Correspondence
Possible Adverse Fetal Effect of Insulin Lispro
N Engl J Med 1997; 337:1009-1010October 2, 1997
- Article
To the Editor:
Insulin lispro is a new insulin analogue that acts more rapidly than regular insulin. To date, there are no reports on fetal outcomes after therapy with insulin lispro in pregnant women; indeed, pregnancy has been a contraindication for its use in all of the drug studies.1
We report on two primiparous women treated with NPH insulin and insulin lispro during pregnancy. Both had well-controlled insulin-dependent diabetes mellitus with no evidence of complications at the time of conception. Excellent glycemic control was maintained throughout their pregnancies, with hemoglobin A 1c values (measured every three months) of less than 7.0 percent and mean blood glucose values (measured at home) of less than 108 mg per deciliter (6.0 mmol per liter). Treatment with insulin lispro was begun before conception in Patient 1 and during the third week of pregnancy in Patient 2. At the time of delivery, the mean doses of insulin lispro were 0.4 and 0.8 unit per kilogram of body weight in Patients 1 and 2, respectively, and the mean dose of NPH insulin was 0.2 unit per kilogram in both patients. Patient 2 also received thyroxine, oxyprenolol, and hydralazine during her pregnancy.
Because of a clinical suspicion of intrauterine growth retardation, ultrasonography and amniocentesis were performed in Patient 1. The results suggested a severe fetal embryopathy; the karyotype was normal. The pregnancy was terminated at 20 weeks of gestation. An autopsy revealed a phenotypically normal female fetus with multiple congenital abnormalities, including 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. Patient 2's baby was delivered electively by cesarean section at 37 weeks of gestation, with a weight of 2.82 kg and normal Apgar scores. No neonatal complications were noted, but the baby died suddenly three weeks after delivery. An autopsy revealed a congenital diaphragmatic hernia with herniation of the stomach and intestine into the chest and bilateral undescended testes.
We are aware of four other pregnant women with diabetes treated with insulin lispro. Three of the women are in the first trimester and have not yet undergone ultrasonography. In the fourth woman, treatment with insulin lispro was started at 26 weeks of gestation, and a normal infant was delivered at 38 weeks.
The report of the two infants with congenital abnormalities raises the possibility that insulin lispro has embryotoxic actions. We cannot rule out other potential causes of the abnormalities in these babies,2 but we do not believe that suboptimal glycemic control contributed to the poor fetal outcome.
Because of patients' increasing satisfaction with insulin lispro,3 physicians can expect to see a greater number of unexpected pregnancies in women taking this new insulin analogue. Our report raises the question of its potential teratogenicity.
3 ReferencesTerrence Diamond, M.D.
Nic Kormas, M.D.
St. George Hospital, Kogarah, NSW 2217, Australia1
Holleman F ,Hoekstra JBL . Insulin lispro. N Engl J Med 1997;337:176-183
Full Text | Web of Science | Medline2
Kitzmiller JL ,Buchanan TA ,Kjos S ,Combs CA ,Ratner RE . Pre-conception care of diabetes, congenital malformations, and spontaneous abortions. Diabetes Care 1996;19:514-541
Web of Science | Medline3
Anderson JH Jr ,Brunelle RL ,Koivisto VA , et al. Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Diabetes 1997;46:265-270
CrossRef | Web of Science | Medline
Author/Editor Response
Spokespersons for Lilly Research Laboratories reply:
To the Editor: Diamond and Kormas report two cases of congenital anomalies in the offspring of women with type I diabetes treated with insulin, including insulin lispro, during pregnancy. The risk of major fetal malformations is known to be increased in infants of women with diabetes, with reported rates as high as 5.2 to 16.8 percent, as compared with 1.2 to 3.7 percent in infants of mothers without diabetes.1 In particular, the cardiovascular system is often affected. In one study, the risk of cardiovascular anomalies was increased 18 times in infants of women with type I diabetes.2 Although optimizing glycemic control before conception and throughout pregnancy reduces the risk of congenital anomalies, that risk is not eliminated.
