THE LONG-TERM PROGNOSIS OF SEVERE INFANTILE MALNUTRITION

Saturday 7 January 1967 THE LONG-TERM PROGNOSIS OF SEVERE INFANTILE MALNUTRITION

J. S. GARROW M.D., Ph.D. St. And., M.R.C.P.E. ACTING DIRECTOR, MEDICAL RESEARCH COUNCIL’S TROPICAL METABOLISM RESEARCH UNIT, UNIVERSITY OF THE WEST INDIES, JAMAICA, WEST INDIES*

M. C. PIKE Ph.D. Aberd. MEDICAL RESEARCH COUNCIL’S STATISTICAL RESEARCH UNIT, UNIVERSITY COLLEGE HOSPITAL MEDICAL SCHOOL, LONDON W.C.1

&dag er;

JAMAICAN children who had been treated for severe malnutrition in hospital were traced and examined 2-8 years after their discharge from hospital. They were found to be small by North American standards, but not when they were compared with Jamaican children, similar genetically and from the same economic background. When 56 of the previously malnourished children were matched with siblings or close relatives as controls they were slightly taller and heavier, broader in the chest, and had thicker bone and muscle in the leg than the siblings who had never been severely malnourished. There is no clear evidence that a period of severe malnutrition in infancy per se causes stunting of growth in children as it does in some animals. On the contrary, children who have been successfully treated for malnutrition tend to outgrow their siblings when they return home; this may have a genetic basis. 65

Summary

Introduction

IF a newborn rat is undernourished for the first three weeks of life it will never attain a normal size, even if it subsequently has access to unlimited quantities of food of good quality (McCance 1962). The long-term effect of infant malnutrition in man is less well established: it would be unethical to conduct an experiment in healthy children even if it were possible, and in those countries in which infantile malnutrition is common it is very difficult to find a suitable group of children to serve as controls. Suckling and Campbell (1956) followed up 27 South African children who had kwashiorkor at mean age 15-9 months (standard deviation, 4-0 months). Five years later these children were on average the same weight as other children attending a welfare clinic, but somewhat shorter. MacWilliam and Dean (1965) also concluded that children who had kwashiorkor were stunted " at least for several years ". But Cabak and Najdanvic (1965) found that 36 Serbian children who had been 27-52% below normal weight at the age 4-23 months were not below the normal local standards for weight and height at the age of 7-11 years, but they had a lower-than-normal i.Q. A prospective study is in progress in South Africa of 100 children with kwashiorkor who were discharged from hospital after *

Present address: Medical Research Council Laboratory, Mint Stables, St. Mary’s Hospital, London W.2. &dag er; Present address: department of pathology, Makerere College, P.O. Box 2072, Kampala, Uganda, East Africa.

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treatment; after 3 years the children who had had overtaken their sibling controls in them had attained the normal (Boston) and half of weight, In percentile range. height both ex-patients and controls were similar, the majority of both groups were below the range for normal North American children (Brock and Hansen 1965). McFie and Welbourn (1962) considered the possibility that the long-term effects of early malnutrition may involve an alteration in fat, and/or muscle, and/or bone, rather than in total body-weight. They measured X-rays of the lower leg of 52 Ugandan children who were 31/2-71/2 years old. The compared " light " children-i.e., children who had " unsatisfactory " weight curves during the first 2 years of life-to " heavy " children, whose weight curves during the first 2 years of life had been above the average for English children. The " light " children were approximately 10% lower in mean bone width, fat, and muscle. (McFie and Welbourn [1962] ignored the result for fat since only the results for bone width and muscle were statistically significant; we feel that this is a misuse of significance tests and confuses " statistical significance and " significance "). In the search for long-term effects of infantile malnutrition Jamaica offers several advantages. Children are often weaned at a very early age, so we often see severely malnourished children who are 6 months’ old or even less, and animal work shows that the earlier in life the period of malnutrition occurs the more likely it is to leave permanent effects (McCance 1962). The island has fairly good communications, so it is possible to trace a high proportion of patients who have been discharged from hospital. Moreover, a relevant standard is now available since a recent nutritional survey has provided reliable information about the height and weight of children in the rural population (Ashcroft and Lovell 1964). We have to discover if children who had been treated for malnutrition at an early age were subsequently distinguishable from their siblings who had never been severely malnourished. Clinical Material and Methods

adequate been in

hospital

tried

severe

Children who have been admitted as inpatients to the metabolic ward of the M.R.C. Tropical Metabolism Research Unit are normally followed as outpatients for about 2 years after their discharge. At the end of that period, they are normally discharged as outpatients also. In this paper we describe previously treated children who were no longer being followed as outpatients as " ex-patients ". 70 ex-patients were found at their homes, and the permission of their guardians was sought to bring the children to hospital for a day for examination. For a control group the guardian was asked to nominate a child, preferably a sibling, who had been brought up with the ex-patient but who had not had any serious illnesses. Some guardians were unable to nominate a suitable control, some insisted on bringing more than one, and a few defaulted at the last moment. Finally, we examined 65 ex-patients and 67 controls. A

