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TRANSPLACENTAL FETAL BLEEDING IN SPONTANEOUS ABORTION
1161
TRANSPLACENTAL FETAL BLEEDING IN SPONTANEOUS ABORTION HOWARD F. TASWELL OSCAR LITWAK EDWARD A. BANNER Sections of Clinical Pathology and Obstetrics and Gynœcology,
Mayo Clinic and Mayo Foundation, and Mayo Graduate School of Medicine, Rochester, Minnesota, U.S.A. Of thirty-six patients undergoing sponabortion, thirteen had fetal erythrocytes in their circulation compared with only two in a control group of twenty healthy pregnant women. Dilatation and curettage of the uterus for incomplete abortion increases the volume and number of transplacental hæmorrhages. Administration of anti-Rho immunoglobulin should be considered for Summary
those
taneous
Rh-negative
women
at
risk who
undergo
an
abortion. Introduction FETAL erythrocytes have been found in the circulation of pregnant women from the second month of gestation to term.1 For the Rh-negative mother bearing an Rh-positive fetus, the major immunising threat posed by the fetal erythrocytes is during labour and delivery. Administration of anti-D (Rho) hyperimmune gammaglobulin at this time or within 72 hours of the delivery prevents Rh-isoimmunisation of those mothers who are at risk and who have not been previously
Patients and Methods We studied thirty-six aborting women whose pregnancies had advanced to between the 8th and 20th weeks of gestation. Of these, fifteen had completely aborted, fourteen had aborted incompletely, and seven were threatening to abort. When the patient was admitted to the hospital, 2 ml. of maternal venous blood was taken and anticoagulated with edetate. A second sample was obtained postoperatively on all patients requiring uterine curettage. All samples were refrigerated and processed within 24 hours; the acid elution technique of Kleihauer et a1. was used for identification of fetal erythrocytes. Twenty healthy pregnant women, at 8-20 weeks of gestation, served as controls. Smears of adult blood, cord blood obtained after term deliveries, and mixtures of both were examined repeatedly for control of the technique. Two smears of each sample were prepared and, at a magnification of x 450, 100 fields were scanned in each smear. Bright red, highly refractile erythrocytes were considered to be fetal in origin. If the average number of fetal erythrocytes in both smears was 1 or more per 100 fields, the specimen was considered to be positive. Results
Of the thirty-six aborting patients, thirteen (36%) had fetal erythrocytes in their circulation (mean number per 100 fields: 1, 1, 1-5, 2, 2, 2-5, 3-5, 4, 4-5, 5, 6-5, 8, 40) compared with only two (10%) of the twenty controls (1-5 cells per 100 fields in each). This difference is statistically significant (P=0-04, X2 test). The average fetal cell score was 6 erythrocytes per 100 fields in the aborting group compared with 1-5 in the control
sensitised.2
group.
Potter3 suggested that, in either spontaneous or induced abortions, fetal erythrocytes penetrated the maternal circulation in sufficient amounts to be immunising; moreover, she felt that cervical dilatation and uterine curettage made this penetration more likely. Gellen et a1.4 and Matthews and Matthews5 noted increased numbers of fetal erythrocytes in the maternal circulation after surgical termination of pregnancy. We assume that, in those immunised Rh-negative women who have a history of abortion preceding the birth of their first affected infant, a shower of fetal cells into the maternal circulation had occurred in association with the abortion. However, in one series of spontaneous abortions 5 the incidence of fetal bleeding was only 6%. We have investigated the frequency of transplacental fetal bleeding in spontaneous abortion and the effect of uterine curettage for incomplete abortion.
fields).
11.
12. 13.
Adinolfi, M., Gardner, B., Gianelli, F., McGuire, M. Experientia, 1967, 23, 271. van Furth, R., Schmit, H. R. E., Hijmans, W. Immunology, 1966, 11, 29. Takahashi, M., Yagi, Y., Moore, G. E., Pressman, D. J. Immun.
1969, 102, 1274. Coombs, R. R. A., Gurner, B. W., Janeway, C. A., Wilson, A. B., Gell, P. G. H., Kelus, A. S. Immunology (in the press). 15. Coombs, R. R. A., Gell, P. G. H. in Clinical Aspects of Immunology (edited by P. G. H. Gell and R. R. A. Coombs); p. 3. Oxford,
14.
