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An evaluation of aminopterin as an abortifacient
An evaluation of aminopterin as an abortifacient CARL GOETSCH, M.D. Berkeley, California
J.
B. THIER s c H, in 1952, pointed out the ability of aminopterin ( 4-aminopteroyl glutamic acid) to produce abortion in human beings. Having become interested in this, I have used aminopterin for 15 therapeutic abortions. In addition, I have observed 5 more patients who took the drug with criminal intent. These 20 cases have been divided into three groups for study as follows.
days. The time from the first day of medication to the day of abortion was 19 to 37 days, with a median of 24 days. The only reaction to aminopterin was stomatitis in 2 cases. Hemorrhage associated with abortion was a complication in 4 cases. Group III. Patients who failed to abort. Of the 5 patients in this group, 3 received 12 mg. of aminopterin in doses of 2 mg. every 12 hours, one received 16 mg. in doses of 2 mg. every 12 hours, and one received 12 mg. in doses of 2 mg. every 12 hours and 10 days later received 17 mg. with the same schedule. The time from the last menstrual date to the first day of medication was 45 to 72 days, with a median of 66 days. The time from the first day of medication to the day of termination of pregnancy was 29 to 129 days, with a median of 40 days. Severe stomatitis occurred in 4 cases, rash in 2, and falling hair in 3 cases. A depressed white blood cell count occurred in one case in which the patient, after receiving 15 mg. of aminopterin, had a leukocyte count too low to be determined 7 days after the drug was taken. The count returned to normal 3 weeks later. All patients in Group III had pregnancies terminated surgically. In 2 cases a curettage was done, and the fetus was mutilated beyond the point where it could be studied. Microscopic studies of the placentas showed that they were normal. Pregnancies in the other 3 cases were terminated by hysterotomy in 2 cases and hysterectomy in one. In on(' case the fetus sufft.'red from gross multiple, severe anomalies incompatible with life and was stillborn. In 2 cases the fdus was grossly normal in size and development for the period of gestation.
The three groups
Group I. Patients who aborted with dispatch and without difficulty. There were 11 patients in this group. Ten patients received 12 mg. of aminopterin in doses of 2 mg. every 12 hours. One received 36 mg. in doses of 1.5 mg. every 6 hours. The time which elapsed from the last menstrual date to the first day of medication was 34 to 65 days, with a median of 53 days. The time from the first day of medication to the day of abortion was 18 to 40 days, with a median of 21 days. There were no reactions to the drug in 4 cases, mild stomatitis in one, severe stomatitis in 6, rash in 2, and falling hair in 3. Group II. Patients who aborted with difficulty. All 4 patients in this group received 12 mg. of aminopterin in doses of 2 mg. every 12 hours. The time from the last menstrual date to the first day of medication was 45 to 69 days, with a median of 55.5
From the Department of Obstetrics and Gynecology, University of California. Presented at the Twenty-eighth Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Yosemite National Park California, Sept. 20-23, 1962.
