Insulin for the treatment of women with gestational diabetes

Abstract

Gestational diabetes mellitus (GDM) is associated with short‐ and long‐term complications for the mother and her infant. Women who are unable to maintain their blood glucose concentration within pre‐specified treatment targets with diet and lifestyle interventions will require anti‐diabetic pharmacological therapies. This review explores the safety and effectiveness of insulin compared with oral anti‐diabetic pharmacological therapies, non‐pharmacological interventions and insulin regimens. To evaluate the effects of insulin in treating women with gestational diabetes. We searched Pregnancy and Childbirth's Trials Register (1 May 2017), ClinicalTrials.gov , WHO International Clinical Trials Registry Platform ( ICTRP ) (1 May 2017) and reference lists of retrieved studies. We included randomised controlled trials (including those published in abstract form) comparing: a) insulin with an oral anti‐diabetic pharmacological therapy; b) with a non‐pharmacological intervention; c) different insulin analogues; d) different insulin regimens for treating women with diagnosed with GDM. We excluded quasi‐randomised and trials including women with pre‐existing type 1 or type 2 diabetes. Cross‐over trials were not eligible for inclusion. Two review authors independently assessed study eligibility, risk of bias, and extracted data. Data were checked for accuracy. We included 53 relevant studies (103 publications), reporting data for 7381 women. Forty‐six of these studies reported data for 6435 infants but our analyses were based on fewer number of studies/participants. Overall, the risk of bias was unclear; 40 of the 53 included trials were not blinded. Overall, the quality of the evidence ranged from moderate to very low quality . The primary reasons for downgrading evidence were imprecision, risk of bias and inconsistency. We report the results for our maternal and infant GRADE outcomes for the main comparison. Insulin versus oral anti‐diabetic pharmacological therapy For the mother, insulin was associated with an increased risk for hypertensive disorders of pregnancy (not defined) compared to oral anti‐diabetic pharmacological therapy (risk ratio (RR) 1.89, 95% confidence interval (CI) 1.14 to 3.12; four studies, 1214 women; moderate‐quality evidence). There was no clear evidence of a difference between those who had been treated with insulin and those who had been treated with an oral anti‐diabetic pharmacological therapy for the risk of pre‐eclampsia (RR 1.14, 95% CI 0.86 to 1.52; 10 studies, 2060 women; moderate‐quality evidence ); the risk of birth by caesarean section (RR 1.03, 95% CI 0.93 to 1.14; 17 studies, 1988 women; moderate‐quality evidence ); or the risk of developing type 2 diabetes (metformin only) (RR 1.39, 95% CI 0.80 to 2.44; two studies, 754 women; moderate‐quality evidence ). The risk of undergoing induction of labour for those treated with insulin compared with oral anti‐diabetic pharmacological therapy may possibly be increased, although the evidence was not clear (average RR 1.30, 95% CI 0.96 to 1.75; three studies, 348 women; I² = 32%; moderate‐quality of evidence ). There was no clear evidence of difference in postnatal weight retention between women treated with insulin and those treated with oral anti‐diabetic pharmacological therapy (metformin) at six to eight weeks postpartum (MD ‐1.60 kg, 95% CI ‐6.34 to 3.14; one study, 167 women; low‐quality evidence ) or one year postpartum (MD ‐3.70, 95% CI ‐8.50 to 1.10; one study, 176 women; low‐quality evidence ). The outcomes of perineal trauma/tearing or postnatal depression were not reported in the included studies. For the infant, there was no evidence of a clear difference between those whose mothers had been treated with insulin and those treated with oral anti‐diabetic pharmacological therapies for the risk of being born large‐for‐gestational age (average RR 1.01, 95% CI 0.76 to 1.35; 13 studies, 2352 infants; moderate‐quality evidence ); the risk of perinatal (fetal and neonatal death) mortality (RR 0.85; 95% CI 0.29 to 2.49; 10 studies, 1463 infants; low‐quality evidence );, for the risk of death or serious morbidity composite (RR 1.03, 95% CI 0.84 to 1.26; two studies, 760 infants; moderate‐quality evidence ); the risk of neonatal hypoglycaemia (average RR 1.14, 95% CI 0.85 to 1.52; 24 studies, 3892 infants; low‐quality evidence ); neonatal adiposity at birth (% fat mass) (mean difference (MD) 1.6%, 95% CI ‐3.77 to 0.57; one study, 82 infants; moderate‐quality evidence ); neonatal adiposity at birth (skinfold sum/mm) (MD 0.8 mm, 95% CI ‐2.33 to 0.73; random‐effects; one study, 82 infants; very low‐quality evidence ); or childhood adiposity (total percentage fat mass) (MD 0.5%; 95% CI ‐0.49 to 1.49; one study, 318 children; low‐quality evidence ). Low‐quality evidence also found no clear differences between groups for rates of neurosensory disabilities in later childhood : hearing impairment (RR 0.31, 95% CI 0.01 to 7.49; one study, 93 children), visual impairment (RR 0.31, 95% CI 0.03 to 2.90; one