What is the issue?
Globally the number of women being diagnosed with gestational diabetes mellitus (GDM) is increasing. GDM is an intolerance to glucose leading to high blood sugars, first recognised during pregnancy and usually resolving after birth. Standard care involves lifestyle advice on diet and exercise. Treatment for some women includes oral anti-diabetic medications, such as metformin and glibenclamide, which are an alternative to, or can be used alongside, insulin to control the blood sugar. This review aimed to investigate benefits of taking oral medication to treat GDM in pregnant women. Another Cochrane Review compares the effects of insulin with oral anti-diabetic pharmacological therapies ( Brown 2016).
Why is this important?
Women diagnosed with GDM are at a greater risk of experiencing complications such as high blood pressure during pregnancy and at birth. They have an increased risk of developing diabetes later in life. The babies of women who have been diagnosed with GDM can be larger than normal and this can cause injuries to the mother and the baby at birth. The birth is more likely to be induced or the baby born by caesarean section. These babies are at risk of developing diabetes as children or young adults. Finding the best medications to treat the women and prevent the complications that are linked to GDM is therefore important.
What evidence did we find?
We searched for studies on 14 May 2016. We included 11 randomised controlled trials involving 1487 mothers and their babies (but only eight trials contributed data to our analyses). The evidence was limited by the quality and number of studies and we advise caution when looking at the results.
The criteria for diagnosis of GDM and treatment targets varied between studies, and each outcome is based on few studies with low numbers of women. Three studies compared oral medication with placebo/standard care but the following findings are from a single study (375 women). The quality of the evidence was very low or low. We found no differences between the oral medication and placebo group for the risk of high blood pressure, birth by caesarean section, induction of labour or perineal trauma. The number of babies born large-for-gestational age, with low blood sugars or dying at birth was not clearly different between the groups. Two studies (434 women) reported no difference in the need for insulin between the oral medication and placebo group.
Six studies compared metformin with glibenclamide. The quality of the evidence was very low to moderate. We found no difference between metformin and glibenclamide for the risk of high blood pressure (three studies, 508 women, moderate-quality evidence), birth by caesarean section (four studies, 554 women, low-quality evidence), perineal trauma (two studies, 308 women, low-quality evidence) or induction of labour (one study, 159 women, low-quality evidence). We found no difference between metformin and glibenclamide for the baby having low blood sugars (four studies, 554 infants, low-quality evidence), being born large-for-gestational age (two studies, 246 infants) or dying at birth (all low- or very low-quality evidence). In one study, the babies of the mothers taking metformin were at reduced risk of having any serious outcome (low blood sugar, jaundice, being born large, breathing problems, injury at birth or death combined) (low-quality evidence). One small study (43 women) comparing glibenclamide with acarbose reported no differences in outcomes for mothers or their babies.
None of the included studies provided any data on many of the outcomes pre-specified in this review, including long-term outcomes for the mother or for the baby as a child or an adult.
What does this mean?
There is not enough high-quality evidence available to guide us on if oral medication has better outcomes for women with gestational diabetes, and their babies, compared with a placebo or if one oral medication has better health outcomes than another oral medication. Because we are still unclear, further research is needed. Future studies should be encouraged to report on the outcomes suggested in this review and in particular the long-term outcomes for the woman and the infant that have been poorly reported to date.
There were insufficient data comparing oral anti-diabetic pharmacological therapies with placebo/standard care (lifestyle advice) to inform clinical practice. There was insufficient high-quality evidence to be able to draw any meaningful conclusions as to the benefits of one oral anti-diabetic pharmacological therapy over another due to limited reporting of data for the primary and secondary outcomes in this review. Short- and long-term clinical outcomes for this review were inadequately reported or not reported. Current choice of oral anti-diabetic pharmacological therapy appears to be based on clinical preference, availability and national clinical practice guidelines.
The benefits and potential harms of one oral anti-diabetic pharmacological therapy compared with another, or compared with placebo/standard care remains unclear and requires further research. Future trials should attempt to report on the core outcomes suggested in this review, in particular long-term outcomes for the woman and the infant that have been poorly reported to date, women's experiences and cost benefit.
Gestational diabetes mellitus (GDM) is a major public health issue with rates increasing globally. Gestational diabetes, glucose intolerance first recognised during pregnancy, usually resolves after birth and is associated with short- and long-term complications for the mother and her infant. Treatment options can include oral anti-diabetic pharmacological therapies.
To evaluate the effects of oral anti-diabetic pharmacological therapies for treating women with GDM.
We searched Cochrane Pregnancy and Childbirth's Trials Register (14 May 2016), ClinicalTrials.gov, WHO ICTRP (14 May 2016) and reference lists of retrieved studies.
