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The Elderly Primigravida
696 A
new observation of great potential importance made. Among the cases treated with the drug were several febrile patients who did not conform to the early clinical syndrome of scrub-typhus, and
The
was
as expected, proved by laboratory tests to typhoid (enteric) fever. A preliminary report on the first ten cases of typhoid treated with chloromycetin has already been published,77 and
who,
have
further information should soon be forthcoming. In brief it may be said that improvement of the general condition, and lessened toxicity, usually became apparent within 24 hours of the beginning of treatment ; the temperature fell to permanent normal levels within four days ; and though occasionally there were relapses, these responded promptly to a second course of the drug. Last July, after encouraging in-vivo tests of the new synthetic chloromycetin in Dr. SMADEi/s laboratory in Washington, all that remained of this synthetic - drug, barely enough for two human cases of scrubtyphus, was sent to Malaya for trial in man. Two Gurkha soldiers, infected during the jungle war against bandits, were selected : in one the infection was very severe ; in the other it was moderate. They were treated respectively on the 5th and 6th days of the febrile reaction. In both the temperature reached normal within 48 hours and remained so ; toxicity vanished and convalescence was uneventful. Since then the work in Kuala Lumpur has continued and the range of diseases investigated has been enlarged. Attempts are being made to establish a chemoprophylactic scheme of dosage, with its obvious importance to troops, planters, survey parties, forest officials, and the like. Alternative dosages aiming at simplification are under trial. A number of detailed reports are in the press, and we must not
anticipate their conclusions.
The above is but a brief narrative of events that have culminated in several unique findings. A muchdreaded disease, scrub-typhus, has been successfully treated by oral administration of an antibiotic prepared from a mould by fermentation methods, - and later by the same antibiotic prepared synthetically. Typhoid fever, for which we have hitherto had no satisfactory remedy, has responded to chloromycetin of the fermentation type. The limits of the drug’s action have not yet been explored, but the director of Messrs. Parke, Davis’s department of clinical investigation is quoted 8 as saying that it has been used with great success in primary atypical pneumonia, and that it is expected to be valuable against whooping-cough. Undulant fever, lymphoand bacillary other conditions, mentioned. dysentery among But beyond all this there are the implications of successful synthesis of an antibiotic. The search for synthetic closely related antibiotics will be intensified, in the hope that the spectrum of diseases affected by this class of drugs will be widened. We must hope that reduced costs, approximating perhaps to those of the sulphonamides, will gradually free this and other such antibiotics from the restriction of use imposed by the expense of fermentation methods of preparation.
granuloma inguinale, urinary infections, are
Woodward, T. E., Smadel, J. E., Ley, H. L., Green, R., Mankikar, D.S. Ann. Intern. Med. 1948, 29, 131. 8. New York Times, March 27.
7.
Elderly Primigravida
To the woman approaching or past the forty mark a first pregnancy may well cause misgiving, for she knows that considerable social and domestic adjustment will be required of her ; and her adaptability is already on the wane. Some are indignant at having " fallen " at a time when-like Abraham’s wife, Sarah, who laughed-they have begun to feel To others, looking back on long years of secure. involuntary sterility, the gamble with hope may appear desperate indeed. All, moreover, are versed in the obstetrical adventures of talkative friends. This emotional background profoundly influences pregnancy, labour, and lactation. Emotion also colours the medical attendant’s judgment, for he is keenly aware of the woman’s limited obstetric future and the unique importance of the foetus ; and he would therefore do well to arm himself with a balanced view of the risks to mother and child. Pregnancies in 1000 women over forty have been reviewed by DAvis and SESK], who found that of the 168 primigravidse in this group only 16% had
spontaneous deliveries ; 46% required forceps delivery, and
were delivered by caesarean section. There maternal mortality of 1-2%, and a combined fcetal mortality (including both primigravidae and multiparae) of about 10%. By contrast, BROMBERGYA and BRZEZINSKI2 reported from Jerusalem a smaller series of 67 cases where spontaneous deliveries took place in 71 % and csesarean section was performed in only 1-5% ; the maternal mortality was nil, and the combined foetal mortality 72%. A more radical trend was detectable in the figures recorded by DUNCAN and GIBSON, in Canada; they noted a rise in the caesarean-section rate from 15% in women between thirty-five and forty to 36% in those over forty. Under modern conditions csesarean section is a fairly safe operation, but it remains an unnatural insult to the peritoneal cavity and the abdominal parietes. With increasing maternal age there is an unfortunately growing readiness to undertake this operation ; too often pessimism about the outcome of labour is allowed to obtrude..,Apprehension, it is true, is seldom felt for the elderly multipara ; with her, caesarean section does not loom upon
31 %
was a
the therapeutic horizon until some gross complication supervenes. But multiparity is not necessarily an advantage : the multipara is often a tired woman, and previous childbirth may have impoverished her blood, endowed her with recurrent urinary infection, ruined her teeth, afflicted her with haemorrhoids and varicose veins, accelerated the onset of hypertension, and played havoc with her abdominal wall and sacroiliac joints. Many years ago BETHEL SOLOMONS drew attention to the " dangerous multipara " and pointed out the increasing risks in parity beyond the fifth from such factors as the pendulous belly with its effects on presentation, and the greater liability to placenta proevia, adherent placenta, uterine rupture, and similar dramatic incidents. The elderly primigravida has less obvious handicaps ; the chief are a more rigid perineum and uncertain expulsive powers in labour, aggravated undoubtedly by anxiety and 1. Davis, M. E., Seski, A. Surg. Gynec. Obstet. 1948, 87, 145. 2. Brombergya, Y. M., Brzezinski, A. J. Obstet. Gynœc. 1942, 49, 672. 3. Duncan, J. W., Gibson, W. E. Canad. med. Ass. J. 1940, 42, 240.
697
possibly by fear. Labour may certainly be prolonged. VIOLET SPILLER,4analysing the cases of 1400 primiparse at the Royal Free Hospital, established a low but
that in lead intoxication there is restricted formation of protoporphyrin-a vital stage in the development of the pigment portion of haemoglobin. This supported definite positive correlation between age and the the theory that dyshaemopoiesis, and not h2emolysis, duration of labour ; and the belief is widely held- was the important change in lead intoxication. and supported by the observations of DuNCAN and NTCFADZEAN -and DAVIS9 seem to have reconciled GiBsoN-that the longer the preceding period of the two theories. They examined bone-marrow, chance that labour will be the the is obtained and studied by smear techniques, sterility, greater by biopsy the inertia. from lead and from guineapigs subjected Furthermore, elderly workers, complicated by has a less certain prospect of establishing to lead intoxication. primigravida They found stippling in the and maintaining satisfactory lactation. On the other normoblasts, but only in those normoblasts that side of the balance, she scores heavily over the multi- showed haemoglobin formation—the polychromatic para in the matter of postpartum haemorrhage; stages included. There were more stippled cells-both DAVIs and SESKI quote a 3 % rate, compared with normoblasts and erythrocytes-in the bone-marrow 7% in multipart. Furthermore, the prematurity- smears than in the peripheral blood. Special staining rate in primigravidae is certainly not nearly as high showed that a varying proportion of the basophilic as the 9% figure ascribed by these workers to elderly granules gave a positive iron reaction ; and again multiparae. Pre-eclampsia is somewhatmore com- there were more of these cells in the marrow than in mon in primigravidae, but at least it is not-in the the blood. These findings are remarkably similar to nature of’ things-recurrent ; and a first attack those recorded by the same authors 1°in some patients is less dangerous than a second or third. In the two with acquired hsemolytic .anaemia—patients whose classes the chances of foetal abnormality are about red cells contained the so-called Pappenheim bodies," equal and are materially higher than in younger which gave a positive iron reaction in the peripheral women. BARRY,5 for instance, showed that mon- blood and in the marrow. When splenectomy was was related to increasing maternal age, which performed on these patients, ,the proportion of red golism was also held to predispose to psychosis in the offspring. blood-cells containing Pappenheim bodies was greatly With pregnancy in women who are past their first increased. McFADZBAN and DAVis therefore removed youth an especially careful watch has to be kept for the spleens of some of their guineapigs subjected to hypertension and renal disorder ; less commonly experimental lead poisoning ; andthe results were fibroids, and other disabilities which crop up as illuminating. Two groups of guineapigs, one normal milestones on the, road to the grave, have a more or and the other without spleens, were given daily doses less direct bearing on the outcome. Hence in giving of a lead salt; with the onset of intoxication and " a reassuring answer to the question " Am I too old ? the appearance of stippled cells in the blood, the there is occasion for vigilance. But there is also much proportion of these cells rose to 40% in the splenecfrom which to draw comfort. tomised animals compared with a maximum of 7-5% in the controls. When the lead was stopped, stippled cells persisted longer in the blood of the splenectomised Lead and the Red Cells animals than in the controls ; furthermore, the THE association of lead poisoning with punctate splenectomised animals showed little anaemia whereas basophilia of the red blood-cells has been recognised in the controls anaemia was definite. In a second for fifty years. With punctate basophilia the red experiment, daily doses of lead were given to a cells look as if they were stippled with black dots, group of guineapigs until stippled cells appeared in and this stippling is used as a measure of intoxication the peripheral blood and- anaemia, developed. Half in lead workers ; the presence of more than 1000 the animals then had their spleens removed ; the stippled cells per c.mm. is a signal that lead intoxica- stippled cells in the blood of these animals rose tion may be present. If poisoning is severe, actual rapidly to 40-50 %, whereas in the controls the level an2emia occurs; and this anaemia is often said to be remained at 25-75%. In the splenectomised animals hsemolytic because of the presence, among other stippled cells were more numerous than reticulocytes ;s of persistent reticulocytosis. Many workers in the controls this relation was reversed. There have tried to find out why stippling appears and how were also qualitative differences in the stippling ; it is connected with the anaemia of lead poisoning. in the splenectomised animals most of the basophilic Some years ago KEY6 showed that the basophilic granules gave a positive iron reaction, whereas in material of the stippling is not derived from nuclear the controls only a minority gave" this reaction. material but is formed in the cytoplasm. AUB and his McFADZEAN and DAvis conclude that lead does act co-workersthought that the effect of lead was to formation ; primarily by disturbing make the surface of the red cells inelastic and brittle, instead of becoming fully converted into haemoglobin, so that they were more easily destroyed and a basophilic substance persists in a granular form hsemolytic type of anaemia appeared. This haemolytic associated with demonstrable iron ; the iron in the theory held the field for a long time. Eventually haemoglobin molecule will not, of course, give " free ’’ studies of porphyrin metabolism suggested that lead iron reactions. When red blood-cells containing these acted on red cells by interfering with haemoglobin are released into the circulation, granules formation ; KENCH, Ga,rM, and LANE 8 showed iron-positive in the are destroyed spleen much more rapidly they 4. Spiller, V. Lancet, 1939, ii, 733. than cells containing no granules, or _only few. "
signs,
haemoglobin
5. 6.
Barry, H. jun. Arch. Neurol. Psychiat., Chicago, 1945, 54, 186. Key, J. A. Arch. intern. Med. 1921, 28, 511. 7. Aub, J. C., Fairhall, L. T., Minot, A. S., Reznikoff, P. Medicine, Baltimore, 1925, 4, 1. 8. Kench, J. E., Gillam, A. E., Lane, R. E. Biochem. J. 1942,
36, 384.
Consequently
a
truly haemolytic anaemia
9. McFadzean, A. J. S., Davis, L. J. 10. McFadzean, A. J. S., Davis, L. J. See Lancet, 1947, ii, 840.
appears.
Quart. J.Med. 1949, 18, 57. Glasg. med. J. 1947, 28, 237 ;
new observation of great potential importance made. Among the cases treated with the drug were several febrile patients who did not conform to the early clinical syndrome of scrub-typhus, and
The
was
as expected, proved by laboratory tests to typhoid (enteric) fever. A preliminary report on the first ten cases of typhoid treated with chloromycetin has already been published,77 and
who,
have
further information should soon be forthcoming. In brief it may be said that improvement of the general condition, and lessened toxicity, usually became apparent within 24 hours of the beginning of treatment ; the temperature fell to permanent normal levels within four days ; and though occasionally there were relapses, these responded promptly to a second course of the drug. Last July, after encouraging in-vivo tests of the new synthetic chloromycetin in Dr. SMADEi/s laboratory in Washington, all that remained of this synthetic - drug, barely enough for two human cases of scrubtyphus, was sent to Malaya for trial in man. Two Gurkha soldiers, infected during the jungle war against bandits, were selected : in one the infection was very severe ; in the other it was moderate. They were treated respectively on the 5th and 6th days of the febrile reaction. In both the temperature reached normal within 48 hours and remained so ; toxicity vanished and convalescence was uneventful. Since then the work in Kuala Lumpur has continued and the range of diseases investigated has been enlarged. Attempts are being made to establish a chemoprophylactic scheme of dosage, with its obvious importance to troops, planters, survey parties, forest officials, and the like. Alternative dosages aiming at simplification are under trial. A number of detailed reports are in the press, and we must not
anticipate their conclusions.
The above is but a brief narrative of events that have culminated in several unique findings. A muchdreaded disease, scrub-typhus, has been successfully treated by oral administration of an antibiotic prepared from a mould by fermentation methods, - and later by the same antibiotic prepared synthetically. Typhoid fever, for which we have hitherto had no satisfactory remedy, has responded to chloromycetin of the fermentation type. The limits of the drug’s action have not yet been explored, but the director of Messrs. Parke, Davis’s department of clinical investigation is quoted 8 as saying that it has been used with great success in primary atypical pneumonia, and that it is expected to be valuable against whooping-cough. Undulant fever, lymphoand bacillary other conditions, mentioned. dysentery among But beyond all this there are the implications of successful synthesis of an antibiotic. The search for synthetic closely related antibiotics will be intensified, in the hope that the spectrum of diseases affected by this class of drugs will be widened. We must hope that reduced costs, approximating perhaps to those of the sulphonamides, will gradually free this and other such antibiotics from the restriction of use imposed by the expense of fermentation methods of preparation.
granuloma inguinale, urinary infections, are
Woodward, T. E., Smadel, J. E., Ley, H. L., Green, R., Mankikar, D.S. Ann. Intern. Med. 1948, 29, 131. 8. New York Times, March 27.
7.
Elderly Primigravida
To the woman approaching or past the forty mark a first pregnancy may well cause misgiving, for she knows that considerable social and domestic adjustment will be required of her ; and her adaptability is already on the wane. Some are indignant at having " fallen " at a time when-like Abraham’s wife, Sarah, who laughed-they have begun to feel To others, looking back on long years of secure. involuntary sterility, the gamble with hope may appear desperate indeed. All, moreover, are versed in the obstetrical adventures of talkative friends. This emotional background profoundly influences pregnancy, labour, and lactation. Emotion also colours the medical attendant’s judgment, for he is keenly aware of the woman’s limited obstetric future and the unique importance of the foetus ; and he would therefore do well to arm himself with a balanced view of the risks to mother and child. Pregnancies in 1000 women over forty have been reviewed by DAvis and SESK], who found that of the 168 primigravidse in this group only 16% had
spontaneous deliveries ; 46% required forceps delivery, and
were delivered by caesarean section. There maternal mortality of 1-2%, and a combined fcetal mortality (including both primigravidae and multiparae) of about 10%. By contrast, BROMBERGYA and BRZEZINSKI2 reported from Jerusalem a smaller series of 67 cases where spontaneous deliveries took place in 71 % and csesarean section was performed in only 1-5% ; the maternal mortality was nil, and the combined foetal mortality 72%. A more radical trend was detectable in the figures recorded by DUNCAN and GIBSON, in Canada; they noted a rise in the caesarean-section rate from 15% in women between thirty-five and forty to 36% in those over forty. Under modern conditions csesarean section is a fairly safe operation, but it remains an unnatural insult to the peritoneal cavity and the abdominal parietes. With increasing maternal age there is an unfortunately growing readiness to undertake this operation ; too often pessimism about the outcome of labour is allowed to obtrude..,Apprehension, it is true, is seldom felt for the elderly multipara ; with her, caesarean section does not loom upon
31 %
was a
the therapeutic horizon until some gross complication supervenes. But multiparity is not necessarily an advantage : the multipara is often a tired woman, and previous childbirth may have impoverished her blood, endowed her with recurrent urinary infection, ruined her teeth, afflicted her with haemorrhoids and varicose veins, accelerated the onset of hypertension, and played havoc with her abdominal wall and sacroiliac joints. Many years ago BETHEL SOLOMONS drew attention to the " dangerous multipara " and pointed out the increasing risks in parity beyond the fifth from such factors as the pendulous belly with its effects on presentation, and the greater liability to placenta proevia, adherent placenta, uterine rupture, and similar dramatic incidents. The elderly primigravida has less obvious handicaps ; the chief are a more rigid perineum and uncertain expulsive powers in labour, aggravated undoubtedly by anxiety and 1. Davis, M. E., Seski, A. Surg. Gynec. Obstet. 1948, 87, 145. 2. Brombergya, Y. M., Brzezinski, A. J. Obstet. Gynœc. 1942, 49, 672. 3. Duncan, J. W., Gibson, W. E. Canad. med. Ass. J. 1940, 42, 240.
697
possibly by fear. Labour may certainly be prolonged. VIOLET SPILLER,4analysing the cases of 1400 primiparse at the Royal Free Hospital, established a low but
that in lead intoxication there is restricted formation of protoporphyrin-a vital stage in the development of the pigment portion of haemoglobin. This supported definite positive correlation between age and the the theory that dyshaemopoiesis, and not h2emolysis, duration of labour ; and the belief is widely held- was the important change in lead intoxication. and supported by the observations of DuNCAN and NTCFADZEAN -and DAVIS9 seem to have reconciled GiBsoN-that the longer the preceding period of the two theories. They examined bone-marrow, chance that labour will be the the is obtained and studied by smear techniques, sterility, greater by biopsy the inertia. from lead and from guineapigs subjected Furthermore, elderly workers, complicated by has a less certain prospect of establishing to lead intoxication. primigravida They found stippling in the and maintaining satisfactory lactation. On the other normoblasts, but only in those normoblasts that side of the balance, she scores heavily over the multi- showed haemoglobin formation—the polychromatic para in the matter of postpartum haemorrhage; stages included. There were more stippled cells-both DAVIs and SESKI quote a 3 % rate, compared with normoblasts and erythrocytes-in the bone-marrow 7% in multipart. Furthermore, the prematurity- smears than in the peripheral blood. Special staining rate in primigravidae is certainly not nearly as high showed that a varying proportion of the basophilic as the 9% figure ascribed by these workers to elderly granules gave a positive iron reaction ; and again multiparae. Pre-eclampsia is somewhatmore com- there were more of these cells in the marrow than in mon in primigravidae, but at least it is not-in the the blood. These findings are remarkably similar to nature of’ things-recurrent ; and a first attack those recorded by the same authors 1°in some patients is less dangerous than a second or third. In the two with acquired hsemolytic .anaemia—patients whose classes the chances of foetal abnormality are about red cells contained the so-called Pappenheim bodies," equal and are materially higher than in younger which gave a positive iron reaction in the peripheral women. BARRY,5 for instance, showed that mon- blood and in the marrow. When splenectomy was was related to increasing maternal age, which performed on these patients, ,the proportion of red golism was also held to predispose to psychosis in the offspring. blood-cells containing Pappenheim bodies was greatly With pregnancy in women who are past their first increased. McFADZBAN and DAVis therefore removed youth an especially careful watch has to be kept for the spleens of some of their guineapigs subjected to hypertension and renal disorder ; less commonly experimental lead poisoning ; andthe results were fibroids, and other disabilities which crop up as illuminating. Two groups of guineapigs, one normal milestones on the, road to the grave, have a more or and the other without spleens, were given daily doses less direct bearing on the outcome. Hence in giving of a lead salt; with the onset of intoxication and " a reassuring answer to the question " Am I too old ? the appearance of stippled cells in the blood, the there is occasion for vigilance. But there is also much proportion of these cells rose to 40% in the splenecfrom which to draw comfort. tomised animals compared with a maximum of 7-5% in the controls. When the lead was stopped, stippled cells persisted longer in the blood of the splenectomised Lead and the Red Cells animals than in the controls ; furthermore, the THE association of lead poisoning with punctate splenectomised animals showed little anaemia whereas basophilia of the red blood-cells has been recognised in the controls anaemia was definite. In a second for fifty years. With punctate basophilia the red experiment, daily doses of lead were given to a cells look as if they were stippled with black dots, group of guineapigs until stippled cells appeared in and this stippling is used as a measure of intoxication the peripheral blood and- anaemia, developed. Half in lead workers ; the presence of more than 1000 the animals then had their spleens removed ; the stippled cells per c.mm. is a signal that lead intoxica- stippled cells in the blood of these animals rose tion may be present. If poisoning is severe, actual rapidly to 40-50 %, whereas in the controls the level an2emia occurs; and this anaemia is often said to be remained at 25-75%. In the splenectomised animals hsemolytic because of the presence, among other stippled cells were more numerous than reticulocytes ;s of persistent reticulocytosis. Many workers in the controls this relation was reversed. There have tried to find out why stippling appears and how were also qualitative differences in the stippling ; it is connected with the anaemia of lead poisoning. in the splenectomised animals most of the basophilic Some years ago KEY6 showed that the basophilic granules gave a positive iron reaction, whereas in material of the stippling is not derived from nuclear the controls only a minority gave" this reaction. material but is formed in the cytoplasm. AUB and his McFADZEAN and DAvis conclude that lead does act co-workersthought that the effect of lead was to formation ; primarily by disturbing make the surface of the red cells inelastic and brittle, instead of becoming fully converted into haemoglobin, so that they were more easily destroyed and a basophilic substance persists in a granular form hsemolytic type of anaemia appeared. This haemolytic associated with demonstrable iron ; the iron in the theory held the field for a long time. Eventually haemoglobin molecule will not, of course, give " free ’’ studies of porphyrin metabolism suggested that lead iron reactions. When red blood-cells containing these acted on red cells by interfering with haemoglobin are released into the circulation, granules formation ; KENCH, Ga,rM, and LANE 8 showed iron-positive in the are destroyed spleen much more rapidly they 4. Spiller, V. Lancet, 1939, ii, 733. than cells containing no granules, or _only few. "
signs,
haemoglobin
5. 6.
Barry, H. jun. Arch. Neurol. Psychiat., Chicago, 1945, 54, 186. Key, J. A. Arch. intern. Med. 1921, 28, 511. 7. Aub, J. C., Fairhall, L. T., Minot, A. S., Reznikoff, P. Medicine, Baltimore, 1925, 4, 1. 8. Kench, J. E., Gillam, A. E., Lane, R. E. Biochem. J. 1942,
36, 384.
Consequently
a
truly haemolytic anaemia
9. McFadzean, A. J. S., Davis, L. J. 10. McFadzean, A. J. S., Davis, L. J. See Lancet, 1947, ii, 840.
appears.
Quart. J.Med. 1949, 18, 57. Glasg. med. J. 1947, 28, 237 ;