Medicina

Obstet Gynecol Clin N Am 34 (2007) 275–291

Insulin Analogues in the Treatment of Diabetes in Pregnancy
Charanpal Singh, MD, Lois Jovanovic, MD
Sansum Diabetes Research Institute, 2219 Bath Street, Santa Barbara, CA 93105, USA

Before the advent of insulin in 1922, less than 100 pregnancies in diabetic women were reported; most likely these women had type 2 and not type 1 diabetes [1]. Evenwith this assumption, these cases of diabetes and pregnancy were associated with a greater than 90% infant mortality rate and a 30% maternal mortality rate. As late as 1980, physicians were still counseling diabetic women to avoid pregnancy. This philosophy was justified because of the poor obstetric history in 30% to 50% of diabetic women. Improved infant mortality rates finally occurred after1980, when treatment strategies stressed better control of maternal plasma glucose levels, once selfblood glucose monitoring and glycosylated hemoglobin became available. As the pathophysiology of pregnancy complicated by diabetes has been elucidated and as management programs have achieved and maintained near normoglycemia throughout pregnancy complicated by diabetes mellitus, perinatal mortalityrates have decreased to levels seen in the general population [2–9]. This review reports the literature on the safety and efficacy of insulin analogues in pregnancy and thereby enables the clinician to choose the optimal insulin treatment protocol to achieve and maintain normoglycemia throughout pregnancies complicated by diabetes.

Rationale for the use of nonimmunogenic insulins during pregnancyMaternal glucose freely crosses the placenta. Maternal insulin does not cross the placenta unless it is bound to IgG antibody, which carries it through the placenta, or insulin is forced through the placenta by high perfusion [10,11]. Diabetic fetopathy is thought to be the result of fetal hyperinsulinemia [1–9]. Thus treatment must be designed to normalize maternal blood glucose concentrationswithout the use of exogenous insulins that
E-mail address: ljovanovic@sansum.org (L. Jovanovic). 0889-8545/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ogc.2007.03.003 obgyn.theclinics.com

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cross the placenta. Placental transfer of insulin complexed with immunoglobulin has also been associated with fetal macrosomia in mothers who havenear-normal glycemic control during gestation. Menon and colleagues [12] reported that antibody-bound insulin transferred to the fetus was proportional to the concentration of antibody-bound insulin measured in the mother. Also, the amount of antibody-bound insulin transferred to the fetus correlated directly with macrosomia in the infant and was independent of maternal blood glucose levels. Incontrast, Jovanovic and colleagues [13] discovered that it was only improved glucose control, as evidenced by lower postprandial glucose excursions, but not lower insulin antibody levels, correlated with lower fetal weight. They showed that insulin antibodies to exogenous insulin do not influence infant birth weight. The literature is now well documented that maintenance of postprandial glucoseconcentrations in the normal range decreases the risk of glucosemediated macrosomia [6–8]. Rapid-acting insulin analogues have been shown to improve postprandial glucose control compared with the concentrations resulting from treatment with human regular insulin. Data [14] suggest that rapid-acting insulin analogues do not transfer through the human placenta, thus they can be considered suitabletherapeutic candidates as treatment during pregnancies complicated by diabetes [10,11,15–20]. However, to date, the clinical data currently available for the long-acting insulin analogues is not sufficient to advocate their use in pregnancy. This article reviews the literature on the insulin analogue during pregnancy and presents the authors’ opinion as to the safety and efficacy of insulin analogue...