In our study we evaluated retrospectively the effectiveness and safety of insulin detemir versus NPH in 192 pregnant women with GDM. In this large cohort of pregnant women, the use of insulin detemir for glucose control was found to be equally effective compared with NPH, with a slightly lower HbA1c in the detemir group in late gestation. Furthermore, no differences were observed with respect to maternal adverse outcomes or neonatal complications.
The number of studies investigating insulin Detemir in pregnant women is limited and the majority of them refer to pregestational diabetes, T1DM or T2DM. [6–9, 15, 16, 17, 18, 20–24] The first published data concerning insulin detemir in diabetic pregnancy are those of the retrospective assessment of 10 Type 1 diabetic pregnant women by Lapolla et al in 2009 [6] and of 18 women (14 with Type 1 and four with type 2 diabetes) by Shenoy et al [7] in 2012. These studies demonstrated improved glycemic control during pregnancy and satisfactory maternal and fetal outcomes. The largest prospective randomized trial evaluating the efficacy and safety of insulin detemir in pregnancy vs NPH, both with prandial insulin aspart, was performed in 310 women with T1DM, as already mentioned. Detemir was demonstrated to be as safe and effective as NPH insulin. [8, 9] A subsequent observational study and a recent randomized trial investigating insulin detemir versus NPH in pregnant women with T2DM confirmed the aforementioned results. [21, 22] This was further corroborated by the EVOLVE study, where insulin detemir was compared to other basal insulins (mainly glargine and NPH). [17]
Information about insulin detemir in GDM is scarce and originates mainly from studies with both pregestational and gestational diabetes. [15, 16, 18, 24, 26] Herrera et al. and Ji et al. in their randomized controlled trials comparing insulin detemir versus NPH included both women with GDM and pregestational T2DM who also received short-acting insulin before meals as needed. To our knowledge, our study is the first to investigate exclusively insulin NPH versus detemir in a peer cohort of women with real GDM diagnosed from 24th to 28th week of gestation. In our cohort all women received a single bedtime injection of NPH or detemir per day, in order to correct fasting BG without any additional prandial insulin. Postprandial BG was controlled with proper diabetes pregnancy diet.
Traditionally, improvements in glycemic control during insulin therapy are associated with weight gain. [27] In non-pregnant adults, clinical studies have shown that insulin detemir, compared to NPH, results in less weight gain, especially in the morbidly obese subgroup. [14, 28, 29] Possible pathophysiologic mechanisms include a reduced rate of hypoglycemic events, suppression of hepatic glucose output and elevated satiety signaling within the central nervous system. [30, 31] Weight gain is crucial in the pathophysiology of diabetes, particularly during pregnancy, and is associated with higher risks of adverse pregnancy outcomes, including arterial hypertension and pre-eclampsia, caesarean section, stillbirth, perinatal mortality, macrosomia, premature birth, obesity in childhood and T2DM occurrence in the offspring. [32, 33] Under these circumstances the use of insulin detemir may be beneficial.
