- Email: [email protected]
MENSTRUAL BLOOD-LOSS IN IRON-DEFICIENCY ANÆMIA
407
by an awareness of the association and by routine and serial E.C.G. and enzyme studies. Recognition of this syndrome is important, since active treatment of the cardiac lesion and its complications may directly influence the prognosis in the patient. Further study of E.C.G. changes, including continuous electrical monitoring of the heart, in a wide variety of cerebral lesions will undoubtedly lead to better understanding of the relationship between disordered cardiac function and cerebral disease.
may be resolved
Summary In 5 patients painless myocardial infarction and acute cerebral vascular disease occurred simultaneously. The recognition of such cases is important in prognosis and may be achieved both by awareness of the possible association and by electrocardiography and enzyme studies. We thank Dr. Helen Dimsdale and Dr. F. V. Gardner for their permission to report cases under their care.
encouragement and
repeated after the anaemia had been treated and the fully haemoglobin level had returned to normal. The results confirm that some women with " idiopathic " iron-deficiency anaemia have a greater menstrual blood-loss than normal women. There is no evidence that any improvement results from iron therapy, but on the contrary that blood-loss may be increased after treatment of the anaemia.
measurement was
Materials and Methods 17
healthy women, aged 21-40, were studied; none had a history of gynaecological disorders or of anaemia. Blood examination showed none of them to have a hxmoglobin concentration of less than 12-0 g. per 100 ml. The patients with iron-deficiency anaemia all had a haemoglobin concentration of less than 9-0 g. per 100 ml. and a mean corpuscular haemoglobin concentration (M.C.H.C.) of 30% or less. They were selected according to the following criteria: (1) no treatment for anaemia had been received; (2) no organic cause for the iron deficiency discovered; (3) no obvious gynaecological abnormality dis-
REFERENCES
Acheson, J., Hutchinson, E. C. (1964) Lancet, ii, 871. Bean, W. B., Flamm, G. W., Sapadin, A. (1949) Am. J. Med. 7, 765. Burch, G. E., Delasquale, N., Malaret, G. (1960) Ann. intern. Med. 52, 587. Meyers, R., Abiloskov, J. A. (1954) Circulation, 9, 719. Cropp, G. J., Manning, G. W. (1960) ibid, 22, 25. Denny Brown, D. (1951) Med. Clins N. Am. 35, 1457. (1953) Bull. New Engl. Med. Cent. 15, 53. Gupta, P. D., Wahi, P. L., Bawa, Y. S. (1963) Ind. Heart J. 15, 140. Harrison, M. T., Gibb, B. H. (1964) Lancet, ii, 429. Heron, J. R., Anderson, E. G., Noble, I. (1965) ibid. ii, 214. Johnson, R. H., Smith, A. C., Spalding, J. M. K., Wollner, L. (1965) ibid. i, 731. Koskelo, P., Punsar, S., Sipila, W. (1964) Br. med. J. i, 1479. Menon, I. S. (1964) Lancet, ii, 433. Poole, J. L. (1957) Archs Neurol. Psychiat. 78, 355. Rogers, F. B. (1955) J. Am. Geriat. Soc. 3, 714. Shuster, S. (1960) Br. Heart J. 22, 6. Srivastava, S. C., Robson, A. O. (1964) Lancet, ii, 431. Wasserman, F., Choquette, G., Cassinelli, R., Bellet, S. (1956) Am. J. med. Sci. 231, 502.
TABLE I-MENSTRUAL BLOOD-LOSS IN NORMAL
SUBJECTS
—
—
MENSTRUAL BLOOD-LOSS IN IRON-DEFICIENCY ANÆMIA M.D.
A. JACOBS Lond., M.C.Path.
SENIOR LECTURER IN HÆMATOLOGY
E. BLANCHE BUTLER M.B. Wales, M.R.C.O.G. RESEARCH
ASSISTANT,
DEPARTMENT OF OBSTETRICS AND GYNÆCOLOGY *
WELSH NATIONAL SCHOOL OF
MEDICINE, CARDIFF
IRON-DEFICIENCY anaemia is extremely common among British women and is most prevalent in those aged 15-44 years (Kilpatrick 1961). Anæmia develops when the bodystores of iron are depleted and the amount of iron remaining for haemoglobin synthesis is inadequate. Blood lost during menstruation is a major factor in producing iron depletion. Direct measurement of menstrual loss in normal women indicates that in some cases more iron is lost from the body than can be replenished from the diet under normal conditions and iron-deficiency results (Jacobs et al. 1965). It has been suggested that iron
deficiency itself gives rise to menorrhagia, and that the increased blood-loss resulting from this aggravates the anaemic state. Treatment of the iron deficiency is said to result in decreased menstrual blood-loss and thus an improved iron balance (Taymor et al. 1960, 1964, Stafford and Kemp 1964). In the present study menstrual blood-loss was measured in 17 normal women, aged 21-40, and in 15 women with iron-deficiency anaemia. In 13 of the anæmic women the *Present address: Department of Cytopathology, Baltimore, Maryland, U.S.A.
