Antidiabetic Agent
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
The animal and human data suggest that the use of insulin lispro during pregnancy can be considered low risk for the embryo–fetus. Insulin lispro is very closely related to human insulin, differing only in the reversal of two amino acids in the B chain. There is no reason to believe that insulin lispro would pose a risk to the embryo or fetus different from that of other insulins. Older forms of insulin, whether of human or of porcine origin, are considered compatible with pregnancy and insulin lispro can be classified similarly. As with all insulins, the primary concern is severe maternal hypoglycemia.
FETAL RISK SUMMARY
Insulin lispro is a rapid-acting human insulin analog that differs from regular human insulin by the reversal of the amino acids at positions B28 and B29. It is produced by recombinant DNA technology. Insulin lispro is indicated for the treatment of adult patients with diabetes mellitus for the control of hyperglycemia. It may be given by SC injection or as an SC infusion by an external insulin pump. The mechanism of action of insulin lispro is similar to human insulin, in that it binds to receptors in muscle and fat cells to facilitate the cellular uptake of glucose and, at the same time, inhibits glucose release from the liver. The elimination half-life of SC insulin lispro is 1 hour, compared with 1.5 hours for human regular insulin (1).
Reproduction studies have been conducted in pregnant rats and rabbits. In these species, SC doses up to 4 and 0.3 times the average human dose (40 U/day) based on BSA revealed no evidence of impaired fertility or fetal harm due to insulin lispro. Long-term studies of carcinogenicity have not been conducted. The drug was not mutagenic or clastogenic in tests (1).
A 2001 study briefly described the use of normal, term human placentas to determine if insulin lispro crossed to the fetal circulation (2). Two concentrations, 0.1 and 0.5 U/mL, were studied in the dual-perfused isolated cotyledon system. Time-dependent transfer of insulin lispro to the fetal side was observed, but the concentrations used were >50 times the normal human therapeutic doses (2).
A 2003 study used a similar system to determine the amount of insulin lispro crossing the placenta (3). Placental transfer was not observed during perfusions with 100 and 200 micro-U/mL, but did occur at concentrations ≥580 micro-U/mL. To determine clinically relevant levels, serum concentrations were measured in 11 women at 31–40 years of age (9 pregnant; 1 in 1st trimester, 8 in 2nd or 3rd trimester) receiving insulin lispro. Concentrations ranged from 2 to 576 micro-U/mL. There was an apparent linear relationship between dose and serum levels. Ten women had levels <200 micro-U/mL (single doses less than 50 U), whereas one woman, who received a 52-U dose, had a serum level of 576 micro-U/mL (3). Using a human-perfused placental cotyledon, a 2004 study found no detectable insulin lispro on the fetal side with the highest maternal steady-state concentration of 48 micro-U in the maternal artery (4). However, very high concentrations of insulin lispro (1836 micro-U without specifying a denominator) were found in placental tissue.
Based on the above studies, insulin lispro, depending on the dose, could cross to the embryo–fetus. Moreover, there may be endogenous carrier proteins that allow passage of insulin, including insulin lispro (molecular weight 5808; identical to human insulin), to the embryo early in gestation. After that period, the fetus produces its own insulin as insulin-secreting cells in the fetal pancreas become differentiated near the end of the 1st trimester (5).
A 1997 case report described the pregnancy outcomes of two women with type 1 diabetes who were treated with insulin lispro and NPH insulin during pregnancy (6). In the first case, insulin lispro was started before conception. The pregnancy was terminated at 20 weeks’ gestation because of intrauterine growth restriction and severe fetal embryopathy but a normal karyotype. The female fetus had left-sided pulmonary and atrial isomerism, a right-sided aortic arch, a single atrium with one atrioventricular valve, a large ventricular septal defect, a double-outlet right ventricle, polysplenia, and abdominal situs inversus. In the second mother, insulin lispro was started in the third week of gestation. An elective cesarean section at 37 weeks delivered a 2.82-kg male infant with normal Apgar scores. No neonatal complications were noted, but the infant died suddenly at 3 weeks of age. At autopsy, a congenital diaphragmatic hernia with herniation of the stomach and intestine into the chest and bilateral undescended testes were found. The cause of the defects in the two cases was unknown, but the authors did not believe they were due to suboptimal glycemic control. They also mentioned four other cases involving insulin lispro during pregnancy. Three of the women were still in the 1st trimester. The fourth woman was started at 26 weeks and she gave birth to a normal infant at 38 weeks (6).