1474
Volume S:S Number 11
Comment
In the reports of Thiersch1 • 2 there was a total of 24 cases. Eight patients ( 33 per cent) failed to abort. This compared with 5 patients (25 per cent) failing to abort out of 20 cases in the series reported here. Two fetuses of patients who failed to abort were grossly normal and apparently unaffected hy the aminopterin. One of the fetuses in this series suffered from gross abnormalities comparable to the cases reported in detail by Warkany, Beaudry, and Hornstein 3 and by Meltzcr. 4 It is apparent from all of these reports that aminopterin is not a reliable abortifacient. For it to be effective, it must be ,given early in pregnancy, and yet 2 of the failures reported here occurred when the drug was given on the forty-fifth and fiftieth clays after the last menstrual date. After the results of the use of aminopterin to induce therapeutic abortions in 15 cases were reviewed, it was decided to discontinue this practice because of untoward side effects, such as stomatitis, falling hair, and skin rashes, and also because of 2 failures. However, during and subsequent to this time we saw 5 patients who had used aminopterin for the purpose of criminally inducing an abortion. These 5 cases were of interest in several ways. The first point of interest is the source of the drug. Four received aminopterin from a friend or relative who was a physician. Three of these physicians were internist~ and one was a urologist. One patient received her supply of drug from a graduate student in pharmacy whom she met in a bar. This was the patient who took two courses of aminopterin for a total of 29 mg. and then was delivered 129 days later of a stillborn, badly deformed fetus. This patient and 2 other patients in this group illustrate the second point of interest, that those attempting criminal abortion tend to take excrssivt· amounts of the aminopterin. The second patient received 36 mg. and the third received 15 mg. of the drug. This may reflect the patients' sense of desperation. Along with increased dosages, these patients also
Aminopterin as abortifacient
1475
tended to receive the aminopterin later in pregnancy, as one might expect. Correlated with this was the high incidence of failure to abort. Three out of the 5 patients found themselves in this plight. This failure to abort raises the last question, which I would like to discuss. What should the physician do when faced with a patient who has taken aminopterin without interrupting the pregnancy? The pressure from the patient to do something because she has taken aminopterin will be very great, and yet it is apparent that, if the fetus has been damaged, the only real problem present is the social and physical discomfort that the pregnancy causes while she awaits the spontaneous terminal event which will offer no obstetric difficulty. The problem centers about the fetus. Many take the position that there are no fetal indications for inducing an abortion. However, some obstetricians have taken the position that potential problems with the fetus are at times a reason for interrupting a pregnancy. If the material presented here can be a guide, it would seem that the administration of aminopterin to a pregnant patient will so seriously interfere with the development of the fetus that, if early abortion fails to occur, the defective fetus will not survive. If the fetus has escaped the effect of aminopterin, it will be normal. No action by the physician will be necessary. Greenhill, in 1952, warned against the use of aminopterin to induce abortion on the grounds that failure to achieve an abortion might yield a monstrosity. There arf' better arguments against using aminopterin as an abortifacient. In the first place, the drug is hazardous and capable of inducin.u: in the patient very serious complications which on occasion may prove to be fatal to the patient. Second, it is inefficient as an abortifacient, and failure to achieve an ztbortion is Vf'ry clisconcertin.g to all conCt>rm·d. Summary and conclusion
1. Twenty instances of the use of aminopterin to induce abortion are reported.
1476
Goetsch
2. There were 5 cases of failure. 3. The side reactions in the patient are potentially serious. 4. Failure of the patient to abort usually results in a monstrosity, but 2 apparently
REFERENCES
1. Thiersch, J. B.: AM. J. 0BsT. & GYNEC. 63: 1298, 1952. 2. Thiersch, J. B.: Acta endocrinol. (suppl. 28) 23: 37, 1956.
Discussion DR. RussELL R. DE ALVAREz, Seattle, Washington. In the early development of the Pacific Northwest Obstetrical and Gynecological Association, the organization was solicited by Dr. J. B. Thiersch, then a member of the Department of Pathology of our School of Medicine, to make a presentation before its annual meeting in 1952. The intriguing title and the inherent difficulties experienced by the Program Committee in obtaining papers from the membership of this embryonic society made the offer quite welcome. The paper was accepted for presentation and then subsequently for publication in the AMERICAN JoURNAL OF OBSTETRICS AND GYNECOLOGY. Unfortunately, however, several listeners and readers interpreted the work as emanating from the Department of Obstetrics and Gynecology, and therefore as departmental condonation and recommendation of the use of antifolic acid metabolites for the production of therapeutic abortion. Nothing could have been more unbelievable. Thiersch, in his report, stated that the drug had been used in 12 patients to produce therapeutic abortion, but details of these cases wen; not included in the report. Two patients failed to abort so that surgical evacuation was necessary; hydrocephalus was found in one case and cleft lip and palatr were noted in the other. In one case in which the patient aborted, meningoencephalocele was found. Each of these patients had received antifolic acid metabolites orally for t lw purpose of inducing therapeutic abortion. In order that the purpose of antimetabolites may he appreciated, a brief introductory comment on the normal function and metabolism of vitamins, and especially folic acid, is per-
c\111.
