Paper - A study of three infants dying from congenital defects following maternal rubella in the early stages of pregnancy

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Swan C. A study of three infants dying from congenital defects following maternal rubella in the early stages of pregnancy. (1944) J. Pathol. Bact. 41(3): 289-295.

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This historic 1944 paper by Swan is an early clinical description the occurrence of malformations associated with maternal Rubella infection. Modern Notes: Template:Virus Links

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A study of three infants dying from congenital defects following maternal rubella in the early stages of pregnancy

Charles Swan

From the Institute of Medical and Veterinary Science, Adelaide, South Australia (1944)

Working with a grant from the National Health and Medical Research Council, Australia.

(PLATES XLII -XLIV)

Introduction

The fact that mothers contracting rubella in the early months of pregnancy may give birth to infants suffering from congenital cataract, often associated with congenital heart disease, was first recorded by Gregg (1941). His observations were confirmed and extended by Swan et al. (1943), who reported other congenital defects, including deaf-mutism, cardiac disease Without apparent ophthalmic defect, and microcephaly. In the course of this Work material was obtained at three autopsies. The results of its investigation are recorded in this paper.

Clinical histories

Case I (case 11 in the series of Swan et al.). A. B., a female born three weeks prematurely and aged 2 days, was admitted to “ Mareeba ” Babies Hospital on 14th April 1943, under the care of Dr Helen Mayo. The baby’s mother had suffered from rubella when 1% months pregnant. On admission the baby “ seemed to have a cold ”. The temperature was 101-8° F., pulse rate 82, respiratory rate 70 per minute. With minor variations the pulse and respiratory rates were maintained at these levels throughout the course of the illness. Despite treatment the baby remained pyrexial, had frequent bowel actions and failed to gain Weight. Some difliculty was experienced in feeding "her ; occasionally she had to be fed with the aid of a pipette or by gavage. On 3rd May 1943 the child’s condition was much worse and cyanosis was evident. Brandy and injections of “ Anacardone ” led to no improvement and death occurred at 4 p.m.

Case II (case 24 in the series of Swan et al.). R. H. VV., a male born three weeks prematurely and aged 5 weeks, was admitted to “ Mareeba ” Babies Hospital on 27th March 1943, under the care of Dr Helen Mayo. He was suffering from bilateral congenital cataract and heart disease. The mother had contracted rubella when about two months pregnant. Previously the baby had been admitted to the Adelaide Children’s Hospital with a history of cyanosis at birth, failure to thrive and exhaustion after feeding. At that hospital the baby was very drowsy and slow in feeding. There was no clinical evidence of cardiac disease, but X-ray examination showed that the heart shadow was definitely enlarged and globular, suggesting a congenital abnormality. There was gradual deterioration in the baby’s general condition associated with loss of weight and death occurred on 27th April 1943.

Case III (case 25 in the series of Swan ct al.). M. D. H., a female aged 15 days, was admitted to “ Mareeba ” Babies Hospital on 13th May 1943, under the care of Dr Constance Finlayson. The baby had a left-sided congenital cataract. She had been sent from the Queen Victoria Maternity Hospital with a history of cyanosis and breathlessness, especially during feeding.. The child’s mother had suffered from rubella when about two months pregnant. On examination there was a systolic-diastolic murmur and feeble breath sounds at the bases of the lungs. Considerable difficulty was experienced in feeding the baby and she gradually lost weight. Later she had frequent relaxed green motions. Death occurred on 26th May 1943.

Post-mortem findings

All three autopsies were carried out in the presence of the author by Professor J. B. Cleland.

The children were small, thin and undernourished. In case II the nose was broad and rather J eWish—looking. Lanugo was still present on the limbs of case I.

Anterior fontcmelle. In two of the children the fontanelle was larger than normal. In case I it measured 1% in. laterally and 1% in. antero-posteriorly ; in case II 2 in. and 2 in.

Brain. The brain weighed 11 oz. in case II and 12% oz. in case III. Except for congestion of the pial vessels the brain appeared ‘normal in each case.

Eyes. In case II there were bilateral pupillary opacities, more apparent in the left eye. A similar opacity of more irregular outline was present in the left eye of case III.

