NOREPINEPHRINE

Fetal Risk Summary

Norepinephrine (noradrenaline; levarterenol) is a direct-acting adrenergic agent that is used for acute hypotension and as an adjunct in the treatment of cardiac arrest. It is a mixture of the racemic stereoisomer and is given by IV infusion. Norepinephrine readily crosses the placenta (1), consistent with its relatively low molecular weight (about 169).

In animal reproduction studies, norepinephrine has caused situs inversus (rat embryos) (l-isomer only; no effect from d-form) (2), cataract (rat embryos) (3), hemorrhages of cephalic, skin, and extremity structures (chick embryo) (4), and microscopic liver abnormalities and delayed skeletal ossification (hamsters) (5).

In a 1995 study in pregnant ewes (123–137 days' gestation), a high maternal dose (40 µg/minute) of norepinephrine given by IV infusion caused a significant decrease in maternal placental blood flow (6). Although fetal arterial pressure did not change, transient (£2.5 hours) but statistically significant decreases in fetal oxygenation, fetal urine flow, and lung liquid flow were observed. Because the average human maintenance dose is much less (about 2–4 µg/minute), the clinical significance of these changes to a human fetus is unknown.

Uterine vessels are normally maximally dilated, and they have only a-adrenergic receptors (7). Use of the a- and b-adrenergic stimulant norepinephrine could cause constriction of these vessels and reduce uterine blood flow, thereby producing fetal hypoxia (bradycardia). Norepinephrine may also interact with oxytocics or ergot derivatives to produce severe persistent maternal hypertension (7). Rupture of a cerebral vessel is possible. If a pressor agent is indicated, other drugs, such as ephedrine, should be considered.

Breast Feeding Summary

No reports describing the use of norepinephrine in lactation have been located. Use of the agent during breast feeding would not be expected because of the indications for use.

References

1. Morgan CD, Sandler M, Panigel M. Placental transfer of catecholamines in vitro and in vivo. Am J Obstet Gynecol 1972;112:1068–75.
2. Fujinaga M, Maze M, Hoffman BB, Baden JM. Activation of a-1 adrenergic receptors modulates the control of left/right sidedness in rat embryos. Development Biology 1992;150:419–21. As cited in Shepard TH. Catalog of Teratogenic Agents. 9th ed. Baltimore, MD: The Johns Hopkins University Press, 1998:340.
3. Pitel M, Lerman S. Studies on the fetal rat lens. Effects of intrauterine adrenalin and noradrenalin. Invest Ophthalmol 1962;1:406–12. As cited in Shepard TH. Catalog of Teratogenic Agents. 9th ed. Baltimore, MD: The Johns Hopkins University Press, 1998:340.
4. Gatling RR. The effect of sympathomimetic agents on the chick embryo. Am J Pathol 1962;40:113–27.
5. Hirsch KS, Fritz HI. A comparison of mescaline with epinephrine and norepinephrine in the hamster. Teratology 1974;9:A19–A20. As cited in Schardein TH. Chemically Induced Birth Defects. 3rd ed. New York, NY: Marcel Dekker, 2000:360, 364.
6. Stevens AD, Lumbers ER. Effects of intravenous infusions of noradrenaline into the pregnant ewe on uterine blood flow, fetal renal function, and lung liquid flow. Can J Physiol Pharmacol 1995;73:202–8.
7. Smith NT, Corbascio AN. The use and misuse of pressor agents. Anesthesiology 1970;33:58–101.