Develop. Med. Cliild Ncwol . 1974, 16, 528-547

Annotations

1NTRAUTERlNE TRANSFUSION LILEY in 1961' defined certain levels and trends in amniotic fluid optical densities at which early intrauterine hydrops or death could be anticipated. In rhesus haemolytic disease the management of such patients was revolutionised by his report in 19632 of a successful out- come following closed intrauterine transfusion. The technique he described involved injection of a small amount of radio-opaque dye at the time of diagnostic amniocentesis, allowing X-ray visualisation of the fetal gut within the next 48 hours. Then, using a Touhy needle, a fine polyvinyl catheter was introduced into the fetal peritoneal cavity and its position checked by further injection of radio-opaque material. A calculated volume of packed cells (deter- mined by the estimated fetal haemoglobin and gestational age) was then injected intraperi- toneally through the catheter.

Since LILEY'S report, many centres throughout the world have used similar techniques and have been able to achieve a fetal survival of around 40 to 50 per cent3-I0. It is widely accepted that without this procedure as many as 90 per cent of these pregnancies would have ended in stillbirth or neonatal death. Although it has been suggested", a controlled trial has never been carried out.

The most severely affected or late-treated cases already have ascites at the time of in- trauterine transfusion. and in these circumstances the chances of successful delivery of a viable infant are poor. The relatively severely affected fetus requires early obstetric interven- tion by means of an intrauterine transfusion, and the risks associated with the combination of early transfusion and severe disease are very great. Thus the salvage rate of fetuses requiring transfusion between 24 to 26 weeks gestation (these infants needing a further three or four transfusions before 35 weeks) is much lower than a group ofpatients not requiring transfusion until after 26 weeks gestation. A further poor prognostic factor is a previous history of one or more stillbirths.

Common obstetric complications which are attributable to the procedure include early rupture of the membranes, placental haemorrhage and premature labour (within a few days of the transfusion). Fetal complications include accidental trauma (which may involve penetration of the thoracic cavity, the cranium, a limb, or of almost any intra-abdominal viscus. including bladder, liver or spleen) and fetal death due to the above or associated with the infusion of blood. The use of fresh blood for the transfusion carries with it further theoretical and practical risks: the transmission of certain live viruses has been recorded, for example cytomegalovirus12 and hepatitis antigen4. Colonisation of the fetus by donor lymphocytes from fresh blood has been r e~orded '~ - '~ , with one case of graft versus host reaction13. These complications are rare and may be avoided by suitable screening of donors, and removal of the buffy coat of the packed cells used for the transfusion.

Most centres aim to allow the pregnancy to proceed to around 35 weeks, thus reducing the

528

ANNOTATIONS

hazard of respiratory distress syndrome complicating pre-term birth. The predictive value of amniotic fluid lecithin and lecithin sphingomyelin ratios in relation to hyaline membrane disease has already reduced the incidence of this serious complication in centres where it is practisedl79 18. The perinatal mortality among live-born infants is due, approximately equally, to the haemolytic disease itself (presenting usually as hydrops fetalis) and to problems of extremely premature birth which may follow intrauterine transfusion. Infants born after intrauterine transfusion may have acute respiratory embarrassment at delivery as a result of the large volume of blood in the abdomen; in this situation emergency para- centesis may be life-saving.

Nearly all these infants require immediate exchange transfusion, based on cord-blood values of haemoglobin and bilirubin (see, for example, the Newcastle criteria3) and most require multiple exchanges. This procedure, whether performed via a single umbilical vein catheter or via catheters in both vein and artery, carries an appreciable though low risk of complications, of the order of 1 to 2 per cent. These include pyaemic infection, necrotising enterocolitis, later onset of hepatic fibrosis or portal hypertension, and the transmission of blood-borne viral infection and death (though the latter is rare).

The hydropic infant presents a very difficult problem of management, the problems being compounded by a striking lack of understanding of the aetiology and pathology of this conditionlg. Treatment of the hydropic infant is largely empirical and based on experience of individual centres rather than published clinical trials. Results vary considerably, some reporting survival of up to 30 per cent5 while others are able to save only 10 to 15 per cent4. Most workers have found that the central venous pressure is high at delivery and that immediate venesection lowers this and appears to produce clinical improvement. The additional use of digoxin, diuretics and alkalis before, during or after the first urgent ex- change probably all have a place in the over-all management. Hypoglycaemia, which has long been recognised as a complication of severe haemolytic disease (e.g.”), may be more common and more severe after intrauterine transfusion2O9 21. Other complications such as disseminated intravascular coagulation with pulmonary and intracranial haemorrhage and hypothermia may occur.

