The influence of estrogens on genuine pre-eclampsia and eclampsia

THE INFLUENCE OF ESTROGENS ON GENUINE PREyECLAMPSIA AND ECLAMPSIA EVAN

SHUTE,

M.D.

LONDON, ONTARIO

T

HAT estrogens are heIpfu1 in the prophyIaxis of true convuIsive ecIampsia has been cIaimed by both SiegIer’ and the author.2 3 The basis for such treatment, of course, is the finding that in eclampsia the estrogen vaIues in both bIood and urine are Iow,~~~ and the interesting experiments of Margaret Barrie3 who produced eclampsia-Iike conditions in rats. The Smiths6 have recentIy stated their beIief that the Iow estogen IeveI is the fundamental endocrine imbaIance in ecIampsia. It is probabIy unfortunate for the future of the hormone management of ecIamptic toxemia that certain workers have, on this basis, begun to administer SimuItaneousIy prodigious doses of estrogens and progesterone, which are antagonistic substances. To the previously published histories, the foIIowing case reports of ecIamptics may be added. They substantiate what has been cIaimed for oestrogen therapy in this disaster of pregnancy : CASE REPORTS CASE I. (Courtesy Dr. W. Hughes.) This primipara, aged sixteen years, was first seen at IO P.M. December 7, 1941. She had seemed normaI unti1 December 6, when she had had a one plus aIbuminuria. Her pressure then was 135/70. She was at term and had gone into labor spontaneously at 3.00 A.M. on December 6 at a hospita1 twenty-five miIes from here. The pains subsided, only to return at 2.30 A.M. on December 7. She mentioned some headache and dizziness during the three hours prior to deIivery and a mild stupor soon developed. She was given 54 cc. of pituitrin fifteen minutes before delivery. She had nembuta1 but no anesthetic for the labor, indicating the depth of her stupor. She finaIIy deIivered spontaneousIy at 8 A.M. on that day. The pIacenta 478

showed no infarction. The child was a 7 pound 3 ounce norma chiId. Her first convulsion came on at 12.30 noon and there were eight aItogether before I saw her at 10.00 P.M. At that time there was no edema. She was restIess, disoriented, but admitted no headaches nor eye symptoms. She had been given 3’~ gr. of morphine suIfate for her Iast convuIsion at 8.00 P.M. There was no liver tenderness. There was acetone on the breath. Her blood pressure was 135/65. A retention catheter was inserted at once, and IOO,OOOInternational Units of progynon B was injected intramuscuIarIy at the same time. Doses of 50,000 units were ordered for 3.00 A.M., 8 A.M. and 12.00 noon next day. On account of the acidosis she was given 500 cc. of IO per cent glucose intravenously at once. The catheter urine showed a two plus albuminuria but no red cells or bile. The blood estrogen’ was weakIy negative. I did not see her after that evening. At 1.20 A.M. she was given gr. 3; morphia as there had been a convuIsion at 1.00 A.M. She had an eight-minute Iong convulsion at 2.25 A.M. During that night her output was 28 ounces, almost free of aIbumen. At noon her pressure was 136/70. The intravenous glucose had been repeated at 10.00 A.M. by her own physician. On the morning of December 9 there were three more brief convulsions, involving only the arms or face. She had had no estrogens since noon of December 8. Accordingly, she was given 5 mg. of stilbestrol three times on the ninth and twice on the tenth day. She was quite cIear mentaIIy during a11 that day and there were no more convulsions. On December I o a puerperal psychosis began. This cleared up by December 17 and she was discharged from hospita1 on December 20. She has since displayed some schizophrenic tendencies. CASE II. This woman had previousIy had a term stiIIbirth, due to a hard forceps, and a spontaneous abortion. Her third pregnancy began on November I I, 1940, when she was

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thirty-seven years oId. When she was seen first on January 7, 1941, her weight was 163 pounds, 148/94 and her blood her bIood pressure estrogen was positive. She began to vomit a great dea1. This was controIIed quite well by repeated hypodermic injections of testosterone propionate.8 On March IO her weight was 168 pounds, blood pressure 136/90, and there was no edema. On March 25 146/94 and the dose of germ oil (Kelly’s) taking was accordingly raised to tablespoons weight was 177, her pressure jumped to 170/96 there was a moderate degree of of the I was called sister had noticed a for two days before there had been of the and for four days before. I gave her gr. 34 of morphia and sent her to the hospital tongue was greatIy ounces of were obtained, containing 40 Gm. of albumin per Iiter. given 50,000 InterUnits of progynon bIood estrogen stiI1 positive. every four hours, doses by nightfall. A.M.

