- Email: [email protected]
SERUM-FOLIC-ACID IN RECURRENT ABORTIONS
670
drug requirement, for not more than ten of the thirtythree patients required any change of dose within 2 weeks of starting oral therapy. Assuming that hypersensitivity will be revealed by the intramuscular test, there appears to be little risk of drug accumulation so long as dosage is "
tailored " in this manner: even when oral treatment has been initiated with a dose as large as 100 mg. no symptoms of overdosage have been encountered. At the time of this report all the patients under treat-
showing guanethidine.
ment are
a
satisfactory hypotensive
guanethidine (’Ismelin’) for intramuscular use. Ismelin ampoules are not marketed, but may be obtained for investigation purposes from the Medical Director, Ciba Laboratories Limited, Horsham, Sussex. REFERENCES
Johnston, A. W., Prichard, B. N. C., Rosenheim, M. L. (1964) Lancet, ii, 659. Leishman, A. W. D., Matthews, H. L., Smith, A. J. (1959) ibid. ii, 1044.
response to
SERUM-FOLIC-ACID IN RECURRENT ABORTIONS
Discussion
The slow
development of hypotensive
effect with guanethidine and the slow elimination of the drug have both benefits and disadvantages. On the one hand, bloodpressure levels may be more stable and less subject to diurnal " swing " than with a drug of shorter action. On the other hand, in very severe hypertension and particularly in cases of accelerated or malignant hypertension the delay in achieving effective blood-pressure control is undesirable, and yet it is precisely in these cases that a drug of guanethidine’s potency is required. To bridge the gap until oral guanethidine becomes effective, ganglionblocking drugs such as pentolinium and pempidine have often been employed. Recently, Johnston et al. (1964) have reported that the new sympathetic-blocking drug bethanidine is satisfactory for the initial treatment of
malignant hypertension. Where an immediate effect is required (as in hypertensive crisis) we have found the intravenous preparation of methyldopa useful, for this drug is less dependent upon posture for its hypotensive action. To sustain the effect, however, the injection must be repeated at intervals of not more than 6 hours. In less urgent cases, such as malignant or accelerated hypertension without acute cardiac or cerebral complication, the procedure described above has proved successful. Patients nos. 7 and 15 were in this group. The observations required for this study may not be possible outside hospital, and in any case patients with
hypertension severe enough to require guanethidine are usually best admitted to hospital for full study and the start of treatment. With tests for sensitivity to guanethidine taking place alongside other investigations, however, the stay in hospital is usually 7-10 days, after which time most of the patients can be discharged to outpatient supervision with their blood-pressure fully controlled. If, instead of being admitted, our thirtythree patients had paid weekly visits to the outpatient department, blood-pressure control would have taken 4.6 weeks
on
average.
Summary The dose of guanethidine by mouth must be increased slowly to reduce the risk of excessive drug accumulation in sensitive patients. The resulting delay in achieving satisfactory blood-pressure control may be hazardous for certain hypertensive patients. Responsiveness to guanethidine can be judged by the fall of blood-pressure after an intramuscular test dose. Treatment with the drug may then safely be started with an oral dose of 4-5 times the effective t-est dose. In thirty-three patients managed in this way adequate blood-pressure control was achieved in an average of 7-3 days, compared with 4-6 weeks which would have been required with orthodox treatment. We are indebted to Dr. A. K. Pittman, of Ciba Limited, for the
M.B.
R. H. MARTIN Lpool, F.R.C.S.E., M.R.C.O.G.
CONSULTANT OBSTETRICIAN AND GYNÆCOLOGIST
T. A. HARPER Madras, M.C.Path.
M.B.
ASSISTANT PATHOLOGIST
W. KELSO And., M.R.C.O.G.
M.B. St.
SENIOR REGISTRAR IN OBSTETRICS AND GYNÆCOLOGY
WYTHENSHAWE HOSPITAL, MANCHESTER
MEGALOBLASTIC anaemia was originally thought to be only consequence of a deficiency of folic acid and its derivatives-a deficiency which has been widely reported to be present in the second half of pregnancy and the early puerperium. Recently, a relation between folic-acid deficiency and abruptio placentae has been suggested by the finding of formiminoglutamic-acid (FIGLU) in the urine (Hibbard and Hibbard 1963). On the supposition that folic-acid deficiency might be associated with spontaneous isolated abortion of unknown aetiology folic-acid therapy should be helpful in the management of pregnancies in women with a history of recurrent abortion. Serum-folic-acid activity was estimated in patients with complete and incomplete abortion, and a therapeutic trial of folic acid was undertaken in a small series of cases of recurrent abortion. the
Patients and Methods
Assay of Serum-folic-acid Activity The microbiological assay of serum-folic-acid activity with Lactobacillus casei is now recognised as the most sensitive and reliable method of detecting folic-acid deficiency. The method in this investigation was that of Waters and Mollin (1961), in which ascorbic acid is added to the serum and the buffer solution.
