Gestational diabetes: screening for all, which test and which treatment?

Abstract

Gestational diabetes mellitus is rapidly increasing in incidence, due to lifestyle changes, increasing obesity and maternal age. This increase makes universal screening mandatory; however, we are still far from it. Moreover, should we adopt rather strict oral glucose tolerance test cutoff values, resulting in a worldwide incidence of gestational diabetes mellitus of approximately 17.5%, or should we be more liberal and focus more on patients and offspring at increased risk, for example, obese women. Finally, are oral antidiabetic drugs such as glyburide and metformin safe enough to use in gestational diabetes mellitus, or should they still be considered as the ‘poor man’s insulin’? These issues were presented and discussed during lively debates at the Controversies in Obstetrics, Gynecology and Infertility annual meetings, but consensus was not reached.

Keywords::

• gestational diabetes
• oral antidiabetic drugs
• screening

During two recent congresses on Controversies in Obstetrics, Gynecology and Infertility (COGI) in Paris, France (17–20 November 2011) and Bangkok, Thailand (24–27 November 2011), lively debates were held on gestational diabetes mellitus (GDM). GDM is rapidly increasing in incidence mainly because of an increase in maternal obesity and age. This holds especially true for developing countries, where people are much more prone to the development of diabetes given their considerable dietary changes and inability to cope with them. In these traditionally poor diet and high energy expenditure countries, populations may well have been selected for alleles favoring insulin resistance [1]. According to a paper by Hossain et al. in the New England Journal of Medicine[2], diabetes will increase approximately 35% in Europe and 120–160% in most developing countries between 2000 and 2030.

More diabetes, more gestational diabetes

More cases of diabetes implies more cases of gestational diabetes, and that makes universal screening mandatory. However, according to a recent questionnaire in 2011, universal screening has been adopted in only half of the 75 countries that responded, whereby in the latter countries often not much more than 10% of the population was actually screened [3]. In other words, there is still much to gain.

Screening for GDM

Screening for GDM is best carried out between 24 and 28 weeks of gestation using an oral glucose tolerance test (OGTT). The large Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, in which more than 24,000 women in 15 different areas in the world had an OGTT, may well serve as a basis to develop criteria for glucose intolerance [4]. Unfortunately, the HAPO study has shown that there is a gradual linear relationship between fasting, 1 h and 2 h glucose with the incidence of large-for-gestational age (LGA) infants, cesarean sections and cord-C peptide. In other words, there are no clear cutoff values. Based on a 1.75-fold increase in the incidence of LGA infants, new criteria have been proposed, criteria implying that on average 17.5% of the population will be diagnosed as having gestational diabetes [5]. According to the debates during both congresses, not everyone agrees with this theory. Arguments in favor include: global standardization, increase in diabetes and so a corresponding increase in gestational diabetes and treatment in the majority of cases being relatively easy (diet). Arguments against include: poor reproducibility of the OGTT, glucose only being a weak predictor of LGA and obesity a stronger one, GDM only being related to childhood obesity in case of maternal obesity and not in case of GDM only [6], economic factors and medicalization (diagnosis of GDM will result in higher rates of possibly unnecessary interventions). Many of the arguments against have been nicely summarized by Rian [7]. This author also calculated that with OGTT criteria based on a twofold increased risk for LGA – instead of a 1.75-fold increased risk [5]– only 10.5% of pregnant women (not 17.5%) will be diagnosed as having GDM. Moreover, both with the HAPO criteria as with the more liberal criteria, less than 25% of LGA infants will be identified, although these LGA might be those at increased risk for perinatal morbidity. Calculations as to the number of birth injuries prevented by these screening criteria, based on the two randomized controlled trials that show a better outcome in the GDM-treated arms [8,9], are not appropriate since in those trials other screening criteria were used, criteria that most likely identified more severe cases of GDM. For the time being it seemed to us that very strict criteria for diagnosing GDM are still ‘One bridge too far’. The first step should be the implementation of universal screening to identify more severe cases of GDM. This step will already be a major one in most countries. Following this, stricter criteria may be determined, depending, among others, on economical resources: “Tell me how many GDM cases you want and can afford and I will give you the formula’’.

Given the increase in diabetes, there was consensus that more and more pregnant women will have previously undiagnosed Type 2 diabetes. Screening for Type 2 diabetes should preferably take place in the first trimester (or before pregnancy) and might be performed by measuring HbA1c.

The use of oral antidiabetic drugs during pregnancy

A second hot topic was the use of oral antidiabetic drugs in the treatment of GDM or Type 2 diabetes in pregnancy. Two large randomized controlled trials have shown that GDM can be treated with glibenclamide (glyburide) or with metformin [8,9]. The failure rates (additional use of insulin) are approximately 16 and 35%, respectively [10]. Glyburide crosses the placenta in only a low concentration, whereas metformin crosses the placenta freely. This appears to make glyburide the drug of first choice. However, some recent studies have described neonatal hypoglycemia indicative of fetal hyperinsulinemia following glyburide administration, including a study in which more LGA babies were found with higher doses of glyburide. Finally, recent data on a large retrospective cohort from California, USA, of 10,000 women with GDM, of whom 2000 were treated with glyburide, was presented. The use of glyburide was associated with a significantly higher incidence of birth weight >4000 g (odds ratio: 1.29) and a significantly higher incidence of admission to the neonatal intensive care unit (odds ratio: 1.46) [11]. The US FDA has categorized glyburide as class C and most discussants at the meeting thought it should stay in that category.

That leaves metformin to be discussed. Although this drug crosses the placenta, no embryonic or fetal side effects have been reported to date. It has been used widely in polycystic ovary syndrome patients also in the first trimester. Moreover, a follow-up study presented by Rowan at the meeting in Bangkok has shown no adverse effects at 2 years of age [12]. However, metformin appears to be a remarkable drug and its use may be associated with a reduced risk of cancer [13], most likely by killing tumor-initiating stem cells [14], with anti-angiogenetic effects, anti-inflammatory effects, growth inhibitory effects and antioxidative effects [15–17]. That appears to be good for the prevention and/or treatment of cancer, but what about a 9 month exposition to the fetus? In other words, we still do not know enough about possible adverse effects of this drug on the embryo and fetus. Therefore animal and basic human studies seem mandatory. Earlier this year Coetzee, from South Africa, described the oral antidiabetic drugs as the ‘poor man’s insulin’ and that is what they are for the time being [Coetzee EJ, Pers. Comm.]. At the COGI congress, most participants considered oral antidiabetic drugs a serious alternative for insulin, but half of them still considered insulin the drug of first choice.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.