In reply to the above cases, representatives of the manufacturer noted that the risk of congenital defects was known to be increased in infants of women with diabetes, especially cardiac defects (7). During clinical trials with insulin lispro, pregnancy was an exclusion, but 19 women gave birth to live infants. Only one infant had a birth defect (a right dysplastic kidney). The representatives cautioned that although case reports were important to raise hypotheses, they could not be used to infer a causal relationship (7).
Eight studies that included fetal outcomes have described the use of insulin lispro during 836 pregnancies (8–16). Diabetic types included 735 pregestational (types 1 and 2) and 101 gestational (type 3). No embryo, fetal, or neonatal complications attributable to insulin lispro were reported in 303 of the pregnancies (8–15).
The remaining pregnancies came from a multinational, multicenter study (16). The medical charts of 533 pregnancies (496 women) complicated by pregestational diabetes were examined and anomalies were assessed by two independent dysmorphologists. There were 542 outcomes involving 500 live births, 31 spontaneous abortions, 7 elective abortions, and 4 stillbirths. The mothers had a mean age of 29.9 years, 85.6% were white, and 97.2% had type 1 diabetes. All of the women had used insulin lispro for at least 1 month before conception and during at least the 1st trimester. More than 96% continued insulin lispro during the 2nd and 3rd trimesters. Twenty-seven (5.4%) of the offspring, including two that were electively aborted, had major congenital defects and two (0.4%) had minor anomalies. The anomaly rate among pregnancies that resulted in a live or stillbirth was 5.2%. Comparing these rates with the current published rates of 2.1%–10.9% for major defects in infants of diabetic mothers treated with insulin, the investigators concluded that their results suggested no difference in the anomaly rates between insulin lispro and regular insulin (16).
The cases of congenital defects in infants of two women using insulin lispro cited above were most likely due to diabetes or unknown causes. Four reviews concluded that the use of insulin lispro in pregnancy was appropriate and often gave better glycemic control than regular human insulin (17–20). However, a fifth review, published in 2006, cautioned that more comparative data were needed before insulin lispro could be recommended in pregnancy or alternatively avoided (21).
A 2003 study compared the progression of retinopathy in pregnant women with type 1 diabetes who were treated with insulin lispro (N = 36) or human insulin (N = 33) (22). Patients treated with insulin lispro had improved glycemic control with no adverse impact on progression of diabetic retinopathy.
BREASTFEEDING SUMMARY
No reports describing the use of insulin lispro during human lactation have been located. Insulin is a natural component of the blood and is excreted into breast milk (1). Insulin lispro probably also is present in milk.
References
1.Product information. Humalog. Eli Lilly, 2007.
2.Rosenn B, Kosssenjans W, Eis A, Brockman D, Myatt L. Does lispro insulin cross the human placenta? Am J Obstet Gynecol 2001;184:S69.
3.Boskovic R, Knie B, Feig DS, Portnoi G, Derewlany L, Koren G. Transfer of insulin lispro across the human placenta. Diabetes Care 2003;26:1390–4.
4.Holcberg G, Tsadkin-Tamir M, Sapir O, Wiznizer A, Segal D, Polachek H. Transfer of insulin lispro across the human placenta. Eur J Obstet Gynecol Reprod Biol 2004;115:117–8.
5.Buchanan TA, Kjos SL. Diabetes in women. Early detection, prevention, and management. Clin Updates Women’s Health Care. 2002;1(4/Fall):47.
6.Diamond T, Kormas N. Possible adverse fetal effect of insulin lispro. N Engl J Med 1997;337:1009.