12.30 noon the output begun to increase, couId and her tongue first. She remember everything until 7.10 A.M. of that day. At 8.00 P.M. the voIume of urine output was steadiIy increasing and the urine was much Iess bIoody, but the albumin was stiI1 4 pIus and 24 Gm. per liter, and her bIood pressure was sIowIy rising. She seemed we11 and rationa and had less edema of the eyelids. By 10.30 P.M. she was becoming restIess and confused and her pressure had not dropped. A bag induction with rupture of the membranes was carried out under cyclopropane anesthesia. The chiId was alive at that time. Her pressure soon feI1 to 160/1oo thereafter and she dozed quietIy most of the night. On the morning of May 22 she had no pains, and there was a fair amount of bIoody urine output. There was much less edema generally. She feIt and Iooked weI1. AI1 day her pressure varied between rgo/I24 and 180/1 IO. Strong

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uterine contractions began at 3.00 P.M. The bag came out at 9. I 5 P.M. By version and extraction a six months femaIe chiId was deIivered at 10.30 P.M. The placenta seemed norma but was sIightIy adherent. Her pressure was I 70/116 just after delivery. Next day there was onIy a one pIus aIbuminuria, 3 to 5 Gm. per liter. She made an uninterrupted recovery. She Ieft the hospita1 on May 31 with a 2 plus albuminuria (catheter) and some hypertension. On both August 15, and October 20 there was stiI1 a trace of albumin in the urine. Her blood pressure on June 13, 1941, was 156,/102. She felt we11 then and still does. CASEIII. This woman, aged thirty, had had a stillborn premature baby after eclampsia and two Iive children after her next two toxic pregnancies. She was admitted to the hospital in a semiconscious state on February 18, 1942, at 2.45 A.M. She was not due until April 5, had had the usual antenata1 care in the country, and had had a bIood pressure of 160/1oo and a slight ankle edema when she had last reported three days before. There had been great edema of the eyeIids, blurred vision, uterine pain and ‘I indigestion ” the day before admission. A mustard plaster had been used for this. She had also bled from the vagina on that day. She Iater mentioned that there had been no feta1 movement since the afternoon of that day. There had been a convulsion at midnight. At that time her physician in the country had administered 36 gr. of morphine. When she was seen by us she was wiIdIy incoherent and threshing about. Her pressure was 90/70. There was a slight ankle edema. It took three peopIe to hoId her in bed and it was quite impossible to Iisten to the fetal heart. We stayed with her for two and one-haIf hours, and finaIIy she became more manageable with an additiona ?i gr. of morphine. A retention catheter was inserted at the first, of course, and 100,000 International Units of progynon B were given intramuscuIarIy. Her first 2 ounces of urine showed 4 plus albumin and 15 to 20 red cells and 30 to 50 white cells per low power fieId. By 8.00 A.M. she was stiI1 somewhat frantic, and unfortunately got another 34 gr. of morphine from the house officers. Her urine then showed only a 2 plus albumin. Her output had increased greatIy but couId not be measured as she had spiIIed into the bed after tearing out her catheter. At 9.00 A.M. she seemed nearly rational. By 10.00 A.M. she couId count fingers and

