Antidote
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
The limited animal and human pregnancy data suggest that the embryo and/or fetal risks from glucagon are very low or negligible. Apparently, the drug does not cross the placenta.
As with all antidotes, maternal treatment usually is paramount. Thus, in cases of severe hypoglycemia, when IV glucose cannot be administered, glucagon should not be withheld because of concern for embryo–fetal safety. The maternal consequences of withholding treatment might place the pregnancy at far greater risk than the undocumented risk from the drug.
FETAL RISK SUMMARY
Glucagon is a single-chain polypeptide hormone produced by recombinant DNA technology that is identical to human glucagon. Glucagon increases blood glucose by stimulating hepatic glycogenolysis and relaxes smooth muscle of the gastrointestinal tract. It also is used as an antidote for β-blocker overdose. Glucagon must be given parenterally because it is destroyed in the gastrointestinal tract and is not active when taken orally. The polypeptide contains 29 amino acid residues with a molecular weight of 3483. Glucagon treats severe hypoglycemia by the conversion of liver glycogen to glucose. It is also indicated as a diagnostic aid in the radiologic examination of the gastrointestinal tract when diminished intestinal motility is advantageous. The hormone is extensively metabolized in the liver, kidney, and plasma and has a very short elimination half-life (range 8–18 minutes) (1).
Reproduction studies have not been conducted with recombinant glucagon, but have been performed with animal-source glucagon. In rats, doses up to 40 times the human dose based on BSA revealed no evidence of impaired fertility or fetal harm (1).
An in vitro mouse study examined the effect of glucagon and other metabolic factors (insulin, β-hydroxybutyrate, and acetoacetate) on the preimplantation development of mouse embryos (2). Glucagon, as well as the other factors, demonstrated a statistically significant dose-related inhibition of blastocyst development when cultured over 72 hours. However, the relationship of the observed embryotoxicity to a typical human clinical exposure is doubtful.
The metabolic response to glucagon injections (1 mcg/kg to 1 mg/kg) was studied in chronically catheterized fetal lambs near term (3). A significant hyperglycemia occurred within 15–30 minutes but, in contrast to neonatal lambs, did not induce a significant ketogenesis.
In a 1992 study, no effects on renal function were observed in near-term fetal sheep administered pharmacologic doses of glucagon (0.5 mcg/kg/min) for 1.5 hours (4). However, a significant increase in fetal heart rate, without changes in arterial pressure, was noted.
Glucagon does not cross the placenta in sheep or humans (5–8). In an experiment with pregnant sheep at term, no transfer of radioiodine-labeled glucagon was detected either from the mother to the fetus or from the fetus to the mother (5). A 1972 human study failed to find evidence of glucagon placental transfer in three mothers at term (6). Similarly, in an in vitro study using human chorion, no transfer of glucagon to the fetal side was detected (7). In a 1976 study, 15 women received a 1-mg IV dose of glucagon within 40 minutes of delivery (8). Compared with 47 control subjects, no change in glucagon concentrations in umbilical cord blood was observed, suggesting a lack of significant placental transfer.
A 1987 study reported the outcomes of seven pregnant women who had received glucagon for severe hypoglycemia on 12 occasions during pregnancy (9). In each case, a single 1-mg dose was given SC or IM by a spouse or other family member, resulting in glucose levels of 100–200 mg/dL within 30 minutes in 11 cases. In one case, the woman did not respond and required IV glucose in the emergency room. Although the gestational timing of the glucagon doses was not given, all of the infants survived and had normal Apgar scores at birth (9).
Glucagon was used as an antidote in a pregnant woman who had taken a massive overdose (15.2 g) of the β-blocker, metoprolol (10). At 20 weeks’ gestation, the woman ingested 152 100-mg tablets in a suicide attempt. She suffered cardiac arrest in the hospital. Despite prolonged, but successful, cardiopulmonary resuscitation, she remained in severe cardiogenic shock with low systolic blood pressure. When the nature of the ingestion was learned, the woman was given glucagon 1-mg IV. Her condition markedly improved after the glucagon, but intrauterine fetal death had occurred and an induced abortion was performed 10 days later (10).
A 2003 review on the effects of antidotes in pregnancy concluded that there was probably no teratogenic risk because of the endogenous nature of glucagon (11). However, doses >1 mg in human pregnancy have not been reported.
BREASTFEEDING SUMMARY
No reports describing the use of glucagon during lactation have been located. It is doubtful if such reports would be forthcoming because of the nature of its indications (severe hypoglycemia; antidote; diagnostic agent) and its very short elimination half-life (8–18 minutes). Moreover, even if the high molecular weight (3483) polypeptide hormone were excreted into milk, it would be broken down to its constituent amino acids or fragments thereof in the infant’s digestive tract. Thus, the risk to a nursing infant appears to be negligible.
References
1.Product information. Glucagon. Eli Lilly, 2001.
2.Zusman I, Yaffe P, Ornoy A. Effects of metabolic factors in the diabetic state on the in vitro development of preimplantation mouse embryos. Teratology 1987;35:77–85.
3.Philipps AF, Dubin JW, Matty PJ, Raye JR. Influence of exogenous glucagon on fetal glucose metabolism and ketone production. Pediatr Res 1983;17:51–6.
4.Moore RS, Lumbers ER. Renal and metabolic effects of glucagon in the fetus. J Dev Physiol 1992;17:47–9.
5.Sperling MA, Erenberg A, Fiser RH, Oh W, Fisher DA. Placental transfer of glucagon in sheep. Endocrinology 1973;93:1435–8.
6.Johnston DI, Bloom SR, Greene KR, Beard RW. Failure of the human placenta to transfer pancreatic glucagon. Biol Neonate 1972;21:375–80.
7.Moore WMO, Ward BS, Gordon C. Human placental transfer of glucagon. Clin Sci Mol Med 1974;46:125–9.
8.Spellacy WN, Buhi WC. Glucagon, insulin and glucose levels in maternal and umbilical cord plasma with studies of placental transfer. Obstet Gynecol 1976;47:291–4.
9.Rayburn W, Piehl E, Sanfield J, Compton A. Reversing severe hypoglycemia during pregnancy with glucagon therapy. Am J Perinatol 1987;4:259–61.
10.Tai YT, Lo CW, Chow WH, Cheng CH. Successful resuscitation and survival following massive overdose of metoprolol. Br J Clin Pract 1990;44:746–7.
11.Bailey B. Are there teratogenic risks associated with antidotes used in the acute management of poisoned pregnant women? Birth Defects Res A Clin Mol Teratol 2003;67:133–40.