Ergotamine in Pregnancy and Breastfeeding
Fetal Risk Summary
Ergotamine is a naturally occurring ergot alkaloid that is used in the prevention or treatment of vascular headaches, such as migraine. The oxytocic properties of ergotamine have been known since the early 1900s, but because it produces a prolonged and marked increase in uterine tone that may lead to fetal hypoxia, it is not used for this purpose (1). A semisynthetic derivative, dihydroergotamine, has also been abandoned as an oxytocic for the same reason (2). Small amounts of ergotamine have been reported to cross the placenta to the fetus (3).
Ergotamine is not an animal teratogen (4). In pregnant mice, rats, and rabbits, however, doses sufficient to affect maternal weight gain were fetotoxic, producing increased prenatal mortality and growth retardation. The mechanism proposed for these effects was an impairment of blood supply to the uterus and placenta (4). Another study demonstrating fetal death in pregnant rats arrived at the same conclusion (5). Ergotamine (0.25%) fed to pregnant sheep produced severe ergotism, fetal death and abortions (6).
Most authorities consider ergotamine in pregnancy to be either contraindicated or to be used sparingly and with caution, due to the oxytocic properties of the drug (7,8,9 and 10). Fortunately, the frequency of migraine attacks decreases during pregnancy, thus lessening the need for any medication (8,9 and 10).
The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 25 of whom were exposed to ergotamine during the 1st trimester (11). Two malformed children were observed from this group, but the numbers are too small to draw any conclusion.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 59 newborns had been exposed to ergotamine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of nine (15.3%) major birth defects were observed (two expected). Specific data were available for six defect categories, including (observed/expected) 1/0.6 cardiovascular defects, 0/0 oral clefts, 0/0 spina bifida, 1/0 polydactyly, 0/0 limb reduction defects, and 1/0 hypospadias. The total number of defects is suggestive of an association, but other factors, such as the mother's disease, concurrent drug use, and chance may be involved.
A retrospective study published in 1978 evaluated the reproductive outcome of women attending a migraine clinic (12). The study group was composed of 777 women enrolling in the clinic for the first time. A control group composed of 182 wives of new male patients at the clinic was formed for comparison. Of the women with migraine, 450 (58%) had been pregnant vs. 136 (75%) of the women without migraine. The difference in the percentage of pregnancies may have been due to the fact that all of the control women were married while the marriage status of the study women was not known (12). The incidence of at least one spontaneous abortion or stillbirth, 27% vs. 29%, including 1st trimester loss, and the occurrence of toxemia, 18% vs. 18%, were similar for the groups. The total number of pregnancies was 1,142 in the study patients and 342 in the controls, with a mean number of pregnancies per patient of 2.54 vs. 2.51, respectively. The migraine group had 924 (81%) live births compared to 277 (81%) for the control women. Congenital defects observed among the live births totaled 31 (3.4%) for the study group vs. 11 (4.0%) for the controls. The difference was not statistically significant. Major abnormalities, found in 20 (2.2%) of the infants from the women with migraine compared to 7 (2.5%) of the infants from controls, were of similar distribution to those found in the geographic area of the clinic (12). Moreover, the incidence of defects was similar to the expected frequency for that location (12). Although the investigators were unable to document reliable and accurate drug histories during the pregnancies because of the retrospective nature of the study, 70.8% of the women with migraine indicated they had used ergotamine in the past. They concluded, therefore, that ergotamine exposure during pregnancy, especially early in gestation, was highly likely, and that this drug and others used for the prevention or treatment of the disease were probably not teratogenic (12).
In contrast to the above study, six case reports have described adverse fetal outcomes attributable to ergotamine (13,14,15,16 and 17,19). An infant, who expired at 4 weeks of age, was delivered at 24 weeks' gestation with a large rugated, perineal mass, no external genitalia or anal orifice, and a small, polycystic left kidney (13). Two separate sacs made up the mass, one of which resembled a urinary bladder with two ureteral and a vaginal orifice, and the other containing bowel, left ovary, uterus and right kidney (13). The mother had used an ergotamine inhaler once or twice weekly during the first 8 weeks of pregnancy for migraine headaches. The inhaler delivered 0.36 mg of ergotamine per inhalation and she received two or three inhalations during each headache for a total dose of 0.721.08 mg once or twice weekly. The mother also smoked about 10 cigarettes daily.
