Paper - Ante-natal conditions in the new-born child (1946)

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Parsons LG. Ante-natal conditions in the new-born child. (1946) Can Med Assoc J. 55(4): 327-36. PMID 20323911

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This 1946 paper by Parsons reviews abnormal development in the neonate that occur during development.

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Ante-natal Conditions in the New-born Child

The Fifth Blackader Lecture

By Sir Leonard G. Parsons, M.D., F.R.C.P., F.R.C.O.G.

Professor of Paediatrics in the University of Birmingham, England

  • Read at the Seventy-seventh Annual Meeting of the Canadian Medical Association, in General Session, Banff, Alberta, June 12, 1946.

In the closing years of Queen Victoria’s reign two events occurred, the one in Edinburgh and the other in Boston, Mass., which revolutionized the practice of obstetric medicine and might also have revolutionized pediatric practice if only pediatricians had been wise in their day and generation.

In 1900: Ballantyne of Edinburgh published two lectures on ‘‘ Ante-natal diagnosis’’ which he defined as ‘‘the discovery of normal pregnancy and of. plural pregnancy, of fetal death, of diseases and monstrosities of the fetus, of hydramnios and of morbid conditions of the placenta’’. In 1901, the Instructive Nursing Association of Boston commenced to pay visits to some of the expectant mothers who applied to be out-patients at the Lying-In Hospital. These events, although not the first examples of ante-natal care, were the starting point for the present system of ante-natal clinics and for the recognition of the important part which ante-natal care can play in the prevention of abnormal labour and in the reduction of maternal mortality. Ballantyne was, however, particularly concerned with the care of the unborn child, because in 1901 he wrote of attempts to ‘‘cure before birth the diseases and disorders of the fetus’’ and made no. reference to the interests of the mother, but in an address delivered shortly before his death in 1928, these were his paramount concern and the only reference to the value of antenatal care to the fetus was the statement that it would reduce the still-birth rate.

The reason for this change of viewpoint is a mystery and another mystery is why pediatricians did not take up and develop his suggestions. One explanation of the latter may have been the lack of interest in infants displayed by many British pediatricians in the early years of this century. When I started my pediatric career, except for certain arresting conditions in infants such as scurvy and pyloric stenosis, interest was centred on the older child; possibly because nearly all children’s physicians also practised adult medicine. Another probable reason for this indifference was the fact that the obstetrician took charge of the new-born baby. As time went on the infant received more study and in some maternity hospitals the care of the new-born child was handed over to the pediatrician and today the care of the neonate and attempts to lower neonatal mortality are important aspects of British pediatrics. This trend has naturally led to a study of the premature infant and has at last made some of us wonder whether by the care of the mother prematurity and fetal disease could be prevented and the birth of better and healthier babies ensured.

I have ventured to call this aspect of antenatal care ‘‘ante-natal pediatries’’, and I feel justified in asserting that in future the pediatrician and the general practitioner must be concerned with the health of the baby from the moment of conception and, indeed, even before that occurrence when there is a possibility of genetic disorders arising. One of the earliest enquiries about the effect of antenatal conditions on the new-born with which I am familiar was the question put to our Lord by his disciples ; ‘‘Master who did sin, this man or his parents that he was born blind?’’ You remember the reply, ‘‘Neither hath this man sinned nor his parents; but that the works of God might be made manifest in him’’. Is it fanciful to think that therein lies an explanation of the existence of disease and that the research worker is a fellow worker with God?

From the time of conception two forces, heredity and environment—nature and nurture —act upon the cell as a unit and upen the fetus as a whole. A knowledge of their interplay is essential to an understanding of the laws of human inheritance; the nature of disease; and the circumstances which may modify or prevent it. Every characteristic of the developing fetus and new-born child is the result of interaction between the genes and their environment.

Congenital hemolytic disease furnishes an excellent example ef this interplay since the development of Rh antibodies in the mother is due to genetic causes, whereas their transference to the fetus alters its environment. Nurture rather than nature is responsible for the well-being and vigour of the child; for the development of certain diseases and its immunity to others; whereas all genetic diseases and deformities are due to nature. Certain malformations, however, may be caused either by defective genes or defective nurture; in other words, ‘‘a bad egg in a good environment or a good egg in a bad environment’’ may produce the same abnormality. Intellectual and other resemblances, even similarity in disease, occur more frequently in identical than in non-identical twins, and are genetic in origin since with one exception, providing that the cords and placente of non-identical twins are approximately the same size, the environmental conditions for both varieties of twins must be the same. The exception is the occurrence of congenital hemolytic disease in one of non-identical twins; the twins being of different genotypes whereas the maternal antibodies were of one type only (Stratton, Langley and Lester).