H cart. The heart in case II appeared much larger than normal. The right auricle was distended in all three cases. In case III the right ventricle was dilated, appearing. about twice the size of the left. In all three the ductus arteriosus was widely patent, the diameter being 4, 4-5 and 3 mm. respectively. In each of the first two cases these diameters were approximately the same as thoseof the pulmonary artery. In case III the diameter of the ductus arteriosus at its junction with the aorta appeared larger than that of the aorta itself. In every case the foramen ovale was patent. In case I it just admitted the end of a match ; in case II it was slit—like and measured 7 mm. in longest diameter; in case III it was also slit-like and readily admitted a catheter 3 mm. in diameter. In the membranous portion of the interventricular septum of case I, there was a defect which, probably with a little dilatation, admitted a catheter 4 mm. in diameter. It was situated just below the right posterior aortic cusp.

PLATE XLII

FIG. l. —Case III. Normal lens, right eye. There are a few artefacts brought about by fixation and staining. Celloidin section. Haematoxylin and van Gieson. X 20.

FIG. 2. —Case III. Cataractous lens, lcft eye. The nuclear portion is amorphous and stains poorly. The "degenerated lens fibres colnprising the cortical zone are separated by vacuoles, especially in the equatorial region. Celloidin section. Haematoxylin and van Grieson. X 20.

Lungs. In all three cases the lungs were mottled with deep purple patches. These were firm and: airless and occurred especially on the posterior aspect. On section in case III the consolidated areas were rather friable. In case II the pleura Was speckled with petechial heemorrhages.

Ureters. The lower ends of the ureters in case II appeared to be distended.

Testes. In case II the right testis was undescended, being situated at the abdominal inguinal ring.

Except for occasional congestion the remainder of the viscera appeared normal.

Histological examination

Brain. In all three cases cellular aggregations were demonstrable in the sub-ependymal tissue of the lateral ventricles, especially in the region of the sulcus terminalis and anterior horns. There was a tendency for the cells to be arranged around blood vessels. In a few instances small groups of cells were detected also in the white matter of the centrum semi-ovale. These cells consisted of neuroblasts and spongioblasts in various stages of maturation. As has been pointed out by Schwarz, Groolker and Globus (1932) and Globus and Kuhlenbeck (1942), such appearances are normal in the brains of infants.

Eyes. In case III, where the cataract was unilateral, the afiected eye was only three-quarters the size of the other (see Swan et al.) and it-s lens was reduced proportionally (figs. 1 and 2).

There was a certain degree of similarity in the pathological changes involving the lens of the left eye in cases II and III (figs. 3 and 2 respectively). In each instance the lens was composed of a central (nuclear) portion and peripheral (cortical) zone. The nuclear portion formed about three-quarters of the lens ; it stained very poorly and appeared to have undergone necrosis en masse. In case III the nuclear portion was amorphous and stained pale buif, instead of the normal yellowish green with heematoxylin and van Gieson. Similar necrosis and staining were noted in case II, but here the nuclear core appeared more sclerotic and tended to break away from the cortical zone and from the posterior capsule. Moreover, traces of lamination and of karyorrhectic nuclei of lens fibres were seen. In both case II and case III, secondary as well as primary lens fibres were involved. In the cortical and especially the equatorial region, many of the lens fibres had disintegrated and were replaced by vacuoles of various sizes. Some of the vacuoles were very large, apparently as the result 292 0'. SWAN

of confluence of smaller ones. Occasional vacuoles contained pale» staining serous material. A few more highly refractile droplets were sometimes present. The majority of the lens fibres still living showed pronounced degenerative changes———-swelling, irregular staining, granu- larity and vacuolation of cytoplasm. Many of the fibres were short and squat and their nuclei swollen and pale. Degenerated lens fibres could be seen in the cortical zone lying between the anterior aspect of the nuclear core and the anterior lens epithelium. There was little attempt at formation of new fibres on the posterior aspect of the lens, where the central core came to the surface and was in contact with the posterior capsule. This description of the cortical zone applies mainly to case III. In case II almost all the lens fibres of this region had progressed beyond degeneration to necrosis.

The lens of the right eye of case II showed somewhat different appearances (fig. 4). Approximately the anterior five—eighths and the posterior one-eighth were composed of pale—staining amorphous material similar to that forming the central core of the cataractous lenses described above. Sandwiched between these two masses was an area composed of extremely degenerate lens fibres interspersed with large vacuoles. The fibres were squat and distorted and some were fragmented: many contained small vacuoles. The nuclei of the fibres were pale and swollen. There was occasional proliferation of the anterior lens epithelium. In a few instances these epithelial cells were much larger than usual and oval instead of cuboidal in shape. Such cells probably represented abortive attempts at new fibre formation.

