What is behind the increasing birthweight in offspring of women with type 1 diabetes?
As maternal glycaemic control has improved in women with type 1 diabetes before and during pregnancy, so too has birthweight and adiposity in their offspring, posing health risks later in life. A new theory was presented in a recent issue of Diabetologia. Dr Susan Aldridge reports.
The incidence of type 1 diabetes is rising all around the world. This suggests that there are increasing numbers of pregnant women with type 1 diabetes – a trend already reported in research from Canada and Scotland. Despite improvement in maternal glycaemic control in recent years, a type 1 pregnancy is still risky. While reduced in frequency, complications such as congenital malformations, pre-eclampsia, pre-term labour and stillbirth are still more prevalent among women with type 1 diabetes than in those without diabetes.
Foetal growth is also affected in pregnancies with type 1 diabetes. Up to the 1970s, overgrowth with signs of excessive fat accumulation was the main finding, although growth restriction was also noted. More recently, a paradoxical trend has been noted – babies born to women with type 1 diabetes increasingly show overgrowth, despite improved maternal glycaemic control. For instance, a continuous increase in the proportion of large-for-gestational-age (LGA) neonates born to women with type 1 diabetes was observed between 1992 and 2013 in Scotland, and between 1982 and 2007 in Sweden.
Meanwhile, the proportion of small-for-gestational-age (SGA) neonates born to women with type 1 diabetes remained stable at around 3-4% up to 2010, followed by a small increase to 6-7% in the last 10 years. In a recent large, multi-centre trial, rates for LGA offspring were 62-65% and SGA offspring 1-2%.
Foetal overgrowth increases the risk of shoulder dystocia, birth trauma and operative delivery. It is often based on birthweight and therefore defined as a foetus being LGA. However, in diabetes, foetal overgrowth tends to mean excessive fat deposition at various anatomical locations. It can occur not only in LGA infants, but in those of normal birthweight.
In the longer term, babies born to a woman with type 1 diabetes are more likely to become obese and have an increased risk of developing type 2 diabetes, cardiovascular disease and other features of the metabolic syndrome. It is likely that an adverse intrauterine environment sets up the foetus for these future problems, so it’s important to avoid foetal overgrowth during pregnancy.
Poor glycaemic control over a long period can lead to microangiopathy, expressed clinically as diabetic retinopathy and diabetic nephropathy. The presence of diabetic nephropathy in pregnancy is associated with a higher prevalence of SGA. Microangiopathy may impair placental development and growth which, in turn, leads to restricted foetal growth.
In a new review, Gernot Desoye of the Medical University of Graz, Austria, and colleagues elsewhere, argue that the increase in LGA neonates in recent years is actually a consequence of the corresponding improvement in glycaemic control in the pre- and periconceptional periods. Their hypothesis is based on the idea that it is now far less common for women to experience severe hyperglycaemia and so adverse processes in early pregnancy around placentation, including microangiopathy of maternal blood vessels, have decreased. Improved placentation leads to unimpeded foetal overnutrition via the still present, but milder, maternal hyperglycaemia.
What determines birthweight?
Birthweight is determined by the interplay between the genetics of the foetus and the supply of nutrients transferred from the mother via the placenta. Successful development of the placenta requires some significant changes in the maternal arteries around the uterus. Restricted growth due to foetal hypoxia may be seen when this remodelling is impaired in type 1 diabetes, particularly when the condition is long-standing and poorly controlled.
However, major advances in diabetes management among women with type 1 diabetes have resulted in pre- and periconceptional mean HbA1c decreasing from ≥ 59 mmol/mol in 1996-1999 to 52 mmol/mol in 2012-2016. Blood pressure control has also improved and smoking rates have decreased. All these changes may have impacted the remodelling of blood vessels, as mentioned above, resulting in improved placentation. This, in turn, improves oxygen delivery to the foetus, reducing the risk of growth restriction.
Measurement of first trimester concentrations of protein biomarkers related to placental size and function supports the idea that improved placentation may be leading to LGA babies in women with type 1 diabetes. Levels are lower in women with diabetes than in those without diabetes, which suggests poor placentation but, with the effect of hyperglycaemia, their babies were born with normal birthweights. And when women with type 1 diabetes had levels of these biomarkers the same as those without diabetes – suggesting a ‘healthy’ placenta – their babies were LGA, reflecting the contributing effect of hyperglycaemia.
Why are there more LGA babies today?
Early events in pregnancy that may impair placentation and foetal oxygenation are not the only factors affecting birthweight in pregnancies of women with type 1 diabetes. Despite improvements in glycaemic control, maternal and foetal glucose levels still tend to be elevated beyond what would be expected in a healthy pregnancy, leading to foetal overnutrition.
Sometimes poor placentation may initially impair foetal growth, but then hyperglycaemia results in the baby being born with normal birthweight. This actually represents a phenotype of overgrowth with excessive fat deposition. It resembles the ‘thin-fat’ phenotype often seen in Asian populations, where babies are born with a ‘normal’ birthweight but with disproportionately high body fat. However, if placentation has been adequate, then later hyperglycaemia, however subtle, may lead to an LGA neonate.
