What is the best insulin type and regimen for pregnant women with pre-existing diabetes?

What is the issue?

The insulin needs of pregnant women with type 1 or 2 diabetes change during pregnancy. Insulin is available in many forms, which affect how often and when the insulin is given. These forms vary in the time needed before the insulin has its effect, how long the effect may last, and whether it is made from animals or humans, which may be important personally or culturally. This review looked at the safest and most effective types and ways of giving insulin during pregnancy.

Why is this important?

Women with type 1 or 2 diabetes are at increased risk of complications during pregnancy and birth. They are more likely to experience pregnancy loss (stillbirth, miscarriage), high blood pressure and pre-eclampsia (high blood pressure associated with swelling and protein in the urine), and have large babies (called macrosomia, when the baby is 4 kg or more at birth) that result in injury to the mother or baby. The likelihood of having a caesarean is increased. Mothers and babies may have complications related to managing blood glucose levels. The baby is more likely to become overweight and develop type 2 diabetes. We wanted to find out the best type of insulin and regimen to use during pregnancy.

What evidence did we find?

We found five randomised trials (N = 554 women and 554 babies) in October 2016. Each trial looked at different insulin types and ways of giving the insulin. Different outcomes were looked at in each trial. One trial did not include any of the review's main outcomes. All five trials were small, and at a high or unclear risk of bias because of limitations in how the trials were conducted. The quality of the evidence was very low.

When rapid-acting human insulin (Lispro) was compared to regular insulin (N = 33), investigators found no clear differences between the groups for pre-eclampsia, abnormalities in the baby, or the need for a caesarean. Macrosomia, perinatal death, birth trauma including shoulder dystocia, nerve palsy, and fracture, and the composite measure of neonatal morbidity were not reported.

One trial (N = 43) that compared human insulin to animal insulin did not show any clear difference in the number of babies with macrosomia. Perinatal death, pre-eclampsia, caesarean section, fetal anomaly, birth trauma including shoulder dystocia, nerve palsy, and fracture, and the composite measure of neonatal morbidity were not reported.

One trial (N = 93) found no clear differences between pre-mixed and self-mixed insulin groups in the number of babies with macrosomia, and the number of women who had a caesarean section. This trial also compared insulin injected with a pen and a needle (syringe). Women in the insulin pen group were less likely to have a caesarean section, although the number of macrosomic babies was not clearly different. Perinatal death, pre-eclampsia, fetal anomaly, birth trauma including shoulder dystocia, nerve palsy, and fracture, and the composite measure of neonatal morbidity were not reported.

One trial (N = 223) comparing insulin Aspart to human insulin did not include any of the review's primary outcomes (macrosomia, perinatal death, pre-eclampsia, caesarean section, fetal anomaly, birth trauma including shoulder dystocia, nerve palsy, and fracture, or the composite measure of neonatal morbidity).

One trial (N = 162), which compared long-acting insulin Detemir with the intermediate-acting neutral protamine Hagedorn (NPH) insulin found the number of fetal abnormalities was not clearly different between groups. The trial did not measure macrosomia, perinatal death, pre-eclampsia, caesarean section, birth trauma including shoulder dystocia, nerve palsy, and fracture, or the composite outcome measure of neonatal morbidity.

What does this mean?

The trials did not provide sufficient evidence to identify clear differences between the various insulin types and regimens. Each study looked at a different type of insulin or regimen, so we could not combine the results. The studies were small, with overall high risk of bias. Therefore, we could not conclude which insulin type or regimen was best for pregnant women with pre-existing diabetes. More research is needed with larger groups of women, better reporting of how the trials were conducted, and more reported outcomes.

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.

Read the full 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 strategy: 

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.

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