There have been few reports6? l 1 7 2o of follow-up studies of infants who have survived multiple intrauterine transfusions, premature delivery and multiple exchange transfusions, so that recent reports with follow-up information are welcome. Groups of up to 50 surviving children have been followed up over periods of from one month to seven years. Apart from a high incidence of hernia+ 17, there appear to be few anatomical complications and these children grow normally and maintain normal haemoglobin levels after any necessary top-up transfusions in early infancy. More detailed neurological and developmental assessments are reported in some of the recent studies6-l09 22 and are comparable with follow-up studies on children with neonatal hyperbilirubinaemia (e.g.23). No attempt at controlled studies has been made, the inherent difficulties in selecting adequately matched controls being obvious. The Table shows broad agreement between most of the follow-up studies, with around 90 per cent of the children seen being developmentally, intellectually and neurologically ‘nor- mal’, and a relatively small number (around 4 to 5 per cent) having severe sequelae. Two of the studies69 9 show a larger number with minor neurological or developmental deficit, and this aspect demands further investigation. As expected in a group of children whose bilirubin was carefully monitored and controlled in the neonatal period, there are very few deaf children. Further studies are obviously desirable and are in progress.

The advent of the rhesus immunisation programme, initially for high-risk pregnancies

529

DEVELOPMENTAL MEDICINE A N D CHILD NEUROLOGY. 1974, 16

TABLE Summary of findings in several follow-up studies

Gregg and

Walker" HutchinsonLo 15 - 1

Francini et a/.6 Girling r t a/.' Whitfield i't oI.8

16 26 50

Peniche r t rrl.y 18

Richings'" 19 Holt et rr1.92 44 Trippzi 46

__-__ __ Tota1.r 272

3-39 1 9-? 2 (2) 3 (2)

'? I

6-60 - ?

48-96 1 I 3 4 8 1

48-90 1 ( I ) 2 ( I )

6 (4) 12 (4)

2 5

I -

1 I child had fits 3

13 4 4 *Otitis media

2 deaths: 1 cot death at home; 1 hydroceph. and myelomeningocele

7 Onlv 18 of 54 infants seen for follow-up

2 2 1 1

2 2 4 1 cot death at home

-

6 ( 2 ) 15 16(1) 8 39

t Numbers in parentheses indicate that they are included in another column of the Table

but now available to all at risk in the U K , is proving extremely effective in the prevention of new patients becoming sensitised to the rhesus-D antigen. Thus the number of patients who will need intrauterine transfusions must decrease, though other factors, such as different types of Rh and non-Rh iso-immunisation, previous sensitisation during pregnancy or during an abortion, and a higher rate of referral, mean that most centres practising this technique can expect a substantial number of new patients for several years to come.

The Hospital for Sick Children. Great Ormond Street, London W C l N 3JH.

JOHN TRIPP

REFERENCES I . Liley, A. W. (1961) 'Liquor amnii analysis in the management of pregnancy complicated by rhesus

2. Liley, A. W. (1963) 'Intrauterine transfusion of foetus in haemolytic disease.' British Medical Journal, 2,

3 . Walker, W. (1971) 'Haemolytic disease of the newborn.'In Gairdner, J., Hull, D. (Eds.) Recent Advances

-1. Queenan, J . T. (1969) 'Intrauterine transfusion: a co-operative study.' American Journal of Obstetrics

5 . Bowman, J . L., Friesen, R. F., Bowman, W. D. (1969) 'Fetal transfusion in severe Rh iso-inimunisation.'

6. Francini, A. M., Cattaneo, F., Marini, A., Dambrosius, F., Caccamo, M. L. (1971) 'Follow-up study of

5 30

sensitisation.' Atnericart Joirriial of Obstetrics and G.vneco/ogj), 82, 1359.

1 107.

in Pacdiatrics. London: Churchill. p. 119.

and G.ynecology, 104, 397.

Journal of tile American Medical Associarion, 207, 1101.

intrauterine transfused infants.' Antiali di Osretricia e Ginecologia, 92, 617.

ANNOTATIONS

7. Girling, D. J., Scopes, J. W., Wigglesworth, J. S. (1972) ‘Babies born alive after intrauterine transfusions for severe rhesus haemolytic disease.’ Journal of Obstetrics and Gynaecology of the British Common- wealth, 79,565.

