Effectiveness of Insulin Analogs Compared with Human Insulins in Pregnant Women with Diabetes Mellitus: Systematic Review and Meta-analysis.
Topic: Hormone Therapy

Diabetes during pregnancy has been linked to unfavorable maternal-fetal outcomes. Human insulins are the first drug of choice because of the proven safety in their use. However, there are still questions about the use of insulin analogs during pregnancy. The objective of the present study was to determine the effectiveness of insulin analogs compared with human insulin in the treatment of pregnant women with diabetes through a systematic review with meta-analysis. The search comprised the period since the inception of each database until July 2017, and the following databases were used: MEDLINE, CINAHL, EMBASE, ISI Web of Science, LILACS, Scopus, SIGLE and Google Scholar. We have selected 29 original articles: 11 were randomized clinical trials and 18 were observational studies. We have explored data from 6,382 participants. All of the articles were classified as having an intermediate to high risk of bias. The variable that showed favorable results for the use of insulin analogs was gestational age, with a mean difference of - 0.26 (95 % confidence interval [CI]: 0.03-0.49; 

PICO
Population: Pregnant women with diabetes mellitus
Intervention: Insulin analogs
Comparison: Human insulins
Outcomes: Effectiveness in terms of gestational age

Included studies:
title: [A case of isolated volar-ulnar dislocation of the base of the 5th metacarpus].
title: Progression of retinopathy during pregnancy in type 1 diabetic women treated with insulin lispro.
abstract: To evaluate the progression of retinopathy during pregnancy and postpartum in (insulin-dependent) women with type 1 diabetes treated with insulin lispro or with regular human insulin.
title: [Neurohistological pattern of senile changes of the vulva. IV. Reactive changes in the nerve fibers and endings in vulva tissues in senile women].
title: Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women.
abstract: To assess the safety and efficacy of insulin aspart (IAsp) versus regular human insulin (HI) in basal-bolus therapy with NPH insulin in pregnant women with type 1 diabetes.
title: A comparison of lispro and regular insulin for the management of type 1 and type 2 diabetes in pregnancy.
abstract: To describe perinatal outcomes of women with pregestational diabetes treated with short-acting, regular insulin and the short-acting insulin analogue, lispro.
title: Risk of complications of pregnancy in women with type 1 diabetes: nationwide prospective study in the Netherlands.
abstract: To investigate maternal, perinatal, and neonatal outcomes of pregnancies in women with type 1 diabetes in the Netherlands.
title: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
abstract: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial.
title: [Effects of ethanol on GTP binding protein function in rat cerebral cortex: strain difference between Wistar and Fischer 344 rats].
abstract: The effect of ethanol on GTP-binding protein of cortical adenylate cyclase (AC) system in the Wistar and Fischer 344 rats was examined. In both Wistar and Fischer 344 rats, ethanol (100mM) potentiated Gpp (NH) p-stimulated AC activity and decreased EC50 for Gpp (NH)p in the cerebral cortical membrane (CCM). Ethanol treatment also augmented Mn-stimulated AC activity in Wistar CCM, whereas there was no significant change in Fischer 344 CCM. IC50 calculated from the Gpp (NH)p (0.01-0.3 microM) inhibition of forskolin-stimulated AC was decreased by ethanol treatment in Wistar CCM, but this was not the case in Fischer 344 CCM. There was no appreciable change in ADP-ribosylation of Gs and Gi in CCM with pertussis or cholera toxin. These results suggest that ethanol in vitro enhances the Gi function as well as affecting the Gs function in Wistar rat cortical AC system, and the effect of ethanol on Gi protein are different in Wistar and Fischer 344 CCM.
title: Gerontological nursing: the state-of-the-art.
title: Fetal and perinatal outcomes in type 1 diabetes pregnancy: a randomized study comparing insulin aspart with human insulin in 322 subjects.
abstract: The objective of the study was a comparison of insulin aspart (IAsp) with human insulin (HI) in basal-bolus therapy with neutral protamine Hagedorn for fetal and perinatal outcomes of type 1 diabetes in pregnancy.
title: Malformations in infants of diabetic mothers.
abstract: Maternal insulin-dependent diabetes has long been associated with congenital malformations. As other causes of mortality and morbidity have been eliminated or reduced, malformations have become increasingly prominent. Although there is not universal agreement, the great majority of investigators find a two- to threefold increase in malformations in infants of insulin-dependent diabetic mothers. This increase is not seen in infants of gestational diabetics. It probably is not present in women whose diabetes can be controlled by diet or oral hypoglycemic agents. The risk does not appear to be primarily genetic since diabetic fathers do not have an increased number of malformed offspring. Most studies show a generalized increase in malformations involving multiple organ systems. Multiple malformations seem to be more common in diabetic than nondiabetic infants. Caudal regression has the strongest association with diabetes, occurring roughly 200 times more frequently in infants of diabetic mothers than in other infants. The teratogenic mechanism in diabetes is not known. Hyperglycemia may be important but human studies focusing on the period of organogenesis are lacking. Hypoglycemia has also been suggested based mainly on animal experiments. Insulin appears unlikely. Numerous other factors including vascular disease, hypoxia, ketone and amino acid abnormalities, glycosylation of proteins, or hormone imbalances could be teratogenic. None has been studied in sufficient detail to make a judgment. A large-scale prospective study is required to determine early fetal loss rates, correlate metabolic status during organogenesis with outcome, and assess the effect of diabetic control on malformation rates.
title: Insulin lispro therapy in pregnancies complicated by type 1 diabetes mellitus.