1968.
16. 17.
Coombs, Coombs,
18. 19.
Gold,
R. R. A., Franks, D. Progr. Allergy, 1969, 13, 174. R. R. A., Gleeson-White, M. H., Hall, J. G. Br. J. exp.
Path. 1951, 32, 195. E. R., Fudenberg, H. H. J. Immun. 1967, 99, 859. Chalmers, D. G., Coombs, R. R. A., Gurner, B. W., Dausset, J. Br. J. Hœmat. 1959, 5, 225.
All fourteen patients with incomplete abortion underwent dilatation and curettage of the uterus; five (36%) of these had fetal erythrocytes in their circulation preoperatively. Postoperatively, the number of positive smears had increased to eight (57%). In two of the five patients with fetal erythrocytes preoperatively, the fetal cell score increased from 2 to 22 and from 2 to 34 per 100 fields; except for these two patients, the increases in fetal cell score were small (0-2 per 100 Discussion We found fetal erythrocytes in the circulation of a third of our patients who were in the process of abortion. The Rh antigen develops very early in life and has been demonstrated in the blood of a 38-day-old fetus.7 an abortion the Rh-negative is confronted with a potentially immunising dose of fetal erythrocytes. Therefore, these women should only be subjected to dilatation and curettage of the uterus when absolutely necessary and, in general, should be subjected to as little uterine manipulation as possible, to avoid a further antigenic insult. Further work is in progress to enlarge this series and to determine the relationship of transplacental haemorrhage to the stage of gestation, gravidity, and other variables. However, the possibility of maternal sensitisation to the Rh antigen by spontaneous abortion should be borne in mind, and strong consideration should be given to the administration of anti-Rho immunoglobulin to those unsensitised Rh-negative patients who are married to a Rh+ man and who undergo abortion. Requests for reprints should be addressed to H. F. T., Mayo Clinic, Rochester, Minnesota 55901, U.S.A.
Consequently, during
woman
1162
FENFLURAMINE OVERDOSAGE IAN RILEY
Poisoning
Treatment Centre,
JOHN CORSON Royal Infirmary of Edinburgh
IAN OSWALD IJAZ HAIDER and Royal Infirmary of Edinburgh Department of Psychiatry, University of Edinburgh Three young
who had ingested 800, 600, and 400 mg. of fenfluramine are described. Clinical features included dilated, nonreactive pupils, rotary nystagmus, hypereflexia, jaw tremor, and feelings of heat, without loss of consciousness. Electroencephalographic sleep studies indicated features similar to those of mild amphetamine intoxication and, later, withdrawal. Summary
women
was a continuous tremor of the lower jaw with chattering of the teeth. Stomach washout was done, and tablet material was retrieved. At 9 A.M. she was hyperventilating and the widely dilated pupils reacted sluggishly to light. Arterial blood-gas analyses showed a respiratory alkalosis-serum pH 7-55, standard bicarbonate 25 meq. per litre, and pc02 21 mm. Hg. Blood-glucose was 59 mg. per 100 ml. A forced acid diuresis was started at 1 P.M. She was given 3 litres of fluid including 70 meq. of ammonium ion intravenously during 4 hours. At the end of this time she was ventilating normally, was less agitated, and the tremor of the lower jaw was absent. The arterial blood-gas analysis now showed a pH of 7-32, standard bicarbonate 16-6 meq., per litre, and pco2 28.5 mm. Hg. The table shows the total excretion of urinary fenfluramine. URINARY EXCRETION OF FENFLURAMINE
Introduction
FENFLURAMINE (’Ponderax’) is an amphetamine derivative and an antiobesity drug. It increases forearm-muscle glucose uptake in man,! and affects fat mobilisation in a manner different from methamphetamine.2 It lacks the " stimulant " action of dexamphetamine, and tends to cause sleepiness. In consequence, studies of sleep are included in our description of three patients with acute overdosage. The normal daily dose is two to six tablets (40-120 mg.). Methods Since the management of acute amphetamine overdosage may include forced acid diuresis,3 this treatment was undertaken on one patient. Electroencephalographic (E.E.G.) studies were carried out (a) during wakefulness after Most amphetamines admission and (b) during sleep. R.E.M. (rapid-eye-movement) sleep and, when suppress withdrawn, a rebound excess of R.E.M. sleep occurs, especially in the early hours of sleep (e.g., after dexamphetamine and phenmetrazine,4 tranylcypromine,5 and
diethylpropion).6g Volatile amphetamine-like substances were quantitatively determined in the urine by the method of Tompsett.The presence of fenfluramine, and its desmethyl metabolite in minor amounts, was confirmed by gas-liquid chromatography.a Case-reports FIRST CASE
A
16-year-old girl was admitted to the Regional Poisoning Treatment Centre, Royal Infirmary of Edinburgh at 2.30 A.M., 31/2 hours after the ingestion of forty tablets (800 mg.) of fenfluramine. She was agitated, anxious, uncooperative, flushed, sweating, and slightly obese. Her height was 155 cm. and weight 59-4 kg. Blood-pressure was 120/80 mm. Hg., pulse 134 per minute, regular in time and force, temperature 99-0°F, and respirations 22 per minute. She was fully conscious with dilated pupils, unreactive to light; there was a rotary nystagmus, and the deep tendon reflexes were brisk and symmetrical. A pronounced feature
A further 36-7 mg. of fenfluramine after which excretion ceased.