J.
Juue I, l~lh~ Obst. & Gynec.
normal fetuses are reported in the cases of failure to abort in this series. 5. Because of the hazards from the administration of aminopterin and the inefficiency of the drug as an abortifacient, it should not be used for this purpose.
:). Warkany, J., Beaudry, P. H., and Hornstein. S.: A. M. A. J. Dis. Child. 97: 274, 1959. ·L Meltzer, H. J.: ]. A. M. A. 161: 1253. !956. 2915 Telegraph Ave. Berkeley, California
tinent. Vitamins arc essential requirements for normal nutrition. Since they cannot be synthesized by the human body, they must be provided exogenously in food or in the form of supplement. Whereas amino acids are required in lar,gc amounts, vitamins are required in trace amounts and serve to catalyze given reactions in the body <1nd arP not burned to produce energy. Folic acid, commonly called a vitamin, really rPpresents the common nomenclature for pteroyiL- ~lutamic acid (PGA) and those of its derivatives which have vitamin activity for higher animals and microorganisms. It, too, is required to sustain life and cannot be synthesized from its constituents; hence it must be supplied from without. It is represented by the formula composed of pterin and para-aminobenzoic arid (which make up the pteroyl portion of the formula) and glutamic acids. It is usually a polyglutamate and ordinarily consists of odd numbers of the glutamates (for example, 3, 5. or 7). Since para-aminobenzoic acid is considPr<'d to be the growth factor of folic acid, it was originally considered that anti-PABA mi~ht be a suitable antimetabolite to combat dissemminatrd cancer, which was the reason for my first <'ncounter with the drug. We tried it, with disappointing results, in the chemotherapy of far-advanced gynecologic malignancy in 194(). Evm though the exact pathways of synthrsis of foli< acid arr as yet unknown, it is known th<1t th<· PCA derivatives play an important role in <'rythrncytopoicsis and leukocytopoiesis. DPfici•·nci<•s of folic acid often are associatf'd with larg•· round cell anemia, decreased ~astric function, rcduc<>d lipid absorption, and oftPn alterations in the glucose tolerance test curve. The
VoluHH: B')
!'\umber 11
macrocytic anemias of diseases such as pernicious anemia and sprue, as well as those of pregnancy, respond impressively after the administration of folic add. It is now well known that folic acid is actively needed in growth proct";scs. This fact accounts for the high fetal requirement for folic acid and probably accounts for the relatively frequent occurrence of macrocytic anemias of pregnancy. It has also been determined that folic acid is needed by such rapidly growing tissues in the fetus as intestinal epithelium, bone marrow, and tl1e fetal reproductive organs. Because of these known requirements in normal growth, much has been learned regarding the need for these same nutrients by all rapidly proliferating tissues, whether normal or malignant, to enhance protein synthesis. Protein synthesis represents the net conver«ion of amino adds to proteins. This conversion is und<~r the control of RNA. Thus, RNA is an obligatory partner in the process of protein synthesis. DNA also tends to enter into net synthesis of protein but not to the degree that RNA does. DNA and RNA synthesis are mediated through the production of the nucleosides and nucleotides of purines and pyrimidines, both of which arise from one-carbon fragment pn'cursors. Folic acid enters into the production of purines and pyrimidines in catalyzing their formation from the one-carbon fragment precursors. Thus, it is seen that, in order to inhibit protein synthesis, any one of these many steps may be attacked. Farber noted that the administration of folic acid to patients with leukemias rcsultrd in a progression of the leukemia. When he introduced the use of folic acid analogues nr antagonists to attack leukemia, a successful reduction of proliferation of leukemic cells occurred. One of the folic acid antagonists which emerged was 4-aminopteroylglutamic acid ( 4amino PGA), also known as aminopterin, which inhibits the incorporation of formate into purines or thymine or the interconversion of serine and ~·lycine. Another and equally if not more powerful antagonist is 4-amino-10-methyl PGA, knovm as amethopterin or mrthotrexate. Since rapid division of cells is characteristic