Johns Hopkins Hospital,
covered; (4) patient intelligent enough
to
cooperate
fully in the
tests.
Menstrual blood-loss was measured by labelling the subjects’ red cells with 51Cr and measuring the radioactivity in the pads collected during a complete menstrual period. The red cells were labelled with 50 I-LC of 51Cr about 3-4 days before menstruation was due to start. On the 1 st day of the period and immediately after it had finished, a sample of venous blood was taken to act as a standard. During the period all pads and tampons were collected in plastic bags, and scrupulous care was taken to ensure a complete collection, especially with regard to blood likely to be lost during defæcation or micturition. The activity of the blood collected in the plastic bags was measured in a shielded ring of eight G.26 Pb Geiger tubes connected to an IDL 1700 scaler. This was compared with the activity of pads impregnated with 10 ml. of each of the two venous samples of blood taken at the beginning and the end of the
period. All the anaemic patients were treated either with a full course of oral iron or by a total dose of ’Imferon’. When the haemoglobin concentration had reached a steady normal level, the estimation of menstrual blood loss was repeated. In 2 cases the second measurement was not made: 1 patient did not return for follow-up, and the other left the region at the end of her treatment.
Results
shows the amount of blood lost in the normal The mean blood-loss per period is 34.7±5.8 ml., subjects. with a range of 3-87 ml. Blood-loss in patients with iron-deficiency anaemia is shown in table 11. The mean loss in the patients with untreated anxmia is 121°4 38-5 ml., but this figure is unduly high because of the inclusion of case 15. The degree of blood-loss in this patient cannot be considered typical, and statistically she does not fall within the anxmic group as a whole. Exclusion of this patient from the group results in a mean menstrual blood-loss of 85-514-9 ml. in the untreated cases of anxmia. This is significantly higher than the When blood-loss was normal blood-loss (r < 0°0025). measured after the anaemia had been fully treated, many Table
i
408 TABLE II-MENSTRUAL BLOOD-LOSS IN PATIENTS WITH IRON-DEFICIENCY ANEMIA
complaining of menorrhagia. The loss ranged 970 ml., but even visual assessment of the pads by the doctor did not distinguish completely those with an
women
from 9
to
excessive loss from those whose loss
patients were found to have an increased menstrual flow (see accompanying figure). Case 15 was a striking exception to this finding. The mean blood-loss after treatment (excluding case 15) is 157.3±36.4 ml., which is significantly higher than before treatment (p < 0-025). The mean value including case 15 is 157.7 ± 28.0 ml. The increase in blood-loss following treatment seemed to be greatest in those patients whose initial loss was above the normal range. Case 15 appeared exceptional in every way.
Despite an alarming degree of haemorrhage during her period, quite unperturbed, no gross gynaecological abnormality was detected. She was treated with an intravenous
which left her
infusion of 2250 mg. of iron in the form of imferon; this resulted in complete remission of her anaemia, and menstrual measurement then showed an excessive loss but not an amount comparable to that in the first period measured. 18 months after her infusion of iron she is again slightly anaemic, and hysterectomy is being considered.
Discussion Menstrual blood-loss cannot be assessed from the clinical impressions of an observer or even by the subject herself. Barer and Fowler (1936) found no relation between duration of the period and total blood-loss, and Cheyne and Hytten (1963) found no correlation between the patient’s estimate of blood-loss and the amount actually lost. The number of pads used gives no guide to the volume of flow (Barer and Fowler 1936), and this is hardly surprising since a recent survey showed that different brands of sanitary towels vary in their power to absorb blood from 1-4 ml. to 71 ml. per towel (Consumers Association 1964). Our own observations lead us to agree that menstrual loss cannot be assessed from the patient’s evidence. Direct measurement of blood-loss may reveal that a patient complaining of menorrhagia has a normal loss, while excessive loss is considered normal by another patient. Rankin et al. (1962) measured blood-loss in 20
was
normal.