Selection
of Patients patients were those seen in the wards and clinics at Withington Hospital and Wythenshawe Hospital, Manchester, and were investigated in two series: (1) a spontaneous isolatedabortion series, to study the relation between serum-folic-acid activity and abortion (150 cases); and (2) a recurrent-abortion series, to assess the therapeutic value of folic acid in the management of pregnancies in women with a history of recurrent abortion (19 cases). Spontaneous Isolated-abortion Series The
There were 150 consecutive cases of isolated spontaneous abortion in which no genital abnormality was found and in which evidence of systemic disease was lacking. In these circumstances, the condition was classed as isolated abortion of unknown xtiology. All the women had been pregnant for eighteen weeks or less at the time of the abortion. Those who had a history of previous recurrent abortion were excluded, as also were those in whom there was no histological evidence of trophoblastic tissue in the recovered products. Admittedly, an unknown number of concealed criminal abortions will have been included, but we tried to exclude these. A specimen of clotted blood was obtained as soon as possible
671 TABLE I-LEVELS
OF
SERUM-FOLIC-ACID ACTIVITY IN SPONTANEOUS ABORTION
presentation at their first attendance: group A, threatened abortion; group B, not pregnant; and group C, early pregnancy. Their obstetric histories
their method of
summarised in table
are
ill.
A: Threatened Abortion presented with threatened miscarriage: pregnancy tests were positive at this time. Of 33 previous pregnancies, only 7 had been successful, giving an abortion rate of 3-7 per patient. The range of serum-folicacid activity in these patients was 1-0 to 10-5m[Lg. per ml. 2 patients had levels below 2-6 m[Lg. per ml.
Group 7
TABLE II-PROPORTIONS OF SPONTANEOUS ABORTIONS BELOW VARIOUS LEVELS OF SERUM-FOLIC-ACID ACTIVITY
for the determination of the serum-folic-acid activity. At the same time, haemoglobin was estimated and the peripheral blood-film was examined.
Findings Table i gives the number of isolated abortions which occurred at the various levels of serum-folic-acid activity; the percentage of abortions below various levels of serumfolate are summarised in table 11. In 25% of the abortions, the level of serum-folic-acid activity was below 2-6 m[.Lg. per ml.; in 35% the level was below 3-1 m[.Lg. per ml.; while in 53% a level below 4-1 m[.Lg. per ml. was found. Table I also shows the number of abortions with hxmoglobin values of less than 10-5 g. per 100 ml. In the area from which these patients are drawn, haemoglobin readings of 10-8 g. per 100 ml. in early pregnancy are usual. Examination of the peripheral blood-films revealed no evidence of hypochromic or macrocytic anaemia. Subsequent haemoglobin estimations showed that, although 15% of the patients had a value of less than 10-5 g. per 100 ml. on admission, 42% had fallen below this level during the next twenty-four hours. Even if no allowance is made for pre-admission hxmodilution, these results indicate that over 85% of the patients were not
anaemic. Recurrent-abortion Series The value of folic-acid therapy in early pregnancy was assessed in 19 patients with a history of miscarriage on at least two consecutive occasions immediately before the investigation began. Some of them had been delivered of live children before the onset of the abortion sequence; in
there any evidence of a genital abnormality or gross systemic disease. The serum-vitamin-B12 was normal in all the patients. The cases were divided into three groups, according to none was
TABLE III-RECURRENT ABORTION
women
Group B: Not Pregnant 2 patients, not pregnant at the time, sought advice about their recurring miscarriages. 1 had a live child, but this had been followed by 3 histologically confirmed abortions. The other had had 2 pregnancies, both ending in abortion at ten weeks. The serum-folic-acid activity of these 2 patients was 2-0 m per ml. and 5-0 mfLg. per ml. Group C: Early Pregnancy 10 pregnant women, without signs of abortion, were seen. The duration of their pregnancies varied between five weeks and twelve weeks, except for 1 who was in the nineteenth week. Abortion had occurred 24 times and 9 live children had been born, all of whom were shared between 4 of the women. 6 patients had had 15 abortions without a living child: 1 of these women had aborted on 5 consecutive occasions. The abortion-rate for these 10 cases was 2-4 per patient. The serum-folic-acid activity ranged between less-than-1-0 mg. per ml. and 13-0 m[Lg. per ml. 3 cases had levels below 2-6 m[Lg. per ml.
