Risk Factor: B
Class: Hormones/ Antidiabetic agents
Fetal Risk Summary
Insulin, a naturally occurring hormone, is the drug of choice for the control of diabetes mellitus in pregnancy. Because it is a very large molecule, it has been believed that insulin does not cross the human placenta. Research published in 1990, however, found that animal (bovine or porcine) insulin does cross the human placenta as an insulin-antibody complex, and that the amount of transfer directly correlated with the amount of anti-insulin antibody in the mother (1). Moreover, high concentrations of animal insulin in cord blood were significantly associated with the development of fetal macrosomia, suggesting that the transferred insulin had biologic activity and that the fetal condition was determined by factors other than the mother’s glycemic control (1). This latter conclusion has been challenged (2,3) and defended (4) and, at present, requires additional study. The results of the study do underscore the argument that immunogenic insulin should not be used in women who may become pregnant (1,2).
Infants of diabetic mothers are at risk for an increased incidence of congenital anomalies, 3 to 5 times that of normal controls (5,6,7,8,9,10,11 and 12). The rate of malformations appears to be related to maternal glycemic control in the 1st trimester of pregnancy, but the exact mechanisms causing structural defects are unknown. A 1996 review examined this issue and concluded that uncontrolled diabetes, occurring very early in gestation (i.e., before 8 weeks of gestation), causes an abnormal metabolic fuel state and that this condition leads to a number of processes, operating via a common pathway, that results in cell injury (11).
Congenital malformations are now the most common cause of perinatal death in infants of diabetic mothers (5,6). Not only is the frequency of major defects increased but also the frequency of multiple malformations (affecting more than one organ system) (5). Malformations observed in infants of diabetic mothers include the following (9,10,12,13 and 14): Caudal regression syndrome (includes anomalies of lower neural tube resulting in sacral agenesis and defects of lumbar vertebrae; defects of lower extremities, gastrointestinal and genitourinary tracts (15)) Femoral hypoplasia and unusual facies syndrome Spina bifida, hydrocephalus, other central nervous system defects Anencephalus Cardiovascular: transposition of great vessels, ventricular septal defect, atrial septal defect Anal and rectal atresia Renal: agenesis, multicystic dysplasia, ureter duplex Gastrointestinal: situs inversus, tracheoesophageal fistula, bowel atresias, imperforate anus, small left colon Infants of diabetic mothers may have significant perinatal morbidity, even when the mothers have been under close diabetic control (12). Perinatal morbidity in one series affected 65% (169/260) of the infants and included hypoglycemia, hyperbilirubinemia, hypocalcemia, and polycythemia (16).
In contrast to the data relating to the adverse fetal effects of poor maternal hyperglycemia control, animal studies have documented that short periods of hypoglycemia during early organogenesis are associated with malformations of the skeleton and heart (17,18 and 19), and reduced growth, including some major organs (20). Although hypoglycemia in humans has not been shown to be teratogenic (21,22), at least one author has concluded that this has not been adequately studied (23).
Breast Feeding Summary
Insulin is a naturally occurring constituent of the blood. It does not pass into breast milk.
- Menon RK, Cohen RM, Sperling MA, Cutfield WS, Mimouni F, Khoury JC. Transplacental passage of insulin in pregnant women with insulin-dependent diabetes mellitus. N Engl J Med 1990;323:30915.
- Kimmerle R, Chantelau EA. Transplacental passage of insulin. N Engl J Med 1991;324:198.
- Ben-Shlomo I, Dor J, Zohar S, Mashiach S. Transplacental passage of insulin. N Engl J Med 1991;324:198.
- Menon RK, Sperling MA, Cohen RM. Transplacental passage of insulin. N Engl J Med 1991;324:199.
- Dignan PSJ. Teratogenic risk and counseling in diabetes. Clin Obstet Gynecol 1981;24:14959.
- Friend JR. Diabetes. Clin Obstet Gynaecol 1981;8:35382.
- Miller E, Hare JW, Cloherty JP, Dunn PJ, Gleason RE, Soeldner JS, Kitzmiller JL. Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers. N Engl J Med 1981;304:13314.
- Soler NG, Walsh CH, Malins JM. Congenital malformations in infants of diabetic mothers. Q J Med 1976;45:30313.
- American College of Obstetricians and Gynecologists. Diabetes and pregnancy. Technical Bulletin. No. 200, December 1994.
- Towner D, Kjos SL, Leung B, Montoro MM, Xiang A, Mestman JH, Buchanan TA. Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care 1995;18:144651.
- Reece EA, Homko CJ, Wu Y-K. Multifactorial basis of the syndrome of diabetic embryopathy. Teratology 1996;54:17182.
- Steel JM, Johnstone FD. Guidelines for the management of insulin-dependent diabetes mellitus in pregnancy. Drugs 1996;52:6070.
- Cousins L. Etiology and prevention of congenital anomalies among infants of overt diabetic women. Clin Obstet Gynecol 1991;34:48193.
- Hinson RM, Miller RC, Macri CJ. Femoral hypoplasia and maternal diabetes: consider femoral hypoplasia/unusual facies syndrome. Am J Perinatol 1996;13:4336.
- Escobar LF, Weaver DD. Caudal regression syndrome. In Buyse ML, Editor-in-Chief. Birth Defects Encyclopedia. Volume 1. Dover, MA:Center for Birth Defects Information Services, 1990:2967.
- Gabbe SG, Mestman JH, Freeman RK, Goebelsmann UT, Lowensohn RI, Nochimson D, Cetrulo C, Quilligan EJ. Management and outcome of pregnancy in diabetes mellitus, classes B to R. Am J Obstet Gynecol 1977;129:72332.
- Tanigawa K, Kawaguchi M, Tanaka O, Kato Y. Skeletal malformations in rat offspring. Long-term effect of maternal insulin-induced hypoglycemia during organogenesis. Diabetes 1991;40:111521.
- Peet JH, Sadler TW. Mouse embryonic cardiac metabolism under euglycemic and hypoglycemic conditions. Teratology 1996;54:2026.
- Smoak IW. Brief hypoglycemia alters morphology, function, and metabolism of the embryonic mouse heart. Reprod Toxicol 1997;11:495502.
- Lueder FL, Buroker CA, Kim S-B, Flozak AS, Ogata ES. Differential effects of short and long durations of insulin-induced maternal hypoglycemia upon fetal rat tissue growth and glucose utilization. Pediatr Res 1992;32:43640.
- Kimmerle R, Heinemann L, Delecki A, Berger M. Severe hypoglycemia incidence and predisposing factors in 85 pregnancies of type I diabetic women. Diabetes Care 1992;15:10347.
- Kalter H. Letter to the editor. Teratology 1996;54:266.
- Sadler TW. Letter from the editor. Teratology 1996;54:266.