A female infant with multiple congenital malformations was delivered from a woman who had used a proprietary preparation containing ergotamine, caffeine, belladonna, and pentobarbital during the 2nd month of pregnancy for migraine (14). Two other similar cases in pregnant women who did not receive an ergotamine preparation were included in the report. The birth defects included hydrocephalus, sacral or coccygeal agenesis, digital and muscle hypoplasia, joint contractures, short stature, short perineum, and pilonidal sinus. Because of the similarity of the cases, the authors thought it might be a new syndrome, which they termed cerebroarthrodigital syndrome, in which the primary pathogenetic event is a neural tube-neural crest dysplasia (14). Although they could not determine the cause, they considered an environmental agent, such as ergotamine, or a genetic cause as possibilities (14).
A 1983 report described a 27-year-old woman with migraine headaches who consumed up to 8 tablets/day of a preparation containing 1 mg of ergotamine tartrate and 100 mg of caffeine throughout a total of six pregnancies (15). The 1st pregnancy resulted in the birth of a 2200-g female infant, whose subsequent growth varied between the 3rd and 10th percentiles. She had no medical problems other than enuresis and hay fever. The woman's 2nd, 4th, 5th, and 6th pregnancies all ended in spontaneous abortions. A male infant was delivered in the 3rd pregnancy at 35 weeks' gestation. Birth weight, 1892 g, and length, 43 cm, were at the 20th percentile for gestational age. The infant died at 25 days of age secondary to hyaline membrane disease and after two surgical attempts to correct jejunal atresia. At autopsy, a short small intestine with portions of incomplete or absent muscular coat around the bowel lumen was found. The authors could not exclude a hereditary cause for the anomaly, but they believed the most likely cause was a disruptive vascular mechanism resulting from an interruption of the superior mesenteric arterial supply to the affected organ (15).
In a suicide attempt, a 17-year-old pregnant woman, at 35 weeks' gestation, took a single dose of 10 ergotamine tablets (20 mg) (16). Five hours after ingestion, the fetal heart rate was 165 beats/minute with fetal movement. Uterine contractions were mild but frequent, with little relaxation between contractions. Fetal death occurred approximately 8.5 hours later, about 13.5 hours after ingestion. The most likely mechanism for the fetal death was impairment of placental perfusion by the uterine contractions resulting in fetal hypoxia (16). However, the authors considered two other possible mechanisms: arterial spasm causing decreased uterine arterial perfusion, and altered peripheral resistance and venous return resulting in fetal myocardial ischemia (16).
A 1988 case report described the result of a pregnancy complicated by severe migraine headaches (17). The mother consumed a variety of drugs, including 14 rectal suppositories/week during the first 14 weeks of gestation, with each dose containing ergotamine (2 mg), belladonna (0.25 mg), caffeine (100 mg), and phenobarbital (60 mg). Other medications, frequency of ingestion, and gestational weeks of exposure were propranolol (40 mg; 2/day; 020 weeks), acetaminophen/codeine (325 mg/8 mg; 620/day; 016 weeks), and dimenhydrinate (75 mg; 03/week; 012 weeks). The term, female infant was a breech presentation weighing 2860 g, with a length of 46 cm. The infant was microcephalic and paraplegic with underdeveloped and hypotonic lower limbs. The anal, knee, and ankle reflexes were absent. Sensation was absent to the level of the knees and variably absent on the thighs. This pattern was suggestive of a spinal cord defect in the upper lumbar region (17). Other abnormalities apparent were dislocated hips and marked bilateral talipes equinovarus. Computed tomography of the brain revealed a small organ with lissencephaly, a primitive Sylvian fissure, and ventriculomegaly (17). The above findings were compatible with arrest of cerebral development that occurred after 1013 weeks (17). The authors concluded that the most likely etiology was a disruptive vascular mechanism, and that the combination of ergotamine, caffeine, and propranolol may have potentiated the vasoconstriction (17).