Other ophthalmic structures (retina, iris, etc.) appeared normal. H cart. Examination of the margins of the interventricular septa_l

defect in case I revealed occasional replacement of muscle fibre by connective tissue. Otherwise in all three cases the heart muscle appeared normal. In each instance comparison of the structure of the ductus arteriosus with that of children of about the same age dying from other causes showed a number of differences. For instance the lumen was much larger and the wall thinner. Usually the amount of elastic tissue was about the same, but a definite internal elastic lamina was either absent or ill-defined. There was a moderate degree of replacement of muscle and occasionally of elastic tissue by collagen" fibres. Intimal proliferation, of considerable degree in the control cases, was totally absent.

Lungs. In cases I and III areas of partial or complete collapse were associated with bronchopneumonia. In case II the lungs were congested but collapse was less evident.

Liver. Scattered minute foci of degeneration (sometimes necrosis) occurred in cases I and III.

K idneys. In case II occasional glomeruli were smaller than normal and showed partial or complete replacement of their capillaries by hyalinised fibrous tissue (fig. 5). In these glomeruli there was a variable degree of proliferation of the whole of the parietal layer of Bowman’s capsule, but the crescentic appearance seen in chronic glomerulo-nephritis was absent. Sometimes adhesions between the parietal and visceral layers of Bowman’s capsule led to a variable degree of obliteration of the glomerular space. Similar lesions were seen in cases I (fig. 6) and III, but much less commonly; in two control cases they were absent.

PLATE XLIII

FIG. 3.——Case II. Cataractous lens, left eye. Compared with fig. 2 the nuclear core is more sclerotic and tends to break away from the cortical zone and from the posterior capsule; the lens fibres of the equatorial region are necrotic rather than degenerated. Celloidin section. Haematoxylin and van Gieson. X 20.

FIG. 4.—Case II. Cataractous lens, right eye. The amorphous central core is separated into two portions by degenerate lens fibres and vacuoles. Celloidin sectioil. Haematoxylin and Van Gieson. X 20.

Other viscera. N o lesions were detected in the other viscera, including the testes, pancreas, spleen and adrenals, and the pituitary, thyroid and thymus glands.

Discussion

Clinically the three infants had a number of points in common. All were born of mothers who had contracted rubella during the second month of pregnancy. Like many of those in Gregg’s series, all the infants “ were of small size, i1l—nourished and diflicult to feed ”. Two (cases I and II) were born some three weeks" prematurely. All suffered from congenital heart disease; two (cases II and III) had congenital cataract. None survived for more than ten weeks. Death was attributed to prematurity associated with the cardiac condition and pulmonary collapse. In cases I and III bronchopneumonia was also evident.

Post-mortem examination confirmed the presence of cardiac lesions as recorded in Gregg’s paper; in all three cases the ductus arteriosus was widely patent, all showed variable patency of the foramen ovale and one (case I) had a defect of the interventricular septum.

According to Bedford and Brown (1937) the suggested mtiological factors of congenital heart disease include abnormality of the germ plasm, heredity, consanguinity of parents, alcoholism, syphilis and tuberculosis in the parents, physical and mental trauma in the early weeks of pregnancy and pathological conditions of the uterus and amnion. These authors state that foetal disease probably plays only a minor role. In the light of the observations embodied in this and earlier papers (Gregg ; Swan et 5152.), it is evident that this opinion needs revision.

Bedford and Brown (p. 208) consider that the critical period for the development of congenital cardiac defects “is from the fifth to the eighth week of intra-uterine life, during which the septa are forming, the bulbus cordis is undergoing involution, and torsion of the great vessels is taking place ”. It is of interest to note that in the present cases this was the precise period during which the mothers suffered from rubella, and that one infant (case I) exhibited an interventricular septal defect. The precise method of closure of the ductus arteriosus at birth has been a matter of considerable speculation (Wells, 1908 ; Windle, 1940 ; Noback and Rehman, 1941; Kennedy, 1942; Jager and Wollenman, 1942). In the present cases it would seem not unreason- able to infer that the setiological agent of rubella had produced some structural alteration in the wall of the ductus arteriosus which prevented its closure. These three specimens were obtained 3-10 weeks after birth and it is possible that further structural alteration may have taken place during that period. It can be said, however, that there was no attempt at obliterative endarteritis. Moreover, the well defined internal elastic lamina and intimal mounds described by J ager and Wollenman even in the 28-centimetre foetus were absent.

