The World’s Deformities search for the causes of congenital has followed two main approaches: the malformations THE
long and slow
study of a malformed individual, human or animal, and the assembly of information about him; and the examination of a group and the incidence of defects within it (the group may be a family, a city, or a country). The varying prevalence of certain malformations in different parts ofi the world has been recognised for many years. PENROSE pointed out the apparent decrease in the incidence of anencephaly in Europe as one travelled eastward from Ireland. NEEL2 showed that cleft lip and palate were relatively common amongst the Japanese, while neuraltube defects were less common than among Caucasians. Among Negro races neural-tube defects are relatively rare, but polydactyly is more common. Comparisons between independent surveys such as these must always be guarded, because variations in definition, classification, methods of ascertainment, period of follow-up, and the selection of the people studied will all affect the results. There has long been a need for a cooperative international study using agreed techniques. This has now been achieved under the auspices of the World Health Organisation, and the results are reported3 by Dr. A. C. STEVENSON and his colleagues at the M.R.C. Population Genetics Research Unit in Oxford. The survey was carried out at 24 centres in 16 countries in Europe, the Middle and Far East, Australia, South Africa, and South and Central America, and covered the outcome of almost 500,000 pregnancies of not less than twenty-eight weeks’ gestation. The overall incidence of malformations was 12-7 per 1000 total births. Down’s syndrome was reported most often from Yugoslavia, whereas only 1 case was noted amongst the offspring of 66,000 Indian mothers. Neural-tube defects were most common in Belfast (more than 1% of all births) and in Alexandria: the incidence was lowest in Calcutta, but high in Bombay. The striking socioeconomic and geographic variations, together with the low concordance-rate in monozygotic twins, strongly suggest that neural-tube defects are predominantly environmental in origin. Only 311 cases of congenital heart-disease were recorded. Without a follow-up it was impossible to determine the true incidence of cardiac defects, and no significance could be attached to this figure. The survey confirms the belief that cleft palate alone is xtiologically distinct from cleft lip with or without cleft palate. The incidence of cleft lip in different ethnic groups is inconsistent. It is high among Malays in Singapore and Kuala Lumpur, but little above average in the Malays of Manila and low among the Capecoloured population of Cape Town. The incidence of twinning in the 24 centres was studied independently of malformations. The variation was considerable, and predominantly due to differences in the rate of dizygotic twinning. Thus, the frequency of monozygotic twins ranges from 1-9 to 6-9 per 1000 L. S. J. ment. Defic. Res. 1957, 1, 4. Neel, J. V. Am. J. hum. Genet. 1958, 10, 398. Stevenson, A. C., Johnston, H. A., Stewart, P., Golding, D. R. Bull. Wld Hlth Org. 1966, 34, suppl.
1. Penrose, 2. 3.
births, but of dizygotic twins from 2-7 to 32-2 per 1000, both the upper figures coming from Alexandria. Examination of the data from all centres showed a strong positive correlation between neural-tube defects and dizygotic twinning. This is a previously unrecognised phenomenon and is only one of the pieces of the jigsaw likely to come from the surveyThis was a study of hospital births. There is bound to be great variation between centres in the proportion of all births which take place in hospital and in the methods of selection. These in turn will influence the incidence of defects amongst infants born in hospital. We hope that this important survey and the experience gained from it will pave the way for population studies on an international basis. These will be very much more difficult to carry out, but a rich harvest may be reaped.