In our study, there were no statistical differences concerning maternal weight gain (both per week and throughout pregnancy) between the two groups. These results are in agreement with most other observational cohorts or randomized controlled trials comparing the use of detemir versus NPH in pregnancies with T1DM, T2DM or GDM. [8, 15, 16] Only one recent randomized controlled study comparing detemir versus NPH in 108 pregnant women with T2DM by Bartal et al found that insulin detemir was associated with less weight gain compared with NPH. [22]
In our cohort, no hypoglycemias were recorded in either group and this is probably due to the fact that there was no need for intensification of insulin treatment. Insulin detemir or NPH were injected once daily, while there was no need for rapid-acting insulin. In two observational studies investigating insulin NPH versus detemir in pregnancies with T2DM or GDM the rate of hypoglycemias between the two groups (Detemir vs NPH) was comparable. [21, 24] However, in the randomized controlled trial by Herrera et al in 87 pregnant women with GDM and T2DM, NPH was associated with a higher risk of hypoglycemia compared to insulin detemir. In line with this there are other studies investigating detemir versus NPH in pregnancies with pregestational and gestational diabetes, possibly due to the intensive insulin regimen including short-acting insulins. [15, 16, 22]
Furthermore, no hypertensive disorders were recorded in either group. Previous studies comparing insulin detemir versus NPH in pregnancies with T1DM, T2DM or GDM have shown comparable rates of hypertension. [9, 16, 21, 24] Only the already mentioned randomized study in pregnant women with T2DM by Bartal et al found lower adverse maternal outcomes including hypertensive disorders in the detemir group compared to NPH. [22]
No allergic reactions were recorded in our study in both treatment arms. According to most previous studies adverse drug reactions were rare and similar between the NPH and detemir groups. [16, 21, 22, 24] Notably, in the study by Mathiesen et al only eight women of the 152 of the Detemir group reported adverse events relating to injection sites with one of them withdrawing from the study. [8] In addition, in the study by Herrera et al a higher rate of allergic reactions in women treated with insulin detemir was found, forcing them to switch to an alternate medication. [15]
We found no differences between the two groups with respect to mean fasting and postprandial BG levels in the beginning of insulin treatment and at the end of gestation. These findings are similar to previous observational and randomized controlled studies comparing detemir and NPH in pregnancy. [15, 26] In the randomized trial by Herrera et al no difference was found between the NPH and detemir group concerning mean fasting and postprandial glucose levels, in the percentage of patients who achieved overall glucose control or in time to achieve glucose control. [15]
In our study the detemir group presented a slightly lower HbA1c level at the end of gestation but we consider it of limited clinical significance. Mean BG levels during pregnancy are more sensitive to changes in glucose control over the short time period that these patients are treated for. In addition, the randomized trial of Ji et al comparing NPH versus Detemir in 240 pregnant women with pregestational and gestational diabetes showed that in the early period of treatment, detemir had a better performance than NPH in terms of controlling blood glucose, as fasting and postprandial BG levels after one week of treatment were lower in the detemir group, and the time to reach target was shorter. Further, insulin detemir was at least as effective as NPH in a long-termtreatment as after 3 months HbA1c between the two groups was similar. [16]
In agreement with the study by Mathiesen et al. we found no differences between the two groups in relation to the duration of insulin treatment or the daily insulin dose. [8] Only in the study by Ji et al the total insulin dose in the detemir group was higher than in the NPH group. [16] Nonetheless, in our study insulin doses between the two groups were comparable after adjustment for weight.
Overall, there were no statistically significant differences in neonatal outcomes including birth weight, birth weight adjusted for gestational age, percentage of macrosomia or SGA and rates of preterm delivery or cesarean section. There were no congenital malformations or severe neonatal hypoglycemias, which suggested that insulin detemir was as good as NPH in terms of safety. Our results are consistent with the findings reported by most previous studies. [9, 15, 16, 17, 21, 24] Only the recent randomized study by Bartal et al reported lower rates of adverse neonatal outcomes but with a higher rate of LGA in the detemir group. [21]
To the best of our knowledge this is the largest retrospective study investigating exclusively insulin detemir versus NPH, either of these administered in a single dose at night, in pregnancies with GDM only. In addition, the study has the strength that it has been performed under real life routine conditions in unselected patients in a single center by the same medical team, where the glycemic goals for treatment have been constant during the study period. The majority of the patients were of Caucasian origin and insulin therapy was initiated taking into consideration the increase of the fetal abdomen circumference on ultrasound.
Although a limitation might be the retrospective nature of the design, the study provides real life data complementary to information derived from randomized controlled trials. Most of the women were of the same ethnicity with mean pre-pregnancy BMI under 30 kg/m2. Outcomes from this study should be applied carefully in cases of more serious GDM, where intensive insulin regimen is needed and especially in pregnancies with T2DM.
In conclusion, this study provided evidence that insulin detemir and NPH are equally effective and safe with respect to glycemic control and total insulin dose needed, maternal outcomes and complications (hypoglycemia, allergic reactions, weight gain and hypertension), as well as neonatal outcomes (time and mode of delivery, birth weight and rates of macrosomia and SGA). The only significant difference, though minor, was observed in relation to final HbA1c. The lower HbA1c in the detemir group seems not to have clinical significance, as evidenced by the absence of differences with regard to maternal adverse outcomes or neonatal complications, between the two GDM groups. Finally, the only differentiating factor appears to be the cost of the two options, where NPH is the more economical one.