Menstrual loss may be measured by estimation of extracted haemoglobin (Hallberg and Nilsson 1965), by chemical digestion followed by iron estimation (Barer and Fowler 1936), or by labelling the subject’s blood with a radioactive isotope and measuring the activity of the menstrual loss (Baldwin et al. 1961, Hagedorn et al. 1961, Rankin et al. 1962). The method of radioactive labelling of red cells used in this investigation has proved acceptable to patients and has enabled estimations to be carried out easily and simply in the laboratory. Barer and Fowler (1936) measured blood-loss in 100 normal women and found values ranging from 6-5 ml. to 179 ml. with a mean of 50-5 ml. A haemoglobin concentration of 10-2 g. per 100 ml. was considered to be the lower limit of normal in their series, and calculation of the M.C.H.c. from the data provided shows that some cases of iron-deficiency anaemia were included. There was no correlation between the haemoglobin concentration and the amount of menstrual blood-loss. Millis (1951) carried out repeated measurements on 14 normal subjects, some of whose hxmoglobin concentrations were as low as 10 g. per 100 ml. Losses varied from 8 to 154 ml. per period with an overall mean of 50 ml. There was some variation in the losses of 3 women who had heavier periods than the average. Baldwin et al. (1961) measured losses in 21 normal subjects and found a range of 10-55 ml. (mean 25 ml.). Both Barer and Fowler (1936) and Millis (1951) found a few normal individuals with a menstrual loss of over 100 ml., but they included in their series women who were undoubtedly iron-deficient. Menstrual blood-loss seems to be fairly constant in individual normal subjects, variations appear to be more likely in subjects with excessive loss. Cheyne and Hytten (1963) found little difference between successive periods in normal subjects. Hallberg and Nilsson (1965) measured menstrual blood-loss for a whole year in 12 normal women and found no significant difference between periods during this time. They concluded that a single determination of the menstrual blood-loss was a guide to the average blood-loss for that subject.
The present investigation showed normal women to lose 3-87 ml. blood per period (mean 35 ml.). This agrees with previous studies. The data on normal women obtained by Barer and Fowler (1936), Millis (1951), and Baldwin et al. (1961) and in the present investigation indicate that over a third of normal women have a blood-loss of 40 ml. or more per month. This is equivalent to an average daily iron-loss of over 06 mg., assuming the mean haemoglobin concentration of women in this age group to be 127 g. per 100 ml.the figure obtained by Kilpatrick (1961). The loss of non-haemoglobin iron from the body, by way of the skin, gastrointestinal tract, and urine, has been estimated at 0-5-1 mg. per day (Moore 1964). A daily loss of 16 mg. iron from the body will result either in a negative iron balance or, in many cases, in a partially compensated state of iron deficiency. The average daily consumption of iron in the United Kingdom is 142 mg. (National Food Survey 1963) and the mean absorption of food-iron 65% (Moore 1964), which indicates that women with a menstrual loss of 40 ml. or more per month must have either an iron intake above the average or an increased iron absorption to maintain iron balance. Increased iron absorption is a feature of the iron-deficient state. It is impossible to say how many women manage to satisfy their iron requirements, but the present study confirms that iron-deficient women in whom no other cause for the condition is found tend to have a greater menstrual loss than non-anaemic women. Of 15 such anxmic women, 6 had a blood-loss in excess of the normal range, 6 had a blood-loss above
409 the normal
value, and only 2 gave results below the value. The view that excessive menstrual loss is an important cause of iron-deficiency anasmia has been held for many years, but objective measurements have not been made until recently. Haden and Singleton (1933) found that 17 out of 29 menstruating women with iron-deficiency ansemia had abnormal menstruation. Gray and Wintrobe (1936) studied 40 women with chronic hypochromic anaemia and found unexplained menorrhagia in 14 of them. Hagedorn et al. (1961) measured blood-loss in 15 patients with iron-deficiency anaemia and found a range of 103-579 ml. compared with a range of 6-50 ml. in a group of 12 healthy women. Some workers have taken the view that menorrhagia may be due to iron deficiency itself, and that treatment of the iron deficiency reduces menstrual loss to normal levels (Haden and Singleton 1933, Taymor et al. 1960, 1964, Stafford and Kemp 1964). In none of these investigations was blood-loss measured. Taymor et al. (1964) treated 123 patients complaining of menorrhagia with oral or intramuscular iron. In 74 out of 83 patients with a serum-iron concentration of 90 µg. per 100 ml. or less, improvement of the menorrhagia was reported. Improvement was also found, however, in 25 out of 44 patients with serum-iron concentrations above 90 µg. per 100 ml. and 11 out of 27 patients treated with a placebo. The greater subjective improvement in patients treated with iron than in those treated with a placebo is taken as evidence of the xtiological role of iron deficiency in menorrhagia. Stafford and Kemp (1964) suggest that iron-deficiency