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henceforth was we11 oriented. Her bIood pressure then was 106/90. She was given 5 mg. of stiIbestro1 every three hours that day, and daiIy thereafter, with no further sedatives. Opthalmoscopic examination of the fundi showed no abnormaIity. There was a sIight edema of the abdomina1 wall. At 10.30 A.M. weak pains began but soon stopped. She slept much of the day. Her urine at noon had only a 2 pIus albumin. At 2.00 P.M. her pressure was 108186 and 12 more ounces of urine had been obtained. There was much pus but almost no red cells. The fetal heart beat could not be heard. By 7.00 P.M. her output had been 8 ounces, her pressure was 120/86, and the membranes were ruptured artificialIy. Her speech was sIightIy thick and her tongue numb. There was old bIood in the amniotic fluid. Weak pains soon began. At I I .OO P.M. her output was another 18 ounces and by 4.00 A.M. on February 19 another 38 ounces had been passed, with a 3 pIus aIbumin, much pus, and some red cells. She precipitated, at 5.35 A.M. of the same day, a stiIIborn femaIe chiId, not macerated. The pIacenta was normal in appearance. At 10.00 A.M. her pressure was 135190 and she seemed norma in every way. On the foIIowing day her bIood pressure was 160/108 and on February 23 134/76. Her recovery was

uninterrupted. An intravenous estrogen of high potency is a real desideratum for these cases. This has been pointed out before9 and certairdy merits the consideration of the pharmaceutica1 houses. EstradioI benzoate given intramuscuIarIy takes about seven hours to act, and much can happen to a convuIsive patient in that time. TRUE

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CASE IV. This patient, a primipara aged twenty-seven years, was first seen on May 22, 1940. Her Iast menses had begun on February 23. Her weight was 135, her bIood pressure 106/76 and her urine was free of aIbumin. Her bIood estrogen was positive and, therefore, she was put on a dram of KeIIy’s wheat germ oi daiIy. This was raised to a tabIespoonfu1 per day in September because of uterine tenderness and vagina1 “pressure,” and she went to Muskoka on a vacation. Suddenly, on September 20, she developed considerable edema extending up to the knees, a morning headache,

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and some vague visua1 symptoms. There was no Iiver tenderness nor eIevation of blood pressure. Her weight was 138 pounds. Her urine was cIear. There was nothing to suggest either a nephritis or nephrosis. Suspecting that the wheat germ oi1 was precipitating an early ecIampsia,3f10 we gave no more. After three and a haIf days, by which time al1 vitamin E effects shouId have worn off, the estrogen test was still negative; therefore, we concIuded that she might do better on an estrogen. She was given 2 mg. of stiIbestro1 per day. Her symptoms and edema disappeared promptly. Late in October some Ieg edema recurred. On November I I, her weight was 155 and pressure I 10/66, on 4 mg. of stiIbestro1 per day at that time. On December 3, her bIood pressure had risen to 140/100, there was a trace of albumin in the urine, her weight was 154, there was a sIight leg edema, and she had begun to have morning headaches and spots before her eyes for the first time in months. AccordingIy, her dose was raised to 5 mg. of stiIbestro1 per day. On December 5, there was no edema, no albuminuria, her pressure was I 26/76, she felt we11 and she reported that she had had profuse urinations in the preceding two days. She had occasiona spots before her eyes in the next nine days, but no headaches nor edema. Labor began spontaneousIy on December 14. A maximaIIy diffIcuIt breech delivery resuIted in a fine 8 pound baby girl. Both mother and chiId did weI1. On March 25, 1941, her weight was 146 and bIood pressure 102/70. There was no aIbuminuria. CASE v. This was an unmarried primipara, eighteen years of age, whose Iast menstrua1 date was ApriI 28, 1941. She was first seen October 27, 1941, when her weight was 130 pounds, her pressure I 10/64, her urine clear, and her bIood estrogen negative. She had a compIeteIy uneventfuI pregnancy. On January 31, 1942, her weight was 135, her pressure 144/70 and her urine clear. There was no edema. On February 6, 1942, she began Iabor Spontaneously at 10.00 A.M. She was sent to the hospital. By 5.00 P.M. she was diIated aImost 7 cm., with moderate pains occurring every three to five minutes. At 8.30 P.M. she was 9 cm. diIated, and was drowsy between pains. She was compIeteIy oriented and had no headaches nor visua1 complaints. There were strong pains every two minutes but