The Calvinistic doctrine of predestination is now demoded in regard to things of the spirit but continues to hold firm sway in genetics and although it is true that some adverse genetic effects can be modified by a good environment there are others on which environment has no effect. Hence some babies are foreordained to suffer, and perhaps to die, at or shortly after birth. It is interesting to speculate on the contribution that these children might have made to the community, and it may well be that in them we have lost—to quote from a poem that has become part of Canadian history :

"Hands that the rod of empire might have swayed Or waked to ecstasy the living lyre:
But knowledge to their eyes her ample page Rich with the spoils of time, did ne’er unroll.’’

In the present state of our knowledge such a state of affairs can only be prevented by careful mating, or by taking refuge in a negation— the avoidance of pregnancy.

Any attempt to assess the relative importance of environment and heredity in the development of character and of the spiritual virtues partakes more of an exercise in philosophy than of one in experimental medicine. Ante-natal environment can, however, have little influence on character since ‘‘sweet thoughts are no more soluble in maternal blood plasma nor are more able to pass a semipermeable membrane of living protoplasm than are sour moods or tragic emotions’’ (Corner). Heredity plays a somewhat greater part but, in my opinion, post-natal environment, particularly in the form of a happy home and family life, is by far the most important factar and the comparatively great temperamental differences which may be found in monovular twins (Dahlberg) is strong evidence in support of this view.

Concluding a brilliant essay on ‘‘The interplay of nature and nurture’, my colleague, Lancelot Hogben says: ‘‘In so far as a balance sheet of nature and nurture has any intelligible significance it does not entitle us to set limits to changes which might be brought about by regulating the environment’. In ante-natal pediatrics, environment is, in my opinion, more important than nature and it certainly is much more under our control; its effect on the fetus can be discussed under three heads: (1) the diet of the mother; (2) her nutritional state; and (3) the condition of her health. These factors produce different results in different periods of pregnancy; chiefly malformations in the first three months and in the last three months fetal immaturity and fetal disease.

I. Maternal Diet

During the war years there was a striking fall in the still-birth rate in Great Britain. In 1930 in England and Wales, the rate was 41 per 1,000 total births, in 1939 it was 38, but in 1944 and 1945 it had dropped to 28; in Scotland the figures were 42 in 1939 and 32 in 1944 and in neither country did the rate rise in any of the war years. Baird has shown that in Aberdeen this fall was due to a reduction in the categories ‘‘eause unknown’’, ‘‘trauma’’ and ‘‘toxemia’’, but not to any fall in deaths due to fetal deformity. The risk of still-birth is ten times greater in a premature than in a full term child and both prematurity and stillbirths are highest in the lowest social classes. The neonatal death rate in Great Britain rose in 1940 and 1941, but since then has fallen to a lower level than in 1939. This diminution has been due to fewer deaths from prematurity, asphyxia, trauma and congenital debility; the death rate from infection being rather higher than the pre-war figures. The rise in neonatal deaths in 1940 and 1941 was more marked in large cities like Glasgow and Birmingham, in the latter of which the rise continued to 1942 and was due to ‘‘infections’’,—probably the result of war conditions, evacuation, bombing, shelter-life, ete,—and also to deaths from direct enemy action. Neonatal deaths from prematurity and congenital debility are, like stillbirths, highest in the lowest social classes. This is the consequence either of an inherited inferiority in reproductive capacity—for which there is no evidence—or of the inferior general health and nutrition of expectant mothers and of the unfavourable environmental conditions in which they live. It is improbable that the diminution in neonatal deaths in the later war years was the result of better nursing and doctoring, if only for the reason that nurses and doctors were in short supply and over-worked ; furthermore, except for the introduction of penicillin and new sulfonamide preparations, there was not any important therapeutic advance in this field. The value of these drugs is to combat infection but despite them the incidence of infections actually increased. Therefore since the fall in deaths has been greatest in the lower social elasses it seems logical to conclude that this is due to the inerease in wages; the abolition of unemployment; and the improved nutrition of the mothers.

