IDIOPATHIC JAUNDICE IN PREMATURE INFANTS

847

We believe that, in patients for whom partial thyroidectomy is the treatment of choice, the presence of high titres of thyroid antibodies may be of value in predicting the onset of early postoperative hypothyroidism, and that this should be anticipated by the prophylactic administration of thyroxine. The rapid onset of postoperative hypothyroidism is not desirable but may well be preferable to protracted treatment with antithyroid drugs which have their own potential dangers. There is, as yet, insufficient evidence that the physician should take into account the presence of thyroid antibodies in deciding whether or not radioactive-iodine therapy is indicated. There are still too many imponderable factors relating to this form of treatment to make undue emphasis on the presence of antibodies justifiable. The degree of lymphoid infiltration indicated by a raised complement-fixation titre might be a factor in determining that a lesser dose, be given than would otherwise be thought suitable; but most systems of calculating dosage are still somewhat empirical (Macgregor 1957). The most difficult factor to assess in arriving at the correct dose of radioactive iodine is the susceptibility of the patient’s thyroid tissue to any given amount of radiation. Consequently, the poor correlation between the level of thyroid antibodies before treatment and the clinical response to a single dose of radioactive iodine does not necessarily imply that the presence of circulating thyroid autoantibodies is irrelevant to the natural history of the condition. In the radioactive-iodine group, any effect that autoimmunity may have in determining the patient’s response to treatment never becomes apparent because of the difficulty of assessing a standardised dose which will produce the same amount of thyroid damage as that inflicted at operation. The prognostic significance of antibodies in patients treated with antithyroid drugs is not clear. Fulthorpe et at, (1961) say that if patients with high antibody titres in their sera are given antithyroid drugs they often require small maintenance doses and eventually go into prolonged remission of their hyperthyroid symptoms ". They provide no evidence to justify such a statement; nor do we know of any published or unpublished data-either with a wide statistical basis or derived from a few individual patients-which would help to prove this hypothesis. Antibody titres should first be determined before therapy in many more patients who are to be treated conservatively with drugs alone; only thus will we discover whether or not the presence of antibodies provides any indication as to which patients will go into spontaneous remission. ’

patients should not necessarily preclude surgery or radioactive-iodine therapy which is otherwise indicated; but postoperative hypothyroidism should be expected in the presence of a positive precipitin test or a high titre of complement-fixing antibody. In the middle-aged or elderly thyrotoxic patient, with strongly positive tests for thyroid antibodies, surgery (followed by prophylactic thyroxine) or radioactive-iodine therapy is preferable to long-term conservative treatment with antithyroid drugs. We are grateful to our surgical colleagues, Mr. J. R. Cameron and Mr. D. MacIntosh, for their helpful collaboration and to Dr. Anne Fulton for her invaluable assistance. We are also grateful to the department of clinical chemistry, Royal Infirmary, Edinburgh, for carrying out serum electrophoresis, flocculation tests, and the serum protein-bound iodine estimations. W. J. I. is in receipt of a grant from the Medical Research Council and A. E. S. of one from the Scottish Hospitals Endowment Trust. REFERENCES