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no outcry. Indeed, she probabIy couId have delivered without anesthesia. A catheter urine sampIe reveaIed but the faintest trace of albumin, but onIy two ounces was obtained, the first since admission. There were jerky little hand and arm movements if her body were touched and her reflexes were markedIy hyperactive. Her blood pressure had jumped to 14o/g6. She was a direct O.D.P. at the outIet at 9.45 P.M. and accordingIy a manua1 and forceps rotation and Iow forceps delivery were done. The chiId was an 8 pound 13 ounce boy and his shouIders were very diffIcuIt to extract. The pIacenta came in thirty minutes and showed onIy one, oId white infarct z cm. in diameter near one margin, penetrating the pIacenta1 substance. She was given IOO,OOOInternationaI Units of progynon B during deIivery and 50,000 units more at 1.00 A.M. Next morning she seemed norma in every way, had a bIood pressure of I 16/84, but a catheter urine showed a I pIus aIbuminuria. She was put on 5 mg. of stiIbestro1 daiIy and made an easy convaIesence. CASE VI. This woman, aged forty years, had had two normal pregnancies, then a spontaneous abortion, and finaIIy a macerated premature. Her Iast menstruation began November 12, 1939, and she was first seen February 2, 1940, when her weight was 142 pounds, urine cIear, blood pressure 140/84 and bIood estrogen negative. She was we11 unti1 May g when her weight had risen to 155 and her pressure to she was given 2 mg. of I 50/78; therefore, stiIbestro1 per day. On June I I, her weight was I 56, her pressure 140/78, and she had a minima1 leg edema, but a clear urine. Her stiIbestro1 dose was raised to 4 mg. on June 25. On JuIy 2, her weight was 160, pressure 184/112 and her stiIbestro1 was reinforced with 50,000 Internationa Units of progynon B. On July 5, her weight had faIIen to 159, her pressure to I 56/105 and her urine was stiI1 normal. She was put on a daiIy dose of 5 mg. of stiIbestro1 henceforth. She had 50,000 InternationaI Units of progynon B twice a week and by JuIy 18 her weight was I 62 and her pressure had dropped to I 56/go. There was some leg edema at this time. On July 30, her weight was 164, her pressure was I 76/104, there was considerabIe leg edema and the urine had a pIus albumin for the first time. On August 15, her weight was 162, pressure I 78/go and there was a 2 pIus aIbuminuria. She went into Iabor spontaneousIy on August

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18, but was slow in getting under way; her membranes were artificiaIIy ruptured at 10.30 A.M. the foIlowing day. Strong pains began at 8.00 P.M. At noon on August 20 a 7 pound IO ounce gir1 was deIivered. The pIacenta came easiIy, dispIaying a white infarction of a cotyIedon at one margin. She had some postpartum bIeeding and severe shock, but thereafter made an easy convaIescence. On October 24, her pressure was 16o/g6. The foIIowing March she had an operation for gIaucoma. CASE VII. This primipara, aged twentyeight years, menstruated Iast on July 20, 1940. When she was first seen on September 12 she had a bIood pressure of 156/108, a cIear urine, and weighed 132 pounds. Her bIood estrogen was weakIy negative. On October 2 I her weight was 134, her pressure 138/go and she was therefore given 2 mg. of stiIbestro1 per day. This dose was reduced to I mg. on October 28 when her bIood pressure had faIIen to 106/68, but was raised to 2 mg. again on January 27, when her weight was 155, pressure I 14/76 and a minima1 amount of Ieg edema had appeared. On March 13, the edema of the Iegs was very marked, her weight was 160, and her pressure 144/76. She was then taking 5 mg. per day of stiIbestro1. On March 20, her weight was 163 and pressure 104/68. She went into labor spontaneousIy on March 27 with onIy moderate pains and was compIeteIy dilated in four hours. A boy weighing 6 pounds g ounces was soon delivered. The pIacenta came easily. There was one smaI1, shaIIow, marginal crescent. There was some bIeeding after I had Ieft the hospita1 and therefore 1,000 cc. of intravenous glucose was given She made a good recovery. On May 26, 1941, her blood pressure was 140/86 and her weight 142 pounds. CASE VIII. This woman had had one normaI pregnancy. She was twenty-nine years old when seen on January 23, 1941, in her second pregnancy. Her Iast menstruation had begun on September 8. When seen she weighed 136 pounds, had a pressure of I 26/80 and a negative blood estrogen, with cIear urine. On February 20, her weight was 140, her pressure 150/88, her urine still was cIear and there was no edema. She was put on 2 mg. of stiIbestro1 per day. On March IO, her weight was 145 and pressure I 34/76, with no edema. On ApriI I 5, her weight was 150 and pressure 12a/go, with slight leg edema. She was raised to 3 mg. of stiIbestro1 per

