Sinéad M O'Neill1, Louise C Kenny1, Ali S Khashan1,2, Helen M West3, Rebecca Md Smyth4, Patricia M Kearney2. 1. Irish Centre for Fetal and Neonatal Translational Research (INFANT), University College Cork, 5th Floor, Cork University Maternity Hospital, Wilton, Cork, Munster, Ireland. 2. Department of Epidemiology and Public Health, University College Cork, Cork, Ireland. 3. Institute of Psychology, Health and Society, The University of Liverpool, Liverpool, UK. 4. School of Nursing, Midwifery and Social Work, The University of Manchester, Jean McFarlane Building, Oxford Road, Manchester, UK, M13 9PL.
Abstract
BACKGROUND: Insulin requirements may change during pregnancy, and the optimal treatment for pre-existing diabetes is unclear. There are several insulin regimens (e.g. via syringe, pen) and types of insulin (e.g. fast-acting insulin, human insulin). OBJECTIVES: To assess the effects of different insulin types and different insulin regimens in pregnant women with pre-existing type 1 or type 2 diabetes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 October 2016), ClinicalTrials.gov (17 October 2016), the WHO International Clinical Trials Registry Platform (ICTRP; 17 October 2016), and the reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared different insulin types and regimens in pregnant women with pre-existing diabetes.We had planned to include cluster-RCTs, but none were identified. We excluded quasi-randomised controlled trials and cross-over trials. We included studies published in abstract form and contacted the authors for further details when applicable. Conference abstracts were superseded by full publications. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, conducted data extraction, assessed risk of bias, and checked for accuracy. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: The findings in this review were based on very low-quality evidence, from single, small sample sized trial estimates, with wide confidence intervals (CI), some of which crossed the line of no effect; many of the prespecified outcomes were not reported. Therefore, they should be interpreted with caution. We included five trials that included 554 women and babies (four open-label, multi-centre, two-arm trials; one single centre, four-arm RCT). All five trials were at a high or unclear risk of bias due to lack of blinding, unclear methods of randomisation, and selective reporting of outcomes. Pooling of data from the trials was not possible, as each trial looked at a different comparison.1. One trial (N = 33 women) compared Lispro insulin with regular insulin and provided very low-quality evidence for the outcomes. There were seven episodes of pre-eclampsia in the Lispro group and nine in the regular insulin group, with no clear difference between the two groups (risk ratio (RR) 0.68, 95% CI 0.35 to 1.30). There were five caesarean sections in the Lispro group and nine in the regular insulin group, with no clear difference between the two groups (RR 0.59, 95% CI 0.25 to 1.39). There were no cases of fetal anomaly in the Lispro group and one in the regular insulin group, with no clear difference between the groups (RR 0.35, 95% CI 0.02 to 8.08). Macrosomia, perinatal deaths, episodes of birth trauma including shoulder dystocia, nerve palsy, and fracture, and the composite outcome measure of neonatal morbidity were not reported.2. One trial (N = 42 women) compared human insulin to animal insulin, and provided very low-quality evidence for the outcomes. There were no cases of macrosomia in the human insulin group and two in the animal insulin group, with no clear difference between the groups (RR 0.22, 95% CI 0.01 to 4.30). Perinatal death, pre-eclampsia, caesarean section, fetal anomaly, birth trauma including shoulder dystocia, nerve palsy and fracture and the composite outcome measure of neonatal morbidity were not reported.3. One trial (N = 93 women) compared pre-mixed insulin (70 NPH/30 REG) to self-mixed, split-dose insulin and provided very low-quality evidence to support the outcomes. Two cases of macrosomia were reported in the pre-mixed insulin group and four in the self-mixed insulin group, with no clear difference between the two groups (RR 0.49, 95% CI 0.09 to 2.54). There were seven cases of caesarean section (for cephalo-pelvic disproportion) in the pre-mixed insulin group and 12 in the self-mixed insulin group, with