2 We do not know if the child who had been in hospital received more parental attention than his siblings when he returned home. However, the food intake of these children is determined more by economic circumstances than by parental sympathy, and the health education provided by visiting nurses should affect siblings as much as ex-patients, so it is unlikely that these factors caused ex-patients to be bigger than their controls many years after discharge from hospital. The recruitment and transport of these

children

was

supervised by

two

public-health

All the children were examined clinically by J. S. G. who did not know if a given child was an ex-patient or a control. Weight and height were measured with the child unclothed and an anteroposterior X-ray was made of the lower legs and of an aluminium step wedge (Garrow and Fletcher 1964). An Fig. 2-Heights and ages of ex-patients and controls. For key, see fig. 1. electrocardiogram and chest X-ray was also taken, in connection with a cardiovascular survey by Dr. calculated for each pair of legs. The widths of the tibial shaft, the calf muscle, and the subcutaneous fat were then expressed W. E. Miall. as mm. per cm. of tibial length and called " tibial width ", The weight of each child was expressed as a percentage of the " muscle width ", and " fat width " respectively (this stansame in a district of the rural a child of age poor average weight dardisation could equally well have been done relative to of Jamaica, an area similar to that from which the children in this study came (Ashcroft and Lovell 1964), and termed " % standing height, the correlation between standing height and ". The same was done for height, termed tibial length being very close). weight-for-age " From the chest X-rays " chest width " was obtained as the % height-for-age ". To obtain a weight-for-height measure, " a standard " graph of weight against height was first congreatest diameter across the rib-cage in the posteroanterior structed : for each of the age-groups of Ashcroft and Lovell view. The tube-to-film distance for the leg X-rays was 40 in., and (1964) the median height and median weight were noted, these values were then plotted against one another and a curve was for the chest X-rays 6 ft. No correction was made for projection drawn through them by eye. This we regarded as the standard enlargement. To standardise these X-ray measures for age we weight-for-height curve. The actual weight of each child in our plotted, for each measure separately, the control values against series was compared with the expected value for his height age and drew a regression line through these points. These obtained from this graph and termed his "% weight-for-height". lines were regarded as giving the standard values for age. The From the X-rays of the lower leg, measurements were made actual measurements on each child were then expressed as in both legs of the length of the tibial shaft and the width at the " % tibia width ", " % muscle width ", " % fat width ", and midpoint of the shaft, and the width of calf muscle and sub- " % chest width ". cutaneous fat were measured on the radiograph as described by Finally, for the ex-patients, their age on admission to hospital, Gam (1962). An average value for each measurement was their weight and height on admission, and their duration of stay in hospital, were abstracted from their earlier inpatients’ notes. From these data the

nurses.

% weight-for-age, % weight-for-height, and % height-for-age were calculated for each child at

the time he was admitted malnutrition.

to

the unit with

severe

Results

Clinical examination failed

to

reveal any

significant difference between the expatients and their controls. Fig. 1 shows the weights of the expatients when they were admitted with severe malnutrition, their weights at follow-up, and the weights of the controls.

ages of 65 children on admission to hospital for malnutrition and when seen at follow-up compared with 67 controls.

Fig. 1-Weights and

The broken lines indicate the 10th and 90th percentiles calculated by Ashcroft and Lovell (1964), and the continuous line indicates the 50th percentile for children in Boston (Nelson 1959). It seems that the ex-patients, as a group, do not differ in weight from the control group, but they do differ slightly from the community from which they were drawn. From fig. 2, it seems that the ex-patients as a group do not differ in height from the control group, nor does either group differ from the community from which they were drawn. The results obtained by measurement of the X-rays of the lower leg are summarised in fig. 3; there is no signi-

3

ficant difference between the groups in the width of muscle, or bone.

