Molecular studies are beginning to improve our understanding of the events linking a diabetic environment to altered fetal growth through actions on the placenta. Exploiting these findings may lead to further improvements in pregnancy outcomes and the long term health of infants exposed to diabetes in utero.
ABIGAIL R BYFORD, ELEANOR M SCOTT AND KAREN FORBES
University of Leeds
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