Aminopterin as abortifacient
1477
of pregnancy and their utilization of folic acid is thought to be extremely high, anything which would interfere with the metabolism of folic acid, formate or other one-carbon derivatives or purines and pyrimidines in the chain of protein synthesis, would also influence growth with thP production of marked fetal damage ensuing in fetal death followed by spontaneous abortion. When fetal damage is not pronounced enough to produce death hut is enough to influence growth of a part or the total fetus, congenital anomalies result. If folic acid antagonists arc administercd early in pregnancy, it is indeed fortunate that fetal death and abortion occur. Unfortunately, however, all such paticnts do not abort. We have, unfortunately, had experience with 2 instances in which fetal death or abortion did not occur. Pregnancy in each of these patients continued to term, when they were delivered of living, hydrocephalic infants and were confronted with the inauspicious sequelae of carin,g for the>c children. On the basis of our experience and the other experiences published. W<' can do nothing but condemn the administration of this group of drugs for the prime intent of producing abortion. Therefore, we canot advise' too emphatically that recommendation of th,. administration of any antimetabolite, regardless of point of action, should be vigorously contraindicated during pregnancy, not only because of the production of serious fetal anomalies hut because of the marked alterations in intrrmediary mdabolism. DR. EDWIN T. MAcCAMY, Seattle, Washington. I am interested in the role of the Therapeutic Abortion Committee in this qurstion. I would like to ask Dr. Goetsch if his 15 cas<'s were presented to the Therapeutic Abortion Committf:'e of this hospital brfore the arninopterin was used. DR. GoETSCH (Closing). Bdore administering aminopterin to these patients, I did follo-w the prescribed procedures that were in effect in Berkeley at the time. I had a suitable consultation in the appropriate field, which in earh cas<' wnrranted thr induction of the abortion.
J.
B. THIER s c H, in 1952, pointed out the ability of aminopterin ( 4-aminopteroyl glutamic acid) to produce abortion in human beings. Having become interested in this, I have used aminopterin for 15 therapeutic abortions. In addition, I have observed 5 more patients who took the drug with criminal intent. These 20 cases have been divided into three groups for study as follows.
days. The time from the first day of medication to the day of abortion was 19 to 37 days, with a median of 24 days. The only reaction to aminopterin was stomatitis in 2 cases. Hemorrhage associated with abortion was a complication in 4 cases. Group III. Patients who failed to abort. Of the 5 patients in this group, 3 received 12 mg. of aminopterin in doses of 2 mg. every 12 hours, one received 16 mg. in doses of 2 mg. every 12 hours, and one received 12 mg. in doses of 2 mg. every 12 hours and 10 days later received 17 mg. with the same schedule. The time from the last menstrual date to the first day of medication was 45 to 72 days, with a median of 66 days. The time from the first day of medication to the day of termination of pregnancy was 29 to 129 days, with a median of 40 days. Severe stomatitis occurred in 4 cases, rash in 2, and falling hair in 3 cases. A depressed white blood cell count occurred in one case in which the patient, after receiving 15 mg. of aminopterin, had a leukocyte count too low to be determined 7 days after the drug was taken. The count returned to normal 3 weeks later. All patients in Group III had pregnancies terminated surgically. In 2 cases a curettage was done, and the fetus was mutilated beyond the point where it could be studied. Microscopic studies of the placentas showed that they were normal. Pregnancies in the other 3 cases were terminated by hysterotomy in 2 cases and hysterectomy in one. In on(' case the fetus sufft.'red from gross multiple, severe anomalies incompatible with life and was stillborn. In 2 cases the fdus was grossly normal in size and development for the period of gestation.