There is considerable evidence that as a result of rationing and better distribution of food the diet of a large part of the population has improved during the war years. In 1940 and 1941 there was a sharp fall in food supplies, particularly in meat, fats, sugar and fruits, but from 1942 until the termination of lend lease and chiefly as a result of it and of generous help from the Dominions, the diet in Great Britain was balanced and adequate although at times monotonous and unattractive. It is too early as yet to assess the effect of the present more restricted dietary. The factors responsible for the improvement are probably: the national loaf—which from April 1942 to January 1945 was made from flour having an extraction rate of 85% and the increased consumption of milk, together with additional rations of milk and of vitamins A, B, C and D for expectant mothers and for children. Prior to the war, many mothers could not afford these supplements or were ignorant of their value, and even now it is estimated that less than 50% of the mothers take away from the ante-natal centres the vitamins provided for them. Before. the war even the poorer people had a wider choice of foods than they have now, but exercised it unwisely ; now, although the choice is limited, it is confined to good food of which hunger compels them to partake. Moreover, the reduction in sugar has improved the diet because less vitamin B is required for its oxidation (Magee).

Malformations, whether genetic or nutritional in origin, commence early in pregnancy; the fifth to the ninth weeks being the critical period in the development of the lens, teeth, palate, and septa of the heart. The work of Warkany and his colleagues at Cincinnati must be well known to you. They have shown that by restricting the diet of rats in the early stages of pregnancy the young showed deformities such as shortening of the mandible; cleft palate; shortening and distortion of the limbs; syndactyly; fusion of the ribs; some of which are identical with those produced by genetic conditions. Warkany has also shown that the young of rats fed on a vitamin A deficient diet in early pregnancy show congenital defects of the eyes and Hale found the same in pigs. Moreover, none of these defects can be prevented by giving a normal diet in the latter part of pregnancy. Similar experiments cannot be carried out deliberately in the human being, although under famine conditions they may become inevitable. We know that the number of deaths from deformities in new-born babies has neither increased nor perceptibly diminished in Britain during the war years, but there is no information as to whether there has been any diminution in the number of those congenital deformities which are compatible with sustained life.

The effect of maternal diet and nutrition on the general development of the fetus in the earlier part of pregnancy compared with that in the last third of pregnancy is well shown in a series of interesting animal experiments by Wallace. These experiments, which were designed to test the effect on the offspring of the diet in general but not of any particular constituent, showed that the weights of the embryos were the same whether ewes during the first two-thirds of pregnancy were fed on a poor diet on which they lost considerable weight or on a liberal one on which their weight showed marked increase. During the last third of pregnancy, a liberal diet given to those previously on a poor diet produced a large gain im weight by the ewes, and their lambs were almost identical in size with those fed on the liberal diet throughout ; whereas the lambs of those fed on the liberal diet for the first two-thirds of pregnancy and on a poor diet in the last third on which they lost weight were enly slightly larger than those fed on the poor diet throughout pregnancy. «Moreover, all the ewes who were well fed during this period developed large udders, while the udders of those which were poorly fed remained small. These results clearly indicate that the weight of the fetus and the preparation for lactation depend upon the nutrition of the mother in the last third of pregnancy.

In any attempt to apply these results to pregnant women, two points should be borne in mind. First, although, in the absence of obvious cedema, the weight of a baby can be regarded as important evidence of its state of nutrition, this is not the case with its mother, because of the effect of water retention, especially in toxemia of pregnancy; therefore, any enquiry must be confined to women who show only a slight increase in weight. Secondly, a baby is born in a much less. advanced state of development than a lamb.