Management and Results
The 7
cases of threatened abortion (table ill, group A) treated from the time of their first attendance with intramuscular folic acid 45 mg. daily for three days, followed by oral folic acid 15 mg. daily. They all miscarried within two weeks. These cases were followed up after the miscarriage. They, together with 2 non-pregnant women in grcup B, were given additional folic acid (15 mg. daily by mouth) for periods up to two months. Meanwhile, serum-folicacid activity was checked to ensure its absorption and the continuance of the therapy by the patients. 7 of these 9 patients became pregnant. The 2 women who have not conceived again are still under review. Folic-acid therapy, supplemented by oral iron, was continued throughout the pregnancies of these patients. The 10 pregnant patients in group C were managed similarly from the time of their first attendance at the antenatal clinic until delivery. 15 of these 17 pregnant women have been delivered successfully at term of a live child without any foetal abnormalities. Of the remaining 2 patients, one is now eighteen weeks pregnant, having previously miscarried twice at ten and twelve weeks. The other patient is now in the thirty-second week of her pregnancy, so far without incident; she has 1 live child but the birth of this child had been followed by 3 abortions. The only complication in any of these 17 patients was a megaloblastic anxmia which developed at twenty-two weeks in the patient who was in the nineteenth week of her pregnancy when first seen. At this visit, her serumfolic-acid activity had been 1-0 m[Lg. per ml., and she subsequently admitted that she had not taken the prescribed folic-acid tablets. She was intensively treated and the pregnancy continued successfully to term.
were
672 Discussion
abortion suggest that folic acid by itself is of value in the management of this type of case, provided that the therapy is begun early in pregnancy and certainly before signs of abortion appear. The management of these cases between pregnancies remains a problem. The present results justify a further trial of folic acid where low serum-folic-acid activity is found. It :- prudent to exclude vitamin-B12 deficiency before embarking on folic-acid therapy, because megaloblastic anxmia of the addisonian type can occur in young women during the childbearing years. Our knowledge of the factors that maintain normal pregnancy is far from complete, and a great deal more must be learnt before abortion can always be prevented.
Serum-folic uid Activity in Isolated Abortion The resalts of this investigation indicate an association between spontaneous isolated abortion of unknown aetiology and a deficiency of folic acid and its derivatives, as reflected in the levels of the total serum-folic-acid activity. This association has also been shown by Hibbard (1964) who reported urinary excretion of FIGLU in 22% of abortions occurring as isolated incidents and in 41% of abortions in patients with a history of recurrent abortion. Latterly, a significant correlation has been shown between low serum-folic-acid activity and threatened and inevitable
abortion (Martin and Davis 1964). The degree of this association cannot yet be conclusively assessed. Ball and Giles (1964) have reported 2.6 m[Lg. per ml. as the lower limit of total serum-folic-acid activity in the first twenty weeks of normal pregnancy. But they, have also demonstrated that, at the lower end of the normal range, the values overlap in normal pregnant women and in women with megaloblastic anaemia of pregnancy. As a result of a preliminary investigation, they suggested that the level of the labile factor of serum-folic-acid activity was of greater diagnostic importance than the tcal activity. Nevertheless, there seems to be a critical lower level for each individual patient. If the activity falls or is below this level in early pregnancy, then the risk of abortion is increased, whereas in later pregnancy abruptio placentae or megaloblastic anasmia may occur. Whether din inished serum-folic-acid activity is due to demand exceeding supply, dietary deficiency, malabsorption, or malutilisation in the form of a metabolic block, remains to be decided. In this series, malabsorption was not investigated; but diet and drugs, especially the antiemetics, were eliminated as a major cause. To suggest that in pregnancy the demand exceeds supply may be an over-simplification, but a high folic-acid content is found in rapidly developing tissue, and foetal blood has been shown to have a folate level higher than that present in maternal blood (Baker et al. 1958, Solomons et al. 1962). A deficiency of folic acid and its derivatives in later pregnancy is not necessarily reflected by anaemia or the