In response to the case report above, a 1989 letter cited prospective and retrospective data from the Hungarian Case-Control Surveillance of Congenital Anomalies, 19801986 system (18). Among controls (normal infants, but including those with Down's syndrome), 0.11% (18 of 16,477) had used ergotamine during pregnancy whereas 0.14% (13 of 9,460) of pregnancies with a birth defect had been exposed to the drug (difference not significant). Four of the index cases, however, involved neural tube defects compared to none of the controls (p<0.01), a finding that prompted the author to state that further study was required.
A female infant, the smaller of dizygotic twins, was born at 32 weeks' gestation (19). Paraplegia and arthrogryposis multiplex was present at birth and thought to be due to prenatal cord trauma. The mother had had a severe reaction (intractable nausea, vertigo and dizziness requiring bed rest for 3 days) following the use of one rectal suppository containing ergotamine, caffeine, belladonna, and butalbital at 4.5 months' gestation. Because of this reaction, the authors speculated that ergotamine may have caused vascular spasm of a fetal medullary artery that resulted in spinal cord ischemia and neuronal loss (19).
The accidental use at 38 weeks' gestation of a rectal suppository containing ergotamine (2 mg) and caffeine (100 mg) in a woman with nonproteinuric hypertension produced sudden fetal distress that led to an emergency cesarean section (20). A growth-retarded, 2660-g female infant was delivered with Apgar scores of 4 and 8 at 1 and 5 minutes, respectively. The obstetrician, who was unaware of the drug administration, noted the strikingly small amount (100 mL) of blood loss during the procedure. The infant was doing well at 10 years of age.
A 1995 Reference reviewed the teratogenicity of ergotamine (21). Because many of the reports of adverse outcomes following the use of the drug during pregnancy are consistent with vascular injury, and because ergotamine toxicity is known to cause vasospasm, the author recommended that the drug should be avoided during all parts of pregnancy (21). The use of the agent in small, appropriate doses, however, was thought to have a low teratogenic potential because ergotamine appeared to be teratogenic only at higher doses, or possibly in those cases involving idiosyncratic susceptibility (21). Recommendations for counseling of exposed women included not only determining the dosage and timing of exposure, but also asking questions relating to the presence or absence of signs and symptoms of ergotism, past usage, and possible continuing abuse (21).
In summary, small, infrequent doses of ergotamine used for migraine headaches do not appear to be fetotoxic or teratogenic, but idiosyncratic responses may occur that endanger the fetus. Larger doses or frequent use, however, may cause fetal toxicity or teratogenicity that is probably due to maternal and/or fetal vascular disruption. Based on one report, the combination of ergotamine, caffeine, and propranolol may represent an added risk. Because the risk has not been adequately defined, and also due to the oxytocic properties of the agent, ergotamine should be avoided during pregnancy.
Breast Feeding Summary
Ergotamine is excreted into breast milk, but data quantifying this excretion have not been located. A 1934 study reported that 90% of nursing infants of mothers using an ergot preparation for migraine therapy had symptoms of ergotism (22). Because of the vomiting, diarrhea, and convulsions observed in this study, the American Academy of Pediatrics considers the use of ergotamine during breast feeding to be contraindicated (23). Moreover, ergotamine 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 ergotamine on lactation, ergot alkaloids may hinder lactation by inhibiting maternal pituitary prolactin secretion (24).
- Gill RC, Farrar JM. Experiences with di-hydro-ergotamine in the treatment of primary uterine inertia. J Obstet Gynaecol Br Emp 1951;58:7991.
- Altman SG, Waltman R, Lubin S, Reynolds SR. Oxytocic and toxic actions of dihydroergotamine-45. Am J Obstet Gynecol 1952;64:1019.
- Griffith RW, Grauwiler J, Holdel CH, et al. Toxicologic considerations. In Berde B, Schild HO, eds. Ergot Alkaloids and Related Compounds. Handbook of Experimental Pharmacology. Volume 49. Berlin:Springer Verlag, 1979:80551. As cited in Hughes HE, Goldstein DA. Birth defects following maternal exposure to ergotamine, beta blockers, and caffeine. J Med Genet 1988;25:3969.
