600

SCREENING FOR NEURAL-TUBE DEFECTS

SiR,—The DHSS Working Group on Screening for Neural-tube Defects’ has recently produced its report. Among itsrecommendations is one that maternal serum alpha-fetoprotein(AFP) assays "should be performed only in laboratories witha large workload (for example 400 assays per week, with exten-sion to 800 assays per week in emergency)". We disagree thatsuch a large workload is necessary, or that a workload of "lessthan 100 per week can be dangerous".The working group felt that smaller workloads would lead

to technical deficiencies and difficulties in the construction ofnormal ranges. This is not borne out in practice; satisfactoryresults have been obtained from laboratories with smaller

workloads, and the results from some have been published "*

Certainly a workload can be too small, although a lower limitis hard to define. An international workshop sponsored by theU.S. National Institute of Child Health and Human Develop-ment, which met in 1978, concluded that a reasonable mini-mum workload would be tests on 50 women per week. More-over there are disadvantages in performing AFP assays on alarge scale5 and the size of workload is probably best judgedin relation to local conditions.The DHSS report also states that a screening laboratory

"must possess considerable expertise in radioimmunoassay ofAFP, best demonstrated by acceptable performance in theexternal national quality control scheme for this assay over aperiod of at least six months before a full screening service isoffered". This is, in our view, an unreasonable recommenda-tion since there is no evidence to show that laboratories that

participate in centrally organised AFP quality-control schemesachieve, as a result, a lower screening false-positive rate andhigher detection rate than those which do not. There is also nogeneral agreement regarding the criteria by which assay per-formance should be assessed, and if participation is linked tothe use of recommended standards, reagents, or technical pro-cedures this may restrict development. If central quality-con-trol schemes are to be compulsory a case needs to be made thatthe benefits are likely to outweigh the disadvantages.I.C.R.F. Cancer Epidemiology and Clinical

Trials Unit,Radcliffe Infirmary,Oxford

HOWARD CUCKLENICHOLAS WALD

Department of Human Genetics,Western General Hospital,Edinburgh DAVID BROCK

SIR,-Pregnant women confronted with the informationthat their serum a-fetoprotein (AFP) is raised are bound to ex-perience acute anxiety. At the same time they have to decidewhether to agree to abortion should fetal abnormality be con-firmed, and whether to permit their infant to be exposed to therisks of diagnostic amniocentesis, estimated by a MedicalResearch Council study6 to include an increased fetal loss of1-1-5% and a similar increase in certain types of major infantmorbidity. Against this background the Working Group onScreening for Neural Tube Defects’ firm recommendation thatwomen should be counselled fully and given the chance to opt

1. Report by the Working Group on Screening for Neural Tube Defects. Lon-don: Department of Health and Social Security, 1979.

2. Brock DJH, Scrimgeour JB, Steven J, Barron L, Watt M. Maternal plasmaalpha-fetoprotein screening for fetal neural-tube defects. Br J ObstetGynœcol 1978; 85: 575

3. Wald NJ, Cuckle HS, Boreham J, et al. Antenatal screening in Oxford forfetal neural-tube defects. Br J Obstet Gynœcol 1979; 86: 91-100.

4. Woolfson J, Holt EM, Whyman AE, Mabbs DV. Maternal serum alpha-feto-protein screening in a provincial Health District. Brit J Obstet Gynœcol1979, 86: 87-90.

5. Brock DJH, Wald NJ, Cuckle H. Organisation of maternal serum-&agr;-fetopro-tem screening for fetal neural-tube defects. Lancet 1977; i: 700.

6. Medical Research Council Working Party on Amniocentesis. An assessmentof the hazards of amniocentesis. Br J Obstet Gynœcol 1978; 85: suppl 2,1-41.

into the screening programme before blood is taken, is to be

warmly welcomed. The practice of putting the onus on the pa-tient to opt out of the scheme and of only fully counselling herafter the serum AFP level has been found to be raised, cansurely no longer be condoned.

’

The cautious approach of the working group to any rapidexpansion of the screening programme is also wise. Much in-formation is still required if we are to assess properly theadvantages, disadvantages, and costs of screening. Further-more, the data base on which many current estimates havebeen made continues to change rapidly in two ways. First, thenatural incidence of CNS malformations appears to have beendeclining in the U.K., and elsewhere, since the 1950s.Between 1973 and 1978 alone there was a 22% decline in thenotification rate in the U.K. The explanation may lie in im-proved nutrition. Indeed, if the exciting observations by Pro-fessor Smithells and his colleagues (Feb. 16, p. 339) on the pre-vention of neural tube defects by periconceptional vitaminsupplementation are confirmed then spina bifida may largelybecome a disease of the past and make prenatal screening forthis condition unnecessary. The second important change tak-ing place during the last decade has been the development ofa more conservative medical and surgical approach to themanagement of the severely handicapped child at birth. Thus,the working group’s report reveals that while 50% of infantsborn alive with CNS anomalies in 1969 were still living at theage of 5, the figure for the 3-year survival of infants born in1975 was only 30%. An unpublished survey of five Englishcounties in 1977 revealed that the proportion of survivorsamong the infants with severe handicap due to open spinabifida was actually very considerably smaller. These two trendscontinue to reduce the potential benefit of prenatal screeningand make the associated risks and anxieties less acceptable.