Anderson, J. R., Goudie, R. B., Gray, K. G. (1959) Scot. med. J. 4, 64. Albutt, C. (1897) System of Medicine; vol. iv, p. 502. London. Beare, R. L. B. (1958) Brit. med. J. i, 480. Blagg, C. R. (1960) Lancet, ii, 1364. Boyden, S. V. J. (1951) J. exp. Med. 93, 107. Buchanan, W. W., Alexander, W. D., Crooks, J., Koutras, D. A., Wayne, E. J., Anderson, J. R., Goudie, R. B. (1961a) Brit. med. J. i, 843. Crooks, J., Alexander, W. D., Koutras, D. A., Wayne, E. J., Gray, K. G. (1961b) Lancet, i, 245. Koutras, D. A., Crooks, J., Alexander, W. D., Brass, W., Anderson, J. R., Goudie, R. B., Gray, K. G. (1962) J. Endocrin. 24, 115. Eason, J. (1928) Edinb. med. J. 35, 169. Fulthorpe, A. J., Roitt, I. M., Doniach, D., Couchman, K. (1961) J. clin. Path. 14, 654. Goudie, R. B., Anderson, J. R., Gray, K. G. (1959) J. Path. Bact. 77, 389. Greene, R. (1950) J. Endocrin. 7, 1. (1953) Mem. Soc. Endocrin. no. 1, p. 16. Cambridge. Irvine, W. J. (1960) Scot. med. J. 5, 511. (1961) Advances in Thyroid Research; p. 154. Oxford. (1962) Brit. med. J. i, 1444. Macgregor, A. G. (1957) ibid. i, 492. (1960) Mem. Soc. Endocrin. no. 9, p. 90. Cambridge. Oakley, C. L., Fulthorpe, A. J. (1953) J. Path. Bact. 65, 49. Oudin, J. (1948) Ann. Inst. Pasteur, 75, 30. Picado, C., Rotter, W. (1938) Endokrinologie, 21, 93. Schade, R. O. K., Owen, S. G., Smart, G. A., Hall, R. (1960) J. clin. Path. 13, 499. Short, C. L., Bauer, W., Reynolds, W. E. (1957) Rheumatoid Arthritis. Cambridge. Skillern, P. G., Crile, G., McCullagh, E. P., Hazard, J. B., Lewis, L. A., Brown, H. (1956) J. clin. Endocrin. 16, 35. Stuart, A. E. (1958) Ph.D. thesis. University of Edinburgh Library. Whitesell, F. B., Black, B. M. (1949) J. clin. Endocrin. 9, 1. —

—

—

—

—

—

"

’

I

i

I

I

Summary

1

A

made in which the titres of and thyroglobulin complement-fixing antibodies were determined in 78 patients before treatment. The response to partial thyroidectomy, radioactive-iodine therapy, or antithyroid-drug treatment was assessed after at least three years.

i

prospective study

was

Early postoperative hypothyroidism

.

I

I ,

was

common

where the precipitin test was positive and, more particularly, where there was a high titre of complement-fixing antibody; but hypothyroidism after radioactive-iodine therapy could not be predicted from the titre of thyroid antibodies present. There was no evidence that the response to treatment with antithyroid drugs could be predicted from the presence of raised titres of thyroid autoantibodies. The presence of antibodies in the sera of thyrotoxic

IDIOPATHIC JAUNDICE IN PREMATURE INFANTS MARGARET E. BARTON* M.B. Cantab., M.R.C.P.E.

JOHN WILSON M.B.

LUCCOCK RESEARCH FELLOW

Lond., M.R.C.P. REGISTRAR

WILLIAM WALKER M.D. Durh. SENIOR LECTURER

DEPARTMENT OF CHILD

HEALTH; SCHOOL, KING’S COLLEGE,

DURHAM UNIVERSITY MEDICAL NEWCASTLE UPON TYNE

HYPERBILIRUBINAEMIA carries the risk of kernicterus. This is greatest in infants with haemolytic disease of the newborn, but appreciable also in normal " premature infants (Aiden et al. 1950) and, rarely, in " normal " mature infants (Butler and Spector 1952). We have investigated the development and significance of jaundice in newborn premature infants without haemolytic anaemia. Because the incidence of hyperbilirubinxmia varies from one hospital to another (Lucey 1960), we have made our observations in two maternity units of similar size serving similar communities. "

Procedures 589 infants were studied: these comprised all infants born in the two units in 1959 with a birthweight of under 5 lb. 8 oz. and all those born in 1960 with a birthweight of 4 lb. or less. 20 of these had hxmolytic disease of the newborn and were not *

Present address: The Children’s

Hospital, Ladywood Road, Birmingham.