no clear difference between groups (RR 0.57, 95% CI 0.25 to 1.32). Perinatal death, pre-eclampsia, fetal anomaly, birth trauma including shoulder dystocia, nerve palsy, or fracture and the composite outcome measure of neonatal morbidity were not reported.4. In the same trial (N = 93 women), insulin injected with a Novolin pen was compared to insulin injected with a conventional needle (syringe), which provided very low-quality evidence to support the outcomes. There was one case of macrosomia in the pen group and five in the needle group, with no clear difference between the different insulin regimens (RR 0.21, 95% CI 0.03 to 1.76). There were five deliveries by caesarean section in the pen group compared with 14 in the needle group; women were less likely to deliver via caesarean section when insulin was injected with a pen compared to a conventional needle (RR 0.38, 95% CI 0.15 to 0.97). Perinatal death, pre-eclampsia, fetal anomaly, birth trauma including shoulder dystocia, nerve palsy, or fracture, and the composite outcome measure of neonatal morbidity were not reported.5. One trial (N = 223 women) comparing insulin Aspart with human insulin reported none of the review's primary outcomes: macrosomia, perinatal death, pre-eclampsia, caesarean section, fetal anomaly, birth trauma including shoulder dystocia. nerve palsy, or fracture, or the composite outcome measure of neonatal morbidity.6. One trial (N = 162 women) compared insulin Detemir with NPH insulin, and supported the outcomes with very low-quality evidence. There were three cases of major fetal anomalies in the insulin Detemir group and one in the NPH insulin group, with no clear difference between the groups (RR 3.15, 95% CI 0.33 to 29.67). Macrosomia, perinatal death, pre-eclampsia, caesarean section, birth trauma including shoulder dystocia, nerve palsy, or fracture and the composite outcome of neonatal morbidity were not reported. AUTHORS' CONCLUSIONS: With limited evidence and no meta-analyses, as each trial looked at a different comparison, no firm conclusions could be made about different insulin types and regimens in pregnant women with pre-existing type 1 or 2 diabetes. Further research is warranted to determine who has an increased risk of adverse pregnancy outcome. This would include larger trials, incorporating adequate randomisation and blinding, and key outcomes that include macrosomia, pregnancy loss, pre-eclampsia, caesarean section, fetal anomalies, and birth trauma.
BACKGROUND:Insulin requirements may change during pregnancy, and the optimal treatment for pre-existing diabetes is unclear. There are several insulin regimens (e.g. via syringe, pen) and types of insulin (e.g. fast-acting insulin, humaninsulin). OBJECTIVES: To assess the effects of different insulin types and different insulin regimens in pregnant women with pre-existing type 1 or type 2 diabetes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 October 2016), ClinicalTrials.gov (17 October 2016), the WHO International Clinical Trials Registry Platform (ICTRP; 17 October 2016), and the reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared different insulin types and regimens in pregnant women with pre-existing diabetes.We had planned to include cluster-RCTs, but none were identified. We excluded quasi-randomised controlled trials and cross-over trials. We included studies published in abstract form and contacted the authors for further details when applicable. Conference abstracts were superseded by full publications. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, conducted data extraction, assessed risk of bias, and checked for accuracy. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: The findings in this review were based on very low-quality evidence, from single, small sample sized trial estimates, with wide confidence intervals (CI), some of which crossed the line of no effect; many of the prespecified outcomes were not reported. Therefore, they should be interpreted with caution. We included five trials that included 554 women and babies (four open-label, multi-centre, two-arm trials; one single centre, four-arm RCT). All five trials were at a high or unclear risk of bias due to lack of blinding, unclear methods of randomisation, and selective reporting of outcomes. Pooling of data from the trials was not possible, as each trial looked at a different comparison.1. One