111

fxcal fat excretion, gastrointestinal X-rays, glucose and xylosetolerance, and serum-calcium were all normal. There was

nothing to suggest malnutrition. The only likely cause of thispatient’s ansemia was, then, glutethimide, of which he had taken100-400 mg. daily for five years.Megaloblastic anaemia after taking phenytoin and pheno-

barbitone was reported in 1954.1 Since then, further cases havebeen attributed to barbiturates,z-4 primidone,° and nitrofuran-toin.1 The anxmia may be caused by interference with theperipheral metabolism of folic acid.5 The known toxic effectsof glutethimide include nausea, rashes, and habituation, andone case each of agranulocytosis and thrombocytopenia. 9In view of the chemical and pharmacological similarity ofglutethimide and phenobarbitone,10 they could well have thesame effect on erythropoiesis. Indeed, there is some structuralresemblance between all the drugs said to cause megaloblasticanaemia: barbiturates, phenytoin, nitrofurantoin, and glutethi-mide. This first report comes a long time after the introductionof glutethimide, but there was a similar interval with theanti-convulsant drugs."

I wish to thank Dr. T. R. Littler for permission to publish thiscase and for helpful criticism, and Dr. T. Gordon for interpretingthe bone-marrow smears.

DONALD PEARSON.Walton Hospital,Liverpool, 9.

FIBRINOLYSIS IN OBESITY

D. OGSTONG. M. MCANDREW.

Department of Medicine,Foresterhill,Aberdeen.

SIR,-With reference to the point raised by Dr.Chakrabarti and Dr. Fearnley (Dec. 26), 20 of the 24subjects whose observed/standard weight ratio exceeded130 were women. The mean plasma fibrinolytic activityin these women was 1.89 units, compared with a value of5-07 units in women whose weight ratio was between 80and 130.This observation is not in agreement with the finding by

Dr. Fearnley and Dr. Chakrabarti that the correlationbetween obesity and low fibrinolytic activity exists in

healthy males but not in healthy females.

POST-EXCHANGE ANÆMIA IN Rh

HÆMOLYTIC DISEASE

A. D. F. HURDLE.St. Thomas’s Hospital,

London, S.E.1.

SIR,-I should like to point out that the remark attri-buted to Hurdle and Walker 12 by Dr. Fraser and hiscoworkers (Dec. 19) that

" infants who have very active

erythropoiesis at birth are unable to produce enougherythropoietin in early life to maintain red cell productionat the in-utero level " was not a statement of fact butwas put forward as a hypothesis.There is little information on erythropoietin levels at this

age, but such as there is suggests that the infant produces anormal amount of the hormone. 13 The data were not publishedat the time of our paper. To my knowledge the cause of this’’ late " anaemia in hsmolytic disease of the newborn has notbeen established. It does seem to be the result of marrow

hypoplasia, but beyond this one cannot say. Some observa-tions on antibody levels in these cases have since shown nocorrelation between antibody titre at birth, or the persistenceof antibody, and the occurrence of this anxmia. 14

1. Badenoch, J. Proc. R. Soc. Med. 1954, 47, 426.2. Hobson, Q. J. G., Selwyn, J. G., Mollin, D. L. Lancet, 1956, ii, 1079.3. Calvert, R. J., Hurworth, E., MacBean, A. L. Blood, 1958, 13, 894.4. Chanarin, I., Laidlaw, J., Loughridge, L. W., Mollin, D. L. Brit. med. J.

1960, i, 1099.5. Chanarin, I., Elmes, P. C., Mollin, D. L. ibid. 1958, ii, 80.6. Bass, B. H. Lancet, 1963, i, 530.7. De Veber, L. L., Valentine, G. H. ibid. 1964, ii, 697.8. Raffauf, H. J. Dtsch. med. Wschr. 1958, 83, 2063.9. Kirchmair, H. Med. Klin. 1958, 53, 1683.

