MICA: Understanding the glycemic profile of pregnancy: intensive CGM glucose profiling and its relationship to fetal growth.

Lead Research Organisation: University of Leeds
Department Name: School of Medicine


Context of the research:
The UK has one of the highest rates of stillbirth and early infant death in Europe. Abnormal growth of the baby in the womb (a baby that grows too big or too small) has been found to be a major factor leading to this. Many factors affect the way babies grow in the womb, but one of the most important and easiest to modify, is the amount of glucose that they get from their mother. Too much glucose in their mother's blood during pregnancy usually leads to a large baby which increases the chance of serious problems during pregnancy, labour, and immediately after birth. Being born too big, or too small, is also not good for babies' long term health as it markedly increases the chances of becoming obese and getting type 2 diabetes.

Pregnant women are offered a test (called a glucose tolerance test) to look for high glucose levels developing in pregnancy, but it is done late in pregnancy and relies on taking just two blood glucose readings 2 hours apart after taking a sugary drink. Many women already have signs of abnormal growth of the baby by this stage, so it's not a good enough test, but we don't have a better one yet. A mother's blood glucose changes constantly across the 24 hour day, affected by her daily lifestyle and the pregnancy. It is this daily variation in glucose that affects a baby's growth but the current glucose tolerance test does not measure this.

A new way of measuring glucose called 'continuous glucose monitoring' might help. It involves wearing a small sticky patch on the arm (the size of a £1 coin) whilst going about ordinary everyday life. The patch measures glucose levels every few minutes, day and night for up to two weeks, storing this information. It gives more than 4000 glucose readings over this time, which provides far more detail about what is happening with real life 24 hour glucose levels than the current test. However, we do not currently know how 24 hour glucose levels alter from the beginning to the end of a pregnancy, or how changes in 24 hour glucose levels are related to the way babies grow.

Aims and objectives:
To establish how 24 hour glucose levels change across pregnancy and how they relate to the way babies grow and their pregnancy outcomes.

500 healthy pregnant women will be recruited to wear a continuous glucose monitoring patch on five occasions across their pregnancy. On each occasion the participants will have some basic details about themselves recorded and a blood sample taken. They will wear the patch at home while they go about their ordinary everyday activities.

At the end of a fortnight they will simply peel off the patch, put it into a stamped addressed envelope and send it back to the research team, who will download and save the data. The data from the continuous glucose monitoring will be looked at in detail using three different analysis techniques.

At the end of the pregnancy the baby's birthweight will be recorded, as well as information on the results of the glucose tolerance test, measurements of the baby's growth from the ultrasound scans, and any pregnancy complications.

The glucose analysis will show, in detail previously unseen, how glucose changes across pregnancy and how it is related to the baby's growth and pregnancy outcome. It will answer whether continuous glucose monitoring can detect glucose abnormalities related to baby's growth that current tests do not pick up, how common any glucose abnormalities are, when in pregnancy they develop and whether they improve after pregnancy.

Potential applications and benefits:
Addressing this will give important information about how to assess glucose in relation to babies' growth. It is anticipated that this will help to identify and develop new ways in which women can reduce their risk of having abnormally sized babies, to reduce stillbirths, pregnancy complications, and improve the long term health of their children.

Technical Summary

Aim: To characterise longitudinal changes in glycemia across gestation using continuous glucose monitoring (CGM), in order to understand the evolution of dysglycemia and its relationship to fetal growth.

Methods: A multi-centre, prospective, observational, cohort study of 500 healthy pregnant women, recruited in the first trimester of pregnancy. CGM (masked) will be performed for a 14 day period on five occasions across pregnancy at 10-12,18-20,26-28,34-36 weeks gestation and postnatally. Routinely collected anthropometric and sociodemographic information will be recorded at each visit including: weight, height, blood pressure, current medication. Age, parity, ethnicity, smoking will be recorded. Blood samples will be taken at each visit for HbA1c and a sample stored. Details on fetal growth from ultrasound scans and the OGTT results will be recorded. Maternal and neonatal outcomes will be collected. CGM glucose profiling is the exposure of interest, and will be performed using standard summary statistics, functional data analysis and glucotyping. The primary outcome is large for gestational age (LGA) (>90th centile defined by customised birthweight centile) given its established relationship to maternal, neonatal and perinatal morbidity, adolescent obesity and T2DM. The relationship of glucose to key secondary outcomes will be explored.