- Grauwiler J, Schon H. Teratological experiments with ergotamine in mice, rats, and rabbits. Teratology 1973;7:22736.
- Schon H, Leist KH, Grauwiler J. Single-day treatment of pregnant rats with ergotamine (abstract). Teratology 1975;11:32A.
- Greatorex JC, Mantle PG. Effect of rye ergot on the pregnant sheep. J Reprod Fertil 1974;37:3341.
- Foster JB. Migraine-traditional uses of ergot compounds. Postgrad Med J 1976;52(Suppl 1):124.
- Massey EW. Migraine during pregnancy. Obstet Gynecol Surv 1977;32:6936.
- Lance JW. The pharmacotherapy of migraine. Med J Aust 1986;144:858.
- Reik L Jr. Headaches in pregnancy. Semin Neurol 1988;8:18792.
- Heinonen OP, Sloan D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977:35860.
- Wainscott G, Sullivan FM, Volans GN, Wilkinson M. The outcome of pregnancy in women suffering from migraine. Postgrad Med J 1978;54:98102.
- Peeden JN Jr, Wilroy RS Jr, Soper RG. Prune perineum. Teratology 1979;20:2336.
- Spranger JW, Schinzel A, Myers T, Ryan J, Giedion A, Opitz JM. Cerebroarthrodigital syndrome: a newly recognized formal genesis syndrome in three patients with apparent arthromyodysplasia and sacral agenesis, brain malformation and digital hypoplasia. Am J Med Genet 1980;5:1324.
- Graham JM Jr, Marin-Padilla M, Hoefnagel D. Jejunal atresia associated with Cafergot ingestion during pregnancy. Clin Pediatr 1983;22:2268.
- Au KL, Woo JSK, Wong VCW. Intrauterine death from ergotamine overdosage. Eur J Obstet Gynecol Reprod Biol 1985;19:3135.
- Hughes HE, Goldstein DA. Birth defects following maternal exposure to ergotamine, beta blockers, and caffeine. J Med Genet 1988;25:3969.
- Czeizel A. Teratogenicity of ergotamine. J Med Genet 1989;26:6970.
- Verloes A, Emonts P, Dubois M, Rigo J, Senterre J. Paraplegia and arthrogryposis multiplex of the lower extremities after intrauterine exposure to ergotamine. J Med Genet 1990;27:2134.
- de Groot ANJA, van Dongen PWJ, van Roosmalen J, Eskes TKAB. Ergotamine-induced fetal stress: review of side effects of ergot alkaloids during pregnancy. Eur J Obstet Gynecol Reprod Biol 1993;51:737.
- Raymond GV. Teratogen update: ergot and ergotamine. Teratology 1995;51:3447.
- Fomina PI. Untersuchungen uber den Ubergang des aktiven Agens des Mutterkorns in die milch stillender Mutter. Arch Gynaek 1934;157:275. As cited by Knowles JA. Excretion of drugs in milk-a review. J Pediatr 1965;66:106882.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.
Vorherr H. Contraindications to breast-feeding. JAMA 1974;227:676.
Questions and Answers
Is ergotamine salt legal? and if it is, where can i buy it?, i was just wondering.
Morning glories are ****, too many toxins for too little lsa makes you really sick. HBWR has less negative side effects and you need ten times less seeds. Iamshaman.com, ktbotanicals.com, bouncingbearbotanicals.com
Sounds like you need to do ALOT more research into these plants however theyre here to learn from not be abused. Take the time to learn and you will benefit alot more. And no ergotamine salt is scheduled, and no even if you think you can i guarantee you cannot make what you are thinking with it, there a hundreds of types of ergot so supposing you actually got the right one, you need to be an experienced chemist and even then you will have probably fail.
how can i prenvent ergotamine in tablets from being darken and decomposed?,
Read carefully the leaflet containing information about drug use and proper storage that is inside the box.