848

considered further. In 135, satisfactory assessment of jaundice was not possible because death or transfer to another hospital occurred during the first three days of life. There remained 434 infants in whom jaundice was satisfactorily assessed. Each infant was examined daily in good dzylight, and any jaundice was classified as mild, moderate, or severe. In all infants with moderate or severe jaundice the plasma-bilirubin was estimated; this was done daily if the level lay between 10 and 15 mg. per 100 ml. but at least twice daily if the concentration exceeded 15 mg. per 100 ml. Blood for bilirubin estimation was obtained by a deep puncture made in the outer aspect of the warmed heel. 1 ml. of blood was collected in a siliconed tube containing dry heparin; this was sealed in a light-proof envelope and sent to the laboratory. Any specimen showing obvious hxmolysis was discarded and a fresh sample was obtained. The plasma was separated not later than two hours after collection of the specimen and bilirubin estimation was usually done forthwith. Occasionally, plasma was stored at -20°C for up to thirty-six hours before testing. In addition, the hxmoglobin content of these samples was measured, a reticulocyte-count performed, and the specimen examined for Heinz bodies. Similar observations were made, between the second and fifth days of life, in 36 of the infants who had no jaundice and in 64 with only mild jaundice. Exchange transfusion was performed in 2 infants because the bilirubin rose to 25 mg. per 100 ml. Samples of cord blood were obtained for bilirubin estimation from 100 of the infants. Whenever possible-and certainly in all infants with moderate or severe jaundice-the ABO and Rh blood-groups were determined and the direct Coombs test carried out. The mother’s blood-group was determined and tests for immune antibody were made if incompatibility between mother and infant was revealed. Details were recorded of labour, delivery, the mother’s previous medical and obstetric history, her health, and any drugs received during pregnancy. All drugs given to the infant and any illness in the first weeks of life were likewise noted. Nearly all surviving infants have been re-examined between nine and eighteen months later, and we intend to reassess their development when they are five years old. Estimation of Bilirubin Estimations were made by the method of King and Coxon. 1 ml. of serum was used for determinations on cord blood and 0-2 ml. of plasma made up to 1 ml. with phosphate buffer for all later determinations. If the concentration exceeded 18 mg. per 100 ml. a duplicate estimate was made by the method of Lathe and Ruthven (1958). This method gave results 10-15% higher than those obtained by King and Coxon’s method. Preliminary tests showed that results from plasma samples corresponded closely with those from serum: for example, twenty-five duplicate determinations gave a mean value of 2-85 mg. per 100 ml. with serum and of 2-9 mg. per 100 ml. with plasma. Storage at -20°C for up to seven days did not affect the result. 4 workers were responsible for all estimations, and we calculated that, for a bilirubin level of 20 mg. per 100 ml., 70% of their results would be between 19 and 21 mg. per 100 ml. and 95% between 18 and 22 mg. per 100 ml. In the course of the study, 17 samples were tested both in our laboratory and by Dr. C. R. J. Ruthven at Queen Charlotte’s Hospital; in 5 the results differed by more than 2 mg. per 100 ml., but the mean for all estimations at Queen Charlotte’s was 9-7 mg. per 100 ml. compared with 10-5 mg. per 100 ml. in our laboratory. We therefore concluded that the results from our laboratory were reproducible and reasonably accurate.

Findings Serological Tests ABO and Rh groups were determined in 91% of the infants. In 20% the ABO groups of mother and infant were incompatible; such incompatibility was found in 24% of the moderately and severely jaundiced infants and in 18% of the slightly jaundiced. This difference is not

significant. We therefore believe that the results of these tests exclude hxmolytic disease of the newborn as an important cause of jaundice in our series. The direct Coombs test was negative in all 344 infants in whom it was done; these included all infants of Rh(D)negative mothers. Mortality

mortality-rate was similar in each hospital and, in 20-2% for all premature infants. For infants with birthweights of 4 lb. or less it was 48% in 1959, and 45% in 1960. Of 66 infants weighing 2 lb. 8 oz. or less, 59 died. 68% of all deaths occurred in the first twentyfour hours after birth. Necropsy was performed on 43 The

1959,

was

of the 47 infants who died later than this. Kernicterus found post mortem in 2 infants who weighed 2 Ib.1 oz. and 3 lb. 11 oz. at birth; they were born at thirty and thirty-two weeks respectively and lived for thirty-seven and a hundred and two hours. The first of these infants was only moderately jaundiced but the plasma-bilirubin was