On clinical grounds Gregg states that the type of cataract was apparently a new entity and did not “exactly . . . correspond to any of the large number of morphological and developmental lenticular opacities that have been described ”. Histological examination of the cataractous lenses in the present cases fully confirmed this finding. There was no resemblance to any of the types of cataract described in standard text-books (Parsons, 1936; Mann, 1937 ; Duke—Elder, 1940).

Hurst (personal communication, 1943) suggested that the cataract might result from interference with the nutrition of the lens fibres brought about by action. of the causative agent of rubella on the hyaloid artery, but in the specimens examined no trace of the artery was found, so that the hypothesis can neither be substantiated nor disproved.

Whatever the pathological process may be, it is evident that it had led to necrosis en masse of the nuclear portion of the lens. There are gross degenerative changes in and distortion and disorientation of the lens fibres formed subsequently from surviving cells in the equatorial region. The degeneration probably results from pro- longation of action of the aetiological agent for some time after its initial attack upon the lens. The distortion and disorientation probably occur as the result of loss of normal tissue-tension. That the effects of the pathological process continue to be evident after the 7th-8th week is clear from the involvement of secondary as well as primary fibres, since the former are not formed until this period. (Mann, 1928).

The lesions in the kidneys were confined to the glomeruli. They tend further to support Hurst’s suggestion that the causative factor of rubella acts primarily on the vascular tissue.

From the foregoing observations and those embodied in the earlier paper of Swan et al., it would seem probable that the pathological changes (cataract and heart disease) described by Gregg are only the more obvious manifestations of a widespread attack by the eetiological agent of rubella upon the tissues of the embryo, and that embryonic cells are more susceptible to this agent than are those of the adult.

PLATE XLIV

FIG. 5.-—Ca-se II. Kidney. Two glomeruli Show sclerosis. Pa.-I-aflin section. Harma- toxylin and Van Gieson. X 210.

FIG. 6.—-Case I. Kidney. Grlomerular sclerosis. Para-flin section. Haematoxylin and Van Gieson. X 210.. CONGENITAL DEFECTS AND MATERNAL RUBELLA 295

Summary

The naked eye and microscopic characters of the congenital cataract and congenital heart disease encountered in three infants whose mothers had suffered from rubella in the second month of pregnancy are described. The aetiology of these lesions is discussed.

I am indebted to Professor E. Weston Hurst for helpful criticism and advice and to Professor J. B. Cleland for allowing me to use his autopsy notes and for the gift of pathological material. My thanks are due also to Dr Helen Mayo and Dr Constance Finlayson for permission to publish the case records.

References

BEDFORD, D. E., AND BROWN, 1937. The British encyclopsedia of medical J. W. practice, London, vol. Vi, p. 206.

DUKE-ELDER, W. S. . . . . 1940. Text-book of ophthalmology, London, vol. iii, p. 3115.

GLoBUs, J. H., AND KUHLENBECK, 1942. Arch. Path., Xxxiv, 674. H.

GREGG, N. MOA. . . . . . 1941. Trans. Ophthalmol. Soc. Australia, iii, 35.

JAGER, B. V., AND WOLLEHMAN, 1942. Amer. J. Path, xviii, 595. O. J ., Jr.

KENNEDY, J. A. . . . . . 1942. Amer. J. Med. 806., cciv, 570.

MANN, I. C. . . . . . . . 1928. The development of the human eye, Cambridge.

,, . . . . . . . 1937. Developmental abnormalities of the eye, Cambridge, p. 335.

NOBACK, G. J ., AND RCSJHMAN, I. . 1941. Anat. Rec., lxxxi, 505.

PARSONS, J. H. -. . . . . . 1936. Diseases of the eye, 8th ed., London, p. 297.

SOHWARZ, H., GOOLKER, R, AND 1932. Amer. J. Dis. Oh7Ild., xliii, 889. GLOBUS, J. H.

SWAN, C., TOSTEVIN, A. L., 1943. Med. J. Australia, ii, 201.

Moons, B., MAYO, H., AND BARHAM Bmox, G. H.

WELLS, H. G. . . . . . . 1908. Amer. J. Ell.-ed. Sci, cxxxvi, 381.

WINDLE, W. F. . . . . . . 1940. Physiology of the fetus, London and New York, p. 45.

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