In studies with insulin lispro in pregnant rats and rabbits, no evidence of impaired fertility or harm to the fetuses was observed with doses as high as four times the average dose in humans.3 In controlled clinical trials involving more than 2000 women treated with insulin lispro, pregnant women were excluded. However, 19 live births occurred as a result of unplanned pregnancies. Only one infant was found to have an abnormality (a right dysplastic kidney). Clinical trials are currently under way to investigate the use of insulin lispro during pregnancy. As stated in the product labeling, insulin lispro should be used during pregnancy only if clearly needed.4
Although case reports are useful for generating hypotheses, they should not be used to infer a cause–effect relation. Case reports are based on one observation or a small number of observations without the use of a comparison group; consequently, any association may be due to chance. A case report can obscure a relation or suggest an association where none actually exists. We are therefore concerned about the public health consequences of misinterpreting these case reports.
4 ReferencesJames H. Anderson, Jr., M.D.
Edward J. Bastyr, III, M.D.
Kathleen L. Wishner, Ph.D., M.D.
Lilly Research Laboratories, Indianapolis, IN 462851
Kitzmiller JL ,Buchanan TA ,Kjos S ,Combs CA ,Ratner RE . Pre-conception care of diabetes, congenital malformations, and spontaneous abortions. Diabetes Care 1996;19:514-541
Web of Science | Medline2
Becerra JE ,Khoury MJ ,Cordero JF ,Erickson JD . Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based control-study. Pediatrics 1990;85:1-9
Web of Science | Medline3
Buelke-Sam J ,Byrd RA ,Hoyt JA ,Zimmerman JL . A reproductive and developmental toxicity study in CD rats of LY275585, [Lys(B28),Pro(B29)]- human insulin. J Am Coll Toxicol 1994;13:247-260
CrossRef4
Humalog (insulin lispro injection [rDNA origin]). (U.S. product literature.) Indianapolis: Eli Lilly, September 26, 1996.
- Citing Articles (26)
Citing Articles
1
Cintia González Blanco, Ana Chico Ballesteros, Ignasi Gich Saladich, Rosa Corcoy Pla. (2011) Glycemic Control and Pregnancy Outcomes in Women with Type 1 Diabetes Mellitus Using Lispro Versus Regular Insulin: A Systematic Review and Meta-Analysis. Diabetes Technology & Therapeutics 13:9, 907-911
CrossRef2
Celeste P. Durnwald, Mark B. Landon. (2011) Insulin Analogues in the Management of the Pregnancy Complicated by Diabetes Mellitus. Current Diabetes Reports 11:1, 28-34
CrossRef3
Ana Chico, Ignasi Saigi, Apolonia García-Patterson, M. Dolores Santos, Juan M. Adelantado, Gemma Ginovart, Alberto de Leiva, Rosa Corcoy. (2010) Glycemic Control and Perinatal Outcomes of Pregnancies Complicated by Type 1 Diabetes: Influence of Continuous Subcutaneous Insulin Infusion and Lispro Insulin. Diabetes Technology & Therapeutics 12:12, 937-945
CrossRef4
Emily J. Edson, Oswaldo L. Bracco, Anne Vambergue, Veikko Koivisto. (2010) Managing Diabetes During Pregnancy with Insulin Lispro: A Safe Alternative to Human Insulin. Endocrine Practice 16:6, 1020-1027
CrossRef5
Lironn Chitayat, Lois Jovanovic, Moshe Hod. (2009) New modalities in the treatment of pregnancies complicated by diabetes: Drugs and devices. Seminars in Fetal and Neonatal Medicine 14:2, 72-76
CrossRef6
Yusuf Aydın, Dilek Berker, Nafiye Direktör, İhsan Ustün, Yasemin Ateş Tütüncü, Serhat Işık, Tuncay Delibaşı, Serdar Guler. (2008) Is insulin lispro safe in pregnant women: Does it cause any adverse outcomes on infants or mothers?. Diabetes Research and Clinical Practice 80:3, 444-448
CrossRef7
Elisabeth R. Mathiesen, Julius Anthony Vaz. (2008) Insulin treatment in diabetic pregnancy. Diabetes/Metabolism Research and Reviews 24:S2, S3-S20
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Elisabeth R Mathiesen. (2008) Insulin aspart in diabetic pregnancy: state of the art. Women's Health 4:2, 119-124
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Lois Jovanovic, John L. Kitzmiller. 2008. Insulin therapy in pregnancy. , 205-216.