Outcomes: This will establish: 1) the prevalence of dysglycemia detected by CGM in pregnancy; 2) when it occurs and whether it resolves postnatally; 3) which glucose profiling technique is best at detecting it and how reproducible this is; 4) the relationship of maternal dysglycemia to fetal growth and outcomes in healthy 'normal' women, as well as those who go on to have diagnosis and treatment of GDM; 5) whether CGM glucose profiling can detect GDM before the OGTT; and 6) whether CGM glucose profiling may be more useful than the OGTT or HbA1c at detecting LGA and other perinatal outcomes.

Planned Impact

Who will benefit from this research and how?

Academic community
Researchers in the fields of diabetes, maternal and child health will directly benefit from this research as it addresses how to detect abnormal glucose levels that underlie the development of abnormal fetal growth in pregnant women. Obtaining this information has been highlighted as a priority area for research by the RCOG Maternal Medicine GDM CSG, and the NIH NIDDK is currently in the process of awarding $3.5 million to research groups in the USA to form a clinical and biostatistical consortium in 2020 address this (https://grants.nih.gov/grants/guide/rfa-files/RFA-DK-18-018.html and RFA-DK-18-019.html). Our research involves the application of novel statistical techniques to analyse and interpret CGM data, which will also provide wider academic benefit as it opens up possibilities for further research using these techniques in other relevant disciplines

The UK has one of the highest rates of stillbirth and early infant death in Europe and abnormal fetal growth is recognised to be a major underlying factor. Furthermore infants who are born large or small for gestational age are predisposed to developing obesity and type 2 diabetes (7x increased risk) perpetuating an intergenerational cycle of cardiometabolic disease. More accurate, reproducible and timely identification of dysglycemia associated with aberrant fetal growth in pregnant women is needed. This study will produce novel, detailed information about the glucose profiles that are associated with abnormal fetal growth. Working with clinicians, researchers, NHS and industrial partners these findings will be developed into a randomised controlled clinical trial to establish if interventions based on CGM are more effective at improving maternal, fetal and infant outcomes, than those indicated by conventional tests.

Glucose exposure in the intrauterine environment and abnormal fetal growth has a long lasting impact on the future health of a child leading to an increased risk of them developing obesity, diabetes and cardiovascular disease. This is a major public health concern. Understanding the factors leading to the development of abnormal fetal growth, as outlined in this research proposal, and developing strategies to tackle it, has the potential to reduce obesity, diabetes and cardiovascular disease in subsequent generations. In doing so this will have socio-economic benefit.

NHS stakeholder
The UK has one of the highest rates of stillbirth and early infant death in Europe and abnormal fetal growth is recognised to be a major underlying factor. Furthermore infants who are born large or small for gestational age are predisposed to developing obesity and type 2 diabetes perpetuating an intergenerational cycle of cardiometabolic disease. The NHS spends 10% of its budget on managing type 2 diabetes. The new 10yr NHS Plan (https://www.longtermplan.nhs.uk/wp-content/uploads/2019/01/nhs-long-term-plan.pdf) prioritises safer care in pregnancy; work to prevent obesity/diabetes, and promotes the increased use of CGM technology. More timely identification of dysglycemia and targeted treatment to reduce aberrant fetal growth would reduce perinatal complications and help to rationalise care with a positive impact on finite NHS budgets. Furthermore it has the potential to have a major public health impact to reduce obesity and diabetes in future generations.

Minimally invasive, wearable CGM devices are at the forefront of new therapeutic technologies for managing diabetes. Our research applying intensive glucose profiling to CGM data in relation to clinical outcomes is extremely relevant to the manufacturers of such devices. It has the potential to help tailor these technologies for individualised care and real life clinical benefit. We will pursue the integration of automated glucose profiling into CGM software, working with device manufacturers to develop this.