10. Luby, E. D., Domino, E. F. J. Amer. med. Ass. 1962, 181, 46.11. Peaston, M. J. T. Lancet, 1964, i, 1161.12. Hurdle, A. D. F., Walker, Anna G. Brit. med. J. 1963, i, 518.13. Halvorsen, S. Acta pœdiat., Stockh. 1963, 52, 425.14. Hurdle, A. D. F., Davis, J. A. Unpublished.

CLASSIFICATION OF DEVELOPMENTAL

DEFECTS

SIR,-Sir Denis Browne’s letter (Sept. 26) prompts meto write in support of his viewpoint. I have long sharedhis belief in " the Hippocratic hypothesis ... that the bodymay be moulded before birth in the way all know it to bemoulded afterwards ".

For those who believe that the rules of growth and boneformation do not apply until the magic moment the foetusbecomes a baby, it might help to put oneself in the foetal

predicament. To create this situation the ingredients andproper proportion are a 150-lb. man in the space of half abeer-barrel (71/2 lb. offcetus at term is to 800 ml. amniotic fluidas 150 lb. is to 4-25 U.S. gallons). Suppose we decide to makethe half-barrel volume in the form of a hollow ball moulded intwo halves, with a resilient rubber wall three or four inchesthick, and allow him to get inside one half before welding on theother. In this imaginary situation he has no respiratory diffi-culty, and his limbs are adjusted so as not to cause discomfortor pain. He is comfortable and at peace with the world.These are the conditions of a fcetus at term, but let us imagine

that he has been in the barrel for some time. At mid-gestation,4B/a months earlier, this 150-lb. imaginary foetus had twice theamount of space for his size-a whole barrelful-equivalent toplay about in. (Since we cannot reduce the 150-lb. man to amid-gestational proportion of the half barrel, we can picture hisrelative size by altering his containing volume.) He could evenextend his legs then; but of course his thighs were flexed, andso his feet had to be beside his head. It was not as though hewere standing. But even in those good old days, when hisimaginary mother considered him as free to run and tumble as alamb gambolling in a field of clover, he still had all the freedoma beer-barrel could offer a 150-lb. man. He was beginning togrow on the high-rising end of an exponential curve and therewas less fluid surrounding him. As his birth-date approached,the fluid was only half what it was (1800 ml.-mid-gestationalaverage).From mid-gestation onward, the surrounding wall always

resisted attempts to push it out of the spherical shape it wanted.Containing his problem-area was another muscular wall. Theorgans and parts which had occupied it completely before hehad arrived now put the pressure of their weight on himconstantly. This burden he had to bear alone, since thewall confining him had no supportive elements in it to

protect him.Any protrusion he made had to be temporary, and no pro-

trusion was possible with less than the force his whole bodycould muster for the effort. Towards term, neither a hand nora foot could be shifted except in the small part of the 20% of thetotal volume he did not occupy, and much of that 20% wasunavailable. His back and shoulders were against the wall; butbetween the wall and his sides and between the wall and his

abdomen, in the space not occupied by his folded legs, therewas fluid, and this fluid constituted the space he could use forfree space.As if this were not enough, he was compressed periodically

by board-like contractions of his environment which forced thewall back into a shape as round as it could make it by pushingdown on any inside resistance with all the strength of which itwas capable. Eventually, this strength would become greatenough (with some help from the outer wall) to free itself of allinternal resistance and expel the foetus at birth. Meanwhile thefoetus is relaxed, surrounded, warm, and well fed, and yieldswithout conflict-unable to do anything else.

Early in foetal life there had been room. For a while, evenafter limb-buds had become arms and legs, the foetus couldstretch them and swing around the umbilical axis.

Earlier still, the fluid in which the embryo had floated wasfive times its own volume-a fair-sized swimming-pool. Thiswas at the time the mother was just beginning to wonderwhether she was pregnant, and, despite the relatively greatamount of fluid in her uterus, she could not tell by looking at