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Guido Menato, Simona Bo, Anna Signorile, Marie-Laure Gallo, Ilenia Cotrino, Chiara Botto Poala, Marco Massobrio. (2008) Current management of gestational diabetes mellitus. Expert Review of Obstetrics & Gynecology 3:1, 73-91
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Jeff Unger. (2007) Management of Diabetes in Pregnancy, Childhood, and Adolescence. Primary Care: Clinics in Office Practice 34:4, 809-843
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Ivana Zib, Philip Raskin. (2006) Novel insulin analogues and its mitogenic potential. Diabetes, Obesity and Metabolism 8:6, 611-620
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Ali D Kamal, Anthony N Dixon, Stephen C Bain. (2006) Safety and side effects of the insulin analogues. Expert Opinion on Drug Safety 5:1, 131-143
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A. Lapolla, M. G. Dalfrà, D. Fedele. (2005) Insulin therapy in pregnancy complicated by diabetes: are insulin analogs a new tool?. Diabetes/Metabolism Research and Reviews 21:3, 241-252
CrossRef15
Claudio González, Silvina Santoro, Susana Salzberg, Guillermo Di Girolamo, Jorge Alvariñas. (2005) Insulin analogue therapy in pregnancies complicated by diabetes mellitus. Expert Opinion on Pharmacotherapy 6:5, 735-742
CrossRef16
Mukesh M Agarwal, John Punnose. (2004) Recent advances in the treatment of gestational diabetes. Expert Opinion on Investigational Drugs 13:9, 1103-1111
CrossRef17
K. Gamson, S. Chia, L. Jovanovic. (2004) The safety and efficacy of insulin analogs in pregnancy. Journal of Maternal-Fetal and Neonatal Medicine 15:1, 26-34
CrossRef18
Simon Heller. (2003) Insulin lispro: a useful advance in insulin therapy. Expert Opinion on Pharmacotherapy 4:8, 1407-1416
CrossRef19
E. A. Masson, J. E. Patmore, P. D. Brash, M. Baxter, G. Caldwell, I. W. Gallen, P. A. Price, P. A. Vice, J. D. Walker, S. W. Lindow. (2003) Pregnancy outcome in Type 1 diabetes mellitus treated with insulin lispro (Humalog). Diabetic Medicine 20:1, 46-50
CrossRef20
Charles J Glueck, Naila Goldenberg, Patricia Streicher, Ping Wang. (2002) The contentious nature of gestational diabetes: diet, insulin, glyburide and metformin. Expert Opinion on Pharmacotherapy 3:11, 1557-1568
CrossRef21
B Persson, M.-L Swahn, R Hjertberg, U Hanson, E Nord, E Nordlander, L.-O Hansson. (2002) Insulin lispro therapy in pregnancies complicated by type 1 diabetes mellitus. Diabetes Research and Clinical Practice 58:2, 115-121
CrossRef22
David Simmons. (2002) The utility and efficacy of the new insulins in the management of diabetes and pregnancy. Current Diabetes Reports 2:4, 331-336
CrossRef23
Edith W. M. T. ter Braak, Inge M. Evers, D. Willem Erkelens, Gerard H. A. Visser. (2002) Maternal hypoglycemia during pregnancy in type 1 diabetes: maternal and fetal consequences. Diabetes/Metabolism Research and Reviews 18:2, 96-105
CrossRef24
Peter A. Gottlieb, Juan P. Frias, Kelly A. Peters, Bhavani Chillara, Satish K. Garg. (2002) Optimizing Insulin Therapy in Pregnant Women with Type 1 Diabetes Mellitus. Treatments in Endocrinology 1:4, 235-240
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Veikko A Koivisto. (1998) The human insulin analogue insulin lispro. Annals of Medicine 30:3, 260-266
CrossRef26
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