TABLE

I-BIRTHWEIGHT

DISTRIBUTION

ASSESSABLE

OF

434

INFANTS

WITH

JAUNDICE

estimated because the infant’s condition was so precarious. In the second infant the plasma-bilirubin rose to a peak of 22-1 mg. per 100 ml.

was not

Jaundice assessed in 205 boys and 229 girls, of which twins or triplets. The birthweight distribution is shown in table 1. Jaundice was recognised in 56% of infants born in the Princess Mary Maternity Hospital but in only 37% of those born in the Newcastle General Hospital. This difference is significant (P= < 0-001) but can be wholly explained by different observers’ appreciation of mild jaundice, for the discrepancy disappeared if only moderate and severe jaundice were considered. When jaundice was present it was recorded as mild in 52% of infants, moderate in 39-5%, and severe in 8-5%. Table 11 shows the day of onset of jaundice, the day of most intense jaundice, and that of peak plasma-bilirubin level, where these data were available. In 7 infants, weighing between 2 lb. 10 oz. and 5 lb. 4 oz., jaundice developed in the first twenty-four hours of life. In 5 the jaundice was severe, 4 having bilirubin levels over 20 mg. per 100 ml. and the 5th dying with kernicterus. None of these 7 were anxmic in the neonatal period, but 3 had high reticulocytecounts (10%, 16%, and 24%) suggesting that increased haemolysis may have been in progress. When jaundice appeared on the second or third day of life there was a 50% chance that it would become moderate or severe; thereafter the risk lessened progressively. Jaundice was usually This

90

was

were

TABLE II-TIME OF ONSET AND SEVERITY OF

JAUNDICE (1959 CASES 0BLT

849 TABLE III-PLASMA BILIRUBIN AND DEGREE OF

IN

JAUNDICE

210INFANTS

the fourth day, whereas the bilirubin level the fourth or fifth day. The day of onset of highest the rate at which the colour deepened were and jaundice not related to birthweight.

most intense on was

on

The relation between the depth of jaundice and the bilirubin level is shown in table III. The two do not agree precisely. There was a tendency to overestimate the severity of the jaundice: in 68 infants, for example, in whom jaundice was regarded as moderate or severe, the plasma-bilirubin was less than 15 mg. per 100 ml. In only 2 infants with mild jaundice was the bilirubin level higher than 15 mg. per 100 ml., and in both it was less than 17 mg. per 100 ml. Probably, therefore, bilirubin was estimated in almost every infant in whom the level exceeded 15 mg. per 100 ml. Birthweight and Gestational Age Severe jaundice was commoner among the smaller and more

immature infants.

Moderate

or

severe

jaundice

TABLE IV-PEAK PLASMA BILIRUBIN AND LENGTH OF GESTATION IN

210 INFANTS

cases if it is assumed that bilirubin was measured wherever the level exceeded 15 mg. per 100 ml. This occurred in 18% of infants weighing 4 lb. or less and in 25% of those born before the thirty-fifth week of gestation, compared with 7% and 4% respectively for bigger and more mature infants. A bilirubin level of more than 20 mg. per 100 ml. was found in no infant born after thirty-four weeks’ gestation and in only 1 with a birthweight of over 4 lb. More detailed statistical analysis suggests that immaturity was more important than birthweight in determining the occurrence of hyperbilirubinoemia.

Pattern of Bilirubinaemia During the First Week The peak bilirubin level may be reached at any time between the second and seventh days of life (table 11). In 76 infants, six or more bilirubin estimations were performed; we have plotted TABLE V-BILIRUBIN LEVEL AT FORTY-EIGHT HOURS AND PEAK IN

SUBSEQUENT

76 INFANTS

against age in groups selected by birthweight or by gestation period, and the accompanying figure shows the limits within which the majority of determinations fell. The pattern of bilirubinsemia was not related to birthweight or to gestation. A rapid rise in the first forty-eight hours increased the probability that the peak level would exceed 20 mg. per 100 ml. (table v). the results