The three groups
Group I. Patients who aborted with dispatch and without difficulty. There were 11 patients in this group. Ten patients received 12 mg. of aminopterin in doses of 2 mg. every 12 hours. One received 36 mg. in doses of 1.5 mg. every 6 hours. The time which elapsed from the last menstrual date to the first day of medication was 34 to 65 days, with a median of 53 days. The time from the first day of medication to the day of abortion was 18 to 40 days, with a median of 21 days. There were no reactions to the drug in 4 cases, mild stomatitis in one, severe stomatitis in 6, rash in 2, and falling hair in 3. Group II. Patients who aborted with difficulty. All 4 patients in this group received 12 mg. of aminopterin in doses of 2 mg. every 12 hours. The time from the last menstrual date to the first day of medication was 45 to 69 days, with a median of 55.5
From the Department of Obstetrics and Gynecology, University of California. Presented at the Twenty-eighth Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Yosemite National Park California, Sept. 20-23, 1962.
1474
Volume S:S Number 11
Comment
In the reports of Thiersch1 • 2 there was a total of 24 cases. Eight patients ( 33 per cent) failed to abort. This compared with 5 patients (25 per cent) failing to abort out of 20 cases in the series reported here. Two fetuses of patients who failed to abort were grossly normal and apparently unaffected hy the aminopterin. One of the fetuses in this series suffered from gross abnormalities comparable to the cases reported in detail by Warkany, Beaudry, and Hornstein 3 and by Meltzcr. 4 It is apparent from all of these reports that aminopterin is not a reliable abortifacient. For it to be effective, it must be ,given early in pregnancy, and yet 2 of the failures reported here occurred when the drug was given on the forty-fifth and fiftieth clays after the last menstrual date. After the results of the use of aminopterin to induce therapeutic abortions in 15 cases were reviewed, it was decided to discontinue this practice because of untoward side effects, such as stomatitis, falling hair, and skin rashes, and also because of 2 failures. However, during and subsequent to this time we saw 5 patients who had used aminopterin for the purpose of criminally inducing an abortion. These 5 cases were of interest in several ways. The first point of interest is the source of the drug. Four received aminopterin from a friend or relative who was a physician. Three of these physicians were internist~ and one was a urologist. One patient received her supply of drug from a graduate student in pharmacy whom she met in a bar. This was the patient who took two courses of aminopterin for a total of 29 mg. and then was delivered 129 days later of a stillborn, badly deformed fetus. This patient and 2 other patients in this group illustrate the second point of interest, that those attempting criminal abortion tend to take excrssivt· amounts of the aminopterin. The second patient received 36 mg. and the third received 15 mg. of the drug. This may reflect the patients' sense of desperation. Along with increased dosages, these patients also
Aminopterin as abortifacient
1475
tended to receive the aminopterin later in pregnancy, as one might expect. Correlated with this was the high incidence of failure to abort. Three out of the 5 patients found themselves in this plight. This failure to abort raises the last question, which I would like to discuss. What should the physician do when faced with a patient who has taken aminopterin without interrupting the pregnancy? The pressure from the patient to do something because she has taken aminopterin will be very great, and yet it is apparent that, if the fetus has been damaged, the only real problem present is the social and physical discomfort that the pregnancy causes while she awaits the spontaneous terminal event which will offer no obstetric difficulty. The problem centers about the fetus. Many take the position that there are no fetal indications for inducing an abortion. However, some obstetricians have taken the position that potential problems with the fetus are at times a reason for interrupting a pregnancy. If the material presented here can be a guide, it would seem that the administration of aminopterin to a pregnant patient will so seriously interfere with the development of the fetus that, if early abortion fails to occur, the defective fetus will not survive. If the fetus has escaped the effect of aminopterin, it will be normal. No action by the physician will be necessary. Greenhill, in 1952, warned against the use of aminopterin to induce abortion on the grounds that failure to achieve an abortion might yield a monstrosity. There arf' better arguments against using aminopterin as an abortifacient. In the first place, the drug is hazardous and capable of inducin.u: in the patient very serious complications which on occasion may prove to be fatal to the patient. Second, it is inefficient as an abortifacient, and failure to achieve an ztbortion is Vf'ry clisconcertin.g to all conCt>rm·d. Summary and conclusion