8. Whitfield, C. R., Thompson, W., Armstrong, M. J. (1972) ‘Intrauterine transfusion for severe rhesus haemolytic disease.’ Journal of Obstetrics and Gynaecology of the British Commonwealth, 79,931.

9. Peniche, F. A,, Roblero, E. J., Gutiemez, L. S., Aguyo de la PeAa, A. M. (1973) ‘Evaluacion a largo de niiios transfundidas in-utero.’ Ginecologia y Obstetricia de Mexico, 33, 157.

10. Richings, J. (1973) ‘Later progress of infants who received transfusions in utero for severe rhesus haemoly- tic disease.’ Lancet, 1, 1220.

1 I . Walker, W. (1971) ‘Paediatric aspects of intrauterine transfusion.’ Annuli di Ostetricia e Ginecologia, 92, 602.

12. King-Lewis, P. A., Gardner, S. D. (1969) ‘Congenital cytomegalic inclusion disease following intrauterine transfusion.’ British Medical Journal, 2, 603.

13. Cohen, F., Zuelzer, W. W., Kadowaki, J., Thompson, R., Kennedy, D. (1965) ‘Temporary persistence of replizating donor cells after intrauterine transfusions.’ Journal of Pediatrics, 67, 937.

14. Naiman, J. L., Punnett, H. H., DestinB, M. L., Lischner, H. W. (1966) ‘Yy chromosomal chimaerism.’ Lancet, 2, 590.

15. Jones, W. R. (1968) ‘Immunological aspects of intrauterine transfusion.’ British Medical Journal, 3,280. 16. Nuzzo, F., Danibrosio, F., Marini, A., de Carli, L. (1971) ‘Chromosomal chimaerism in a patient trans-

fused in utero.’ Annuli di Ostetricia e Ginecologia, 92, 615. 17. Holman, C. A., Karnicki, J. (1973) Personal communication. 18. Davies, P. A. (1973) Personal communication. 19. Lucey, J. F. (1971) ‘Current problems of haemolytic disease.’ Annuli di Ostetricia e Ginecologia, 92, 588. 20. Gregg, G. S. , Hutchinson, D. L. (1969) ‘Developmental characteristics of infants surviving fetal trans-

fusion.’ Journal of the American Medical Association, 209, 1059. 21. Hey, E. N. (1973) ‘Hypoglycaernia in haemolytic disease of the newborn.’ Archives of Disease in Child-

hood, 48, 79. 22. Holt, E. M., Boyd, I. E., Dewhurst, C. J., Murray, J., Naylor, C. H., Smitham, J. H. (1973) ‘Intrauterine

transfusion: 101 consecutive cases treated at Queen Charlotte’s Maternity Hospital.’ British Medical Journal, 3, 39.

23. Johnson, W. H., Angara, V. A., Baumal, R., Hawke, W. A., Johnson, R. H., Keet, S., Wood, M. (1967) ‘Erythroblastosis fetalis and hyperbilirubinaemia. A five-year follow-up with neurological, psychologi- cd and audio-metric evaluation.’ Pediatrics, 39, 88.

24. Tripp, J. H. In preparation.

COLLAGEN DEFECTS IN GENETIC DISORDERS OF CONNECTIVE TISSUE

IT has long been suspected that the basic defect in certain heritable disorders of connective tissue is an abnormality in the structure of collagen1. The major disorders in this category of disease of collagen are the Marfan and Ehlers-Danlos syndromes, osteogenesis imperfecta and homocystinuria. The evidence that originally suggested a defect in collagen in these various disorders was mainly circumstantial, stemming from such abnormal physical properties of the affected tissues as low tensile strength or poor structuring of the collagen fibres. A defect in the cross-linking of the collagen molecules was often inferred1. However, only in the last year or two have the putative molecular defects of collagen begun to be defined biochemically, and we now know the basic molecular lesion in two sub-types of the Ehlers-Danlos syndrome.

The Ehlers-Danlos syndrome is a generalised disorder of connective tissue and has been classified into as many as seven sub-types2. The first collagen defect to be defined biochemic- ally was identified in a study of two sisters, nine and 12 years of age, who presented with a similar clinical picture of severe scoliosis, recurrent joint dislocation and hyperextensible skin and joints3. Collagen in skin biopsies from the patients was more soluble in denaturing solvents than that from controls, and had a markedly reduced content of hydroxylysine on amino acid analysis (5 per cent of normal). The hydroxylysine content of collagen was also reduced to a lesser extent in samples of fascia and bone, but not significantly in cartilage.

531