7.Anderson JH Jr, Bastyr EJ, Wishner KL. Possible adverse fetal effects of insulin lispro. Reply. N Engl J Med 1997;337:1010.
8.Bhattacharyya A, Brown S, Hughes S, Vice PA. Insulin lispro and regular insulin in pregnancy. QJM 2001;94:255–60.
9.Scherbaum WA, Lankisch MR, Pawlowski B, Somville T. Insulin lispro in pregnancy—retrospective analysis of 33 cases and matched controls. Exp Clin Endocrinol Diabetes 2002;110:6–9.
10.Persson B, Swahn ML, Hjertberg R, Hanson U, Nord E, Nordlander E, Hansson LO. Insulin lispro therapy in pregnancies complicated by type 1 diabetes mellitus. Diabetes Res Clin Pract 2002;58:115–21.
11.Durand-Gonzalez KN, Guillausseau N, Anciaux ML, Hentschel V, Gayno JP. Allergy to insulin in a woman with gestational diabetes mellitus: transient efficiency of continuous subcutaneous insulin lispro infusion. Diabetes Metab 2003;29:432–4.
12.Cypryk K, Sobczak M, Pertynska-Marczewska M, Zawodniak-Szalapska M, Syzmczak W, Wilczynski J, Lewinski A. Pregnancy complications and perinatal outcomes in diabetic women treated with Humalog (insulin lispro) or regular human insulin during pregnancy. Med Sci Monit 2004;10:P129–32.
13.Mecacci F, Carignani L, Cioni R, Bartoli E, Parretti E, La Torre P, Scarselli G, Mello G. Maternal metabolic control and perinatal outcome in women with gestational diabetes treated with regular or lispro insulin: comparison with non-diabetic pregnant women. Eur J Obstet Gynecol Reprod Biol 2003;111:19–24.
14.Dolci M, Mori M, Baccetti F. Use of glargine insulin before and during pregnancy in a woman with type 1 diabetes and Addison’s disease. Diabetes Care 2005;28:2084–5.
15.Masson EA, Patmore JE, Brash PD, Baxtert M, Caldwell G, Gallen IW, Price PA, Vice PA, Walker JD, Lindow SW. Pregnancy outcome in type 1 diabetes mellitus treated with insulin lispro (Humalog). Diabet Med 2003;20:46–50.
16.Wyatt JW, Frias JL, Hoymet HE, Jovanovic L, Kaaja R, Brown F, Garg S, Lee-Parritz A, Seely EW, Kerr L, Mattoo V, Tan M, and the IONS Study Group. Congenital anomaly rate in offspring of mothers with diabetes treated with insulin lispro during pregnancy. Diabet Med 2005;22:803–7.
17.Radermecker RP, Scheen AJ. Continuous subcutaneous insulin infusion with short-acting insulin analogues or human regular insulin: efficacy, safety, quality of life, and cost-effectiveness. Diabetes Metab Res Rev 2004;20:178–88.
18.Lapolla A, Dalfra MG, Fedele D. Insulin therapy in pregnancy complicated by diabetes: are insulin analogs a new tool? Diabetes Metab Res Rev 2005;21:241–52.
19.Gonzalez C, Santoro S, Salzberg S, Di Girolamo G, Alvarinas J. Insulin analogue therapy in pregnancies complicated by diabetes mellitus. Expert Opin Pharmacother 2005;6:735–42.
20.Homko CJ, Reech EA. Insulins and oral hypoglycemic agents in pregnancy. J Matern Fetal Neonatal Med 2006;19:679–86.
21.Carr KJE, Lindow SW, Masson EA. The potential for the use of insulin lispro in pregnancy complicated by diabetes. J Matern Fetal Neonatal Med 2006;19:323–9.
22.Loukovaara S, Immonen I, Teramo KA, Kaaja R. Progression of retinopathy during pregnancy in type 1 diabetic women treated with human lispro. Diabetes Care 2003;26:1193–8.