1. Twenty instances of the use of aminopterin to induce abortion are reported.
1476
Goetsch
2. There were 5 cases of failure. 3. The side reactions in the patient are potentially serious. 4. Failure of the patient to abort usually results in a monstrosity, but 2 apparently
REFERENCES
1. Thiersch, J. B.: AM. J. 0BsT. & GYNEC. 63: 1298, 1952. 2. Thiersch, J. B.: Acta endocrinol. (suppl. 28) 23: 37, 1956.
Discussion DR. RussELL R. DE ALVAREz, Seattle, Washington. In the early development of the Pacific Northwest Obstetrical and Gynecological Association, the organization was solicited by Dr. J. B. Thiersch, then a member of the Department of Pathology of our School of Medicine, to make a presentation before its annual meeting in 1952. The intriguing title and the inherent difficulties experienced by the Program Committee in obtaining papers from the membership of this embryonic society made the offer quite welcome. The paper was accepted for presentation and then subsequently for publication in the AMERICAN JoURNAL OF OBSTETRICS AND GYNECOLOGY. Unfortunately, however, several listeners and readers interpreted the work as emanating from the Department of Obstetrics and Gynecology, and therefore as departmental condonation and recommendation of the use of antifolic acid metabolites for the production of therapeutic abortion. Nothing could have been more unbelievable. Thiersch, in his report, stated that the drug had been used in 12 patients to produce therapeutic abortion, but details of these cases wen; not included in the report. Two patients failed to abort so that surgical evacuation was necessary; hydrocephalus was found in one case and cleft lip and palatr were noted in the other. In one case in which the patient aborted, meningoencephalocele was found. Each of these patients had received antifolic acid metabolites orally for t lw purpose of inducing therapeutic abortion. In order that the purpose of antimetabolites may he appreciated, a brief introductory comment on the normal function and metabolism of vitamins, and especially folic acid, is per-
c\111.
J.
Juue I, l~lh~ Obst. & Gynec.
normal fetuses are reported in the cases of failure to abort in this series. 5. Because of the hazards from the administration of aminopterin and the inefficiency of the drug as an abortifacient, it should not be used for this purpose.
:). Warkany, J., Beaudry, P. H., and Hornstein. S.: A. M. A. J. Dis. Child. 97: 274, 1959. ·L Meltzer, H. J.: ]. A. M. A. 161: 1253. !956. 2915 Telegraph Ave. Berkeley, California
tinent. Vitamins arc essential requirements for normal nutrition. Since they cannot be synthesized by the human body, they must be provided exogenously in food or in the form of supplement. Whereas amino acids are required in lar,gc amounts, vitamins are required in trace amounts and serve to catalyze given reactions in the body <1nd arP not burned to produce energy. Folic acid, commonly called a vitamin, really rPpresents the common nomenclature for pteroyiL- ~lutamic acid (PGA) and those of its derivatives which have vitamin activity for higher animals and microorganisms. It, too, is required to sustain life and cannot be synthesized from its constituents; hence it must be supplied from without. It is represented by the formula composed of pterin and para-aminobenzoic arid (which make up the pteroyl portion of the formula) and glutamic acids. It is usually a polyglutamate and ordinarily consists of odd numbers of the glutamates (for example, 3, 5. or 7). Since para-aminobenzoic acid is considPr<'d to be the growth factor of folic acid, it was originally considered that anti-PABA mi~ht be a suitable antimetabolite to combat dissemminatrd cancer, which was the reason for my first <'ncounter with the drug. We tried it, with disappointing results, in the chemotherapy of far-advanced gynecologic malignancy in 194(). Evm though the exact pathways of synthrsis of foli< acid arr as yet unknown, it is known th<1t th<· PCA derivatives play an important role in <'rythrncytopoicsis and leukocytopoiesis. DPfici•·nci<•s of folic acid often are associatf'd with larg•· round cell anemia, decreased ~astric function, rcduc<>d lipid absorption, and oftPn alterations in the glucose tolerance test curve. The
VoluHH: B')
!'\umber 11