anæmia causes generalised vascular fragility manifested by menorrhagia and excessive haemorrhage after dental extractions, but no evidence on this point is available. Both Taymor et al. (1964) and Stafford and Kemp (1964) suggest that menorrhagia may be caused by latent iron deficiency in the absence of actual anaemia, as well as by the gross forms of iron deficiency with anxmia. If this is so, then treatment of the deficiency would be expected to reduce the amount of blood lost during menstruation. The present investigation does not support this thesis. In only 1 case was blood-loss significantly reduced after treatment of anaemia, and this patient was otherwise atypical of the anaemic group. In the other cases where blood-loss was excessive before treatment, it was increased after treatment. In those cases where blood-loss had been in the normal range before treatment it was little increased, if at all, after treatment. It is not suggested that iron therapy itself results in an increase in menstrual loss. A more probable explanation of our findings is that the menstrual loss measured after treatment represents the original flow, and that with the development of irondeficiency anasmia a compensatory mechanism results in a reduced flow from the endometrium. This would have the effect of reducing iron-loss from the body, since both the volume and the haemoglobin content of the menstrual fluid would be reduced at this time. We havefound no evidence to suggest that menorrhagia may be caused by iron deficiency. Our findings are in keeping with the view that iron deficiency commonly results when dietary intake of iron does not compensate fully for losses. This is especially likely to occur when menstrual losses are above 40 ml., but, if the intake of iron is inadequate, deficiency may develop when menstrual loss is less than this. normal
mean
mean
Summary Menstrual blood-loss
was
measured in 17 normal
and 15 women with iron-deficiency anaemia. The anaemic women had a heavier blood-loss than the normal group, and in many cases this became still heavier after a full course of iron therapy with remission of the anaemia. It is suggested that, when iron-loss from the body exceeds dietary intake and iron deficiency results, there may be a compensatory reduction in menstrual flow. There is no evidence that menorrhagia is commonly produced by iron deficiency. women
We should like
thank the midwives of the Cardiff Maternity the normal subjects were selected, for their interest and cooperation. We are also indebted to Prof. A. S. Duncan and Miss C. C. Rees for their help and advice. to
Hospital, from whom
REFERENCES
Baldwin, R. M., Whalley, P. J., Pritchard, J. A. (1961) Am. J. Obstet. Gynec. 81, 739. Barer, A. P., Fowler, W. M. (1936) ibid. 31, 979. Cheyne, G. A., Hytten, F. E. (1963) Proc. Nutr. Soc. 22, XIX. Consumers Association (1964) Which, March issue. Gray, L. A., Wintrobe, M. M. (1936) Am. J. Obstet. Gynec. 31, 3. Haden, R. L., Singleton, J. M. (1933) ibid. 26, 330. Hagedorn, A. B., Kiely, J. M., Tauxe, W. N., Owen, C. A. (1961) Proceedings of the Eighth Congress of the European Society of Hæmatology; p. 249. Hallberg, L., Nilsson, L. (1965) Acta obstet. gynec. Scand. 43, 352. Jacobs, A., Kilpatrick, G. S., Withey, J. L. (1965) Post-grad, med. J. 41, 418. Kilpatrick, G. S. (1961) Brit. med. J. ii, 1736. Millis, J. (1951) Med. J. Aust. ii, 874. Moore, C. V. (1964) in Iron Metabolism: An International Symposium (edited by F. Gross). Berlin. National Food Survey Committee (1963) Domestic Food Consumption and Expenditure. H.M. Stationery Office. Rankin, G. L. S., Veall, N., Huntsman, R. G., Liddell, J. (1962) Lancet, i, 567.
Stafford, J. L., Kemp, N. H. (1964) Sangre, Barcelona, 9, 410. Taymor, M. L., Sturgis, S. H., Goodale, W. T., Ashbough, D. (1960) Obstet. Gynec. N.Y. 16, 571. Yahia, C. (1964) J. Am. med. Ass. 187, 323. —
—
MANNITOL IN THE SURGERY OF AORTIC ANEURYSM R. J. LUCK Lond., F.R.C.S.
M.B.
LECTURER IN SURGERY
W. T. IRVINE M.D., M.Ch., B.Sc. Glasg., F.R.C.S., F.R.C.S.E. PROFESSOR OF SURGERY
ST.
MARY’S
HOSPITAL MEDICAL
SCHOOL, LONDON, W.2
RESECTION of an aneurysm of the abdominal aorta was first reported by Dubost et al. (1951); since then resection has become the established treatment for the condition. The results are good, despite a 9% mortality-rate in the first postoperative month (DeBakey et al. 1964). Powers et al. (1957) regarded acute renal failure as the major hazard of the operation, and Nanson and Noble (1959) suggested that cross-clamping the aorta just below the renal arteries was responsible for the renal damage, though Gagnon et al. (1960), on the other hand, reported that aortic clamping below the renal arteries produced only mild and transient changes in renal function. Intravenous mannitol solution, a powerful osmotic diuretic, causes good diuresis after experimental hæmorrhage (Robello et al. 1962); Selkurt (1945) found that it increased the glomerular filtration-rate after renalartery occlusion; and Hatcher et al. (1958) reported that it protected against adrenaline-induced renal ischaemia in dogs. Mannitol has been said to be effective in the treatment and prevention of renal failure caused by transfusion reactions (Barry and Crosby 1963), and Barry and Mallory (1962) maintained that mannitol could prevent acute tubular necrosis in man, if it was given early enough in the onset phase. Etheridge et al.
