Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition during pregnancy. It is a common pregnancy complication and, according to the International Diabetes Federation (IDF), it affects approximately 16.7% of pregnancies worldwide and 15% in Europe, with an increasing prevalence over recent decades due to advanced maternal age and maternal obesity(1). GDM generally develops in the second or third trimester of pregnancy, as a consequence of adaptive metabolic changes, overlapping a previously unknown pancreatic b-cell dysfunction(2).
During a healthy pregnancy, several physiological changes occur in order to support the demands of the growing fetus. These include adaptations to the cardiovascular, renal, respiratory, hematologic and metabolic systems. One important metabolic adaptation concerns the insulin sensitivity. In early pregnancy, insulinemia and insulin sensitivity are increased, corresponding to an anabolic phase necessary for the development of the embryo. During the second and third trimesters of gestation, a state of insulin resistance is induced by placental hormones (placental lactogen, placental growth hormone, estrogen, progesterone), leptin, cortisol and growth hormone. As a result, maternal blood glucose is elevated and thus facilitates its transport across the placenta, supporting the rapid growth of the fetus. In order to maintain normal blood glucose levels, animal studies have shown that healthy pregnant women compensate through hypertrophy and hyperplasia of pancreatic b-cells, as well as by increased glucose-stimulated insulin secretion (GSIS). In women who develop GDM, pancreatic b-cells fail to keep up with the increased insulin demand, resulting in hyperglycemia(3).
The major risk factors for GDM include overweight/obesity (BMI>25 kg/m2), advanced maternal age (above 35 years old), family history of insulin resistance and/or diabetes, previous history of gestational diabetes and macrosomia, and the presence of polycystic ovary syndrome (PCOS)(4).
Screening and diagnosis
Many European countries, including Romania, use selective screening (based on risk factors) as a tool for the detection of gestational diabetes mellitus. Because the incidence of type 2 DM is high in our country, all pregnant women are screened for overt type 2 DM at their first prenatal visit, using the fasting plasma glucose threshold of 126 mg/dl for diagnosis. Women at risk and without overt diabetes have 75 g OGTT at 24-28 weeks. The positive diagnostic consists of at least one of the following criteria: fasting plasma glucose ≥92 mg/dl; 1h≥180 mg/dl; 2h≥153 mg/dl(5,6).
Hyperglycemia is associated with serious maternal and fetal complications. Women with GDM are at high risk of gestational hypertension, preeclampsia and caesarean section. The long-term consequences are: an increased risk of developing type 2 diabetes, future cardiovascular disease and recurrent gestational diabetes mellitus(2). The most common fetal/neonatal complications include macrosomia, polyhydramnios, shoulder dystocia, preterm birth, neonatal hypoglycemia, respiratory distress and perinatal death. Intrauterine exposure to GDM also has a long-term impact on offspring health – studies have demonstrated reduced insulin sensitivity and an increased risk of type 2 diabetes, metabolic syndrome, hypertension in adolescence and overweight/obesity compared with the general population(7).
The management of patients with gestational diabetes mellitus involves a multidisciplinary team of obstetricians, maternal-fetal medicine specialists and diabetes specialists with experience in treating pregnant women. The main goal is glycemic control in order to diminish the risk of the associated adverse pregnancy outcomes. International guidelines recommendations on glycemic targets are fasting level ≤95 mg/dl and either 1-hour postprandial ≤140 mg/dl or 2-hour postprandial ≤120 mg/dl(8). Lifestyle intervention, comprising dietary modification, physical activity and weight control, is essential in the management of GDM. If good glycemic control is not achieved, then the pharmacologic treatment should be considered. Historically, insulin has been the preferred medication for treating GDM refractory to lifestyle changes and it continues to be the first-choice agent recommended by the American Diabetes Association (ADA). Over the last decades, there has been a great interest in whether oral antidiabetics (metformin, glyburide) could be used safely and effectively in women with GDM to avoid the need for insulin injections. Several studies have demonstrated that metformin is noninferior to insulin for pregnancy outcomes, and many international guidelines recommend it as an alternative to insulin, but long-term safety data are insufficient(9).
Metformin is a biguanide – an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. It inhibits hepatic gluconeogenesis and intestinal glucose absorption and improves insulin sensitivity by increasing peripheral glucose uptake and utilization(10).
Metformin is the first-line medication for the treatment of type 2 diabetes, and the most commonly prescribed drug for this condition worldwide. Compared to insulin, its risk for hypoglycemia is low, it is not associated with weight gain, it is easy to administer and it’s cheaper. The most common adverse effect is related to the digestive system, including diarrhea, nausea, vomiting and increased flatulence. It is not recommended for use in renal or hepatic impairment due to concern for accumulation leading to lactic acidosis, which is a rare complication(10,11).
The renal clearance of metformin is significantly increased in the second and third trimesters of gestation, as a consequence of increased renal plasma flow and glomerular filtration during pregnancy. Therefore, patients may require higher doses for adequate glycemic control(12). Moreover, it is excreted into breast milk but the amount is clinically insignificant and studies have shown no effect on glycemic values of infants after breastfeeding(13).