macrocytic anemias of diseases such as pernicious anemia and sprue, as well as those of pregnancy, respond impressively after the administration of folic add. It is now well known that folic acid is actively needed in growth proct";scs. This fact accounts for the high fetal requirement for folic acid and probably accounts for the relatively frequent occurrence of macrocytic anemias of pregnancy. It has also been determined that folic acid is needed by such rapidly growing tissues in the fetus as intestinal epithelium, bone marrow, and tl1e fetal reproductive organs. Because of these known requirements in normal growth, much has been learned regarding the need for these same nutrients by all rapidly proliferating tissues, whether normal or malignant, to enhance protein synthesis. Protein synthesis represents the net conver«ion of amino adds to proteins. This conversion is und<~r the control of RNA. Thus, RNA is an obligatory partner in the process of protein synthesis. DNA also tends to enter into net synthesis of protein but not to the degree that RNA does. DNA and RNA synthesis are mediated through the production of the nucleosides and nucleotides of purines and pyrimidines, both of which arise from one-carbon fragment pn'cursors. Folic acid enters into the production of purines and pyrimidines in catalyzing their formation from the one-carbon fragment precursors. Thus, it is seen that, in order to inhibit protein synthesis, any one of these many steps may be attacked. Farber noted that the administration of folic acid to patients with leukemias rcsultrd in a progression of the leukemia. When he introduced the use of folic acid analogues nr antagonists to attack leukemia, a successful reduction of proliferation of leukemic cells occurred. One of the folic acid antagonists which emerged was 4-aminopteroylglutamic acid ( 4amino PGA), also known as aminopterin, which inhibits the incorporation of formate into purines or thymine or the interconversion of serine and ~·lycine. Another and equally if not more powerful antagonist is 4-amino-10-methyl PGA, knovm as amethopterin or mrthotrexate. Since rapid division of cells is characteristic
Aminopterin as abortifacient
1477
of pregnancy and their utilization of folic acid is thought to be extremely high, anything which would interfere with the metabolism of folic acid, formate or other one-carbon derivatives or purines and pyrimidines in the chain of protein synthesis, would also influence growth with thP production of marked fetal damage ensuing in fetal death followed by spontaneous abortion. When fetal damage is not pronounced enough to produce death hut is enough to influence growth of a part or the total fetus, congenital anomalies result. If folic acid antagonists arc administercd early in pregnancy, it is indeed fortunate that fetal death and abortion occur. Unfortunately, however, all such paticnts do not abort. We have, unfortunately, had experience with 2 instances in which fetal death or abortion did not occur. Pregnancy in each of these patients continued to term, when they were delivered of living, hydrocephalic infants and were confronted with the inauspicious sequelae of carin,g for the>c children. On the basis of our experience and the other experiences published. W<' can do nothing but condemn the administration of this group of drugs for the prime intent of producing abortion. Therefore, we canot advise' too emphatically that recommendation of th,. administration of any antimetabolite, regardless of point of action, should be vigorously contraindicated during pregnancy, not only because of the production of serious fetal anomalies hut because of the marked alterations in intrrmediary mdabolism. DR. EDWIN T. MAcCAMY, Seattle, Washington. I am interested in the role of the Therapeutic Abortion Committee in this qurstion. I would like to ask Dr. Goetsch if his 15 cas<'s were presented to the Therapeutic Abortion Committf:'e of this hospital brfore the arninopterin was used. DR. GoETSCH (Closing). Bdore administering aminopterin to these patients, I did follo-w the prescribed procedures that were in effect in Berkeley at the time. I had a suitable consultation in the appropriate field, which in earh cas<' wnrranted thr induction of the abortion.