by an awareness of the association and by routine and serial E.C.G. and enzyme studies. Recognition of this syndrome is important, since active treatment of the cardiac lesion and its complications may directly influence the prognosis in the patient. Further study of E.C.G. changes, including continuous electrical monitoring of the heart, in a wide variety of cerebral lesions will undoubtedly lead to better understanding of the relationship between disordered cardiac function and cerebral disease.
may be resolved
Summary In 5 patients painless myocardial infarction and acute cerebral vascular disease occurred simultaneously. The recognition of such cases is important in prognosis and may be achieved both by awareness of the possible association and by electrocardiography and enzyme studies. We thank Dr. Helen Dimsdale and Dr. F. V. Gardner for their permission to report cases under their care.
encouragement and
repeated after the anaemia had been treated and the fully haemoglobin level had returned to normal. The results confirm that some women with " idiopathic " iron-deficiency anaemia have a greater menstrual blood-loss than normal women. There is no evidence that any improvement results from iron therapy, but on the contrary that blood-loss may be increased after treatment of the anaemia.
measurement was
Materials and Methods 17
healthy women, aged 21-40, were studied; none had a history of gynaecological disorders or of anaemia. Blood examination showed none of them to have a hxmoglobin concentration of less than 12-0 g. per 100 ml. The patients with iron-deficiency anaemia all had a haemoglobin concentration of less than 9-0 g. per 100 ml. and a mean corpuscular haemoglobin concentration (M.C.H.C.) of 30% or less. They were selected according to the following criteria: (1) no treatment for anaemia had been received; (2) no organic cause for the iron deficiency discovered; (3) no obvious gynaecological abnormality dis-
REFERENCES
Acheson, J., Hutchinson, E. C. (1964) Lancet, ii, 871. Bean, W. B., Flamm, G. W., Sapadin, A. (1949) Am. J. Med. 7, 765. Burch, G. E., Delasquale, N., Malaret, G. (1960) Ann. intern. Med. 52, 587. Meyers, R., Abiloskov, J. A. (1954) Circulation, 9, 719. Cropp, G. J., Manning, G. W. (1960) ibid, 22, 25. Denny Brown, D. (1951) Med. Clins N. Am. 35, 1457. (1953) Bull. New Engl. Med. Cent. 15, 53. Gupta, P. D., Wahi, P. L., Bawa, Y. S. (1963) Ind. Heart J. 15, 140. Harrison, M. T., Gibb, B. H. (1964) Lancet, ii, 429. Heron, J. R., Anderson, E. G., Noble, I. (1965) ibid. ii, 214. Johnson, R. H., Smith, A. C., Spalding, J. M. K., Wollner, L. (1965) ibid. i, 731. Koskelo, P., Punsar, S., Sipila, W. (1964) Br. med. J. i, 1479. Menon, I. S. (1964) Lancet, ii, 433. Poole, J. L. (1957) Archs Neurol. Psychiat. 78, 355. Rogers, F. B. (1955) J. Am. Geriat. Soc. 3, 714. Shuster, S. (1960) Br. Heart J. 22, 6. Srivastava, S. C., Robson, A. O. (1964) Lancet, ii, 431. Wasserman, F., Choquette, G., Cassinelli, R., Bellet, S. (1956) Am. J. med. Sci. 231, 502.
TABLE I-MENSTRUAL BLOOD-LOSS IN NORMAL
SUBJECTS
—
—
MENSTRUAL BLOOD-LOSS IN IRON-DEFICIENCY ANÆMIA M.D.
A. JACOBS Lond., M.C.Path.
SENIOR LECTURER IN HÆMATOLOGY
E. BLANCHE BUTLER M.B. Wales, M.R.C.O.G. RESEARCH
ASSISTANT,
DEPARTMENT OF OBSTETRICS AND GYNÆCOLOGY *
WELSH NATIONAL SCHOOL OF
MEDICINE, CARDIFF
IRON-DEFICIENCY anaemia is extremely common among British women and is most prevalent in those aged 15-44 years (Kilpatrick 1961). Anæmia develops when the bodystores of iron are depleted and the amount of iron remaining for haemoglobin synthesis is inadequate. Blood lost during menstruation is a major factor in producing iron depletion. Direct measurement of menstrual loss in normal women indicates that in some cases more iron is lost from the body than can be replenished from the diet under normal conditions and iron-deficiency results (Jacobs et al. 1965). It has been suggested that iron
deficiency itself gives rise to menorrhagia, and that the increased blood-loss resulting from this aggravates the anaemic state. Treatment of the iron deficiency is said to result in decreased menstrual blood-loss and thus an improved iron balance (Taymor et al. 1960, 1964, Stafford and Kemp 1964). In the present study menstrual blood-loss was measured in 17 normal women, aged 21-40, and in 15 women with iron-deficiency anaemia. In 13 of the anæmic women the *Present address: Department of Cytopathology, Baltimore, Maryland, U.S.A.