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day. On May 22, her weight was 157, pressure 144/86, there was no edema and the urine was cIear. She was raised to 5 mg. of stiIbestro1 per day. On June 12, her weight was 159, pressure 140/96, there was no edema, she feIt we11 and the urine was cIear. She was taken off saIt and miIk. On June 21, she precipitated, at home, an 8 pound 4 ounce norma femaIe. The placenta was normaI. Her convaIescence was uneventfu1. CASE IX. This patient was a primipara, aged twenty-one years. Her Iast menses began on March 2, 1940. When seen first on October I 7 her weight was I 66 pounds and her pressure 142/88; there was no edema, but a sIight hydramnios, and the blood estrogen was a weak negative. AccordingIy, she was put on 2 mg. of stiIbestro1 per day. This nauseated her. AccordingIy, she was changed to 0.24 mg. thee101 per day. On November 14, her weight was I 72, pressure I 34/82, and there was a trace of aIbuminuria. The hydramnios had gone. On November 21 she had a plus aIbuminuria, her pressure was I 20/80 and there was sIight edema of the ankIes deveIoping. Labor began spontaneousIy on December I I at midnight. The pains were weak throughout. At 2.20 P.M. I did an extremeIy diffIcuIt midforceps and deIivered a fine 9 pound 2 ounce boy. The pIacenta showed three very shaIIow whitish areas near the margin. There was sIight postpartum hemorrhage. The next day h&r pressure was 144/86. She deveIoped a mastitis after she Ieft the hospita1. CASE x. This woman had had an induced abortion previousIy. When first seen on JuIy I 3, 1940, she was twenty-six years oId. Her last menses had begun on March 23. Her weight was I 18 pounds, her pressure was I 14/60, her urine was cIear, and her bIood estrogen was negative. On October I, her weight was I 33 pounds, and her pressure had suddenIy increased to 126/86. There was a sIight edema of the fingers and legs. The bIood estrin was again negative, and she was therefore given 2 mg. stiIbestro1 per day. On October 8, her pressure had dropped to I 12/66 and she felt well. On November 9, her weight was 141, pressure I 10/70 and she compIained of hot fIushes and spots before her eyes. On November 30, her weight was 144, her pressure 118/70, there was some edema of the fingers, and she admitted that she had been off the stiIbestro1 for a week. There were stiI1 spots before her eyes but no headaches; she said her no head “ pounded ” when she was taking stiIbestro1. The bIood estrogen again was nega-

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tive. She was again given 2 mg. of stiIbestro1 per day. On December 28, her weight was 15 I pounds, her pressure I I Z/74, and there was sIight edema of the Iegs and fingers. She had had great edema three days before, had raised her own dose to 8 mg. per day and voIunteered the observation that a great increase in urine output had ensued. On January 7, her weight was 154 pounds, her pressure I 14/60, she was “sIeepy,” had specks before her eyes, had sIight edema and compIained that her head feIt “fuI1”; and so was given 50,000 InternaGonaI Units of progynon n. She was induced on January 9 when ten days overdue with artificia1 rupture of the membranes. She had a Iow transverse arrest and forceps deIivery of a boy weighing 7 pounds, II ounces. The pIacenta had one narrow, white, margina crescent. She had an acute mastitis of both breasts after her discharge from the hospita1. CASEXI. (Courtesy of CoI. W. Mace.) This patient, aged twenty-nine years, was a primipara. Her Iast menses began on November 15, 1940. When her physician joined the army she was sent to me. On JuIy IO, 1941, her weight was I 75 pounds, her bIood pressure was I 3z/g4, and there was a minima1 edema of the Iegs and fingers. Her bIood estrogen was negative; therefore, she was taken off saIt and miIk and given 2 mg. of stiIboestro1 per day on JuIy 21. On July zg, her weight was 176, her pressure 134/g4 and the edema was the same. There was some choIecystitis. Her urine was clear. The dose of stiIbestro1 was raised to 4 mg. per day. This was maintained unti1 her deIivery. On August 23, her weight was 180, her pressure 132/96, there was a trivia1 Ieg edema, and the urine was clear. Spontaneous Iabor began on August 24. Her pains were very sIuggish and she was rested that night with morphia. In the morning her membranes were ruptured artificiaIIy. A forceps rotation was finaIIy done and a 7 pound, 12 ounce boy was deIivered. The pIacenta came easiIy. There was one tiny marginal crescent on the maternal surface. The recovery was uneventfu1. UndoubtedIy, in the Iight of Iater experience, many of these women shouId have had Iarger doses of estrogens. DISCUSSION It has been said “There situations; there are onIy