If the bilirubin level was less than 10 mg. per 100 ml. at it never. exceeded 20 mg. per 100 ml. thereafter ; it did exceed this level in more than half those cases in which the forty-eight-hour value exceeded 12-5 mg. per 100 ml.

forty-eight hours,

Maternal Factors

developed in 68 (43%) of 160 infants with birthweights of 4 lb. or less but in only 48 (18%) of 274 larger infants. Similarly, 51 % of infants born before thirty-five weeks’ gestation developed moderate or severe jaundice, but only 14% of those born after this time. The bilirubin level was similarly related

to

birthweight

and stage of gestation (table iv). The bilirubin level rose above 15 mg. per 100 ml. in 28 of 104 infants with a birthweight of 4 lb. or less and in 37 of 106 with a gestational age of less than thirty-five weeks. Because bilirubin was estimated only if jaundice was moderate or severe, these figures suggest too high a frequency of hyperbilirubinxmia. A better estimate can be made from all the

Limits of plasma-bilirubin levels in 76 of life.

infants during first week

Moderate or severe jaundice occurred in 21 % of the 148 first-born infants and in 30% of the 286 later infants; the difference is not significant (P > 0-05). Maternal age varied from sixteen to forty-eight years, but maternal age did not influence the risk of jaundice developing in the infant. Pre-eclampsia, often a factor in premature delivery, occurred in the mothers of 105 infants; 15 mothers had pre-existing essential hypertension. In only 2 of these 105 infants did the bilirubin level rise above 15 mg. per 100 ml. whereas this occurred in 47 (14%) of 326 infants whose mothers had no toxasmia. This difference is significant (P=0-001). Similarly, moderate or severe jaundice ensued in 33% of the infants of nontox2emic mothers but in only 6% of those whose mothers had pre-eclampsia. This difference cannot be explained on the grounds that the infants of toxxmic mothers are more mature than their weight suggests. We have calculated the expected frequency of bilirubin levels higher than 15 mg. per 100 ml. for each stage of gestation: 8 cases are expected in the toxasmic and 41 in the nontoxasmic group. We observed 2 and 47 respectively. The difference is significant (?= 0-025) but the explanation is not apparent. 93 mothers had antepartum haemorrhage. 10 cases were due to placenta praevia and the remainder to non-toxic accidental haemorrhage. This happening could not be related to the severity of neonatal jaundice. Coincidental illness in the mother did not seem to increase the risk of jaundice in the infant. Drugs had been given to most of the mothers at some time in

850 the pregnancy. We detected no relation between these and the risk of subsequent neonatal jaundice.

Factors in the Infant Cord-blood bilirubin was determined in 100 cases. In 8 the level exceeded 3 mg. per 1-00 ml, in 24 it lay between 2 and 3 mg., and in 68 it was under 2 mg. per 100 ml.; it subsequently rose above 15 mg. per 100 ml. in 50%, 30%, and 9% of these

respectively. The pattern of jaundice in twins and triplets was in no way remarkable. Moderate and severe jaundice was equally common in boys and girls weighing 4 lb. or less at birth; but among heavier infants it was slightly commoner in boys. The difference,

however, was not significant. Many of the infants were ill in their first week of life (table vi). Illness did not modify the severity of jaundice in infants weighing 4 lb. or less at birth. When bigger infants were sick, they TABLE VI-NUMBER OF INFANTS WITH VARIOUS NEONATAL DISORDERS IN WHOM THE BILIRUBIN LEVEL EXCEEDED 15 MG. PER 100 ML.