I don't remember if there are any specific regiments for this drug but in general drugs are kept in their box, in a cool place without humidity(avoid the bath).
A general rule: if you need this kind of information, you can call by phone the pharmaceutical company that produces the drug.They answer usually also to phone calls, because they are interested in good maintenance of their product.
I can't help more,because the tablets are not anymore in use in my country, but just the suppositories.
ergotamine and its derivatives act on which receptors?,
5-HT1A (which I think is like a dopamine receptor); I've also seen references to catecholamine receptors
ergotamine maleate?, is there available in the pharmacy now a days coz i have migraine?
Ergotamine is available but by prescription only (if you live in the U.S.). I have no idea what the availability is in other countries.
What abortive do you use with hemiplegic migraine?, I have always suffered from severe migraine. Just recently I have been diagnosed with Hemiplegic Migraine. For abortive treatment I have tried almost everything to no avail (NSAIDS, antiemetics, various steroids etc.) Triptans and ergotamines cannot be taken with hemiplegic migraine because of high risk of stroke. The only thing that takes the pain away is narcotics but no doctor will prescribe them unless I've been suffering for weeks and can barely move. Since being diagnosed four months ago I have went from 145lbs to 99lbs because I'm so sick. Any advice would be appreciated
Any doctor that would stand by and do nothing while you are suffering to the extent of losing nearly 50 pounds is utterly incompetent. Keep looking till you find one with some compassion. Have you tried going to the emergency room? I once had migraine that I couldn't get under control with Imitrex so my doctor sent me to the ER to get better pain relief. I'm so sorry you have to suffer like this. I hope you can find someone that will help you.
what is ergotamine?,
A vasoconstrictor used to prevent/cure migraines.
What are the side effects of ergotamine tartarate "anti migraine therapy'?, I know that this drug is banned in many countries , but I am on for my migraine attacks which I must have one regulary every week .
I want to know why is it banned?
and what are its side effects on the long and short run?
honey , if you wanna leave islam then leave it Allah doesnt need you nor the muslims do nor the most hated thing in ur life does(sharia law) however, insultin Muslim countries is a different thing if you dont like it here then pls leave out of Egypt Im sure UK would love to have you
Migraine , latest researches about causes and prophylaxis , pls?, I used to take hydrogen malate ( an appetite stimulator and for migraine prophlaxis ) , but i want to reduce them
I take also ergotamine tartarate in the attack
the causes and the prophylaxis, pls?
There was an interesting programme on BBC Radio 4 recently about migraine, headaches, cluster headaches etc - you can listen to it at http://www.bbc.co.uk/radio4/science/chec... There is also a link there to the Migraine Trust, which has information about the latest research.
what can I do until the ambulance arrives?, mom took medication for treatment of migraine, contraindications:
coronary heart disease (which mom has)
Ergotamine tartrate 1 mg
paracetamol 250 mg
caffeine anhydrous 50 mg
domperidone 10 mg
I think she is dying, she stopped talking a few minutes ago and ambulance is on the way but may take a while, what can I do??
Try and keep her responding to you until they arrive.
Migraine attacks , how to reduce them?, I used to take hydrogen malate ( an appetite stimulator and for migraine prophlaxis ) , but i want to reduce them
I take also ergotamine tartarate in the attack
the causes and the prophylaxis, pls?
YA ISADORA, there are 100 reasons for migraine , you know that (eza wegdah al maa , batolah al tymom), anyway: i used those two methods for migraine and both work very well:
*Supplementation of coenzyme Q10 has a beneficial effect on the condition of some sufferers of migraines
*Botox is being used by many headache specialists for patients with frequent or chronic migraines with encouraging results
I tried both and the the botox is really magic,, (knowing that you are Hyper person , that will work for sure) , and drink tonic water to stimulate your appetite it works well too, as it has quinine (or drink quina if you are into alcohol) which stimulates the appetite ...
The best is to find a boy friend and get married , you will forget the migraine , eat much and get fat lol
PS :* of course you know ergotamine is illegal in half of the world as it causes dependence,
* I would advise you to try Rooibos tea but I know it is not availabe in Egypt...