are no hopeIess men who have

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grown hopeIess about them.” These case histories speak for themseIves. A carefuI perusa1 of them wiI1 indicate the value of estrogens in the management of true preecIampsia and even in convuIsive cases of ecIampsia. It is to be noted that a11 the pre-eclamptics remained ambuIant. This therapy shouId be, and is, more effective for pre-ecIampsia than for ecIampsia, for prophylaxis than for therapy. Therefore, the recognition of true pre-eclampsia is the crux of the situation. l’his is usuaIIy diffrcult on a pureIy clinica basis; a bIood estrogen assay is a sine qua non. Those who object to the author’s assay method7 must find one that is more satisfactory and use it. Otherwise this therapeutic method wiI1 be discredited, for estrogens given to the vast majority of so-called pre-ecIamptics can be of no assistance and may actuaIIy do harm, perhaps precipitating abruptio pIacentae. 2,l l Most so-called “ pre-ecIampsia ” cases aIready possess too high an estrogen, shouId be given vitamin E, convuIsions. It is a pity that Ioose use of the term preecIampsia for every Iate toxemia of pregnancy shouId vitiate most of the Iiterature on the subject. SUMMARY I. The case reports of three convuIsive ecIamptics and of eight true pre-eclamptics are presented in detail. One of the Iatter was induced and a11 remained ambulatory.

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2. AI1 were favorabIy influenced by the administration of estrogens. 3. This therapy is more effective in the prophylaxis than in the contro1 of convuIsive ecIampsia, as couId be anticipated. 4. A bIood estrogen assay is a sine qua non in the recognition of genuine pre-eclampsia. REFERENCES I.

2.

3.

4.

5. 6.

7.

8.

9.

10.

SIEGLER, S. L. Estrogenic and chorionic gonadotrophic hormone in normal pregnancy and in toxaemia of pregnancy. J. Lab. tf Clin. Med., 24: 1277-1281, 1939. SHUTE, E. V. The use of estrin in the treatment of eclampsia. Endocrinology, 2 I : 594-598, 1937. Idem. The effect of estrogens on true pre-ecIampsia and ecIampsia. Am J. Obst. c~ Cynec., 40: 1003101 I, 1940. SMITH, G. V. S. and SMITH, 0. W. Evidence for pIacenta1 origin of excessive prolan of Iate pregnancy toxaemia and ecIampsia. Surg., Gynec. Ed Obst., 61: 175-183, 1935. MUHLBOCK, 0. Free and combined oestrogens in bIood during pregnancy. Lancer, I : 634, 1939. SMITH, G. V. S. and SMITH, 0. W. Estrogen and progestin metabolism in pregnancy; endocrine imbatance of pre-eclampsia and eclampsia. J. Clin. Endocrinology, I : 470-476, 1941. SHUTE. E. V. Determination of the estrorrenic substance in bIood serum by means of an estimation of the antiproteoIytic power of the serum. Am. J. Obst. EdGynec., 35: 970-77, 1938. Idem. Hormone management of the nausea and vomiting of earIy pregnancy. Am. J. Obst. &+ Gynec., 42: 490-492, 1941. Idem. The diagnosis and treatment of the common disorders of menstruation. Canad. M. A. J., 40: 38-43, 1939. Idem. Vitamin E. Symposium. London, England,

1939. I I. Idem. The prophylaxis of abruptio ptacentae with vitamin E. Surg., Cynec. and Obst., (in press).