Sympatholytic (Antimigraine)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Dihydroergotamine is a potent semi-synthetic ergot alkaloid that has oxytocic and sympatholytic properties. The animal data suggest a risk of intrauterine growth restriction probably resulting from reduced uteroplacental blood flow and/or increased myometrial tone. Although there is no evidence that it is a teratogen, dihydroergotamine is contraindicated in pregnancy, especially near term. Inadvertent exposure early in gestation, however, does not appear to represent a major risk.
FETAL RISK SUMMARY
Dihydroergotamine is the hydrogenated derivative of ergotamine (see also Ergotamine). It is available only in formulations for injection and nasal spray because oral absorption is poor. Both preparations are indicated for the acute treatment of migraine headaches with or without aura. In addition, the injectable formulation is indicated for the acute treatment of cluster headaches. The mean bioavailability of the nasal spray is 32% relative to the injectable administration. Plasma protein binding is 93% and the elimination half-life is about 9 hours (1,2). Another source, however, states that elimination is biphasic with half-lives of about 1–2 hours and 22–32 hours, respectively (3).
The oxytocic properties of ergotamine have been known since the early 1900s, producing a prolonged and marked increase in uterine tone that may lead to fetal hypoxia (4). The pharmacologic properties of dihydroergotamine are different from ergotamine, as the former is a much more potent sympatholytic (4). In a 1952 study, the oxytocic and toxic effects of dihydroergotamine were demonstrated (5). Twenty women at term were given 1 mg of dihydroergotamine in 500 mL distilled water IV over a period of 2–4 hours to induce labor. Labor induction was successful in eight women (40%), but in six other women the outcomes were four stillborns, one neonatal death 1.25 hours after delivery, and one severely depressed infant that developed seizures 3 days after delivery (progressing satisfactorily at 3 months of age with no abnormal neurological signs). The investigators concluded that dihydroergotamine should not be used to induce labor (5).
Reproduction studies have been conducted in rats and rabbits. In rats, intranasal administration throughout the period of organogenesis at doses producing maternal plasma exposures (AUC) about 0.4–1.2 times the human exposure (AUC) from the maximum recommended daily dose of ≥4 mg (MRDD) resulted in decreased fetal body weights and/or skeletal ossification. Administration of the dose throughout pregnancy and lactation resulted in reduced body weights and impaired reproductive function in the offspring. The no-effect level for rat embryo–fetal toxicity was not established. In rabbits administered the nasal spray during organogenesis, maternal exposures at about 7 times the MRDD also resulted in delayed skeletal ossification. The no-effect dose for rabbit embryo–fetal toxicity was about 2.5 times the MRDD. The embryo–fetal toxic doses in both species did not cause maternal toxicity. The in utero growth restriction in the animal studies was thought to have resulted from reduced uteroplacental blood flow and/or increased myometrial tone (1,2).
A study in guinea pigs quantified the effect of dihydroergotamine on uteroplacental blood flow (6). Pregnant guinea pigs were given the drug (14 mcg/kg/day) from day 30 to 60 of pregnancy (gestational length for guinea pigs is 64–68 days). At term, placental blood flow was decreased by 51% and, fetal weight and fetal weight/placental weight ratio were significantly decreased compared with controls (6).
It is not known if dihydroergotamine crosses the human placenta. The molecular weight of the free base (about 584) and long elimination half-life suggest that the drug will cross the placenta, but the extensive protein binding will limit passage.
The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 32 of whom were exposed to ergot derivatives (three to dihydroergotamine) other than ergotamine during the 1st trimester (7). Three malformed children were observed from this group, but the numbers are too small to draw any conclusion.
A brief 1993 report described a 31-year-old woman with depression, panic disorder, and migraine headaches who was exposed to a number of drugs in the first 6 weeks of pregnancy, including dihydroergotamine, citalopram, buspirone, thioridazine, and etilefrine (a sympathomimetic agent) (8). An elective abortion was performed at 12 weeks’ gestation. A thorough macroscopic and microscopic examination of the male fetus revealed no evidence of malformation. A detailed neuropathological examination and chromosome analysis (46,XY karyotype) was normal (8).
BREASTFEEDING SUMMARY
No reports describing the use of dihydroergotamine during human lactation have been located. The molecular weight of the free base (about 584) and long elimination half-life (may be as long as 22 hours) suggest that the drug will be excreted into breast milk, but the high protein binding (about 93%) will limit this excretion. The closely related agent ergotamine is excreted into milk (see Ergotamine). An ergot product has been associated with symptoms of ergotism (vomiting, diarrhea, and convulsions) in nursing infants of mothers taking the agent for the treatment of migraine (see Ergotamine). Moreover, dihydroergotamine is a member of the same chemical family as bromocriptine, an agent that is used to suppress lactation. Although no specific information has been located relating to the effects of dihydroergotamine on lactation, ergot alkaloids may hinder lactation by inhibiting maternal pituitary prolactin secretion (9).
References
1.Product information. D.H.E. 45. Novartis Pharmaceuticals, 2001.
2.Product information. Migranal. Novartis Pharmaceuticals, 2001.
3.Parfitt K, ed. Martindale. The Complete Drug Reference. 32nd ed. London: Pharmaceutical Press, 1999:444–5.
4.Gill RC, Farrar JM. Experiences with di-hydro-ergotamine in the treatment of primary uterine inertia. J Obstet Gynaecol Br Emp 1951;58:79–91.
5.Altman SG, Waltman R, Lubin S, Reynolds SRM. Oxytocic and toxic actions of dihydroergotamine-45. Am J Obstet Gynecol 1952;64:101–9.
6.Hohmann M, Künzel W. Dihydroergotamine causes fetal growth restriction in guinea pigs. Arch Gynecol Obstet 1992;251:187–92.
7.Heinonen OP, Sloan D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:358–9.
8.Seifritz E, Holsboer-Trachsler E, Haberthur F, Hemmeter U, Poldinger W. Unrecognized pregnancy during citalopram treatment. Am J Psychiatry 1993;150:1428–9.
9.Vorherr H. Contraindications to breast-feeding. JAMA 1974;227:676.