trial (N = 33 women) compared Lispro insulin with regular insulin and provided very low-quality evidence for the outcomes. There were seven episodes of pre-eclampsia in the Lispro group and nine in the regular insulin group, with no clear difference between the two groups (risk ratio (RR) 0.68, 95% CI 0.35 to 1.30). There were five caesarean sections in the Lispro group and nine in the regular insulin group, with no clear difference between the two groups (RR 0.59, 95% CI 0.25 to 1.39). There were no cases of fetal anomaly in the Lispro group and one in the regular insulin group, with no clear difference between the groups (RR 0.35, 95% CI 0.02 to 8.08). Macrosomia, perinatal deaths, episodes of birth trauma including shoulder dystocia, nerve palsy, and fracture, and the composite outcome measure of neonatal morbidity were not reported.2. One trial (N = 42 women) compared humaninsulin to animal insulin, and provided very low-quality evidence for the outcomes. There were no cases of macrosomia in the humaninsulin group and two in the animal insulin group, with no clear difference between the groups (RR 0.22, 95% CI 0.01 to 4.30). Perinatal death, pre-eclampsia, caesarean section, fetal anomaly, birth trauma including shoulder dystocia, nerve palsy and fracture and the composite outcome measure of neonatal morbidity were not reported.3. One trial (N = 93 women) compared pre-mixed insulin (70 NPH/30 REG) to self-mixed, split-dose insulin and provided very low-quality evidence to support the outcomes. Two cases of macrosomia were reported in the pre-mixed insulin group and four in the self-mixed insulin group, with no clear difference between the two groups (RR 0.49, 95% CI 0.09 to 2.54). There were seven cases of caesarean section (for cephalo-pelvic disproportion) in the pre-mixed insulin group and 12 in the self-mixed insulin group, with no clear difference between groups (RR 0.57, 95% CI 0.25 to 1.32). Perinatal death, pre-eclampsia, fetal anomaly, birth trauma including shoulder dystocia, nerve palsy, or fracture and the composite outcome measure of neonatal morbidity were not reported.4. In the same trial (N = 93 women), insulin injected with a Novolin pen was compared to insulin injected with a conventional needle (syringe), which provided very low-quality evidence to support the outcomes. There was one case of macrosomia in the pen group and five in the needle group, with no clear difference between the different insulin regimens (RR 0.21, 95% CI 0.03 to 1.76). There were five deliveries by caesarean section in the pen group compared with 14 in the needle group; women were less likely to deliver via caesarean section when insulin was injected with a pen compared to a conventional needle (RR 0.38, 95% CI 0.15 to 0.97). Perinatal death, pre-eclampsia, fetal anomaly, birth trauma including shoulder dystocia, nerve palsy, or fracture, and the composite outcome measure of neonatal morbidity were not reported.5. One trial (N = 223 women) comparing insulin Aspart with humaninsulin reported none of the review's primary outcomes: macrosomia, perinatal death, pre-eclampsia, caesarean section, fetal anomaly, birth trauma including shoulder dystocia. nerve palsy, or fracture, or the composite outcome measure of neonatal morbidity.6. One trial (N = 162 women) compared insulin Detemir with NPH insulin, and supported the outcomes with very low-quality evidence. There were three cases of major fetal anomalies in the insulin Detemir group and one in the NPH insulin group, with no clear difference between the groups (RR 3.15, 95% CI 0.33 to 29.67). Macrosomia, perinatal death, pre-eclampsia, caesarean section, birth trauma including shoulder dystocia, nerve palsy, or fracture and the composite outcome of neonatal morbidity were not reported. AUTHORS' CONCLUSIONS: With limited evidence and no meta-analyses, as each trial looked at a different comparison, no firm conclusions could be made about different insulin types and regimens in pregnant women with pre-existing type 1 or 2 diabetes. Further research is warranted to determine who has an increased risk of adverse pregnancy outcome. This would include larger trials, incorporating adequate randomisation and blinding, and key outcomes that include macrosomia, pregnancy loss, pre-eclampsia, caesarean section, fetal anomalies, and birth trauma.
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