*

Sticky

eye,

pustules,

or

mild umbilical

sepsis.

behave as regards jaundice, like infants in the lower weight-group; thus severe jaundice was commoner-especially in infants who developed respiratory distress or " alimentary tended

to

symptoms ". Foetal distress and placental infarction were seldom associated with jaundice, probably because they tend to occur near term and severe jaundice is rare in infants born after thirty-five weeks’ gestation. All infants were given vitamin K 1-2 mg. shortly after birth. No case ofhaemorrhagic disease occurred. Approximately equal numbers of infants, in chronological groups, received ’Synkavit’ andKonakion ’. Bilirubinmmia exceeding 15 mg. per 100 ml. ensued in 7% of infants receiving the former and in 13% of those receiving the latter preparation. Other drugs commonly used included sedatives (sodium amylobarbitone, phenobarbitone, chloral hydrate, and paraldehyde), stimulants (nalorphine, nikethamide, and lobeline), and antibiotics (streptomycin, oxytetracyline, and sulphacetamide eye-drops). None of these could be related to the severity of neonatal

jaundice. Discussion

The risk of kernicterus is related to the degree of hyperbilirubinsemia but also to individual susceptibility. This risk is highest in premature infants (hxmolytic disease of the newborn apart) for they are most likely to develop severe jaundice and to be especially susceptible. There is no agreement, however, about the frequency of hyperbilirubinasmia or kernicterus in premature infants, nor is the risk related precisely to the bilirubin value. Some of the differences probably stem from the influence of iatrogenic factors, but differences in the technique of bilirubin estimation are also important. We therefore conducted the present study in two maternity units where there was a conservative attitude to the administration of drugs to mothers and infants. All our bilirubin estimations were made in one laboratory, and we believe the results were consistent and accurate.

Clinical assessment of jaundice is difficult and, in our experience, not made easier by the use of the icterometer (Gossett 1960). Our finding of jaundice in 50% of all our premature infants agrees with that of Zuelzer and Brown (1961); other estimates have been higher (Davidson et al. 1941, Findlay et al. 1947, Corner 1960). The appearance of jaundice on the first day of life was exceptional and usually indicated that very severe jaundice would later develop; there was evidence of increased haemolysis in some of these infants. Our observation that jaundice was usually most intense by the fourth day, while the bilirubin reached its peak on the fifth day, agrees with that of Harris (1961). In our series, bilirubin values lay between 15 and 20 mg. per 100 ml. in 11 % of premature infants; in 2% they exceeded 20 mg. These percentages are somewhat lower than the corresponding figures of Freedman (1961) and Harris (1961), and much lower than those of Corner (1960). Holman (1957) reported bilirubin values of over 18 mg. per 100 ml. in 59% of premature infants and Dine (1954) found values of over 20 mg. per 100 ml. in 39% of their cases. Unlike Bowman (1956) and Hugh-Jones et al. (1960), we did not find severe jaundice more common in infants whose ABO blood-groups was incompatible with that of their mothers. The main factors related to jaundice and hyperbilirubinoemia were birthweight and maturity. Moderate or severe jaundice developed in 17-5% of infants whose birthweight lay between 4 lb. and 5 lb. 8 oz. but in 42-5% of smaller infants; bilirubin levels rose above 15 mg. per 100 ml. in 7% and 18% respectively. The relation to the length of gestation was even more impressive. Moderate or severe jaundice developed in 51 % of infants born before the thirty-fifth week but in only 14% born after this time; bilirubin levels exceeded 15 mg. per 100 ml. in 25% and 3-5% respectively. In no infant born after the thirty-fourth week or with a birthweight of more than 4 lb. did the bilirubin level ever exceed 20 mg. per 100 ml. In the infants of toxeemic mothers, moderate or severe jaundice was only half as common as expected. We could find no explanation for this, but we excluded the possibility that such infants were small for their gestational age. The reduced risk of neonatal jaundice associated with toxaemia has been noted before by Crosse et al. (1950), Dundon (1956), and Sacrez et al. (1960). Unlike these authors, however, we found no correlation between the severity of jaundice and the occurrence of antepartum

hxmorrhage. Miller and Reed (1958) reported that relatively high bilirubin levels developed in small premature infants with respiratory distress, and others have associated anoxia with severe jaundice (Crosse et al. 1950, Govan and Scott 1953, Holman 1957, Zuelzer and Brown 1961). We found the same but only in infants with a birthweight of over 4 lb. Unlike Tovey et al. (1959) we found that the bilirubin content of the cord blood bore some relation to the level subsequently reached; but the correlation was not close enough to be of practical value. We also found that, if the bilirubin level exceeded 12-5 mg. per 100 ml. at forty-

eight hours,

severe

jaundice

was

probable.