Annotations HYPERVENTILATION AND FŒTAL ACIDOSIS
DEEP breathing is a common reaction to anxiety or in labour, and it is encouraged in some forms of natural childbirth. Deep inhalation of an oxygen mixture may also be advised when intrauterine fcetal distress is suspected. And artificial ventilation is being used more often at cassarean section, especially when general anaesthesia is supplemented by relaxant drugs. The effect of these respiratory changes on the acid-base balance and clinical condition of the infant at birth has been investigated by several groups of workers.1-5 In normal circumstances the acid-base states of mother and foetus are similar, but this relationship is upset during labour and birth; and whereas most mothers show mild respiratory alkalosis, babies are born with varying degrees of respiratory and metabolic acidosis due, possibly, to impairment of placental circulation.6 In ten healthy mothers admitted to hospital two to four hours after the onset of labour, whose infants were delivered without complication at or near term, Reid2 noted a distinct pattern of respiratory change. Early in labour there was little alteration in ventilation or in alveolar carbon-dioxide tension (P AC02)’ As uterine contractions became stronger and more frequent, hyperventilation became more noticeable, and the P AC02 fell. This fall was temporary at first, but consistently low levels were noted towards the end of the first stage of labour (when hyperventilation was most pronounced). During the second stage there was a rise in PAco2 levels due, in Reid’s opinion, to breath-holding and reduced tendency for the mothers to hyperventilate. The fact that none of the babies showed distress at birth was attributed to this rise in alveolar carbon-dioxide tension during the terminal stage of labour. Nevertheless, Reid,22 like Motoyama et all believes that fluctuation in maternal carbon-dioxide tension during labour may contribute to respiratory difficulties in premature infants. Moderate hyperventilation with slight lowering of the maternal PAC02 can reduce the degree of foetal acidosis,
Motoyama, E. K., Rivard, G., Acheson, F., Cook, C. D. i, 286. 2. Reid, D. H. S. ibid. p. 784. 3. Reid, D. H. S., Mitchell, R. G. ibid. p. 786. 4. Moroshima, H. O. Bull. Sloane Hosp. Women, 1966, 12, 5. Moya, F., Moroshima, H. O., Shnider, S. M., James, Obstet. Gynec. 1965, 91, 76. 6. James, L. S. Acta pœdiat., Stockh. 1960, 49, suppl. 122, 1.
35. L. S.
1402 but neither Moroshima4 nor Moya et al.5 found that this improved the condition of the newborn infant as judged by the Apgar score. But increasing degrees of hyperventilation interfere with the exchange of blood-gases across the placenta, produce severe foetal acidosis, and adversely affect the clinical state of the baby at birth. From the work of Moya and his colleagues5 it seems that the critical level of maternal arterial Peo2 is 17 mm. Hg: below this there is likely to be sufficient fcetal acidosis to delay the onset of respiration. This is a very low level of arterial carbon-dioxide tension, unlikely to be brought about by hyperventilation. But some can breathe so rapidly and so deeply in hysterical patients labour that tetany with carpopedal spasm may follow; it would be interesting to establish how low the arterial Pco2 falls in these patients. A more likely danger is the use of artificial hyperventilation when the patient is under general anaesthesia for cassarean section. In order to help the surgeon in the early stages of the operation the anaesthetist may use muscle relaxants (which do not cross the placenta) in preference to deep anaesthesia (which tends to depress the foetal respiratory centre). Artificial ventilation is part of the technique, and there is always a risk of overventilation. There is need for caution here and for more precise information about possible harmful effects on the newborn infant.
BUY WINE AND MILK
THE Old Testament invitation to buy wine and milk without money may have had more to it than the attraction of a gift. On an empty stomach, 90% of a single dose of alcohol has been absorbed by the end of one hour,6 but this rate is much reduced if the alcohol is taken after a meal. Milk and other fatty foods, such as cream and olive oil, are widely held to inhibit alcohol absorption, because, it is thought, these less permeable foods coat the stomach. But fatty foods are not alone in this action, for Tuovinenfound that a good helping of mashed potatoes was a potent inhibitor of alcohol absorption and even beer had some retarding effect. Increased metabolism of alcohol may also account for its reduced potency after food.8 Miller et al. have now investigated the absorption of single doses of 25 ml. of alcohol in 10 subjects after they had taken 11/2 pints of water on one occasion and 11/2 pints of milk on another. The effect of the milk was to reduce the average maximum concentration of alcohol in the blood by nearly 50%-from about 35 to about 20 mg. per 100 ml. Although no objective tests of central nervous activity were carried out, signs of intoxication seemed to be reduced by taking milk first. Without milk ’all the 5 women and 3 of the men showed signs of intoxication. After milk, the effects were reduced in all the 8 previously affected, 5 of whom seemed entirely sober and the other 3 were just mildly sleepy. While this study does not decide whether this effect is due to delayed absorption or to increased rate of metabolism, it confirms the value of milk in the prevention of intoxication. Habituation does not significantly alter the rate of absorption, for chronic alcoholics seem to absorb alcohol from the gastrointestinal tract at least as 6. 7. 8. 9.