fat,

Small differences between ex-patients and controls might have been obscured because the two groups were considered as a whole. Within the series there were 56 ex-patients who had siblings or close relatives as controls. Of these 56 pairs of children, there were 4 in whom the chest X-ray was unsatisfactory for the measurement of chest width, so for this measurement it was possible to make a comparison in only 52 pairs. The average values for the measurements which were made on the ex-patients when they were malnourished, and when they were seen at follow-up 2-8 years later, and also for their siblings controls at the time of the follow-up examination are given in the table. All the differences between ex-patients and controls are very small. For each measurement, except fat, the ex-patients had, on average, a higher score than their controls, but this difference was not significant except for chest width. The ex-patients have statistically significantly greater chest width per metre of tibial length (corrected for age) than their controls despite the fact that they also have slightly greater tibial lengths than their controls. These results, therefore, show that the ex-patients were not permanently stunted by their episode of severe malnutrition ; on the contrary they have, if anything, overhauled their siblings in all measured respects except the thickness of subcutaneous fat in the calf. To discover those factors present during a period of malnutrition which correlate with the subsequent growth of the child we further analysed the group of 56 ex-patients. Their % weight-for-age on follow-up was significantly (r=0’46, P < 0001) related to their % weight-for-age on admission, similarly their % weight-for-height on followup was related (r==0-39, P < 0-05) to their % weight-for-

MEASUREMENTS ON 56 MALNOURISHED CHILDREN ON ADMISSION TO HOSPITAL AND WHEN SEEN AT FOLLOW-UP EXAMINATION, AND ON THEIR CONTROLS AT THE TIME OF THE FOLLOW-UP EXAMINATION

height on admission; but with % height-for-age the relationship, although positive, was not quite statistically significant (r=0-23, p> 0-05). Thus, although early malnutrition per se seems to have no permanent effect, the genetic and environmental influences which lead to the child being very small at the time of admission to hospital probably continue to operate on himself (and his siblings) when he goes home after discharge. The effect of an early period of malnutrition would be substantiated if it could be shown that the younger the child was on admission the smaller he was on follow-up. In fact the relationships were very weakly positive for the effect of age-on-admission on % weight-for-age, % weight-for-height, and % heightfor age on follow-up but in each case P was > 0-25. The influence of the duration of stay in hospital on subsequent growth was also investigated. A priori, it could be argued either that a long stay in hospital would give a malnourished child a better chance for a good recovery or that prolonged maternal deprivation would handicap him on his return home. The children who had been longest in hospital were the smallest at follow-up, but they were also those who were smallest on admission to hospital. After allowance was made for size on admission there was no significant relation between the duration of stay in hospital and size at follow-up. Discussion

In those investigations in which malnourished children have been found to be stunted later in life (Suckling and Campbell 1956, MacWilliam and Dean 1965) the malnourished children have been compared with children from different families. It is likely that the malnourished children came from families which were poorer than average; they certainly were nutritionally poorer. If this is so they would return to poorer homes after discharge and might be expected to do less well than average.

Fig.

3-The width of muscle,

fat,

and tibia related to tibial

0= Ex-patients

at

follow-up.

.. = Controls.

regression line for

control series.

length.

Similarly, the children studied by McFie and Welbourn (1962) who were above average weight for the first 2 years of life were evidently from families who were genetically or nutritionally above average. The fact that they were bigger some years later does not therefore prove that less well endowed children have been stunted in development by an episode of early severe malnutrition. To avoid this difficulty malnourished children have been compared with siblings, and have been shown to be slightly heavier (Brock and Hansen 1965) and broader in the chest (this series). We have been unable to show that the duration of stay in hospital had any effect which might have given the malnourished children an advantage over their siblings at home, so if the effect is a true one it probably arises because the children who were admitted

4

hospital were genetically bigger than their siblings. We would suggest that the child whose genetic make-up is such that he would grow very rapidly if well fed, will suffer more on a restricted diet than one with more modest demands. This hypothesis could explain both the fact that in a given family on a restricted diet some children suffer much less harm than others, and also the tendency of the child who has been successfully treated for malnutrition to outgrow his siblings very slightly. to