Johns Hopkins Hospital,
covered; (4) patient intelligent enough
to
cooperate
fully in the
tests.
Menstrual blood-loss was measured by labelling the subjects’ red cells with 51Cr and measuring the radioactivity in the pads collected during a complete menstrual period. The red cells were labelled with 50 I-LC of 51Cr about 3-4 days before menstruation was due to start. On the 1 st day of the period and immediately after it had finished, a sample of venous blood was taken to act as a standard. During the period all pads and tampons were collected in plastic bags, and scrupulous care was taken to ensure a complete collection, especially with regard to blood likely to be lost during defæcation or micturition. The activity of the blood collected in the plastic bags was measured in a shielded ring of eight G.26 Pb Geiger tubes connected to an IDL 1700 scaler. This was compared with the activity of pads impregnated with 10 ml. of each of the two venous samples of blood taken at the beginning and the end of the
period. All the anaemic patients were treated either with a full course of oral iron or by a total dose of ’Imferon’. When the haemoglobin concentration had reached a steady normal level, the estimation of menstrual blood loss was repeated. In 2 cases the second measurement was not made: 1 patient did not return for follow-up, and the other left the region at the end of her treatment.
Results
shows the amount of blood lost in the normal The mean blood-loss per period is 34.7±5.8 ml., subjects. with a range of 3-87 ml. Blood-loss in patients with iron-deficiency anaemia is shown in table 11. The mean loss in the patients with untreated anxmia is 121°4 38-5 ml., but this figure is unduly high because of the inclusion of case 15. The degree of blood-loss in this patient cannot be considered typical, and statistically she does not fall within the anxmic group as a whole. Exclusion of this patient from the group results in a mean menstrual blood-loss of 85-514-9 ml. in the untreated cases of anxmia. This is significantly higher than the When blood-loss was normal blood-loss (r < 0°0025). measured after the anaemia had been fully treated, many Table
i
408 TABLE II-MENSTRUAL BLOOD-LOSS IN PATIENTS WITH IRON-DEFICIENCY ANEMIA
complaining of menorrhagia. The loss ranged 970 ml., but even visual assessment of the pads by the doctor did not distinguish completely those with an
women
from 9
to
excessive loss from those whose loss
patients were found to have an increased menstrual flow (see accompanying figure). Case 15 was a striking exception to this finding. The mean blood-loss after treatment (excluding case 15) is 157.3±36.4 ml., which is significantly higher than before treatment (p < 0-025). The mean value including case 15 is 157.7 ± 28.0 ml. The increase in blood-loss following treatment seemed to be greatest in those patients whose initial loss was above the normal range. Case 15 appeared exceptional in every way.
Despite an alarming degree of haemorrhage during her period, quite unperturbed, no gross gynaecological abnormality was detected. She was treated with an intravenous
which left her
infusion of 2250 mg. of iron in the form of imferon; this resulted in complete remission of her anaemia, and menstrual measurement then showed an excessive loss but not an amount comparable to that in the first period measured. 18 months after her infusion of iron she is again slightly anaemic, and hysterectomy is being considered.
Discussion Menstrual blood-loss cannot be assessed from the clinical impressions of an observer or even by the subject herself. Barer and Fowler (1936) found no relation between duration of the period and total blood-loss, and Cheyne and Hytten (1963) found no correlation between the patient’s estimate of blood-loss and the amount actually lost. The number of pads used gives no guide to the volume of flow (Barer and Fowler 1936), and this is hardly surprising since a recent survey showed that different brands of sanitary towels vary in their power to absorb blood from 1-4 ml. to 71 ml. per towel (Consumers Association 1964). Our own observations lead us to agree that menstrual loss cannot be assessed from the patient’s evidence. Direct measurement of blood-loss may reveal that a patient complaining of menorrhagia has a normal loss, while excessive loss is considered normal by another patient. Rankin et al. (1962) measured blood-loss in 20
was
normal.