She did
3. 4. 5. 6. 7.
Freese, U. E., Titel, J. H. Obstet. Gynec. 1962, 22, 527. Woodrow, J. C., Clarke, C. A., Donohoe, W. T. A., Finn, R. McConnell, R. B., Sheppard, P. M., Lehane, D., Russell, S. H., Kulke, W., Durkin, C. M. Br. med. J. 1965, i, 279. Potter, E. L. Rh: Its Relation to Congenital Hæmolytic Disease and to Intragroup Transfusion Reactions. Chicago, 1947. Gellén, J., Kovács, Z., Szontágh, F. E., Boda, D. Br. med. J. 1965, ii, 1471. Matthews, C. D., Matthews, A. E. B. Lancet, 1969, i, 694. Kleihauer, E., Braun, H. Betke, K. Klin. Wschr. 1957, 35, 637. Bergström, H., Nilsson, L.-Å., Nilsson, L., Ryttinger, L. Am. Obstet. Gynec. 1967, 99, 130.
not seem to
excreted
over
the
next two
sleep
recorded
the first
night. Her wholeby electroencephalography on on
night sleep nights 3, 4, 5, 6, 8, 9, 11, 12, 14, 15, and 19 after overdose. It was frankly abnormal on night 3, and 11 minutes of R.E.M. sleep occurred at initial sleep onset, instead of after about an hour as is normally the case.9Her all-night percentage of R.E.M. sleep was not abnormal, but was highest on that night. There was some accentuation of E.E.G. sleep spindles on the same night. The percentages of sleep as R.E.M. sleep on the various nights were 29-8, 24-1, 22-8, 27-1, 22-9, 20-2, 24-2, 258, 267, 23-1, and 20-8, respectively, was
all within normal limits. There were two other features which also suggested abnormality of rebound type-a short delay of 45 minutes (night 4) from sleep onset to first R.E.M. sleep and excess R.E.M. sleep within the first 2 hours of sleep, namely, 31 minutes (night 5). This girl had been prescribed the fenfluramine because she was overweight. There were difficulties in her relationship with her father and while away from home she took the overdose in an attempt to avert imminent return home. SECOND CASE
16-year-old girl was admitted at 10 P.M., having ingested 30 tablets (600 mg.) of fenfluramine 21/2 hours earlier. She complained of a burning sensation in her epigastrium, of feeling hot all over, and of some blurring A
of vision. She was
fully conscious and cooperative, but flushed and height was 157-5 cm. and weight 56-25 kg. Blood-pressure was 130/90 mm. Hg., pulse 130 per minute, regular in time and force, respiratory rate 30 per minute, axillary temperature 104°F (39-9°C). The pupils were widely dilated and failed to react to light. A rotary
warm.
1. 2.
was
days,
Her
nystagmus, and a weakness of the left lateral rectus muscle were present. There was a continuous tremor of the lower jaw with chattering of teeth. Generalised hyperflexia and ankle clonus were present. The bloodgases after stomach washout revealed a pH of 7-35, a pco2 of 43 mm. Hg, and a standard bicarbonate of 22 meq.