abstract: To compare the efficacy and safety of preprandial administration of rapid-acting lispro analogue with regular short-acting insulin to pregnant women with type 1 diabetes.
title: Pregnancy complications and perinatal outcome in diabetic women treated with Humalog (insulin lispro) or regular human insulin during pregnancy.
abstract: Pregnancy outcome in diabetic women is strictly related to glycemic control during pregnancy. The aim of our study was to compare pregnancy outcome between patients subjected to intensive insulin therapy using regular human insulin and those treated with insulin lispro (Humalog).
title: Outcome of pregnancies complicated by type 1 insulin-dependent diabetes in Sweden: acute pregnancy complications, neonatal mortality and morbidity.
abstract: This prospective nationwide study conducted during 1982-1985 examined the rates of hypertensive disorders, perinatal mortality and morbidity in 491 insulin-dependent diabetic pregnancies (White's classes: B, 164; C, 129; D, 172; F, 26) and in the total population of 279,000. The rates of pregnancy-induced hypertension (PIH) or pre-eclampsia (20.6%), premature delivery (24.6%), and cesarean section (45.2%) in the diabetic group were more than four times higher than normal. PIH or preeclampsia occurred significantly (p < 0.01) more frequently in patients with diabetic microangiopathy. Mean birthweight was similar in the two populations but gestational age was significantly (p < 0.001) shorter (38 weeks) in the diabetic group. The rate of large for gestational age infants (20%) in the diabetic group was considerably above normal (3.5%). Although perinatal mortality rate in the diabetic group was only 3.1%, it was 4.4 times higher than normal; five of ten fetal deaths were associated with poor glycemic control and thus may not really be unexplained. Neonatal morbidity was significantly more frequent in the diabetic group; still, the incidence of idiopathic respiratory distress syndrome was only 1.6% compared with 0.6% in the general population. Discriminant analysis revealed that gestational age at birth and elevated maternal HbA1c values in early pregnancy independently of each other had a significant impact on the occurrence of neonatal morbidity.
title: Use of glargine in pregnant women with type 1 diabetes mellitus: a case-control study.
abstract: Insulin glargine is a once-daily basal insulin analog with prolonged duration of action and absence of an evident peak. Glargine is associated with reduced frequency of hypoglycemic episodes (mostly nocturnal) as well as effective glycemic control. Maintenance of good metabolic control before conception and throughout pregnancy is essential to lower the risk of fetal malformations. Glargine might be a valuable alternative in the management of pregnancies complicated by diabetes mellitus. However, because its clinical utility has not been established, the use of glargine is not currently recommended during pregnancy.
title: Randomized controlled trial of insulin detemir versus NPH for the treatment of pregnant women with diabetes.
abstract: We sought to determine if insulin detemir (IDet) is noninferior to insulin neutral protamine Hagedorn (NPH) for the treatment of gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) in pregnancy.
title: Acquisition of peroxidase activity by rat alveolar macrophages during pulmonary inflammation.
abstract: The authors investigated the ability of rat alveolar macrophages to acquire peroxidase activity in the course of pulmonary inflammation. Granulomatous pulmonary inflammation was induced in bacille Calmette-Guérin (BCG)-immunized rats by intravenous injection of BCG in mineral oil. In contrast to normal alveolar macrophages, which are peroxidase-negative, alveolar macrophages lavaged from the BCG-treated rats showed significant peroxidase activity in large cytoplasmic inclusions compatible with internalized exogenous material. Alveolar macrophage uptake of intact peroxidase-positive neutrophils was also observed. Maximal numbers of peroxidase-positive alveolar macrophages were observed after the initial influx of neutrophils into the lungs, and peroxidase activity could be demonstrated in cell-free lavage fluid during the acute phase of lung injury. Normal alveolar macrophages acquired peroxidase activity after incubation with peritoneal exudate neutrophils, with purified soluble human myeloperoxidase, and with opsonized erythrocytes. It is concluded that alveolar macrophages acquire peroxidase activity from multiple sources during pulmonary inflammation. Internalization of peroxidase by the alveolar macrophage may serve to clear a potentially toxic enzyme(s) from the alveolar space and contribute to the resolution of pulmonary inflammation.
title: Premixed insulin aspart 30 (BIAsp 30) versus premixed human insulin 30 (BHI 30) in gestational diabetes mellitus: a randomized open-label controlled study.
abstract: A randomized, open-label, parallel study was conducted to assess the efficacy and safety of premixed insulin aspart 30 (biphasic insulin aspart [BIAsp] 30) in managing gestational diabetes mellitus (GDM). A total of 323 women with GDM registered at a single center in India were randomly assigned to receive 6 U of either BIAsp 30 (Group A) or premixed human insulin (biphasic human insulin [BHI] 30; Group B) in a 1:1 ratio. Subjects performed home glucose monitoring and visited their care provider twice a month. The primary outcome was the degree of neonatal macrosomia (neonatal birth weight >90th percentile). Groups A and B were demographically comparable at study entry. Before labor onset, Groups A and B achieved similar degrees of fasting plasma glucose and postprandial plasma glucose control (92.97 ± 14.44 vs. 95.43 ± 18.96 and 127.59 ± 28.99 vs. 126.98 ± 29.89, respectively; both p = NS). Neonatal macrosomia frequency was 6.3% in Group A and 6.9% in Group B; however, this difference was not statistically significant. By last visit, the required insulin dose was significantly lower for Group A than Group B (19.83 ± 15.75 IU vs. 26.34 ± 23.15 IU, respectively; p = 0.006). BIAsp 30 was noninferior to BHI 30, producing comparable fetal outcomes when administered during pregnancy. Based on final doses, BIAsp 30 may offer greater treat-to-target potential for pregnant women.