Menstrual loss may be measured by estimation of extracted haemoglobin (Hallberg and Nilsson 1965), by chemical digestion followed by iron estimation (Barer and Fowler 1936), or by labelling the subject’s blood with a radioactive isotope and measuring the activity of the menstrual loss (Baldwin et al. 1961, Hagedorn et al. 1961, Rankin et al. 1962). The method of radioactive labelling of red cells used in this investigation has proved acceptable to patients and has enabled estimations to be carried out easily and simply in the laboratory. Barer and Fowler (1936) measured blood-loss in 100 normal women and found values ranging from 6-5 ml. to 179 ml. with a mean of 50-5 ml. A haemoglobin concentration of 10-2 g. per 100 ml. was considered to be the lower limit of normal in their series, and calculation of the M.C.H.c. from the data provided shows that some cases of iron-deficiency anaemia were included. There was no correlation between the haemoglobin concentration and the amount of menstrual blood-loss. Millis (1951) carried out repeated measurements on 14 normal subjects, some of whose hxmoglobin concentrations were as low as 10 g. per 100 ml. Losses varied from 8 to 154 ml. per period with an overall mean of 50 ml. There was some variation in the losses of 3 women who had heavier periods than the average. Baldwin et al. (1961) measured losses in 21 normal subjects and found a range of 10-55 ml. (mean 25 ml.). Both Barer and Fowler (1936) and Millis (1951) found a few normal individuals with a menstrual loss of over 100 ml., but they included in their series women who were undoubtedly iron-deficient. Menstrual blood-loss seems to be fairly constant in individual normal subjects, variations appear to be more likely in subjects with excessive loss. Cheyne and Hytten (1963) found little difference between successive periods in normal subjects. Hallberg and Nilsson (1965) measured menstrual blood-loss for a whole year in 12 normal women and found no significant difference between periods during this time. They concluded that a single determination of the menstrual blood-loss was a guide to the average blood-loss for that subject.
The present investigation showed normal women to lose 3-87 ml. blood per period (mean 35 ml.). This agrees with previous studies. The data on normal women obtained by Barer and Fowler (1936), Millis (1951), and Baldwin et al. (1961) and in the present investigation indicate that over a third of normal women have a blood-loss of 40 ml. or more per month. This is equivalent to an average daily iron-loss of over 06 mg., assuming the mean haemoglobin concentration of women in this age group to be 127 g. per 100 ml.the figure obtained by Kilpatrick (1961). The loss of non-haemoglobin iron from the body, by way of the skin, gastrointestinal tract, and urine, has been estimated at 0-5-1 mg. per day (Moore 1964). A daily loss of 16 mg. iron from the body will result either in a negative iron balance or, in many cases, in a partially compensated state of iron deficiency. The average daily consumption of iron in the United Kingdom is 142 mg. (National Food Survey 1963) and the mean absorption of food-iron 65% (Moore 1964), which indicates that women with a menstrual loss of 40 ml. or more per month must have either an iron intake above the average or an increased iron absorption to maintain iron balance. Increased iron absorption is a feature of the iron-deficient state. It is impossible to say how many women manage to satisfy their iron requirements, but the present study confirms that iron-deficient women in whom no other cause for the condition is found tend to have a greater menstrual loss than non-anaemic women. Of 15 such anxmic women, 6 had a blood-loss in excess of the normal range, 6 had a blood-loss above
409 the normal
value, and only 2 gave results below the value. The view that excessive menstrual loss is an important cause of iron-deficiency anasmia has been held for many years, but objective measurements have not been made until recently. Haden and Singleton (1933) found that 17 out of 29 menstruating women with iron-deficiency ansemia had abnormal menstruation. Gray and Wintrobe (1936) studied 40 women with chronic hypochromic anaemia and found unexplained menorrhagia in 14 of them. Hagedorn et al. (1961) measured blood-loss in 15 patients with iron-deficiency anaemia and found a range of 103-579 ml. compared with a range of 6-50 ml. in a group of 12 healthy women. Some workers have taken the view that menorrhagia may be due to iron deficiency itself, and that treatment of the iron deficiency reduces menstrual loss to normal levels (Haden and Singleton 1933, Taymor et al. 1960, 1964, Stafford and Kemp 1964). In none of these investigations was blood-loss measured. Taymor et al. (1964) treated 123 patients complaining of menorrhagia with oral or intramuscular iron. In 74 out of 83 patients with a serum-iron concentration of 90 µg. per 100 ml. or less, improvement of the menorrhagia was reported. Improvement was also found, however, in 25 out of 44 patients with serum-iron concentrations above 90 µg. per 100 ml. and 11 out of 27 patients treated with a placebo. The greater subjective improvement in patients treated with iron than in those treated with a placebo is taken as evidence of the xtiological role of iron deficiency in menorrhagia. Stafford and Kemp (1964) suggest that iron-deficiency anæmia causes generalised