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Use of Insulin Glargine During Pregnancy in Seven Type 1 Diabetic Women

¹ Department of Obstetrics and Gynecology, Martini Ziekenhuis, Groningen, the Netherlands
² Department of Internal Medicine, Mesos Medisch Centrum, Bilthoven, the Netherlands
³ Department of Internal Medicine, Medisch Centrum, Leeuwarden, the Netherlands
⁴ Department of Internal Medicine, Martini Ziekenhuis, Groningen, the Netherlands.

Address correspondence to K. Hoogenberg, MD, PhD, Martini Hospital, Department of Internal Medicine, PO Box 30033, 9700 RM Groningen, Netherlands. E-mail: k.hoogenberg{at}mzh.nl

Insulin glargine is a human insulin analog with an activity that results in a relatively constant concentration/time profile over 24 h with no pronounced peak. It is increasingly recognized to provide good glycemic control and to reduce the risk of hypoglycemia in type 1 diabetes (1). There may be a place for insulin glargine in diabetic pregnancies in which strict glycemic control and prevention of hypoglycemia reduce the higher adverse outcome risk. Despite animal studies showing the safety and efficacy of insulin glargine during pregnancy (2), its use in human pregnancies is currently not recommended. There are two case reports on the occasional use of insulin glargine during pregnancy (3, 4) and a notification of its safety in five patients during the first weeks of pregnancy (5). To date, there are no reports on the use of insulin glargine during the entire pregnancy in patients with diabetes.

We examined the hospital files of three outpatient pregnancy clinics in the Netherlands and identified seven women with type 1 diabetes who deliberately used insulin glargine during pregnancy while being aware of the unknown pregnancy risks. The women (three primiparae and four multiparae) had a mean age of 34 years (range 29–39) and a diabetes duration of 12 years (5–8). Five patients continued their preconceptional use of insulin glargine during the entire pregnancy. Two patients converted from intermediate-acting NPH insulin to insulin glargine after 15 and 27 weeks of amenorrhoea because of recurrent episodes of nocturnal hypoglycemia. Glycemic control during pregnancy was excellent in six patients (HbA_1c [A1C] 5.2–6.9%) and suboptimal in one (A1C 6.4–8.1%), and overall the mean A1C was 6.4%. The occurrence of hypoglycemia reduced in the two patients that converted to insulin glargine. Hypertension complicated two pregnancies, while five were uncomplicated. All patients delivered at term (37–40 weeks), three vaginally and four by cesarean section. Seven children, mean weight 4,180 g (2,475–4,675), were born without congenital abnormalities and had no neonatal complications during routine observation at the neonatal care unit.

Insulin glargine has several potential advantages in the glucose management of type 1 diabetes, as illustrated by the excellent glycemic control with its use in six of the seven women and the disappearance of nocturnal hypoglycemia after conversion in two of them. Insulin glargine differs from human insulin by the addition of two arginine residues to the B-chain and a substitution of an asparagine residue for a glycine at position 21 of the A-chain. This modified human insulin molecule had no adverse effects on reproduction, embryo-fetal development, and postnatal development in rats (2). The present observational study in seven pregnancies puts forward the notion that insulin glargine is a possible safe insulin in human pregnancy.

Insulin glargine shares a similar time course with human insulin for insulin receptor binding, despite a somewhat lower affinity for the insulin receptor (6). In contrast, insulin glargine has a sixfold-higher binding affinity for IGF-1 receptors, and experimental studies suggest an increased mitogenicity on tumor cell-lines at high doses (6). Does this justify a ground to fear the use of insulin glargine in human pregnancy? Only small amounts of maternal insulin (1–5%) pass the placenta and enter the fetal circulation. This has been documented for human insulin (7) and the short-acting insulin analog insulin lispro (8), with insulin levels of (very) high magnitude. It is most likely that the placental transfer of insulin glargine is similar to the transfer of human insulin and that of other insulin analogs (7, 8), although this has to be proven conclusively. Considering the expected marginal amount of placental insulin transfer, if any, the use of insulin glargine in pregnancy is not likely to put the fetus at risk. This, in combination with the present observation of the use of insulin glargine in seven human diabetic pregnancies, justifies a large randomized trial to establish the efficacy and safety of insulin glargine in diabetic pregnancies.

References

1. Rosenstock J, Dailey G, Massi-Benedetti M, Fritsche A, Lin Z, Salzman A: Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care 28:950–955, 2005[Abstract/Free Full Text]
   
2. Hofmann T, Horstmann G, Stammberger I: Evaluation of the reproductive toxicity and embryotoxicity of insulin glargine (LANTUS) in rats and rabbits. Int J Toxicol 21:181–189, 2002[Medline]
   
3. Devlin JT, Hothersall L, Wilkis JL: Use of insulin glargine during pregnancy in a type 1 diabetic woman. Diabetes Care 25:1095–1096, 2002[Free Full Text]
   
4. Holstein A, Plaschke A, Egberts EH: Use of insulin glargine during embryogenesis in a pregnant woman with type 1 diabetes. Diabet Med 20:779–780, 2003[Medline]
   
5. Di Gianni G, Volpe L, Lencioni C, Chatzianagnostou K, Cuccuru I, Ghio A, Benzi L, Del Prato S: Use of insulin glargine during the first weeks of pregnancy in five type 1 diabetic women. Diabetes Care 28:982–983, 2005[Free Full Text]
   
6. Bolli GB, Owens DR: Insulin glargine. Lancet 356:443–445, 2000[Medline]
   
7. Challier JC, Haugel S, Desmaizieres V: Effects of insulin on glucose uptake and metabolism in the human placenta. J Clin Endocrinol Metab62:803–807, 1986
   
8. Boskovic R, Feig DS, Derewlany L, Knie B, Portnoi G, Koren G: Transfer of insulin lispro across the human placenta: in vitro perfusion studies. Diabetes Care 26:1390–1394, 2003[Abstract/Free Full Text]
   

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				D. E. Graves, J. C. White, and J. K. Kirk The Use of Insulin Glargine With Gestational Diabetes Mellitus Diabetes Care, February 1, 2006; 29(2): 471 - 472. [Full Text] [PDF]

This Article Extract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Woolderink, J. M. Articles by Hoogenberg, K. Search for Related Content PubMed PubMed Citation Articles by Woolderink, J. M. Articles by Hoogenberg, K. Social Bookmarking                What's this?