Treating Maternal Hyperglycaemia in Gestational Diabetes Mellitus Without Addressing Maternal Pre-pregnancy Weight: A Case of “Shooting the Messenger”

Triad of hyperglycaemia, high BMI, and macrosomia

Maternal hyperglycaemia and adverse foetal effects have a linear correlation, as evidenced by the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study.^[9] The HAPO study revealed a linear association between maternal glucose levels and adverse foetal outcomes, even below traditional diagnostic thresholds. While this showed that any level of hyperglycaemia might be suboptimal, the absence of an inflexion point made defining a 'pathological' threshold challenging; hence, a cut-off was decided based on the risk for macrosomia.

As we accept the influence of hyperglycaemia on the birth weight of the baby, evidence strongly supports the influence of maternal pre-pregnancy BMI in increasing the risk of foetal macrosomia. High maternal BMI is an independent risk factor for foetal macrosomia, even in the presence or absence of hyperglycaemia. The other mechanisms involved in macrosomia in women with high BMI are the placental changes, which enhance the supply of amino acids through the altered mTOR pathway, free fatty acids, and triglycerides, even in well-controlled GDM.^[10] Many mothers who don’t have diabetes with high BMI are prone to macrosomic babies.

Foetal epigenetics and impact on future health

A Danish longitudinal study, which compared intrauterine growth with children's growth after birth until 9 years of age in GDM and non-GDM mothers, underscored the strong contribution of maternal pre-pregnancy BMI and excessive gestational weight gain to foetal growth and macrosomia, often overshadowing hyperglycaemia's contribution.^[11,12]

The GDM-treated group had a 30.1% incidence of children with overweight compared to 16.9% of the non-GDM group on follow-up. The growth trajectory during intrauterine life and in childhood was influenced by the maternal BMI more than hyperglycaemia.

This observation prompts us to hypothesise that the altered epigenetics of the foetus exposed to maternal hyperglycaemia in the early stages of pregnancy contributes to the growth of children despite the GDM treatment carried out in the midtrimester. The epigenetic changes due to hyperglycaemia occur much earlier (embryonic stage) than the current practice of mid-trimester screening (24-28 weeks) for GDM.

Observations show that early exposure to maternal hyperglycaemia manifests as elevated foetal insulin and increased abdominal circumference as early as 16 and 19 weeks of pregnancy.^[11,13]

Experimental animal/avian studies also support this view of hyperglycaemic embryopathy, even with a brief exposure of embryos to the hyperglycaemic milieu in the culture medium.^[14,15]

The current screening timing of 24-28 weeks is too late to prevent these fundamental developmental programming effects. It is also of value to note that even screening early at 14 weeks and treating women is not beneficial in improving long-term foetal outcomes.

The RCTs done to assess the effect of treating mild GDM, the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) and Treatment of Gestational Diabetes Mellitus Diagnosed Early in Pregnancy (TOBOGM) trials did show a reduction in other adverse outcomes often associated with macrosomia (e.g., shoulder dystocia), large for gestational age babies, and preeclampsia in the mother. ^[16-18] In these studies, with no difference in severe foetal outcomes, the treated arm had more inductions/Neonatal Intensive Care Unit (NICU) admissions. The TOBOGM trial, which recruited women early in gestation between 4 to 19+6 weeks of gestation and compared the differences between treated and observed arms for mild GDM, showed a modest difference in composite specific foetal outcome (24.9% in the immediate treatment group and 30.5% in the observation group), but no difference in lean body mass or maternal outcomes. The children were not followed beyond preschool age to evaluate the cardiometabolic risks.^[16-18]

The argument is not that GDM is benign but that its treatment at current screening times does not address the primary problem or prevent long-term risks to the offspring, particularly when compared to the profound impact of pre-pregnancy maternal BMI.^[19,20]

Mothers with high-fat mass have elevated insulin due to insulin resistance, which acts as a growth factor leading to more maternal weight gain and hyperglycaemia.^[21,22]

Some mothers who have a normal BMI also develop GDM. If we take a closer look, apart from the genetic predisposition, these women give a history of weight gain, which contributes to their BMI, which has moved from the low to the normal category.^[23]

The ideal approach

The preferred point of intervention to add benefit to the screening program is before pregnancy, by idealising maternal body composition to prevent the development of insulin resistance. The benefit of pre-pregnancy weight loss is evidenced by the recently published trial, where the intervention arm, which lost more weight before pregnancy, had a 10% absolute reduction in GDM compared to the control arm without any difference in the birthweight between the two groups.^[24] The intervention group gained more weight during pregnancy than the control arm. The trial is looking for long-term follow-up of these children to study the impact of weight loss prior to pregnancy on early foetal development and its future cardio-metabolic risks.

Primary prevention through pre-conception weight management

We propose that idealising maternal weight and health before conception is a truly effective strategy. We reiterate that the current screening of GDM at mid-trimester is “secondary prevention” at best, missing early epigenetic changes, and cannot “reverse” GDM completely, or reduce the future risk of developing type 2 diabetes in the mother.

Factors impacting weight loss

Implementing weight loss programs is not without challenges. Initiating and sustaining a behavioural change depends on multiple factors that range from personal motivation, husband's or partner's behaviour, social support, to the mental health of the woman concerned.^[25] The above factors are compounded by the lack of awareness among women about the risks of high maternal BMI on the offspring. Hence, our role is to highlight the risks involved in attempting pregnancy with a high BMI and educate about methods to reduce weight, while respecting their autonomy. On the other hand, we need to continue the current standard of care in women at considerable risk for GDM. Directing our focus on creating robust prospective evidence on the positive impact of pre-pregnancy correction of maternal BMI on the long-term health of children should be our immediate goal.

A couplet called “Thirukkural”, written by poet Thiruvalluvar, says the ideal way to treat a disease is to address its root cause. (couplet 948).^[26]