TRANSPLACENTAL FETAL BLEEDING IN SPONTANEOUS ABORTION HOWARD F. TASWELL OSCAR LITWAK EDWARD A. BANNER Sections of Clinical Pathology and Obstetrics and Gynœcology,
Mayo Clinic and Mayo Foundation, and Mayo Graduate School of Medicine, Rochester, Minnesota, U.S.A. Of thirty-six patients undergoing sponabortion, thirteen had fetal erythrocytes in their circulation compared with only two in a control group of twenty healthy pregnant women. Dilatation and curettage of the uterus for incomplete abortion increases the volume and number of transplacental hæmorrhages. Administration of anti-Rho immunoglobulin should be considered for Summary
those
taneous
Rh-negative
women
at
risk who
undergo
an
abortion. Introduction FETAL erythrocytes have been found in the circulation of pregnant women from the second month of gestation to term.1 For the Rh-negative mother bearing an Rh-positive fetus, the major immunising threat posed by the fetal erythrocytes is during labour and delivery. Administration of anti-D (Rho) hyperimmune gammaglobulin at this time or within 72 hours of the delivery prevents Rh-isoimmunisation of those mothers who are at risk and who have not been previously
Patients and Methods We studied thirty-six aborting women whose pregnancies had advanced to between the 8th and 20th weeks of gestation. Of these, fifteen had completely aborted, fourteen had aborted incompletely, and seven were threatening to abort. When the patient was admitted to the hospital, 2 ml. of maternal venous blood was taken and anticoagulated with edetate. A second sample was obtained postoperatively on all patients requiring uterine curettage. All samples were refrigerated and processed within 24 hours; the acid elution technique of Kleihauer et a1. was used for identification of fetal erythrocytes. Twenty healthy pregnant women, at 8-20 weeks of gestation, served as controls. Smears of adult blood, cord blood obtained after term deliveries, and mixtures of both were examined repeatedly for control of the technique. Two smears of each sample were prepared and, at a magnification of x 450, 100 fields were scanned in each smear. Bright red, highly refractile erythrocytes were considered to be fetal in origin. If the average number of fetal erythrocytes in both smears was 1 or more per 100 fields, the specimen was considered to be positive. Results
Of the thirty-six aborting patients, thirteen (36%) had fetal erythrocytes in their circulation (mean number per 100 fields: 1, 1, 1-5, 2, 2, 2-5, 3-5, 4, 4-5, 5, 6-5, 8, 40) compared with only two (10%) of the twenty controls (1-5 cells per 100 fields in each). This difference is statistically significant (P=0-04, X2 test). The average fetal cell score was 6 erythrocytes per 100 fields in the aborting group compared with 1-5 in the control
sensitised.2
group.
Potter3 suggested that, in either spontaneous or induced abortions, fetal erythrocytes penetrated the maternal circulation in sufficient amounts to be immunising; moreover, she felt that cervical dilatation and uterine curettage made this penetration more likely. Gellen et a1.4 and Matthews and Matthews5 noted increased numbers of fetal erythrocytes in the maternal circulation after surgical termination of pregnancy. We assume that, in those immunised Rh-negative women who have a history of abortion preceding the birth of their first affected infant, a shower of fetal cells into the maternal circulation had occurred in association with the abortion. However, in one series of spontaneous abortions 5 the incidence of fetal bleeding was only 6%. We have investigated the frequency of transplacental fetal bleeding in spontaneous abortion and the effect of uterine curettage for incomplete abortion.
fields).
11.
12. 13.
Adinolfi, M., Gardner, B., Gianelli, F., McGuire, M. Experientia, 1967, 23, 271. van Furth, R., Schmit, H. R. E., Hijmans, W. Immunology, 1966, 11, 29. Takahashi, M., Yagi, Y., Moore, G. E., Pressman, D. J. Immun.
1969, 102, 1274. Coombs, R. R. A., Gurner, B. W., Janeway, C. A., Wilson, A. B., Gell, P. G. H., Kelus, A. S. Immunology (in the press). 15. Coombs, R. R. A., Gell, P. G. H. in Clinical Aspects of Immunology (edited by P. G. H. Gell and R. R. A. Coombs); p. 3. Oxford,
14.