The normal. baby starts life with a stock of vitamins, hormones, metals, ete., sufficient for its immediate needs, After birth these stores begin to.diminish—a negative phase—and continue to diminish until the. child is either able to obtain them from its diet or to manufacture them. If the baby is one of twins, or is born prematurely, or its mother has been inadequately nourished or has suffered from an illness or a conditioned deficiency during pregnancy, the baby’s stores at birth may be insufficient and its diet may not be able to bring the levels up to normal. Morbid conditions such as hemorrhagic disease of the new-born, nutritional anemia, tetany, rickets, scurvy, cretinism may then develop; conditions which are even more likely to occur if the baby’s diet is also defective. The fetal reserves are mainly built up during the last third of pregnancy in which time two-thirds of the calcium phosphate, three-quarters of the protein and four-fifths of the iron are laid down. Indirect evidence of the importance of storage during this time is provided by the facts that premature infants develop an iron deficiency anemia at an earlier age and suffer more frequently from rickets than full term babies; furthermore, Ebbs, Tisdall and Scott found that rickets, tetany and anemia were more frequent in babies under six months of age whose mothers, during the last three months of pregnancy, partook of a ‘‘poor’’ diet than in those having a ‘‘good’’ or,a ‘‘poor’’ diet which was supplemented to a “*good’’ diet.

II. Nutritional State of the Mother

If the maternal diet is deficient the fetus has the prior claim to’ the available nutrients but if these deficiencies are too great the mother’s self-sacrifice may be unavailing and the baby may either be born with manifest deficiency symptoms or develop them much earlier than the usual time of incidence. Herein lies the explanation of fetal rickets and of the majority of examples of tetany, polyneuritis and keratomalacia in the new-born; furthermore, the presence of a deficiency disease in the new-born baby almost invariably means that the mother herself suffers from that disease. Iron may be an exception to this rule of fetal priority; sometimes in experimental animals and also in human beings the mother may conserve her store of iron at the expense of her fetus which is then either born. anemic or develops a nutritional anemia at an abnormally early age (Parsons; Parsons and Hickmans). Clearly, therefore, the mother’s diet during pregnancy should be more than adequate and contain full supplies of vitamins, phosphorus, calcium, and iron and every effort should also be made to prevent the premature birth of the fetus, .

The mother not only transfers nutrients to the fetus but also certain immune bodies so that although notoriously prone to many infections the new-born baby has a degree of passive immunity to certain infectious diseases, particularly diphtheria, measles and chicken pox. In this respect babies differ from lambs and calves, which develop an immunity to lamb scour and calf dysentery respectively only after they have partaken of colostrum. This difference in mechanism is due to variations in placental structure; in women the placenta is thin, the blood actually bathing the chorionic villi and thus rendering transference easy, whereas in the cow it is thick. The titre of diphtheria antitoxin is as high in the blood of the new-born baby as in its mother and is not increased by taking colostrum. On the other hand, Rh antibodies may not only be found in the blood of the baby at birth but also in high titre in the colostrum and sometimes, although in much lower titre, in breast milk, suggesting that some antibodies are transferred by human colostrum and milk; indeed, this is the only explanation of the accepted view that breast feeding confers a degree of immunity on young infants.

Human colostrum is richer in Vitamin A, protein and globulin than breast milk, but this does not prevent these bodies showing the usually negative phase after birth. The amount of vitamin A in colostrum is high on the first day and rises to a maximum in the third day of lactation; it then falls rapidly to reach on the 9th and 10th days the concentration in mature milk (Lescher eé al.). On the other hand, the vitamin A content of the baby at birth is extremely small and of the premature baby still smaller when compared with that found a few weeks later. It is, therefore, a logical deduction that although vitamin A can be transferred via the placenta it is chiefly transmitted to the baby through the colostrum and milk. The serum globulin of the new-born baby falls to the 4th week, then remains unchanged until 4 months, after which it rises but does not reach the adult level until the 4th year. This level is higher than that of premature babies. (Hickmans). The amount of globulin in the serum is important, since antibodies are molecules of globulin specifically modified during synthesis by an

‘ antigen and which, from their movement in an electrical field, are called gamma globulins. In the badly nourished or immature fetus the

demand on amino acids for growth may limit the amount of gamma globulin formed, as also may the smaller amount of globulin present in the premature baby; a state of affairs which may explain the greater liability of such infants to infection. The so-called X protein which is said to be an important factor in hemolysis in congenital hemolytic disease is presumably not fully developed in the fetus but is formed shortly after birth, particularly in those babies which, although apparently healthy at birth, suddenly one or more days later develop severe jaundice or anemia (Weiner).