Of the 569 premature infants studied, 2 were treated by exchange transfusion because the bilirubin level reached 25 mg. per 100 ml. 2 died with kernicterus : in 1 the

851

bilirubin level

was 22-1 mg. per 100 ml., but it had not been determined in the other since the jaundice was only mild. All 4 infants had birthweights of less than 4 lb. and were born before the thirty-fifth week. At the present time, exchange transfusion is the accepted treatment for neonatal jaundice, and a bilirubin level of about 20-25 mg. per 100 ml. is the best indication available. But both have their limitations. If our material is representative, only a little over 2% of infants are at risk. Where exchange

transfusion is required, however, the infant will usually weigh 4 lb. or less and have a gestational age of less than

thirty-five weeks. Summary The development of jaundice was studied in all infants with a birthweight of 5 lb. 8 oz. or less born in the Newcastle General Hospital and the Princess Mary Maternity Hospital in 1959. The study was continued throughout 1960 for infants with a birthweight of 4 lb. or less. Jaundice was assessed in 434 infants, and bilirubin estimations carried out in 210, including all with moderate or severe

jaundice.

The bilirubin level after forty-eight hours gave some indication of the highest level likely to be reached. The risk of levels exceeding 15 mg. per 100 ml. was greatest in infants weighing less than 4 lb. at birth or having a gestational age of less than thirty-five weeks. In 11 % the peak concentration lay between 15 and 20 mg. per 100 ml.; in 2%it was still higher. There was no evidence that drugs given to mother or child were responsible for jaundice. Hyperbilirubinxmia was significantly less frequent in the infants of mothers with pre-eclamptic toxasmia than in the group as a whole. The reason for this is not known. We wish to thank Dr. George Knox for his help with the statistical and Prof. S. D. M. Court and Dr. F. J. W. Miller for access to their patients, for encouragement throughout, and for reading the manuscript. We are grateful to Dr. Sheilagh Murray and the staff of the laboratories of the Regional Blood Transfusion Service where all serological tests were performed, and to Miss D. Purvis, Miss M. Allan, and Miss J. Gibson who carried out the numerous hxmatological tests in the laboratory of the children’s department, Royal Victoria Infirmary, Newcastle upon Tyne. We are also grateful to the doctors and nurses in the two hospitals concerned for their help and goodwill. This study was partly supported by a grant from the Dowager Countess Eleanor Peel Trust Fund.

analysis of the data,

REFERENCES

Aiden, R., Corner, B., Tovey, G. (1950) Lancet, i, 1153. Bowman, J. M. (1956) Amer. J. Dis. Child. 92, 482. Butler, N.R., Spector, W. G. (1952) Brit. med. J. i, 1168. Corner, B.(1960) Prematurity; p. 450. London. Crosse, V. M., Meyer, T. C., Gerrard, J. W. (1950) Arch. Dis. Childh. 30, 507. Davidson, L. T., Merritt, K. K., Welch, A. A. (1941) Amer. J. Dis. Child. 61, 1958.

Dine, M. S. (1954) ibid. 88, 801. Dundon, S.(1956) J. Irishmed. Ass. 38, 99. Findlay, L., Higgins, G., Stanier, M. W. (1947) Arch. Dis. Childh. 22, 65. Freedman, A. M. (1961) in Kernicterus (edited by A. Sass-Kortsak); p. 20. Toronto.

Cosset, J.H.(1960) Lancet, i,

87.

Govan; A.D.T., Scott, J. M. (1953) ibid. i, 611. Harris, R. C. (1961) in Kernicterus (edited by

A. Toronto. G. Holman, H.(1957) Amer.J. Dis. Child. 94, 438.

Sass-Kortsak);

p. 10.