1968.
16. 17.
Coombs, Coombs,
18. 19.
Gold,
R. R. A., Franks, D. Progr. Allergy, 1969, 13, 174. R. R. A., Gleeson-White, M. H., Hall, J. G. Br. J. exp.
Path. 1951, 32, 195. E. R., Fudenberg, H. H. J. Immun. 1967, 99, 859. Chalmers, D. G., Coombs, R. R. A., Gurner, B. W., Dausset, J. Br. J. Hœmat. 1959, 5, 225.
All fourteen patients with incomplete abortion underwent dilatation and curettage of the uterus; five (36%) of these had fetal erythrocytes in their circulation preoperatively. Postoperatively, the number of positive smears had increased to eight (57%). In two of the five patients with fetal erythrocytes preoperatively, the fetal cell score increased from 2 to 22 and from 2 to 34 per 100 fields; except for these two patients, the increases in fetal cell score were small (0-2 per 100 Discussion We found fetal erythrocytes in the circulation of a third of our patients who were in the process of abortion. The Rh antigen develops very early in life and has been demonstrated in the blood of a 38-day-old fetus.7 an abortion the Rh-negative is confronted with a potentially immunising dose of fetal erythrocytes. Therefore, these women should only be subjected to dilatation and curettage of the uterus when absolutely necessary and, in general, should be subjected to as little uterine manipulation as possible, to avoid a further antigenic insult. Further work is in progress to enlarge this series and to determine the relationship of transplacental haemorrhage to the stage of gestation, gravidity, and other variables. However, the possibility of maternal sensitisation to the Rh antigen by spontaneous abortion should be borne in mind, and strong consideration should be given to the administration of anti-Rho immunoglobulin to those unsensitised Rh-negative patients who are married to a Rh+ man and who undergo abortion. Requests for reprints should be addressed to H. F. T., Mayo Clinic, Rochester, Minnesota 55901, U.S.A.
Consequently, during
woman
1162
FENFLURAMINE OVERDOSAGE IAN RILEY
Poisoning
Treatment Centre,
JOHN CORSON Royal Infirmary of Edinburgh
IAN OSWALD IJAZ HAIDER and Royal Infirmary of Edinburgh Department of Psychiatry, University of Edinburgh Three young
who had ingested 800, 600, and 400 mg. of fenfluramine are described. Clinical features included dilated, nonreactive pupils, rotary nystagmus, hypereflexia, jaw tremor, and feelings of heat, without loss of consciousness. Electroencephalographic sleep studies indicated features similar to those of mild amphetamine intoxication and, later, withdrawal. Summary
women
was a continuous tremor of the lower jaw with chattering of the teeth. Stomach washout was done, and tablet material was retrieved. At 9 A.M. she was hyperventilating and the widely dilated pupils reacted sluggishly to light. Arterial blood-gas analyses showed a respiratory alkalosis-serum pH 7-55, standard bicarbonate 25 meq. per litre, and pc02 21 mm. Hg. Blood-glucose was 59 mg. per 100 ml. A forced acid diuresis was started at 1 P.M. She was given 3 litres of fluid including 70 meq. of ammonium ion intravenously during 4 hours. At the end of this time she was ventilating normally, was less agitated, and the tremor of the lower jaw was absent. The arterial blood-gas analysis now showed a pH of 7-32, standard bicarbonate 16-6 meq., per litre, and pco2 28.5 mm. Hg. The table shows the total excretion of urinary fenfluramine. URINARY EXCRETION OF FENFLURAMINE
Introduction
FENFLURAMINE (’Ponderax’) is an amphetamine derivative and an antiobesity drug. It increases forearm-muscle glucose uptake in man,! and affects fat mobilisation in a manner different from methamphetamine.2 It lacks the " stimulant " action of dexamphetamine, and tends to cause sleepiness. In consequence, studies of sleep are included in our description of three patients with acute overdosage. The normal daily dose is two to six tablets (40-120 mg.). Methods Since the management of acute amphetamine overdosage may include forced acid diuresis,3 this treatment was undertaken on one patient. Electroencephalographic (E.E.G.) studies were carried out (a) during wakefulness after Most amphetamines admission and (b) during sleep. R.E.M. (rapid-eye-movement) sleep and, when suppress withdrawn, a rebound excess of R.E.M. sleep occurs, especially in the early hours of sleep (e.g., after dexamphetamine and phenmetrazine,4 tranylcypromine,5 and
diethylpropion).6g Volatile amphetamine-like substances were quantitatively determined in the urine by the method of Tompsett.The presence of fenfluramine, and its desmethyl metabolite in minor amounts, was confirmed by gas-liquid chromatography.a Case-reports FIRST CASE
A
16-year-old girl was admitted to the Regional Poisoning Treatment Centre, Royal Infirmary of Edinburgh at 2.30 A.M., 31/2 hours after the ingestion of forty tablets (800 mg.) of fenfluramine. She was agitated, anxious, uncooperative, flushed, sweating, and slightly obese. Her height was 155 cm. and weight 59-4 kg. Blood-pressure was 120/80 mm. Hg., pulse 134 per minute, regular in time and force, temperature 99-0°F, and respirations 22 per minute. She was fully conscious with dilated pupils, unreactive to light; there was a rotary nystagmus, and the deep tendon reflexes were brisk and symmetrical. A pronounced feature
A further 36-7 mg. of fenfluramine after which excretion ceased.