Summary Serum-folic-acid activity was assayed in 150 cases of spontaneous isolated abortion of unknown aetiology. Levels of 2-6 m[Lg. per ml. or less were obtained in 25% of the cases; of 3-1 m per ml. or less in 35%; and of 4-1 m[Lg. per ml. or less in 53% of the patients. 17 pregnant women who had a history of recurrent abortion were treated with folic acid from early pregnancy to term. There were no complications, and 15 were delivered of normal live infants at term; the pregnancies of the remaining 2 patients continue satisfactorily and without incident. 7 pregnant patients with a history of recurrent abortion were first seen when threatening to abort. Despite intensive folic-acid therapy, they all miscarried within two weeks. We are grateful to our obstetric colleagues for their assistance in selecting the patients in these series; to Dr. S. Varadi, consultant haematologist, and to Mr. A. Lewis, F.I.M.L.T., of the City General Hospital, Sheffield, for technical advice; and to Dr. K. V. Lodge, consultant pathologist, Wythenshawe Hospital, Manchester, for advice and encouragement. REFERENCES
Baker, H., Ziffer, H., Pasher, I. (1958) Brit. med. J. i, 978. Ball, E. W., Giles, C. (1964) J. clin. Path. 17, 165. Bevis, D. C. A. (1951) Lancet, ii, 207. British Medical Journal (1963) i, 283. Chanarin, I., MacGibbon, B. M., O’Sullivan, W. J., Mollin, D. L. (1959) Lancet, ii, 634. Hibbard, B. M. (1964) J. Obstet. Gynœc. Brit. Cwlth, 71, 529. Hibbard, E. D. (1963) Brit. med. J. ii, 1430. McRae, D. J., Irani, J. B., Bowker, R. G., Longhurst, P. L. (1964) J. Obstet. Gynœc. Brit. Cwlth, 71, 586. Martin, J. D., Davis, R. E. (1964) ibid. p. 400. Hähnel, R. (1963) Lancet, ii, 716. Osmond-Clarke, F., Murray, M. (1963) Brit. med. J. ii, 1172. Solomons, E., Lee, S. L., Wassermann, M., Malkin, J. (1962) J. Obstet. Gynœc. Brit. Cwlth, 69, 724. Warburton, D., Fraser, F. C. (1959) Clin. Obstet. Gynœc. 2, 22. Waters, A. H., Mollin, D. L. (1961) J. clin. Path. 14, 335. —
p* Auction of megaloblastic erythropoiesis (Chanarin et al. 1959, Ball and Giles 1964). Table i shows that even in early pregnancy this dissociation is also present. Thus, haematological findings are not necessarily a guide to the folic-acid state of patients, and the only satisfactory means of detecting a deficiency is by an assay of the serum-folicacid activity. Folic-add Therapy in Recurrent Abortion After 2 consecutive abortions, the risk of further miscarriage is 23% (Warburton and Fraser 1959). Many therapeutic measures have been adopted to reduce this risk (Bevis 1951, British MedicalJournaZ1963). Recently, limited succe was reported with hormonal therapy in
—
in which diminished hormonal levels were detected the vaginal smear (Osmond-Clarke and Murray 1963, by McRae et al. 1964). Low serum-folate levels have been shown to be associated in pregnancy with diminished urinary excretion of ocstr"ne (Martin et al. 1963), and the poor results with hormone therapy alone have been explained on the grounds L-iat hormone action depends on adequate quantities of folic acid at the critical period of foetoplacental or uterine growth. The results of our preliminary trial with folic-acid therapy in pregnant women with a history of recurrent:
cases
.
—
"... Women have a harder role to sustain in society than men because the combination of the duties of parenthood with the full use of one’s intellectual and spiritual potentialities is more difficult for a mother than for a father. The burden at present is heavier than it need be because of social pressures which make career women feel a sense of guilt if they are not able to cook and sew, do interior decor and make the children’s clothes just as well as those who devote themselves eritirely to housewifery. In reading the biographies of our great forerunners, I am constantly struck by the extent to which the infrastructure supported their magnificent work. Not for them the rush back from work to peel the potatoes and put the casserole in the oven before hastily dressing to look as though they had never heard of a kitchen sink. But social pressures can be resisted and thereby modified. If society wants women to make the full and vital contribution to all aspects of life of which they are capable, it must face the real meaning of the dual role and make provision to give women the opportunity to do both their jobs as wives and workers as efficiently and as satisfyingly as they can."-Professor LADY WILLIAMS: Changing Patrern of Women’s Employment; p. 15. Liverpool University Press, 1965.
