Pii: s0140-6736(02)08658-0

Department of medical history
St Anthony’s fire and living ligatures: a short history ofergometrine Ergometrine, although now declining in use, has been hallucinations, especially a sense that the subject was the most important drug for prevention and treatment of flying; these symptoms were due to serotonin postpartum haemorrhage, which is still a major cause of antagonism by various components of ergot related to maternal mortality. “Ergot of rye”, wrote Francis lysergic acid diethylamide (LSD). The gangrenous and Ramsbotham, founder of the Obstetrical Society of convulsive forms of ergotism could occur concurrently.2,5 London, in 1841, “has been known to possess St Anthony himself was a third century Egyptian deleterious and poisonous qualities for more than 800 ascetic, who lived an unblemished life in the desert near years, and it has been used on the continent by female the Red Sea, fasting for long periods, which was midwives as a promoter of labour pains for nearly 150 probably the reason for the visions and temptations he is years”.1 Ergotism, or epidemic ergot poisoning, caused said to have experienced. He believed them to be the by eating affected rye bread, was indeed one of the work of the devil, and resisted steadfastly. In his own scourges of the Middle Ages, and use and abuse of ergot lifetime, Anthony had no direct connection with as a uterine stimulant by midwives has been frequently ergotism, however his name was taken by an Order of documented. The pharmacological properties of ergot Hospitallers, founded in France about 1100. The were recognised for centuries, although they were not Hospitallers, wearing black robes embroidered with blue well researched and publicised until the early 20th crosses, travelled widely across medieval Europe, ringing little bells to attract alms, and the hospitals they thus Ergot is the alkaloid-containing product of a fungus, funded became pilgrimage centres for sufferers from Claviceps purpurea, that grows on grain, especially rye.
ergotism.6 The Antonite monks were credited with many The fungal spores are carried by the wind to the ovaries cures, and thus Anthony’s name and life story became of young rye, where they germinate into hyphal attached to the disease. What were said to be the saint’s filaments. These grow deeply into the rye, forming a bones were sprinkled with holy water or wine, which was dense tissue that gradually takes over the grain and then drunk by the afflicted; however it seems more likely hardens into a purple curved spur or sclerotium (“ergot” that cures were related to the Hospitallers providing a is derived from “argot”, Old French for the cock’s spur).
diet free from contaminated grain. Amputated limbs The sclerotium is still the main commercial source of were frequently left at the sites of shrines to St Anthony as offerings of thanks and evidence of the saint’s success.
There are a couple of very early references to ergot: it The first mention of a plague of gangrenous ergotism was probably the “noxious pustule in the ear of grain” in Europe comes from Germany in 857; thereafter there noted on an Assyrian cuneiform tablet of around 600 are numerous records of epidemics in France, Germany, BC, and in one of the sacred books of the Parsees (400 BC to 300 BC) are mentioned “grasses that cause physician, gave an account of an epidemic that raged in pregnant women to drop the womb and die in the Kingdom of Hesse in 1596; he was one of the first to childbirth”.3 However rye was not eaten by the early attribute the cause of ergotism to grain.1 In the 17th Greeks and Romans, so there are no undisputed century many writers confirmed this connection.