vascular fragility manifested by menorrhagia and excessive haemorrhage after dental extractions, but no evidence on this point is available. Both Taymor et al. (1964) and Stafford and Kemp (1964) suggest that menorrhagia may be caused by latent iron deficiency in the absence of actual anaemia, as well as by the gross forms of iron deficiency with anxmia. If this is so, then treatment of the deficiency would be expected to reduce the amount of blood lost during menstruation. The present investigation does not support this thesis. In only 1 case was blood-loss significantly reduced after treatment of anaemia, and this patient was otherwise atypical of the anaemic group. In the other cases where blood-loss was excessive before treatment, it was increased after treatment. In those cases where blood-loss had been in the normal range before treatment it was little increased, if at all, after treatment. It is not suggested that iron therapy itself results in an increase in menstrual loss. A more probable explanation of our findings is that the menstrual loss measured after treatment represents the original flow, and that with the development of irondeficiency anasmia a compensatory mechanism results in a reduced flow from the endometrium. This would have the effect of reducing iron-loss from the body, since both the volume and the haemoglobin content of the menstrual fluid would be reduced at this time. We havefound no evidence to suggest that menorrhagia may be caused by iron deficiency. Our findings are in keeping with the view that iron deficiency commonly results when dietary intake of iron does not compensate fully for losses. This is especially likely to occur when menstrual losses are above 40 ml., but, if the intake of iron is inadequate, deficiency may develop when menstrual loss is less than this. normal
mean
mean
Summary Menstrual blood-loss
was
measured in 17 normal
and 15 women with iron-deficiency anaemia. The anaemic women had a heavier blood-loss than the normal group, and in many cases this became still heavier after a full course of iron therapy with remission of the anaemia. It is suggested that, when iron-loss from the body exceeds dietary intake and iron deficiency results, there may be a compensatory reduction in menstrual flow. There is no evidence that menorrhagia is commonly produced by iron deficiency. women
We should like
thank the midwives of the Cardiff Maternity the normal subjects were selected, for their interest and cooperation. We are also indebted to Prof. A. S. Duncan and Miss C. C. Rees for their help and advice. to
Hospital, from whom
REFERENCES
Baldwin, R. M., Whalley, P. J., Pritchard, J. A. (1961) Am. J. Obstet. Gynec. 81, 739. Barer, A. P., Fowler, W. M. (1936) ibid. 31, 979. Cheyne, G. A., Hytten, F. E. (1963) Proc. Nutr. Soc. 22, XIX. Consumers Association (1964) Which, March issue. Gray, L. A., Wintrobe, M. M. (1936) Am. J. Obstet. Gynec. 31, 3. Haden, R. L., Singleton, J. M. (1933) ibid. 26, 330. Hagedorn, A. B., Kiely, J. M., Tauxe, W. N., Owen, C. A. (1961) Proceedings of the Eighth Congress of the European Society of Hæmatology; p. 249. Hallberg, L., Nilsson, L. (1965) Acta obstet. gynec. Scand. 43, 352. Jacobs, A., Kilpatrick, G. S., Withey, J. L. (1965) Post-grad, med. J. 41, 418. Kilpatrick, G. S. (1961) Brit. med. J. ii, 1736. Millis, J. (1951) Med. J. Aust. ii, 874. Moore, C. V. (1964) in Iron Metabolism: An International Symposium (edited by F. Gross). Berlin. National Food Survey Committee (1963) Domestic Food Consumption and Expenditure. H.M. Stationery Office. Rankin, G. L. S., Veall, N., Huntsman, R. G., Liddell, J. (1962) Lancet, i, 567.
Stafford, J. L., Kemp, N. H. (1964) Sangre, Barcelona, 9, 410. Taymor, M. L., Sturgis, S. H., Goodale, W. T., Ashbough, D. (1960) Obstet. Gynec. N.Y. 16, 571. Yahia, C. (1964) J. Am. med. Ass. 187, 323. —
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MANNITOL IN THE SURGERY OF AORTIC ANEURYSM R. J. LUCK Lond., F.R.C.S.
M.B.
LECTURER IN SURGERY
W. T. IRVINE M.D., M.Ch., B.Sc. Glasg., F.R.C.S., F.R.C.S.E. PROFESSOR OF SURGERY
ST.
MARY’S
HOSPITAL MEDICAL
SCHOOL, LONDON, W.2
RESECTION of an aneurysm of the abdominal aorta was first reported by Dubost et al. (1951); since then resection has become the established treatment for the condition. The results are good, despite a 9% mortality-rate in the first postoperative month (DeBakey et al. 1964). Powers et al. (1957) regarded acute renal failure as the major hazard of the operation, and Nanson and Noble (1959) suggested that cross-clamping the aorta just below the renal arteries was responsible for the renal damage, though Gagnon et al. (1960), on the other hand, reported that aortic clamping below the renal arteries produced only mild and transient changes in renal function. Intravenous mannitol solution, a powerful osmotic diuretic, causes good diuresis after experimental hæmorrhage (Robello et al. 1962); Selkurt (1945) found that it increased the glomerular filtration-rate after renalartery occlusion; and Hatcher et al. (1958) reported that it protected against adrenaline-induced renal ischaemia in dogs. Mannitol has been said to be effective in the treatment and prevention of renal failure caused by transfusion reactions (Barry and Crosby 1963), and Barry and Mallory (1962) maintained that mannitol could prevent acute tubular necrosis in man, if it was given early enough in the onset phase. Etheridge et al.