drug requirement, for not more than ten of the thirtythree patients required any change of dose within 2 weeks of starting oral therapy. Assuming that hypersensitivity will be revealed by the intramuscular test, there appears to be little risk of drug accumulation so long as dosage is "
tailored " in this manner: even when oral treatment has been initiated with a dose as large as 100 mg. no symptoms of overdosage have been encountered. At the time of this report all the patients under treat-
showing guanethidine.
ment are
a
satisfactory hypotensive
guanethidine (’Ismelin’) for intramuscular use. Ismelin ampoules are not marketed, but may be obtained for investigation purposes from the Medical Director, Ciba Laboratories Limited, Horsham, Sussex. REFERENCES
Johnston, A. W., Prichard, B. N. C., Rosenheim, M. L. (1964) Lancet, ii, 659. Leishman, A. W. D., Matthews, H. L., Smith, A. J. (1959) ibid. ii, 1044.
response to
SERUM-FOLIC-ACID IN RECURRENT ABORTIONS
Discussion
The slow
development of hypotensive
effect with guanethidine and the slow elimination of the drug have both benefits and disadvantages. On the one hand, bloodpressure levels may be more stable and less subject to diurnal " swing " than with a drug of shorter action. On the other hand, in very severe hypertension and particularly in cases of accelerated or malignant hypertension the delay in achieving effective blood-pressure control is undesirable, and yet it is precisely in these cases that a drug of guanethidine’s potency is required. To bridge the gap until oral guanethidine becomes effective, ganglionblocking drugs such as pentolinium and pempidine have often been employed. Recently, Johnston et al. (1964) have reported that the new sympathetic-blocking drug bethanidine is satisfactory for the initial treatment of
malignant hypertension. Where an immediate effect is required (as in hypertensive crisis) we have found the intravenous preparation of methyldopa useful, for this drug is less dependent upon posture for its hypotensive action. To sustain the effect, however, the injection must be repeated at intervals of not more than 6 hours. In less urgent cases, such as malignant or accelerated hypertension without acute cardiac or cerebral complication, the procedure described above has proved successful. Patients nos. 7 and 15 were in this group. The observations required for this study may not be possible outside hospital, and in any case patients with
hypertension severe enough to require guanethidine are usually best admitted to hospital for full study and the start of treatment. With tests for sensitivity to guanethidine taking place alongside other investigations, however, the stay in hospital is usually 7-10 days, after which time most of the patients can be discharged to outpatient supervision with their blood-pressure fully controlled. If, instead of being admitted, our thirtythree patients had paid weekly visits to the outpatient department, blood-pressure control would have taken 4.6 weeks
on
average.
Summary The dose of guanethidine by mouth must be increased slowly to reduce the risk of excessive drug accumulation in sensitive patients. The resulting delay in achieving satisfactory blood-pressure control may be hazardous for certain hypertensive patients. Responsiveness to guanethidine can be judged by the fall of blood-pressure after an intramuscular test dose. Treatment with the drug may then safely be started with an oral dose of 4-5 times the effective t-est dose. In thirty-three patients managed in this way adequate blood-pressure control was achieved in an average of 7-3 days, compared with 4-6 weeks which would have been required with orthodox treatment. We are indebted to Dr. A. K. Pittman, of Ciba Limited, for the
M.B.
R. H. MARTIN Lpool, F.R.C.S.E., M.R.C.O.G.
CONSULTANT OBSTETRICIAN AND GYNÆCOLOGIST
T. A. HARPER Madras, M.C.Path.
M.B.
ASSISTANT PATHOLOGIST
W. KELSO And., M.R.C.O.G.
M.B. St.
SENIOR REGISTRAR IN OBSTETRICS AND GYNÆCOLOGY
WYTHENSHAWE HOSPITAL, MANCHESTER
MEGALOBLASTIC anaemia was originally thought to be only consequence of a deficiency of folic acid and its derivatives-a deficiency which has been widely reported to be present in the second half of pregnancy and the early puerperium. Recently, a relation between folic-acid deficiency and abruptio placentae has been suggested by the finding of formiminoglutamic-acid (FIGLU) in the urine (Hibbard and Hibbard 1963). On the supposition that folic-acid deficiency might be associated with spontaneous isolated abortion of unknown aetiology folic-acid therapy should be helpful in the management of pregnancies in women with a history of recurrent abortion. Serum-folic-acid activity was estimated in patients with complete and incomplete abortion, and a therapeutic trial of folic acid was undertaken in a small series of cases of recurrent abortion. the
Patients and Methods
Assay of Serum-folic-acid Activity The microbiological assay of serum-folic-acid activity with Lactobacillus casei is now recognised as the most sensitive and reliable method of detecting folic-acid deficiency. The method in this investigation was that of Waters and Mollin (1961), in which ascorbic acid is added to the serum and the buffer solution.