study, 93 children), or any mild developmental delay (RR 1.07, 95% CI 0.33 to 3.44; one study, 93 children). Later infant mortality, and childhood diabetes were not reported as outcomes in the included studies. We also looked at comparisons for regular human insulin versus other insulin analogues, insulin versus diet/standard care, insulin versus exercise and comparisons of insulin regimens, however there was insufficient evidence to determine any differences for many of the key health outcomes. Please refer to the main results for more information about these comparisons. The main comparison in this review is insulin versus oral anti‐diabetic pharmacological therapies. Insulin and oral anti‐diabetic pharmacological therapies have similar effects on key health outcomes. The quality of the evidence ranged from very low to moderate, with downgrading decisions due to imprecision, risk of bias and inconsistency. For the other comparisons of this review (insulin compared with non‐pharmacological interventions, different insulin analogies or different insulin regimens), there is insufficient volume of high‐quality evidence to determine differences for key health outcomes. Long‐term maternal and neonatal outcomes were poorly reported for all comparisons. The evidence suggests that there are minimal harms associated with the effects of treatment with either insulin or oral anti‐diabetic pharmacological therapies. The choice to use one or the other may be down to physician or maternal preference, availability or severity of GDM. Further research is needed to explore optimal insulin regimens. Further research could aim to report data for standardised GDM outcomes. What is the issue? The aim of this Cochrane review was to find out the effectiveness and safety of insulin compared with oral medication or non‐pharmacological interventions for the treatment of gestational diabetes mellitus (GDM, which is diabetes diagnosed in pregnancy). It also looked at different timings for taking insulin during the day. We collected all the relevant studies (May 2017) and analysed the data. Why is this important? GDM can lead to both short‐ and long‐term complications for the mother and her baby. Usually, diet and lifestyle advice is the first step, and women whose blood glucose remains too high may be treated with insulin, which is normally injected every day. Finding out if other treatment options are as safe and effective as insulin, is important, as these other treatments may be preferred by women who do not want to inject themselves with insulin. What evidence did we find? We searched for evidence on 1 May 2017 and found 53 studies reporting data for 7381 mothers and 46 studies reported data for 6435 babies. Overall, the quality of the evidence ranged from very low to moderate. Studies were undertaken in a variety of countries, including low‐, middle‐ and high‐income countries. Three studies reported that financial support or drugs had been provided by a pharmaceutical company and 36 studies did not provide any statement about the source of funding. For mothers with GDM, insulin was associated with an increased likelihood of hypertensive disorders of pregnancy (high blood pressure ‐ not defined) although there was no evidence of any difference in pre‐eclampsia (high blood pressure, swelling and protein in the urine), birth by caesarean section, developing type 2 diabetes, or postnatal weight when women who had been treated with insulin were compared with women who had been treated with oral anti‐diabetic medication. Insulin appeared to possibly increase the likelihood of induction of labour, when compared with oral anti‐diabetic medication but these results are unclear. Damage to the perineum, return to pre‐pregnancy weight or postnatal depression were not reported by the included studies. For the baby, there was no evidence of a clear difference between groups in the risk of being born large‐for‐gestational age, death or serious illness after birth, low blood sugar, being overweight as a baby or as a child, having a hearing or visual impairment, or mild developmental delay at 18 months. None of the included studies looked at the baby’s health in childhood. We also looked at comparisons for regular human insulin versus other insulin types, insulin versus dietary advice with standard care, insulin versus exercise, and we also looked at comparisons of different insulin dosages and frequency. However, there was not enough evidence for us to be certain of any differences for many of the key health outcomes. What does this mean? The available evidence suggests that there are very few differences in short‐term outcomes for the mother and baby between treatment with injected insulin and treatment with oral medication. There is not enough evidence yet for the long‐term outcomes. Decisions about which treatment to use could be based on discussions between the doctor and the mother. Further research is needed to explore optimal insulin regimens for women with GDM. Future studies could aim to report long‐term as well short‐term outcomes for mothers and their babies.