Muehlberger, C. W. J. Am. med. Ass. 1958, 167, 1842. Tuovinen, P. I. Skand. Arch. Physiol. 1930, 60, 1. Miller, D. S., Stirling, J. L. Proc. Nutr. Soc. 1966, 25, 40. Miller, D. S., Stirling, J. L., Yudkin, J. Nature, Lond. 1966, 212, 1051.
But people vary greatly in as do abstainers. 10 their response to alcohol, and it would be rash to say, therefore, that premedication with milk before the Christmas celebrations reduces the risks of combining drinking with driving or other complex and dangerous tasks.
ATOPY AND CANCER
THE idea recurs from time to time that cancer is less in patients with certain other diseases. Sometimes the suggestion springs from the realisation that in his clinic a specialist in a non-neoplastic condition rarely, or never, encounters cancer. Often such impressions do not bear close analysis: either few of the patients concerned are of an age at which cancer might be expected or, because of preselection, patients who have cancer are not sent to the clinic in question. The impression that cancer is less common in patients with allergic disorders may or may not survive critical scrutiny; but it deserves serious attention, in view of the demonstration that immunological factors may modify, perhaps even determine, the onset of malignant disease. Mackay," at King’s College Hospital Medical School, has studied the association between allergic disorders and cancer by comparing the incidence of asthma, hayfever, nettle rash, and eczema in 150 patients with malignant disease, excluding leukxmia or reticulosis, with that in 150 control patients matched for age, sex, and area of residence. The incidence of history of one or more of the four manifestations of allergy was more than twice as high in the control group as in the probands (p < 0-01) and was entirely accounted for by the difference between the females included in the study. Thus, of 111 female cancer patients only 8 gave a history of allergy, whereas 27 of 111 female non-cancer controls did so. No special association between allergy and cancer of a particular site was observed. This report must be received cautiously, for several reasons. Firstly, cancer is not a single entity but a group of diseases in which many aetiological factors are concerned, and there is wide variation between individuals in their exposure to carcinogenic stimuli. It is possible, for reasons that may or may not be related to atopy, that Mackay’s two groups differed significantly in the extent of their exposure to one or more environmental carcinogens. Secondly, the fact that the difference was apparent only in females is not consistent with any of the more widely accepted theories of the role of immune mechanisms in the genesis of neoplastic disease. Thirdly, Mackay’s findings are at variance with those of Logan and Saker,12 though in agreement with those of Fisherman.13 Fourthly, no association, negative or positive, has been found between cancer and rheumatoid arthritis 14 or Hashimoto’s disease, 15 both of which are thought to involve a defect in immunological reactivity. common
suggested that carcinogenesis may be when the immune system is depressed, and H. W. Acute Alcoholic Intoxication.
1941. 11. 12. 13. 14. 15. 16.
Mackay, W. D. Br. J. Cancer, 1966, 20, 434. Logan, J., Saker, D. N. N.Z. med. J. 1955, 52, 210. Fisherman, E. W. J. Allergy, 1960, 31, 74. Duthie, J. J., Brown, P. E., Truelove, L. H., Baragat, F. D., Lawrie, A. J. Ann. rheum. Dis. 1964, 23, 193. Blackburn, G., O’Gorman, P. Guy’s Hosp. Rep. 1961, 110, 379. Burnet, F. M. Br. med. Bull. 1964, 20, 154.