Selection
of Patients patients were those seen in the wards and clinics at Withington Hospital and Wythenshawe Hospital, Manchester, and were investigated in two series: (1) a spontaneous isolatedabortion series, to study the relation between serum-folic-acid activity and abortion (150 cases); and (2) a recurrent-abortion series, to assess the therapeutic value of folic acid in the management of pregnancies in women with a history of recurrent abortion (19 cases). Spontaneous Isolated-abortion Series The
There were 150 consecutive cases of isolated spontaneous abortion in which no genital abnormality was found and in which evidence of systemic disease was lacking. In these circumstances, the condition was classed as isolated abortion of unknown xtiology. All the women had been pregnant for eighteen weeks or less at the time of the abortion. Those who had a history of previous recurrent abortion were excluded, as also were those in whom there was no histological evidence of trophoblastic tissue in the recovered products. Admittedly, an unknown number of concealed criminal abortions will have been included, but we tried to exclude these. A specimen of clotted blood was obtained as soon as possible
671 TABLE I-LEVELS
OF
SERUM-FOLIC-ACID ACTIVITY IN SPONTANEOUS ABORTION
presentation at their first attendance: group A, threatened abortion; group B, not pregnant; and group C, early pregnancy. Their obstetric histories
their method of
summarised in table
are
ill.
A: Threatened Abortion presented with threatened miscarriage: pregnancy tests were positive at this time. Of 33 previous pregnancies, only 7 had been successful, giving an abortion rate of 3-7 per patient. The range of serum-folicacid activity in these patients was 1-0 to 10-5m[Lg. per ml. 2 patients had levels below 2-6 m[Lg. per ml.
Group 7
TABLE II-PROPORTIONS OF SPONTANEOUS ABORTIONS BELOW VARIOUS LEVELS OF SERUM-FOLIC-ACID ACTIVITY
for the determination of the serum-folic-acid activity. At the same time, haemoglobin was estimated and the peripheral blood-film was examined.
Findings Table i gives the number of isolated abortions which occurred at the various levels of serum-folic-acid activity; the percentage of abortions below various levels of serumfolate are summarised in table 11. In 25% of the abortions, the level of serum-folic-acid activity was below 2-6 m[.Lg. per ml.; in 35% the level was below 3-1 m[.Lg. per ml.; while in 53% a level below 4-1 m[.Lg. per ml. was found. Table I also shows the number of abortions with hxmoglobin values of less than 10-5 g. per 100 ml. In the area from which these patients are drawn, haemoglobin readings of 10-8 g. per 100 ml. in early pregnancy are usual. Examination of the peripheral blood-films revealed no evidence of hypochromic or macrocytic anaemia. Subsequent haemoglobin estimations showed that, although 15% of the patients had a value of less than 10-5 g. per 100 ml. on admission, 42% had fallen below this level during the next twenty-four hours. Even if no allowance is made for pre-admission hxmodilution, these results indicate that over 85% of the patients were not
anaemic. Recurrent-abortion Series The value of folic-acid therapy in early pregnancy was assessed in 19 patients with a history of miscarriage on at least two consecutive occasions immediately before the investigation began. Some of them had been delivered of live children before the onset of the abortion sequence; in
there any evidence of a genital abnormality or gross systemic disease. The serum-vitamin-B12 was normal in all the patients. The cases were divided into three groups, according to none was
TABLE III-RECURRENT ABORTION
women
Group B: Not Pregnant 2 patients, not pregnant at the time, sought advice about their recurring miscarriages. 1 had a live child, but this had been followed by 3 histologically confirmed abortions. The other had had 2 pregnancies, both ending in abortion at ten weeks. The serum-folic-acid activity of these 2 patients was 2-0 m per ml. and 5-0 mfLg. per ml. Group C: Early Pregnancy 10 pregnant women, without signs of abortion, were seen. The duration of their pregnancies varied between five weeks and twelve weeks, except for 1 who was in the nineteenth week. Abortion had occurred 24 times and 9 live children had been born, all of whom were shared between 4 of the women. 6 patients had had 15 abortions without a living child: 1 of these women had aborted on 5 consecutive occasions. The abortion-rate for these 10 cases was 2-4 per patient. The serum-folic-acid activity ranged between less-than-1-0 mg. per ml. and 13-0 m[Lg. per ml. 3 cases had levels below 2-6 m[Lg. per ml.