Hugh-Jones, K., Slack, J., Simpson, K., Grossman, A., Hsia, D. Y. Y. (1960)

New Engl.J. Med. 263, 1223. Lathe, G. H., Ruthven, C.R. J. (1958) J. clin. Path. 11, 155. Lacey, J. F. (1960) Pediatrics, 25, 690. Miller, C. A., Reed,H. R. (1958) ibid. 21, 362. Sacrez R., Levy, J.M., Scheppler, E., Klein, M. (1960) Ann. Pœdiat., Paris,

36, 219. G. H., Gillespie, E. N., Guy, J., Valaes, T., Oppé, T. E., Lewis, F J. W. (1959) Lancet, i, 860. Zuelzer,W.W., Brown, A.K. (1961) Amer. J. Dis. Child. 107, 87.

ey,

THE ROLE OF INFECTION IN

TRANSFUSION THROMBOPHLEBITIS

J. G. R. HOWIE * RESIDENT

M.B. Glasg. HOUSE-SURGEON, WESTERN INFIRMARY, GLASGOW

R. L. C. CUMMING &dag er; M.B. Glasg., D.Obst. SENIOR

HOUSE-OFFICER,

UNIVERSITY DEPARTMENT OF BACTERIOLOGY

AT THE WESTERN INFIRMARY

THROMBOPHLEBITIS in patients receiving intravenous fluids is accepted by many as almost unavoidable. No single cause has been satisfactorily identified. It has been tentatively attributed to the action of glucose or of saline on the veins and, more confidently, to material extracted from the rubber tubing of giving-sets (Handneld-Jones and Lewis 1952). Bolton Carter (1951) noted an increased incidence of thrombophlebitis in infusions running for over eight hours. James (1954) mentioned that at one large hospital the frequency increased with the influx of less experienced house-officers. Without citing figures, he maintained that the incidence of thrombophlebitis varies between one operator and another, which is also our impression. He concluded that the giving-set was probably at fault; but he gave no reasons.

Jones (1954) thought that the skill of the operator was of no significance; like others, he also implicated the materials of the giving-set. He stated that because he had " never seen suppuration ensue, so the inflammation is almost certainly not bacterial in origin. Further, ifPolythene’ cannula are passed some distance up veins, thrombophlebitis starts at the tip of the cannula and not at the site of skin puncture ". The report of a subcommittee to the Medical Research Council (1957) confirmed Bolton Carter’s observation in that no thrombophlebitis followed 59 transfusions lasting less than twelve hours, whereas, of 63 transfusions lasting from thirteen to twenty-three hours, 13% of those given through plastic giving-sets and 27% of those given through red rubber giving-sets produced thrombophlebitis. The figures after forty-seven hours were 36% and 55%. Successive trials showed a fall in the incidence of thrombophlebitis with changes in the material of the givingsets, first from red rubber to latex rubber (Handfield-Jones and Lewis 1952) and then to plastic tubing (Medical Research Council 1957). The Lancet (1960) summarised conclusions from previous work by saying that possible causes included trauma to the veins, the nature of the infusion, the duration of the infusion, and the type of the giving-set. Bacterial infection was not discussed as a possible contributory cause.

Our own observations on two consecutive series of 25 transfusions through cannulae into the long saphenous vein show a rate of thrombophlebitis of 14 out of 25 (56%) in the first series and 4 out of 25 (16%) in the second series. The only known difference between the two series was an improvement in the anti-infective measures in the second series. Methods Patients We observed 50 consecutive cases of transfusion into the long saphenous vein by cut-down at the ankle through a tapered polyethylene (’Polythene’) cannula inserted to midcalf. Of the 50 patients 46 were undergoing thoracotomy for cardiac, lung, or upper alimentary surgery; the remaining 4 were receiving

rehydration therapy. All patients were under antibiotic cover, which began forty-eight hours before the operation in the form of ’Seclomycin’ (streptomycin 0-5 g., procaine penicillin 300,000 units, sodium penicillin 100,000 units) given twice daily. All transfusions ran for at least twenty-one hours, and * Present appointment: Senior House-officer, University Department of Pathology, Western Infirmary, Glasgow. &dag er; Present appointment: Senior House-officer, Clinical Medicine, Western

Infirmary, Glasgow.