references to ergotism in the literature of that period. It However; it was not until the late 18th century that was not until the Christian era that rye was introduced measures were suggested to combat ergot poisoning. into western Europe, and therefore not until the Middle S Tessier, observing a huge epidemic at Sologne, Ages that written accounts of ergot poisoning are found.4 France, in 1778 in which more than 8000 people died, Ergotism had two main manifestations: gangrene recommended drainage of fields, compulsory cleaning of (referred to as chronic ergotism) and convulsions (acute grain, and the substitution of potatoes for affected grain.7 ergotism). The first, known as Holy Fire or St Anthony’s Epidemics of ergotism continued to occur sporadically Fire, was characterised by intense burning pain and in Europe until the end of the 19th century; since then, gangrene of feet, hands, and whole limbs, due to the although outbreaks have occurred in less-developed vasoconstrictive properties of ergot. In severe cases, countries, ergotism in the more-developed world has affected tissues became dry and black, and mummified been confined to individual cases of ergotamine limbs dropped off without loss of blood. Spontaneous abortion frequently occurred. Convulsive ergotism was The dramatic symptoms and signs of ergotism gained the attention of many artists, particularly in the lateMiddle Ages. The German painter Matthias Grunewald,a contemporary of Albrecht Dürer and Lucas Cranach, painted for the Antonite friars in the Rhine Valley. Hedepicted figures with abnormal postures and seizures, Department of Obstetrics and Gynaecology, Cairns Base Hospital, probably modelled from patients with ergotism in the PO Box 902, Cairns 4870, Queensland, Australia (C De Costa) monastery.9 Hieronymus Bosch, Dutch contemporary of Grunewald and noted painter of religious allegories, THE LANCET • Vol 359 • May 18, 2002 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
among many other famous works, drew on the of the founders of the city’s Lying-In Hospital. Hosack temptations of St Anthony for his triptych, now in Lisbon observed cases of stillbirth associated with prolonged (figure 1); this picture depicts the saint himself and uterine contraction before delivery, and commented dryly: sufferers from various forms of ergotism with strange “Ergot has been called . . . pulvis ad partum; as it regards flying objects that represent hallucinations.7 the child, it may, with almost equal truth be denominated The first reference to use of ergot in childbirth seems the pulvis ad mortem.”3,10 Astutely, though, he recom- to be from 1582, when A Lonicer in Germany mended use of ergot for cases of postpartum recommended use of three sclerotia of ergot for the flagging contractions of prolonged labour.1,7 In At the time, and indeed for much of the 19th century, 1688, another German physician, R J Camerarius, stated postpartum haemorrhage was greatly feared as a killer of that “in some parts of Germany midwives are in the young mothers, and recognised as frequently due to failure of the recently emptieduterus to contract adequately.
Rights were not granted to include this image in electronic It was treated with various notvery effective remedies, media. Please refer to the printed journal.
including “a lemon imperfectlyquartered” or “a large bull’sbladder distended with water”,both of which were introducedinto the uterus, or douches ofvinegar or iron perchloride.11–13By the end of the century,however, ergot was recognisedby obstetricians as “the mostpowerful substance to stimu-late a uterine contraction” and although the dangers of itsuse in labour were nowrecognised, administration ofits extract in water wasrecommended for postpartum Figure 1: Hieronymus Bosch (c1450–1516), The Temptation of St Anthony
parturition”.1 In France, A-A Parmentier noted in his Journal de Physique of 1774 phrase “pulvis ad partum” (a powder [to aid] birth).7 All these accounts, however, part of the 19th century, but it was less “deleterious qualities” of the fungus. In 1808, John Stearns published in the Medical Repository of G Barger and H Dale in 1906, was initially thought to be New York “An Account of the Pulvis Parturiens, a Remedy a pure substance, but was later found to be a mixture of for Quickening of Childbirth” in which he stated that: “It four alkaloids; the first pure alkaloid, ergotamine, still expedites lingering parturition and saves to the used for its vasoconstrictive properties in treatment of accoucheur a considerable portion of time, without migraine, was obtained by A Stoll in 1918.2 Pure producing any bad effects on the patient . . . Since I have ergotamine had tonic effects on the uterus, but these were adopted the use of this powder I have seldom found a case slower to appear than when an aqueous extract of ergot that detained me more than three hours”.3 was administered. It was clear that there were more active That complications could result from use of the drug in alkaloids, and in their paper of 1932, Chassar Moir labour was, however, soon recognised, most notably by (figure 2) and H Dale described experiments with 2, 3, David Hosack, a prominent New York physician and one THE LANCET • Vol 359 • May 18, 2002 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
A sterilized rubber bag (was) passed into the puerperal postpartum myometrial stimulant.20 Nevertheless, ergo- uterus with full antiseptic precautions, and connected metrine still has a life-saving role in obstetric practice in by water-filled tubing to a mercury manometer. A light more-developed countries, and is likely to do so for the float on the manometer carries an ink point, which foreseeable future. In large parts of the less-developed records variations of intrauterine pressure on a slowly world, women continue to die, every day, who might be revolving drum . . . a remarkably short time . . . elapsed saved by judicious use of a few grams of the extract of between the swallowing of the extract and the onset of powerful uterine contractions . . . there was a rise in thebase line to an extent much greater than observed with In 1935, Moir and Dudley reported isolation of the active substance, “to which ergot rightly owes its long- 1 Ramsbotham F. The principles and practice of obstetric medicine established reputation as the pulvis parturiens. We and surgery. London: Churchill, 1841: 702–06. propose to name it ergometrine”.17 From 1935 on, pure 2 Peroutka S. Drugs effective in the therapy of migraine. In: Hardman JG, Limbird LE, Goodman Gilman A, eds. Goodman preparations of ergometrine (known as ergonovine in the Gilman’s the pharmacological basis of therapeutics (international USA) were given intravenously or intramuscularly both edition). NewYork: McGraw Hill, 1996.