Unlike insulin, which needs an insulin-antibody complex to cross the placental barrier, metformin can freely traverse the placenta, with levels in fetal circulation similar to the maternal ones(14). Due to the potential for acidosis or growth restriction, ADA cautions that metformin should not be used in women with placental insufficiency, hypertension, preeclampsia or at risk for intrauterine growth restriction(15). Nonetheless, due to the maternal safety profile, as well as its low cost and good compliance among patients, the use of metformin in GDM is increasing.
Interest in the role of metformin in GDM gained ground with the Metformin in Gestational Diabetes (MiG) trial published in 2008. MiG trial compared metformin versus insulin in 751 women diagnosed with GDM between 20 and 33 weeks of gestation. There was no difference between the two groups regarding neonatal complications, including respiratory distress, need for phototherapy, birth trauma, low Apgar score or prematurity. The incidence of neonatal hypoglycemia and maternal weight gain was significantly lower with metformin. However, the incidence of preterm births (<37 weeks of gestation) was higher in the metformin group. In a questionnaire, a significantly large number of women responded that they would opt for metformin again (76%) than insulin (27%), suggesting greater patient acceptability(16).
Effects on maternal outcomes
Most trials do not report an increase in adverse maternal outcomes for GDM patients treated with metformin compared to insulin. According to several recent meta-analyses, metformin is rather beneficial because it is associated with lower maternal weight gain and with a lower risk of pregnancy-induced hypertension(17-19). There is evidence that metformin is also associated with a reduced risk of preeclampsia(20,21). Although glycemic control is comparable to insulin or glyburide, metformin has some additional advantages, including a lower risk of maternal hypoglycemia, a lower cost of therapy and less need for intensive self-monitoring blood glucose levels. Moreover, in contradiction to some old studies(22), recent meta-analyses did not demonstrate any increase in rates of preterm deliveries in women with gestational diabetes mellitus or type 2 diabetes who are using metformin(19,23).
Effects on fetal outcomes
The effect of metformin on short-term fetal outcomes has been largely favorable. It was associated with lower incidence of macrosomia and LGA babies (large for gestational age) and with a low risk of neonatal hypoglycemia, including severe neonatal hypoglycemia(19,23). In addition, the rate of neonatal intensive care unit admissions appears to be lower for metformin than insulin(24).
Information on long-term outcomes for offspring exposed to metformin is still limited. The MiG TOFU trial (The Metformin in Gestational Diabetes: The Offspring Follow-Up) showed that the 2-year-old offspring from mothers treated with metformin had larger measures of subcutaneous fat (subscapular, biceps skinfolds), but the overall body fat was the same as in children whose mothers were treated with insulin alone(25). Also, the 9-year-old infants exposed to metformin were heavier and had a higher waist-to-height ratio and waist circumference than those exposed to insulin. Total and abdominal body fat percentage and metabolic measures (fasting glucose, triglyceride, insulin, insulin resistance, HbA1c, cholesterol, liver transaminases, leptin and adiponectin) were similar in both groups(26). Regarding the neurophysiological development, currently available data showed no difference in motor, social or linguistic development for children prenatally exposed to metformin compared to insulin(27).
Metformin is not currently approved by the American Food and Drug Administration (FDA) for the management of diabetes in pregnancy and it is placed in category B of safety, which means that animal reproduction studies did not demonstrate any risk to the fetus, but there is a lack of well-documented studies on pregnant women. Metformin remains the second-line pharmacotherapy choice for many international medical associations, such as the International Diabetes Federation (IDF), the American College of Obstetricians and Gynecologists (ACOG), the American Diabetes Association (ADA) and the International Federation of Gynecology and Obstetrics (FIGO)(28).
Conversely, the British National Institute for Health and Care Excellence (NICE) recommends metformin as first-line therapy for women whose blood glucose levels do not stabilize after 1-2 weeks of diet and exercise. Insulin is recommended only in cases where metformin is contraindicated or unacceptable to the patient(29). Also, the Society for Maternal-Fetal Medicine (SMFM) states that metformin is a reasonable and safe first-line pharmacologic alternative to insulin, recognizing that one-half of women will still require insulin to achieve glycemic control(30).
All these considered, metformin is an effective and well-tolerated glucose-lowering agent with a well-defined mechanism of action. It remains a reliable first-line treatment for type 2 diabetes in most patients. Current animal and human data indicate that metformin is safe and effective in the management of GDM and may improve the immediate pregnancy outcomes. It reduces maternal weight gain during pregnancy and the risk of pregnancy-induced hypertension. In infants, it reduces the incidence of severe hypoglycemia and the incidence of macrosomia. There is no evidence of an increased risk of congenital fetal anomalies when using metformin.
Moreover, some medical associations consider metformin safe and effective as first-line medication in gestational diabetes mellitus when the diet regimen is insufficient, but due to the lack of long-term safety data related to fetal exposure, most of them restrict its use to those cases in which there is no possibility of insulin treatment.
Conflict of interests: The authors declare no conflict of interests.