Current View on Gestational Diabetes Mellitus in Theory and Practice

How concrete is our understanding of why GDM occurs?

Fairly concrete, though not all aspects of the disease's pathophysiology are thoroughly explored. GDM development is attributed to the dysfunction of pancreatic beta cells (which are unable to produce adequately in response to increased demand) in the context of pregnancy-induced insulin resistance.

During pregnancy, there is up to a 50% reduction in insulin-stimulated glucose uptake in muscle and fat tissues via the GLUT4 transporter. This is contributed to by the production of various placental hormones (estrogen, progesterone, human placental lactogen), as well as cortisol and leptin, also produced by the placenta. Neurohormonal dysfunction in satiety/hunger centers and energy expenditure and adipose tissue with mobilization of fatty acids in the second and third trimesters of pregnancy, adipocyte hypertrophy, reduced expression of insulin cascade regulators, fatty acid transporters, and transcription factors such as peroxisome proliferator-activated receptor gamma (PPARγ), and an increase in resident macrophages secreting pro-inflammatory cytokines like interleukin 1 and 6 or tumor necrosis factor-alpha also play a role in GDM development.

Changes associated with the onset of GDM can also be identified in the liver, where there's an increase in gluconeogenesis that is inadequately suppressed in the fed state. Recently, the significance of the gut microbiome in GDM development has also been discussed.

Do we have data or at least practical experience on the prevalence of gestational diabetes in the first pregnancy compared to subsequent ones?

GDM affects approximately 15% of pregnant women. According to a meta-analysis from the Mayo Clinic, the risk of its recurrence in a subsequent pregnancy is 47.6%.

How can one transition from insulin treatment to metformin and vice versa?

When intensifying, metformin is added to lifestyle measures (diet and exercise). If target compensation according to profiles is not achieved with these methods, insulin treatment is initiated in various regimens according to individual needs – basal insulin, prandial insulins, or an intensified insulin regimen. Approximately 40% of patients need insulin added to metformin. Treatment with metformin continues as it typically reduces insulin requirements unless there is intolerance or contraindication – specifically in pregnancy, this includes eclampsia, severe gestational hepatopathy, and nephropathy.

Are there data on compliance with treatment when using metformin compared to insulin?

Pregnant women generally have very good compliance. In a 2019 Mexican study, compliance was 90% in the cohort treated with metformin and 71% in the insulin-treated cohort.

How are metformin doses determined? What dose do you usually start with and how do you titrate to maximum doses?

We usually start treatment with a dose of 500 mg once a day (in the evening) and gradually increase the dose up to a maximum of 3 g daily (divided into 2–3 doses daily) or 2 g for the XR form (which is usually better tolerated, hence preferred).

Do you prefer original therapy in pregnant women?

In the case of metformin (due to good tolerance experience), I personally prefer original therapy for most patients, not just pregnant women.

Is it necessary to adjust metformin treatment if cardiovascular complications such as hypertension occur during pregnancy, which may or may not be part of pre-eclampsia?

In the case of simple hypertension, there is no need to adjust the metformin dose. However, if pre-eclampsia occurs, metformin must be discontinued.

How do hypoglycemia risks affect women with gestational diabetes?

Treatment with metformin, unlike insulin, is not associated with the risk of hypoglycemia. Besides the influence on the fetus, the associated risks are generally comparable to the general population of diabetics. The teratogenic effect of hypoglycemia has been demonstrated in animal studies, but there is insufficient data in humans.

Is there any special treatment approach for women with concurrent thyroid disorders and gestational diabetes?

Regarding the selection of antidiabetic medication, no. As in the general population, in pregnant women, the impact of thyroid disease on diabetes compensation or the risk of hypoglycemia must be considered. I would like to mention the excellent initiative of a pilot project for early detection of thyroid disorders in pregnancy, which was developed in collaboration with several professional societies. As part of this, universal screening for thyroid testing in pregnancy should be launched from January 2024.

Which treatment strategies for gestational diabetes have not proven successful and why?

There are data on the administration of sulfonylurea derivatives – mainly glibenclamide (glyburide) – in GDM. However, compared to insulin, this treatment was associated with a higher risk of higher birth weight, macrosomia, and neonatal hypoglycemia, hence it is not recommended for GDM treatment in the Czech Republic. Other antidiabetics either have a proven teratogenic effect (e.g., GLP-1 receptor analogs) or there is insufficient data on their use in pregnancy, making them contraindicated during pregnancy.

If women with gestational diabetes, who used metformin, continue to have elevated glucose levels in a control examination six months after birth, how is treatment continued during lactation and after it ends?

In this case, it was not (according to the definition) GDM, but another type of diabetes mellitus that manifested during pregnancy. Therefore, standard differential diagnosis of the disease is necessary and treatment should be initiated according to the diagnosed type of disease.

Kristýna Poulová
Editorial Team proLékaře.cz