prophylactically and for treatment of postpartum haem- 3 Thoms, H. John Stearns and pulvis parturiens. Am J Obstet Gynecol orrhage. The prolonged uterine spasm noted by Moir 1931; 22: 418– 23.
meant that the smooth muscle fibres of the myometrium 4 Clark BJ. The versatile ergot of rye. In: Parnham MJ, Bruinvels J, eds. Discoveries in pharmacology: haemodynamics, hormones, and could act as “living ligatures” around the vessels of the inflammation. Amsterdam: Elsevier, 1984: 3–33.
5 Parfitt K. Martindale: the complete drug reference; 32 edn. London: The maternal mortality rate in England in 1870 has been estimated at one woman in 20 births; in Saxony in 6 Farrer D. The Oxford dictionary of saints. Oxford: Clarendon, 1978: 1880, the rate is said to have been one in 66; in New 7 van Dongen PW, de Groot AN. History of ergot alkaloids from South Wales for 1894–96 a figure of one in 148 has been ergotism to ergometrine. Eur J Obstet Gynecol Reprod Biol 1995; 60:
quoted.15 By 1935, the maternal death rate in England and Wales was five per 1000, and by 1967, 0·2 per 1000, 8 King B. Outbreak of ergotism in Wollo, Ethiopia. Lancet 1979; 2:
figures elsewhere in Europe are similar.18 Admittedly, numerous factors contributed to this remarkable decline.
9 Garcia de Yebenes J, Garcia de Yebenes P. Dystonia in the painting of Matias Grunewald. Epidemic ergotism in the late Middle Ages.
However, it is widely accepted that haemorrhage was Arch Neurobiol 1991; 54: 37–40.
and still is the cause of a high proportion of maternal 10 Harrar JA. The story of the lying-in hospital of the city of New York: deaths, 25% being the acknowledged figure, and among society of the lying-in hospital of the city of New York, New York these haemorrhages most are postpartum and due to uterine atony.15,18 Undoubtedly, use, firstly of the 11 Norris RC. An American textbook of obstetrics. London: Rebman, aqueous extract of ergot, and later of the pure alkaloid 12 Davis DD. The principles and practice of obstetric medicine.
ergometrine, contributed enormously to this most London: Tayler and Walton, 1836: 1064–66.
welcome fall in deaths of young mothers in more- 13 Bar P, Brindeau A, Chambrelent J. La pratique de l’art des accouchements. Paris: Asselin Houzeau, 1890: 609.
Postpartum haemorrhage continues to be a major 14 Ramsbotham F. Obstetric medicine and surgery. London: Churchill, cause of maternal mortality in less-developed countries.
15 Edgar JC. The practice of obstetrics. Philadelphia: Blakiston, 1913: WHO statistics indicate that worldwide around 600 000 women die yearly of pregnancy-related complications. Of 16 Moir C, Dale HH. The action of ergot preparations on the puerperal these, about 100 000 have a postpartum haemorrhage uterus. BMJ 1932; 1: 1119–22.
due to uterine atony; a large proportion die without 17 Dudley HW, Moir C.The substance responsible for the traditional access to appropriate medical care, including ergometrine clinical effect of ergot. BMJ 1935; 1: 520–23.
18 Moir JC, Myerscough PR. Munro Kerr’s operative obstetrics. 8th edn. London: Bailliere Tindall and Cassell, 1971: 950–56.
Use of ergometrine has been criticised in recent years, 19 Donnay F. Maternal survival in developing countries: what has been and side-effects including nausea, vomiting, and done, what can be achieved in the next decade. Int J Gynecol Obstet hypertension have led to use of synthetic oxytocin, 2000; 70: 89–98.
misoprostol, and other prostaglandins for prevention and 20 Prendiville WJ, Elbourne DR, Chalmers I. The effects of routine treatment of postpartum haemorrhage. The literature oxytocic administration in the management of the third stage oflabour: an overview of the evidence from controlled trials. Br J Obstet abounds with details of the search for the perfect Gynaecol 1988; 95: 3–16.
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