III. The Health of teh Mother

The state of the mother’s health may not only affect the nurture of her fetus but may be the cause of actual fetal disease. The effect of toxemia of pregnancy in producing premature and still-births is well known, and despite certain adverse criticisms, the investigations carried out in Toronto, South Wales, London, Oslo and Aberdeen strongly support the view that the diet and nutritional state of the mother in the latter third of pregnancy affect the incidence of toxemia, premature and still-births and the health of the new-born child. The effects of other maternal conditions, for instance, diabetes, are, however, less commonly appreciated. According to Miller of New Haven and his colleagues, fetal or neonatal death occurs in about 30% of these pregnancies even when the disease is controlled by insulin, but Lawrence and Oakley in London found the mortality varied from 23% in those who had complete supervision, to 70% in those who had none. Another outstanding finding in diabetes is the large size of the fetus, which may weigh over 12 lb., so that Cesarean section at the 36th to 38th week offers more chance of a live baby than spontaneous delivery at term. Lawrence and Oakley thought that this gigantism was due to hyperglycemia and depended on the degree of diabetic control, but Miller and his colleagues found that gigantism, neonatal and fetal death with characteristic findings at autopsy sometimes occurred five years or more before the mother shows any evidence of diabetes; observations which we have been able to confirm and which shed light on the etiology of diabetes but rule out the theory that hyperglycemia is the cause of the over-sized fetus. Many suggestions have been made as to why the offspring of the diabetic and the pre-diabetic mother behave in this way, but none of them has so far received general acceptance. Recently I was told that Dr. Priscilla White of Boston had been able, by remedying the disordered hormonal pattern present in some diabetic mothers to reduce the fetal and neonatal mortality and the size of the fetus.

Rubella and fetal deformities—Recently great interest has been aroused in the possible association of rubella in the mother and malformations in the fetus. Most of the evidence for this association comes from Australia where Gregg in 1941 first drew attention to it. His interest was aroused by the fact that in the first half of that year he saw a large number of babies with a somewhat unusual form of congenital cataract and on questioning their mothers found that they had nearly all suffered from German measles in the early months of pregnancy, 1.¢., in the period of malformation. The German measles epidemic of 1940 had been a severe one and of a total of 78 children with congenital cataract, 46 of whom also had congenital heart disease, 68 of their mothers were found to have contracted German measles early in pregnancy and between December 1939 and January 1941. Many of these children were also small, badly nourished and bad feeders. These results were confirmed for South Australia by Swann and his colleagues who also feund dental defects, deaf mutism and mental retardation amongst their patients. Table I shows the results of their investigations. Welch has collected lists of the number of children born deaf in each of the years 1931 to 1941 in New South Wales; in only one, year did the number reach double figures, but in 1938 it was 47, and 34 of their mothers ‘had rubella during the first four months of pregnancy. Cases have also been described in America and in England. Many pediatricians have seen isolated cases but the largest number Weston Hurst, whom Swan consulted, thought that these deformities were due to the effect of the virus in vascular tissue, whereas Corner suggests that they are the result either of a disturbance of the ‘‘organizer’’ or of; injury to the ‘‘reactant tissue’’. As a result of their investigations Swan and his colleagues came to the conclusion that when a mother developed rubella in the first two months of pregnancy the chance of her giving birth to a congenitally defective child was in the region of 100%, and if she contracts the disease in the third month about 50%. If there are real grounds for this view it would appear that there are moral if not obviously legal grounds for terminating pregnancy, but before the connection ean be accepted as cause and effect there are certain criticisms which can only be answered satisfactorily by a large scale investigation. One criticism is that in the absence of controls the results are not statistically significant. These controls should be: (@) comparisons with other infectious diseases, particularly with other virus diseases such as measles, mumps, ete.; to a small extent this criticism has been met because 8 of the mothers in Swan’s series had other infectious diseases during pregnancy and only one child showed congenital deformities; (b) comparison with a series of pregnancies in which there were no infectious diseases; and (c) a series of mothers in whom infectious disease occurred and the effects on their babies as subsequently observed and not, as has usually been done, an enquiry made retrospectively into pregnancy conditions when a congenitally deformed child has been encountered. The difficulties of such investigations are shown by the experience of Fox and Borten of Milwaukee. This is a city of over half a million inhabitants and in the years 1942-43-44, 22,226 cases of rubella occurred but of these only 581 were married women. Of this number 151 patients were investigated and the number of babies born to them was only 11, none of them had any congenital abnormalities. There therefore seems good grounds for the suggestion that to obtain a really good statistical result in England and Wales a survey of all married women would be necessary.