We included published and unpublished randomised controlled trials assessing the effects of oral anti-diabetic pharmacological therapies for treating pregnant women with GDM. We included studies comparing oral anti-diabetic pharmacological therapies with 1) placebo/standard care, 2) another oral anti-diabetic pharmacological therapy, 3) combined oral anti-diabetic pharmacological therapies. Trials using insulin as the comparator were excluded as they are the subject of a separate Cochrane systematic review.
Women with pre-existing type 1 or type 2 diabetes were excluded.
Two review authors independently assessed trials for inclusion and trial quality. Two review authors independently extracted data and data were checked for accuracy.
We included 11 studies (19 publications) (1487 women and their babies). Eight studies had data that could be included in meta-analyses. Studies were conducted in Brazil, India, Israel, UK, South Africa and USA. The studies varied in diagnostic criteria and treatment targets for glycaemic control for GDM. The overall risk of bias was 'unclear' due to inadequate reporting of methodology. Using GRADE the quality of the evidence ranged from moderate to very low quality. Evidence was downgraded for risk of bias (reporting bias, lack of blinding), inconsistency, indirectness, imprecision and for oral anti-diabetic therapy versus placebo for generalisability.
Oral anti-diabetic pharmacological therapies versus placebo/standard care
There was no evidence of a difference between glibenclamide and placebo groups for hypertensive disorders of pregnancy (risk ratio (RR) 1.24, 95% confidence interval (CI) 0.81 to 1.90; one study, 375 women, very low-quality evidence), birth by caesarean section (RR 1.03, 95% CI 0.79 to 1.34; one study, 375 women, very low-quality evidence), perineal trauma (RR 0.98, 95% CI 0.06 to 15.62; one study, 375 women, very low-quality evidence) or induction of labour (RR 1.18, 95% CI 0.79 to 1.76; one study, 375 women; very low-quality evidence). No data were reported for development of type 2 diabetes or other pre-specified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant, there was no evidence of a difference in the risk of being born large-for-gestational age (LGA) between infants whose mothers had been treated with glibenclamide and those in the placebo group (RR 0.89, 95% CI 0.51 to 1.58; one study, 375, low-quality evidence). No data were reported for other infant primary or GRADE outcomes (perinatal mortality, death or serious morbidity composite, neurosensory disability in later childhood, neonatal hypoglycaemia, adiposity, diabetes).
Metformin versus glibenclamide
There was no evidence of a difference between metformin- and glibenclamide-treated groups for the risk of hypertensive disorders of pregnancy (RR 0.70, 95% CI 0.38 to 1.30; three studies, 508 women, moderate-quality evidence), birth by caesarean section (average RR 1.20, 95% CI 1.20; 95% CI 0.83 to 1.72, four studies, 554 women, I2 = 61%, Tau2 = 0.07 low-quality evidence), induction of labour (0.81, 95% CI 0.61 to 1.07; one study, 159 women; low-quality evidence) or perineal trauma (RR 1.67, 95% CI 0.22 to 12.52; two studies, 158 women; low-quality evidence). No data were reported for development of type 2 diabetes or other pre-specified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant there was no evidence of a difference between the metformin- and glibenclamide-exposed groups for the risk of being born LGA (average RR 0.67, 95% CI 0.24 to 1.83; two studies, 246 infants, I2 = 54%, Tau2 = 0.30 low-quality evidence). Metformin was associated with a decrease in a death or serious morbidity composite (RR 0.54, 95% CI 0.31 to 0.94; one study, 159 infants, low-quality evidence). There was no clear difference between groups for neonatal hypoglycaemia (RR 0.86, 95% CI 0.42 to 1.77; four studies, 554 infants, low-quality evidence) or perinatal mortality (RR 0.92, 95% CI 0.06 to 14.55, two studies, 359 infants). No data were reported for neurosensory disability in later childhood or for adiposity or diabetes.
Glibenclamide versus acarbose
There was no evidence of a difference between glibenclamide and acarbose from one study (43 women) for any of their maternal or infant primary outcomes (caesarean section, RR 0.95, 95% CI 0.53 to 1.70; low-quality evidence; perinatal mortality - no events; low-quality evidence; LGA , RR 2.38, 95% CI 0.54 to 10.46; low-quality evidence). There was no evidence of a difference between glibenclamide and acarbose for neonatal hypoglycaemia (RR 6.33, 95% CI 0.87 to 46.32; low-quality evidence). There were no data reported for other pre-specified GRADE or primary maternal outcomes (hypertensive disorders of pregnancy, development of type 2 diabetes, perineal trauma, return to pre-pregnancy weight, postnatal depression, induction of labour) or neonatal outcomes (death or serious morbidity composite, adiposity or diabetes).