Management and Results
The 7
cases of threatened abortion (table ill, group A) treated from the time of their first attendance with intramuscular folic acid 45 mg. daily for three days, followed by oral folic acid 15 mg. daily. They all miscarried within two weeks. These cases were followed up after the miscarriage. They, together with 2 non-pregnant women in grcup B, were given additional folic acid (15 mg. daily by mouth) for periods up to two months. Meanwhile, serum-folicacid activity was checked to ensure its absorption and the continuance of the therapy by the patients. 7 of these 9 patients became pregnant. The 2 women who have not conceived again are still under review. Folic-acid therapy, supplemented by oral iron, was continued throughout the pregnancies of these patients. The 10 pregnant patients in group C were managed similarly from the time of their first attendance at the antenatal clinic until delivery. 15 of these 17 pregnant women have been delivered successfully at term of a live child without any foetal abnormalities. Of the remaining 2 patients, one is now eighteen weeks pregnant, having previously miscarried twice at ten and twelve weeks. The other patient is now in the thirty-second week of her pregnancy, so far without incident; she has 1 live child but the birth of this child had been followed by 3 abortions. The only complication in any of these 17 patients was a megaloblastic anxmia which developed at twenty-two weeks in the patient who was in the nineteenth week of her pregnancy when first seen. At this visit, her serumfolic-acid activity had been 1-0 m[Lg. per ml., and she subsequently admitted that she had not taken the prescribed folic-acid tablets. She was intensively treated and the pregnancy continued successfully to term.
were
672 Discussion
abortion suggest that folic acid by itself is of value in the management of this type of case, provided that the therapy is begun early in pregnancy and certainly before signs of abortion appear. The management of these cases between pregnancies remains a problem. The present results justify a further trial of folic acid where low serum-folic-acid activity is found. It :- prudent to exclude vitamin-B12 deficiency before embarking on folic-acid therapy, because megaloblastic anxmia of the addisonian type can occur in young women during the childbearing years. Our knowledge of the factors that maintain normal pregnancy is far from complete, and a great deal more must be learnt before abortion can always be prevented.
Serum-folic uid Activity in Isolated Abortion The resalts of this investigation indicate an association between spontaneous isolated abortion of unknown aetiology and a deficiency of folic acid and its derivatives, as reflected in the levels of the total serum-folic-acid activity. This association has also been shown by Hibbard (1964) who reported urinary excretion of FIGLU in 22% of abortions occurring as isolated incidents and in 41% of abortions in patients with a history of recurrent abortion. Latterly, a significant correlation has been shown between low serum-folic-acid activity and threatened and inevitable
abortion (Martin and Davis 1964). The degree of this association cannot yet be conclusively assessed. Ball and Giles (1964) have reported 2.6 m[Lg. per ml. as the lower limit of total serum-folic-acid activity in the first twenty weeks of normal pregnancy. But they, have also demonstrated that, at the lower end of the normal range, the values overlap in normal pregnant women and in women with megaloblastic anaemia of pregnancy. As a result of a preliminary investigation, they suggested that the level of the labile factor of serum-folic-acid activity was of greater diagnostic importance than the tcal activity. Nevertheless, there seems to be a critical lower level for each individual patient. If the activity falls or is below this level in early pregnancy, then the risk of abortion is increased, whereas in later pregnancy abruptio placentae or megaloblastic anasmia may occur. Whether din inished serum-folic-acid activity is due to demand exceeding supply, dietary deficiency, malabsorption, or malutilisation in the form of a metabolic block, remains to be decided. In this series, malabsorption was not investigated; but diet and drugs, especially the antiemetics, were eliminated as a major cause. To suggest that in pregnancy the demand exceeds supply may be an over-simplification, but a high folic-acid content is found in rapidly developing tissue, and foetal blood has been shown to have a folate level higher than that present in maternal blood (Baker et al. 1958, Solomons et al. 1962). A deficiency of folic acid and its derivatives in later pregnancy is not necessarily reflected by anaemia or the