Taste I. Mothers Disease during pregnancy Infants with defects 57 Rubella. .............. 40 1 Rubella and measles... . 1 2 ? Rubella and ? measles. 0 1 Rubella and mumps..... 0 7 Measles..............- 0 -1 Mumps......:........ 1 1 “Influenza”............ 1 4A None..............0-. 4 74 47

, Australia. .

reported in England were obtained by Martin (1945) as the result of a questionnaire to the mothers of 102 deaf children born in 1940-1941, i.e., in the year following a widespread epidemic of rubella. In 8 instances the deafness was hereditary and in 15 caused-by meningitis and of the remaining 79 children the mothers of 36 had rubella during the first four months of pregnancy and 6 other mothers probably suffered from the disease. In a letter which I received from Gregg (dated May 24, 1946) he stated that the number of instances of which he has details in which congenital defects followed rubella has now reached 206: 130 of these cases were collected in 1944 and the defects observed were distributed as follows:

Table II.

Deaf mutism. ........... 0. cece cece eae Deaf mutism and heart disease.......... Leaee Heart disease. ........... 0. cece ee eee eee eee Eye defects............ 0.0 c eee eee ee eee Eye defects and heart disease........:....... Deaf mutism, eye defects and heart disease... . Deaf mutism and eye defects................

The following table (Table III) shows the number of cases so far reported in Australia, America and England and is as accurate as I can make it. In some tables published some cases have been counted more than once.

Table III.

e Number of babies with congenita defects where mothers had

Country rubella during pregnancy

Gregg... 0.

America... .

England... .

Another criticism is that the disease was a new infection and not true rubella, but from my review of the literature I think this is probably not a valid criticism. A further criticism is that such a mild disease as rubella is unlikely to cause such catastrophic changes in the fetus, to which the reply is made that in mammals embryonic cells are more susceptible to virus infections than adult tissues, and it is known that the placenta is permeable to a number of viruses. This view is supported by the fact that for developmental reasons the deformities concerned must have originated in the fifth to the ninth week of pregnancy, 1.¢., in the more embryonic state of the fetus and at exactly the period at which the mothers concerned stated that they suffered from German measles. On the other hand, other virus diseases occurring during this period, although admittedly few in number, did not result in congenital deformities; they were, however, ‘more severe diseases than rubella and may have produced early fetal deaths and miscarriages rather than deformities.

It is interesting to note that Shakespeare (A Midsummer Night’s Dream, Act V, Se. 2) refers to some of the deformities now associated with German measles but attributed them to ‘‘the foul fiend Flibbertigibbet’’ who ‘“gives the web and pin, squints the eye and makes the hare lip’’. ‘‘Web and pin’’, according to Goldbloom, our authority on Shakespearean pediatrics, probably refers to cataract or a corneal scar. A cynic (Vertue) has said recently that ‘‘science has done nothing about Flibbertigibbet unless you count the suggestion that one of his other names is German measles’’.

It seems curious that the association between maternal rubella and congenital defects had never been noted before 1940. From 1923 to 1937 Australia was free from epidemics of rubella and therefore a large number of Australian young women possessed no immunity to the disease. The 1937 epidemic had not died out in remote districts when the war broke out and the mass movement of young people whicli followed fanned the embers of the epidemic into a blaze which swept over the whole country (Scholes). The resulting high incidence of the disease in pregnant women followed by an epidemic of cataract made recognition unavoidable according to Hurst and completely convinced him that rubella during the first three months of pregnancy does lead to congenital defects.

The Australian investigators suggested that pooled or adult serum should be used to confer immunity upon the expectant mother, but stocks are not available in my country; nor in Great Britain are stocks of gamma globulin available for this purpose, still less a more potent preparation—the gamma globulin fraction of rubella convalescent serum. In any ease, the period of passive immunity is shortlived and the injection would have to be repeated; there is also the added factor that these malformations arise so early in pregnancy that the woman may not know that she is pregnant. It is clear that this problem of German measles urgently requires extensive study and in the meantime it behooves all women in the early weeks of pregnancy to avoid exposure to the disease.