This investigation would not have been possible without the cooperation of Dr. W. E. Miall and the skill and persistence of Sister A. Gibbons, Staff-nurse L. Hall and Staff-nurse C. Carrington who found the ex-patients and control children and persuaded them to come to hospital for examination. Requests for reprints should be addressed to J. S. G., M.R.C. Laboratory, Mint Stables, St. Mary’s Hospital, London W.12. REFERENCES Ashcroft, M. T., Lovell, H. G. (1964) Trop. geogl Med. 16, 346. Brock, J. F., Hansen, J. D. L. (1965) in Human Body Composition (edited by J. Brozek); p. 245. Oxford. Cabak, V., Najdanvic, R. (1965) Archs Dis. Childh. 40, 432. Garn, S. M. (1962) Am. J. clin. Nutr. 11, 418. Garrow, J. S., Fletcher, K. (1964) Br. J. Nutr. 18, 409. McFie, J., Welbourn, H. F. (1962) J. Nutr. 76, 97. McCance, R. A. (1962) Lancet, ii, 621, 671. MacWilliam, K. M., Dean, R. F. A. (1965) E. Afr. med. J. 42, 299. Nelson, W. E. (1959) Textbook of Pediatrics; p. 50. Philadelphia. Suckling, P. V., Campbell, J. A. H. (1956) J. trop. Pediat. 2, 173.

RED EYES IN RENAL FAILURE G.M. BERLYNE M.D. Manc., M.R.C.P. SENIOR LECTURER IN MEDICINE AND HONORARY CONSULTANT PHYSICIAN

Ca x P of more than 70 in the hypercalcxmia, and if steps are taken to reduce serum-phosphate levels the conjunctival inflammation subsides.

deposition

and

a serum

absence of

Patients and Methods with renal failure seen in the University Departpatients ment of Medicine, Manchester Royal Infirmary, 1965-66, were examined for signs of conjunctival reddening and irritation, conjunctival plaques of metastatic calcification, and corneal limbal calcification. In these patients serial estimation of serum levels of calcium, phosphorus, alkaline phosphatase, and albumin was carried out; glomerular filtration-rate (G.F.R.) was determined by urea clearance. These chemical determinations were carried out by ’ AutoAnalyser ’. All

Results

Typical Case-report A 22-year-old male model-maker had been found to have symptomless proteinuria at age 15. A renal-biopsy specimen at age 18 showed chronic membranous glomerulonephritis. In January, 1965, he had malignant hypertension which responded to treatment with ot-methyldopa. In March, 1966, he was put on a modified Giordano-Giovannetti diet because of a rising blood-urea, pruritus, and epistaxis, and on this regimen his blood-urea fell from 225 to 123 mg. per 100 ml. although his renal function continued to deteriorate. In May, 1966, he complained of soreness of the eyes, which were red, with conjunctival hyperaemia extending to the limbus. Band keratopathy was also present (fig. 1). Serum-calcium was 9-9 mg. per 100 ml., serum-inorganic-phosphate 11-6 mg. per 100 rnl.; serum CaxP 115; blood-urea 175 mg. per 100 ml.; serumalbumin 4-36 mg. per 100 ml.; arterial-plasma pH 7-34; and urea clearance 3-4 ml. per minute. He was given aluminium hydroxide tablets B.P. 6 g. per day. The serum-inorganicphosphate fell to 5-8 mg. per 100 ml. and the soreness of the

A. B. SHAW M.B. Lond., M.R.C.P. MEDICAL RESEARCH COUNCIL RESEARCH FELLOW

From the

University Department of Medicine, Manchester Royal Infirmary, Manchester 13 15

PATIENTS

with

severe

renal failure had

Summary red eyes in association with a raised serum-

inorganic-phosphate (mean 13·2 mg. per 100 ml.) but a normal or low serum-calcium (mean 8·7 mg. per 100 ml.). The mean serum-calcium x serum-inorganic-phosphate was 114, and was invariably greater than 70. Conjunctival biopsy disclosed metastatic calcification. Treatment with aluminium hydroxide 4-8 g. daily resulted in improvement in the conjunctival injection, with a statistically significant fall in serum-inorganic-phosphate to a mean level of 7·1 mg. per 100 ml., and a statistically significant fall of serum Ca × P to 66·4. The corneoconjunctival complications of renal failure are discussed. The significance of red eye in relation to a raised serum Ca×P product is discussed, and the importance of hyperphosphatæmia is stressed. Introduction

BAND keratopathy and conjunctival deposits of metastatic calcification are well-recognised complications of hypercalcasmia (Meesman 1938, Haldimann 1941, Walsh and Howard 1947, Cogan et al. 1948). We have observed 15 patients with acute or chronic renal failure who had red eyes with conjunctival calcium deposition and variable limbal calcification in the absence of hypercalcasmia. In these patients we find that the serum-calcium x serumphosphate (Ca x P) is invariably more than 70. We record here the presence of red eyes in renal failure, and show that this sign is associated with conjunctival calcium

Fig. 1-case 8: red

eye due to

conjunctival injection in chronic

renal failure.

(A) Both eyes. (B) Close-up of right plaques.

eye to show

conjunctival hyperxmia and