Summary Serum-folic-acid activity was assayed in 150 cases of spontaneous isolated abortion of unknown aetiology. Levels of 2-6 m[Lg. per ml. or less were obtained in 25% of the cases; of 3-1 m per ml. or less in 35%; and of 4-1 m[Lg. per ml. or less in 53% of the patients. 17 pregnant women who had a history of recurrent abortion were treated with folic acid from early pregnancy to term. There were no complications, and 15 were delivered of normal live infants at term; the pregnancies of the remaining 2 patients continue satisfactorily and without incident. 7 pregnant patients with a history of recurrent abortion were first seen when threatening to abort. Despite intensive folic-acid therapy, they all miscarried within two weeks. We are grateful to our obstetric colleagues for their assistance in selecting the patients in these series; to Dr. S. Varadi, consultant haematologist, and to Mr. A. Lewis, F.I.M.L.T., of the City General Hospital, Sheffield, for technical advice; and to Dr. K. V. Lodge, consultant pathologist, Wythenshawe Hospital, Manchester, for advice and encouragement. REFERENCES
Baker, H., Ziffer, H., Pasher, I. (1958) Brit. med. J. i, 978. Ball, E. W., Giles, C. (1964) J. clin. Path. 17, 165. Bevis, D. C. A. (1951) Lancet, ii, 207. British Medical Journal (1963) i, 283. Chanarin, I., MacGibbon, B. M., O’Sullivan, W. J., Mollin, D. L. (1959) Lancet, ii, 634. Hibbard, B. M. (1964) J. Obstet. Gynœc. Brit. Cwlth, 71, 529. Hibbard, E. D. (1963) Brit. med. J. ii, 1430. McRae, D. J., Irani, J. B., Bowker, R. G., Longhurst, P. L. (1964) J. Obstet. Gynœc. Brit. Cwlth, 71, 586. Martin, J. D., Davis, R. E. (1964) ibid. p. 400. Hähnel, R. (1963) Lancet, ii, 716. Osmond-Clarke, F., Murray, M. (1963) Brit. med. J. ii, 1172. Solomons, E., Lee, S. L., Wassermann, M., Malkin, J. (1962) J. Obstet. Gynœc. Brit. Cwlth, 69, 724. Warburton, D., Fraser, F. C. (1959) Clin. Obstet. Gynœc. 2, 22. Waters, A. H., Mollin, D. L. (1961) J. clin. Path. 14, 335. —
p* Auction of megaloblastic erythropoiesis (Chanarin et al. 1959, Ball and Giles 1964). Table i shows that even in early pregnancy this dissociation is also present. Thus, haematological findings are not necessarily a guide to the folic-acid state of patients, and the only satisfactory means of detecting a deficiency is by an assay of the serum-folicacid activity. Folic-add Therapy in Recurrent Abortion After 2 consecutive abortions, the risk of further miscarriage is 23% (Warburton and Fraser 1959). Many therapeutic measures have been adopted to reduce this risk (Bevis 1951, British MedicalJournaZ1963). Recently, limited succe was reported with hormonal therapy in
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in which diminished hormonal levels were detected the vaginal smear (Osmond-Clarke and Murray 1963, by McRae et al. 1964). Low serum-folate levels have been shown to be associated in pregnancy with diminished urinary excretion of ocstr"ne (Martin et al. 1963), and the poor results with hormone therapy alone have been explained on the grounds L-iat hormone action depends on adequate quantities of folic acid at the critical period of foetoplacental or uterine growth. The results of our preliminary trial with folic-acid therapy in pregnant women with a history of recurrent:
cases
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"... Women have a harder role to sustain in society than men because the combination of the duties of parenthood with the full use of one’s intellectual and spiritual potentialities is more difficult for a mother than for a father. The burden at present is heavier than it need be because of social pressures which make career women feel a sense of guilt if they are not able to cook and sew, do interior decor and make the children’s clothes just as well as those who devote themselves eritirely to housewifery. In reading the biographies of our great forerunners, I am constantly struck by the extent to which the infrastructure supported their magnificent work. Not for them the rush back from work to peel the potatoes and put the casserole in the oven before hastily dressing to look as though they had never heard of a kitchen sink. But social pressures can be resisted and thereby modified. If society wants women to make the full and vital contribution to all aspects of life of which they are capable, it must face the real meaning of the dual role and make provision to give women the opportunity to do both their jobs as wives and workers as efficiently and as satisfyingly as they can."-Professor LADY WILLIAMS: Changing Patrern of Women’s Employment; p. 15. Liverpool University Press, 1965.