Congenital hemolytic disease. — We have seen that during the later months of pregnancy the human placenta allows the passage of antibodies from the mother to the fetus; a fact that is made use of in the prophylaxis of measles by the administration of placental extract. Rh antibodies are transferred in this way and may produce severe results in or even the death of the fetus; indeed, according to Haldane, congenital hemolytic disease is responsible for more deaths than any other inherited disease or possibly than all of them put together. Its intra-uterine manifestations are slightest and perhaps non-existent in hemolytic anemia of the new-born, which may not develop until 2 or 3 days after birth when sufficient X protein becomes available. They are at their maximum in hydrops fetalis with icterus gravis a close second.

The jaundice of icterus gravis is not due to biliary stasis from excessive hemolysis but to liver damage as is shown by the fact that cirrhosis of the liver sometimes follows icterus gravis just as it follows infective hepatitis, and by the cholesterol partition in the blood serum (Rothe-Meyer and Hickmans). We have never been able to confirm the finding of cirrhosis of the liver in jaundiced still-born babies; indeed, cirrhosis probably only becomes obvious when the child is some months old:and bears the same relationship to liver damage that extra-pyramidal rigidity and other cerebral manifestations do to kernicterus.

The existence of kernicterus raises interesting questions as to whether it is due to excessive hemolysis; to fixation of antibody in nerve cells; or to hepatic disease. We have never found any parallelism between the degree of hemolysis on the one hand and the severity of the jaundice and the presence of kernicterus on the other. Again, in our experience the incidence of kernicterus, as judged by postmortem records and nervous sequele in later childhood, has, contrary to Weiner’s experience, not been diminished by transfusions with Rh negative blood since these only compensate for and limit hemolysis. These two observations show that kernicterus is not due to hemolysis and that the adverse effects of Rh antibodies are not limited to their action on the red cell. Furthermore, we have seen jaundice and kernicterus and indeed all the symptoms of hemolytic disease occur in the course of sepsis neonatorum; again, a postmortem examination on a baby who was. not jaundiced revealed miliary hemorrhagic necroses of the liver and also necrotic foci in the corpus striatum which showed the same microscopical characteristics as those of kernicterus except that the foci were not bile-stained. Finally, neither cirrhosis nor kernicterus has ever been reported in hemolytic disease of the new-born, in which condition there is only the slightest trace of jaundice. These observations point overwhelmingly to the conclusion that kernicterus only occurs when there is severe liver damage and that as a result of this damage necrotic changes take place in the brain and that the necrosed brain cells then become stained with bile. In the majority of cases of kernicterus the staining of the dead brain cells probably occurs shortly after birth, since the jaundice frequently does not become severe until 24 hours or so after birth. In actual fact we have found post-mortem evidence of kernicterus when death occurred on the second day. The after effects of this damage to the liver and brain are cirrhosis of the liver, extra-pyramidal rigidity, athetosis and mental deficiency.

Another rare and interesting sequel of icterus gravis is green teeth. The temporary dentition only is affected and the coloration is usually limited to the incisors, the enamel of which begins to be formed in the 6th and 9th week of pregnancy and is completed after birth at the 4th month. There is no evidence of the premature death of the enamel cells, and the condition is probably related to the intensity and persistence of the jaundice and with the staining of bone with bile of which I haye observed an example in icterus gravis.

From what has been said it is clear that although these grave complications are initiated before they may increase after birth. It is impossible to say why they o¢eur in some babies suffering from icterus gravis and not in others, nor can we tell during the neonatal period whether or not the baby is likely later to show evidence of any of them, although kernicterus may sometimes be suspected if the child has a peculiarly high pitched cry and particularly if this is associated with convulsions,