So there is an important distinction between overgrowth in normal and LGA babies. The authors note that the normalising of placentation resulting from improved glycaemic control may have unmasked the potential for overgrowth in the context of a maternal metabolism that is, in itself, still subject to hyperglycaemia because of type 1 diabetes. Here, the impact of foetal overnutrition because of elevated maternal macronutrients – particularly glucose – become obvious, leading to more LGA neonates than previously seen.
Blood glucose in early and later pregnancy
The CONCEPTT trial was a large, multi-centre, randomised controlled trial of continuous glucose monitoring (CGM) in women with type 1 diabetes who had a mean HbA1c level of 52 mmol/mol. The LGA rate was 53% in the women on CGM and 69% in those on routine capillary glucose monitoring. These rates were higher than the 46% reported in the National Pregnancy in Diabetes UK Audit, but the early mean HbA1c was higher, at 60 mmol/mol, than in the CONCEPTT trial.
These studies cannot be compared directly, but they perhaps illustrate the influence of early pregnancy blood glucose levels on birthweight. However, elevated blood glucose levels in the pre-and periconceptional period are not the only key factor. These early levels likely interact with the influence of glucose levels later in pregnancy to ultimately determine birthweight.
Meanwhile, the increase in obesity means that more women with type 1 diabetes enter pregnancy with a BMI that is in the overweight or obese range. This further increases the risk of having a LGA infant. The underlying reasons for this aren’t clear but may involve maternal hyperglycaemia arising from maternal insulin resistance.
Why foetal overgrowth matters
Foetal overgrowth can lead to excessive fat deposition, which can cause long-term harm to offspring. In more than 4800 mother-offspring pairs in the global Hyperglycaemia and Adverse Pregnancy Outcome study, neonatal fat was positively associated with obesity in the offspring at 11 years. Neonatal obesity was therefore the likely mediator between an unfavourable intrauterine environment and childhood obesity. This is important because individuals who have a higher number of adipocytes at the age of two will have a higher number of adipocytes throughout their lifespan. These adipocytes are ‘hungry’ and will fill up with triacylglycerols, which leads to excessive fat deposition and long-term obesity risk. Foetal overgrowth with excessive fat accumulation in pregnancies with type 1 diabetes may therefore lead to similar long-term consequences to the offspring of women who develop gestational diabetes.
Strict glycaemic control is necessary throughout pregnancy to avoid inappropriate foetal growth. Ideally, glucose levels should be as close as possible to normal physiological levels and daily glucose variability should also be taken into account – although the actual glucose level required to maintain foetal growth, without increased adiposity, is currently unknown.
CGM may improve glycaemic control by levelling out glucose fluctuations and perhaps reduce the number of LGA neonates. However, CGM is costly and not universally available – diet and weight management plans are cheaper alternatives. Excessive gestational weight gain in women with and without type 1 diabetes can lead to higher foetal growth, independent of glycaemic control. Therefore, women with type 1 diabetes should be advised about weight management during pregnancy, particularly if they already have overweight or obesity.
The suitability of HbA1c as a pregnancy outcome predictor in type 1 diabetes has already been questioned. Also, there is mounting evidence of the importance of monitoring temporal glucose profiles during pregnancy and spending as much time in range as possible to improve pregnancy outcomes. Continuous glucose monitoring looks promising for achieving these goals, so it’s hoped that healthcare systems will support their use in pregnancy, as has been done in the UK.
As far as research is concerned, exploring the early growth of the foetus and how it is influenced by the maternal environment is an under-explored area. It is known that maternal diet in the pre- and periconceptional periods can influence the early growth of the embryo, foetus and placenta, but the impact of metabolic changes in the mother is less well understood. Therefore, one research priority should be this early pregnancy period and the factors affecting placental growth trajectories.
Also, to date, human studies have focused on the proportion of LGA babies born to women with type 1 diabetes. However, some have normal birthweight, but excessive adiposity. The focus on birthweight does not capture this, but no alternative classification system is currently available. Thus, it could be important to start measuring neonatal body composition, although this might be challenging to include in routine clinical practice. Skinfold thickness could be used as a starting point, although more advanced techniques, such as air displacement plethysmography or dual-energy x-ray absorptiometry, may be preferred where available.
Studies should also include biomarker measurement for placentation and blood-glucose levels throughout pregnancy and how they relate to the outcome of neonatal adiposity.
In conclusion, the authors are suggesting that improved glycaemic control among women with type 1 diabetes has led to improved placentation in early pregnancy. This sets the scene for foetal overgrowth later on, driven by maternal hyperglycaemia. It means that complex interactions of blood glucose levels at different stages of pregnancy determine foetal overgrowth in pregnancies complicated by type 1 diabetes.
Going forward, there needs to be more intensive efforts to bring blood-glucose levels closer to the physiological range during pregnancy, which may be achieved using CGM. More research is needed into the placentation phase and neonatal adiposity, as well as birthweight, should be routinely measured.
To read this paper, go to: Desoye G, Ringholm L, Damm P, Mathiesen ER, Van Poppel MNM. Secular trend for increasing birthweight in offspring of pregnant women with type 1 diabetes: is improved placentation the reason? Diabetologia 66, 33-43 (2023). https://link.springer.com/article/10.1007/s00125-022-05820-4
Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy