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Ætiology of Anencephalus
218 mean scrapping big stocks of unwanted for types, types may keep changing. We are then faced with the insistent question of cost and the worthwhileness of amassing huge stocks of vaccine to provide temporary protection against a relatively mild and still rather unpredictable disease. Besides its practical interest to all of us, influenza virus is a useful tool for those unravelling the more academic tangles in the relation between viruses and cells. In his report for 1950 on the Walter and Eliza Hall Institute in Melbourne, Professor BuRNET— whose new knighthood is acclaimed everywhere-has much to say about this. An intriguing part of his work is that which suggests gene-recombination, or hybridisation, between two influenza viruses with different properties. In this country, Dr. L. HOYLE1 has described more experiments supporting his stimulating but still unorthodox views on the lifecycle of the influenza virus.
But that may
_
of Anencephalus A GRAVE and relatively common defect like anencephaly might be expected to stir the imagination of research-workers. But until lately neither this nor
Ætiology
any other of the recognised foetal malformations received much attention ; ten years ago it was almost true that the last word on the subject had been said by BALLANTYNEin 1902. Then in 1939 Australia was swept by an unprecedented outbreak of german measles, with an unusually high incidence in adults, and it was not long before GREGG3 spotted the relation between the involvement of pregnant women in this outbreak and the secondary wave of congenital cataracts appearing in his patients in Sydney, N.S.W. When the affected children became old enough for hearing defects to be detected the relationship was extended, by SwAN and TOSTEVIN4 in Adelaide and by GREGG himself, to congenital deaf-mutism and heart The Australian observations were soon lesions. confirmed in the United States and in England, and the general recognition that maternal rubella in the early weeks of pregnancy could interfere with embryonic development initiated little less than a revolution in medical thought. Malformations believed to be unavoidable are now gradually approaching the category of preventable diseases. Moreover, clinical evidenceof the significance of maternal ill health in the causation of fœtal deformity is supported by the experimental findings in animals -for example, malformations in the offspring have been produced by subjecting the mother to vitamin lackinjection with dyes,7 exposure to radiation,88 more recently, anoxia.9 In the face of this formidable array of facts, the influence of genetics in the production of many abnormalities has seemed less important than formerly. However, evidence has been accumulating in favour of a genetic origin for anencephaly 10 11
and,
1. J. Hyg., Camb. 1950, 48, 277. 2. Ballantyne, J. W. Manual of Antenatal Pathology: the Foetus.
Edinburgh, 1902.
3. Gregg, N. McA. Trans. ophth. Soc. Aust. 1941, 3, 35. 4. Swan, C., Tostevin, A.L. Med. J. Aust. 1946. i, 645. 5. Landtman, B. Arch. Dis. Childh. 1948, 23, 237. 6. Warkany, J., Schraffenberger, E. J. Nutrit. 1944, 27, 477. 7. Gillman, J., Gilbert, C., Gillman, T., Spence, I. S. Afr. J. med. Sci. 1948, 13, 47. 8. Kaven, A. Z. menschl. Vererbgs-u. Konst. Lehre, 1938, 22, 247. 9. Ingalls, T. H. New Engl. J. Med. 1950, 243, 67. 10. Schade, H. Erbarzt, 1939, 7, 116. 11. Book, J. A., Rayner, S. Amer. J. hum. Genet. 1950, 2.
congenital hydrocephaly 12 in man, and this is supported by the experiments showing that chromosome translocation induced by radiation can produce anencephaly in mice.13 Preconception irradiation of mothers or fathers does not seem to produce any monsters in the offspring,1415 but it does not follow that there has been no gene change in the irradiated parent. The mutations induced may have been recessive, or, if dominant, may have been incompatible with development beyond a very early stage.
and
The environmental causes of malformations are also being sought for by a method that owes much to the pioneer work of STILL 16 and the insistence of HOGBEN 17 on the value of statistics in social biology. The statistical studies of MALPAS,8 MURPHY,19 and PENROSE,20 on the effects of maternal age and birth order drew inspiration from these sources. Precise conclusions on the significance of " advanced age in the mother and primogeniture have, however, been difficult to reach, because of the lack of information on the distribution of such variables in the general population or other controls. The statistical aetiology of malformations of the nervous system has been intensively studied in Birmingham by Professor McKEOWN and Dr. RECORD, who report some of their findings in this issue. Recent papers from Birmingham have illuminated many obscurities left by previous investigations. Thus, the chances of a second malformed child being born to a mother who has had one child with severe malformations of the nervous system can now be estimated more accurately. The importance of primogeniture as a contributory cause of anencephaly and spina bifida has been established securely, and maternal age has been shown to be significant in congenital hydrocephaly. In their present contribution McKEOWN and RECORD draw attention to the remarkable differences in seasonal incidence shown by anencephaly but not by other types of malformation. Anencephalic births are commonest in December and rarest in June and the influence of season is most apparent among firstborn infants. The difficulty of finding control data has still not been completely overcome, since official returns do not classify births in each month by maternal age and parity separately ; but precautions have been taken to avoid errors of biased sampling. Seasonal fluctuations are commonly evident in statistics of morbidity and mortality, and many The cause of are without satisfactory explanation. the higher incidence of anencephalic malformations among embryos conceived in the month of March or thereabouts might be related to the prevalence of some maternal infection in April or May, to diet, to allergy, or perhaps to abnormal activity of pregnant women during spring-cleaning. Whatever the true meaning of the phenomenon, it should add one more environmental factor to the aetiology, and consequently improve the prospect of finding means of "
prevention.
’
12. Bickers, D. S., Adams, R. D. Brain, 1949, 72, 246. 13. Snell, G.D., Bodemann, E., Hollander, W. J. exp. Zool. 1934, 67, 93. 14. Murphy, D. P. Amer. J. Obstet. Gynec. 1929, 18, 179. 15. Kaplan, Ira I. J. Obstet. Gynœc. 1950, 57, 767. 16. Still, G. F. Lancet, 1927, ii, 795, 853. 17. Hogben, L. Genetic Principles in Medicine and Social Science. London, 1931. 18. Malpas, P. J. Obstet. Gynœc. 1937, 44, 434. 19. Murphy, D. P. Congenital Malformation. Philadelphia, 1947. 20. Penrose, L. S. J. ment. Sci. 1939, 85, 1141.
But that may
_
of Anencephalus A GRAVE and relatively common defect like anencephaly might be expected to stir the imagination of research-workers. But until lately neither this nor
Ætiology
any other of the recognised foetal malformations received much attention ; ten years ago it was almost true that the last word on the subject had been said by BALLANTYNEin 1902. Then in 1939 Australia was swept by an unprecedented outbreak of german measles, with an unusually high incidence in adults, and it was not long before GREGG3 spotted the relation between the involvement of pregnant women in this outbreak and the secondary wave of congenital cataracts appearing in his patients in Sydney, N.S.W. When the affected children became old enough for hearing defects to be detected the relationship was extended, by SwAN and TOSTEVIN4 in Adelaide and by GREGG himself, to congenital deaf-mutism and heart The Australian observations were soon lesions. confirmed in the United States and in England, and the general recognition that maternal rubella in the early weeks of pregnancy could interfere with embryonic development initiated little less than a revolution in medical thought. Malformations believed to be unavoidable are now gradually approaching the category of preventable diseases. Moreover, clinical evidenceof the significance of maternal ill health in the causation of fœtal deformity is supported by the experimental findings in animals -for example, malformations in the offspring have been produced by subjecting the mother to vitamin lackinjection with dyes,7 exposure to radiation,88 more recently, anoxia.9 In the face of this formidable array of facts, the influence of genetics in the production of many abnormalities has seemed less important than formerly. However, evidence has been accumulating in favour of a genetic origin for anencephaly 10 11
and,
1. J. Hyg., Camb. 1950, 48, 277. 2. Ballantyne, J. W. Manual of Antenatal Pathology: the Foetus.
Edinburgh, 1902.
3. Gregg, N. McA. Trans. ophth. Soc. Aust. 1941, 3, 35. 4. Swan, C., Tostevin, A.L. Med. J. Aust. 1946. i, 645. 5. Landtman, B. Arch. Dis. Childh. 1948, 23, 237. 6. Warkany, J., Schraffenberger, E. J. Nutrit. 1944, 27, 477. 7. Gillman, J., Gilbert, C., Gillman, T., Spence, I. S. Afr. J. med. Sci. 1948, 13, 47. 8. Kaven, A. Z. menschl. Vererbgs-u. Konst. Lehre, 1938, 22, 247. 9. Ingalls, T. H. New Engl. J. Med. 1950, 243, 67. 10. Schade, H. Erbarzt, 1939, 7, 116. 11. Book, J. A., Rayner, S. Amer. J. hum. Genet. 1950, 2.
congenital hydrocephaly 12 in man, and this is supported by the experiments showing that chromosome translocation induced by radiation can produce anencephaly in mice.13 Preconception irradiation of mothers or fathers does not seem to produce any monsters in the offspring,1415 but it does not follow that there has been no gene change in the irradiated parent. The mutations induced may have been recessive, or, if dominant, may have been incompatible with development beyond a very early stage.
and
The environmental causes of malformations are also being sought for by a method that owes much to the pioneer work of STILL 16 and the insistence of HOGBEN 17 on the value of statistics in social biology. The statistical studies of MALPAS,8 MURPHY,19 and PENROSE,20 on the effects of maternal age and birth order drew inspiration from these sources. Precise conclusions on the significance of " advanced age in the mother and primogeniture have, however, been difficult to reach, because of the lack of information on the distribution of such variables in the general population or other controls. The statistical aetiology of malformations of the nervous system has been intensively studied in Birmingham by Professor McKEOWN and Dr. RECORD, who report some of their findings in this issue. Recent papers from Birmingham have illuminated many obscurities left by previous investigations. Thus, the chances of a second malformed child being born to a mother who has had one child with severe malformations of the nervous system can now be estimated more accurately. The importance of primogeniture as a contributory cause of anencephaly and spina bifida has been established securely, and maternal age has been shown to be significant in congenital hydrocephaly. In their present contribution McKEOWN and RECORD draw attention to the remarkable differences in seasonal incidence shown by anencephaly but not by other types of malformation. Anencephalic births are commonest in December and rarest in June and the influence of season is most apparent among firstborn infants. The difficulty of finding control data has still not been completely overcome, since official returns do not classify births in each month by maternal age and parity separately ; but precautions have been taken to avoid errors of biased sampling. Seasonal fluctuations are commonly evident in statistics of morbidity and mortality, and many The cause of are without satisfactory explanation. the higher incidence of anencephalic malformations among embryos conceived in the month of March or thereabouts might be related to the prevalence of some maternal infection in April or May, to diet, to allergy, or perhaps to abnormal activity of pregnant women during spring-cleaning. Whatever the true meaning of the phenomenon, it should add one more environmental factor to the aetiology, and consequently improve the prospect of finding means of "
prevention.
’
12. Bickers, D. S., Adams, R. D. Brain, 1949, 72, 246. 13. Snell, G.D., Bodemann, E., Hollander, W. J. exp. Zool. 1934, 67, 93. 14. Murphy, D. P. Amer. J. Obstet. Gynec. 1929, 18, 179. 15. Kaplan, Ira I. J. Obstet. Gynœc. 1950, 57, 767. 16. Still, G. F. Lancet, 1927, ii, 795, 853. 17. Hogben, L. Genetic Principles in Medicine and Social Science. London, 1931. 18. Malpas, P. J. Obstet. Gynœc. 1937, 44, 434. 19. Murphy, D. P. Congenital Malformation. Philadelphia, 1947. 20. Penrose, L. S. J. ment. Sci. 1939, 85, 1141.