The titre of Rh antibodies in the blood may rise during the last three months of pregnancy, but no definite relationship between their titre and the severity of disease in the fetus has ever been demonstrated, due in part to the presence of ‘‘blocking’’ antibodies. It therefore seems reasonable, if the titre is rising rapidly, to perform Cesarean section or to induce labour as soon as the fetus can be regarded as viable, and thus cut short the period in which the child is at the mercy of the Rh antibodies and thus possibly render less likely the development of sequele. Moreover, because a transfusion with Rh negative blood limits and compensates for the hemolysis, complete substitution transfusion has been recommended. This may prove a real lifesaving measure, but there is no evidence that it will prevent the occurrence of sequele; neither does our experience confirm Weiner’s finding that the incidence of kernicterus has been abolished by the use of Rh negative blood, since in two series of more than 100 babies each, in one of which Rh negative blood was used and in the other attention paid only to A, B, O grouping, we found the incidence of kernicterus, as judged by post-mortem findings and nervous sequale, was exactly the same (6.5%). Some people even believe that it is better to give repeated transfusions with Rh positive blood to fix the-antibodies by the Rh positive cells and so prevent further damage in extra-uterine life. There is no method known by which a woman can be desensitized or her antibodies neutralized although Weiner states that injection of typhoid or pertussis vaccine may prevent congenital hemolytic disease in the children of an Rh negative mother whose sister has borne children with that disease, since the simultaneous injection of a stronger antigen may prevent sensitization by a weaker one.

The serum of every expectant mother should be tested against the Rh factor, both in her own interest should she need a transfusion after labour, and also in that of her fetus; moreover, an Rh negative woman or girl requiring a transfusion should always. be given Rh negative blood since Rh positive blood may lead to the development of anti-Rh iso-agglutinins. This usually only occurs after repeated transfusions but Diamond states that the most severe forms of hemolytic disease occur in the children of women sensitized by transfusion.

During the last third of pregnancy, as a result of degenerative or morbid changes in the placenta, actual organisms as well as antibodies and viruses may traverse the placenta and manifestations of disease may be obvious at or shortly after birth. Examples of these conditions are syphilis, septicemia and, more rarely, tuberculosis, scarlet fever, small-pox, toxoplasmosis and allied forms of encephalitis (Parsons). Although syphilis, formerly one of the most serious of these diseases can now be completely controlled and has, therefore, become a relatively unimportant cause of fetal disease and death, there is much that could be said about the effect of other diseases on the fetus and the new-born child. Sufficient has, however, been said concerning the effect of genetic disease on the fetus and the effect of the maternal diet, nutrition and disease on its nurture to indicate the great importance of ante-natal pediatrics. Furthermore, even if the full term fetus is free from disease it may, as a result of poor nutrition, be immature and therefore poorly equipped to withstand the trauma associated with labour or to combat the ‘infections to which it may be exposed in the neonatal period.

I am deeply sensible of the great honour the Canadian Medical Association has conferred upon me, my Medical School and on British Pediatries by, inviting me to deliver this Lecture, and it is impossible for me to convey to you the thrill which this invitation gave me. I can only say, thank you, from the bottom of my heart. I also welcome this opportunity to tell you that people like myself—the common people of the United Kingdom—realize that we can never discharge the debt which we owe to Canadians for their defence of our country and for the example they set us by their courtesy, bravery and kindliness. We now appreciate more. than ever the strength of the ties which bind you and us together as fellow citizens of the British Empire and in devotion to our Sovereign.

This lectureship was founded to commemorate one of whom it was said that ‘‘behind the. knowledge, the erudition, the industry, lay the man great-hearted, the soul of professional ethics, loyal to his friends and charitable to -all’’, and one who was a great pioneer in pediatrics. The sight of these wonderful mountain peaks reminds me of those pioneers in other fields who laid the foundations of our Empire and whose spirit has been so vividly described by Kipling in his poem The Explorer. The Explorer—perhaps Alexander Mackenzie —having reached the edge of civilization and hearing that there was nothing further to discover, settled down:

Till a voice as bad as Conscience rang interminable changes

In one everlasting Whisper day and night repeated—so

‘‘Something hidden go and find it. Go and look behind the Ranges

Something lost behind the Ranges. for you. Go’’,

Lost and waiting

In medicine and particularly in ante-natal pediatrics there are still large and unexplored territories of knowledge hidden behind the ranges of ignorance. The command ‘‘Go and look behind the Ranges’’ is addressed to all of us: fortunately, thanks both to nature and to nurture, we still possess the pioneering spirit of our forefathers. We may never make any great discovery but should we be fortunate enough to do so we shall be able to say with Kipling:

It’s God’s present to our nation: Anybody might have found it, but His whisper came to me.

Cite this page: Hill, M.A. (2024, May 18) Embryology Paper - Ante-natal conditions in the new-born child (1946). Retrieved from

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