She did
3. 4. 5. 6. 7.
Freese, U. E., Titel, J. H. Obstet. Gynec. 1962, 22, 527. Woodrow, J. C., Clarke, C. A., Donohoe, W. T. A., Finn, R. McConnell, R. B., Sheppard, P. M., Lehane, D., Russell, S. H., Kulke, W., Durkin, C. M. Br. med. J. 1965, i, 279. Potter, E. L. Rh: Its Relation to Congenital Hæmolytic Disease and to Intragroup Transfusion Reactions. Chicago, 1947. Gellén, J., Kovács, Z., Szontágh, F. E., Boda, D. Br. med. J. 1965, ii, 1471. Matthews, C. D., Matthews, A. E. B. Lancet, 1969, i, 694. Kleihauer, E., Braun, H. Betke, K. Klin. Wschr. 1957, 35, 637. Bergström, H., Nilsson, L.-Å., Nilsson, L., Ryttinger, L. Am. Obstet. Gynec. 1967, 99, 130.
not seem to
excreted
over
the
next two
sleep
recorded
the first
night. Her wholeby electroencephalography on on
night sleep nights 3, 4, 5, 6, 8, 9, 11, 12, 14, 15, and 19 after overdose. It was frankly abnormal on night 3, and 11 minutes of R.E.M. sleep occurred at initial sleep onset, instead of after about an hour as is normally the case.9Her all-night percentage of R.E.M. sleep was not abnormal, but was highest on that night. There was some accentuation of E.E.G. sleep spindles on the same night. The percentages of sleep as R.E.M. sleep on the various nights were 29-8, 24-1, 22-8, 27-1, 22-9, 20-2, 24-2, 258, 267, 23-1, and 20-8, respectively, was
all within normal limits. There were two other features which also suggested abnormality of rebound type-a short delay of 45 minutes (night 4) from sleep onset to first R.E.M. sleep and excess R.E.M. sleep within the first 2 hours of sleep, namely, 31 minutes (night 5). This girl had been prescribed the fenfluramine because she was overweight. There were difficulties in her relationship with her father and while away from home she took the overdose in an attempt to avert imminent return home. SECOND CASE
16-year-old girl was admitted at 10 P.M., having ingested 30 tablets (600 mg.) of fenfluramine 21/2 hours earlier. She complained of a burning sensation in her epigastrium, of feeling hot all over, and of some blurring A
of vision. She was
fully conscious and cooperative, but flushed and height was 157-5 cm. and weight 56-25 kg. Blood-pressure was 130/90 mm. Hg., pulse 130 per minute, regular in time and force, respiratory rate 30 per minute, axillary temperature 104°F (39-9°C). The pupils were widely dilated and failed to react to light. A rotary
warm.
1. 2.
was
days,
Her
nystagmus, and a weakness of the left lateral rectus muscle were present. There was a continuous tremor of the lower jaw with chattering of teeth. Generalised hyperflexia and ankle clonus were present. The bloodgases after stomach washout revealed a pH of 7-35, a pco2 of 43 mm. Hg, and a standard bicarbonate of 22 meq.