In discussing the financial implications of a national screen-ing programme, the report is on less sure ground. For example,the cost of a mother’s extra visit to the antenatal clinic for

counselling and blood testing is rated at a mere 63 p. Nor isthere any mention of the cost of examining any availableamniotic fluid for chromosomal disorders. Surely, it would beunethical not to do so, especially after the fetus had beenexposed to the risks of amniocentesis? Considerations such asthese take on greater significance in the light of the D.H.S.S.health notice HN(79)116 warning that no additionalresources will be made available for any developments in thescreening programme.

I would like to end with a plea that, in future, monitoringthe outcome of screening studies should not only be concernedwith the incidence of neural tube defects and their detectionbut also should investigate the impact that the programme hashad on the mothers themselves, especially those unfortunateenough to have had raised serum AFP levels. I know of womenwho have found the news that their level was high and theperiod of uncertainty that followed so harrowing, that theyhave vowed never to be screened again. How common is thissort of experience?

Department of Child Health,University of Bristol,Southmead Hospital,Bristol BS10 5NB PETER M. DUNN

VANCOUVER WOES

SIR,-The desolateduet from Glasgow (March 1, p. 486)must have touched the hearts of all authors; but a doughtyfighter like Professor Lennox can cleave a way for his secretarythrough "a coterie of clinical editors",9 B.C., CiBa, or ELSE.

7. Rogers SC, Wilkins J. Congenital malformations in Europe in war andpeace. Health Trends 1976; 8: 21.

8. Note. Declining incidence of CNS malformations. Lancet 1979; ii: 1387.9. O’Connor M. Typing reference lists. Lancet 1978; ii: 1373.

601

Many years ago Elsevier published a book on submicro-scopic morphology in which the list of references had the usualauthor(s), date, abbreviated journal title, volume, and page,but instead of the title, there were two or three words to indi-cate what it was in the article that was relevant to the book’stheme. I am sure that Professor Lennox could characterise the

significance of that paper on paraphlogistons in one or twofour letter words.

I have encouraged authors of theses working in my depart-ment to adopt this Elsevier technique, and it has met with theapproval of examiners, but would-be authors, hesitant to

annoy publishers or editors, preferred to take the easy way andcollaborate.

However, Clive Taylor and I have "in press" a book, unra-velling, we hope, some of the mysteries of the reticular maze;the publishers were agreeable to the Elsevier technique for thereferences, so the experiment may be interesting.

I agree that a Widdicombe Fair of authors can be a

nuisance-a paper of three pages to which we have referred,carried a rugby team of authors-but since it is usually impos-sible to determine who really did the work, I am unwilling togive the credit to Senor Etal or Herr Undsoweiter.When Professor Lennox has satisfied the publisher now

snapping at his heels, perhaps he would lead a trahison desclercs or take part in a performance of "Little Bernard and theStruggle against the Eunuchs"; many would support him.

Chaucer’s House,Woodstock, Oxfordshire OX7 1SP A. H. T. ROBB-SMITH

SIR,-I agree with Professor Lennox, especially with regardto the demand for the number of the last page of a reference.I am unable to think of any reason for this: it is nothing buta nuisance for writers. Is it thought that the longer a paper isthe better it is likely to be?

’. -

8 Harley Road,Sheffield S11 9SD RONALD ILLINGWORTH

MYRINGOTOMY FOR ACUTE OTITIS MEDIASIR,-Dr Cooper and his colleagues (Feb. 23, p. 418) report

a case of acute otitis media with a fatal outcome, probably dueto a brain abscess. They stress and discuss in detail the antibi-otic treatment of acute otitis media which they consider tohave been started too late in this case. However, they do notmention a treatment which carries fewer risks, acts more

quickly on fever and pain, and is cheaper. It is based on thecenturies old and universal principle of medical, or rather sur-gical, care-ubi pus, ibi evacua. In my opinion, myringotomyis the best way to treat acute otitis media not accompanied byprofuse middle-ear discharge. I estimate that more than 90%of the 10 000 or so such myringotomised ears treated by mein the Netherlands recovered without any antibiotic treatment.I usually prescribe antibiotics only when fever and/or pain donot subside within two days-or when the condition is accom-panied by other infections such as pneumonia or meningitis.My experience in East Africa suggests that children with

meningitis recover more quickly when treated with myringo-tomy and antibiotics than with antibiotics alone. On anatomi-cal grounds this experience-and, perhaps, Cooper’s case-isunderstandable, since usually only a few millimetres of bone,penetrated by lymph vessels, separate the meninges from themiddle ear. Any relief of pressure of the middle ear fluidsdiminishes the risk of bacteria spreading to the meninges.My impression is that the policy described by Cooper et al.

may well be representative of that of many doctors treatingacute otitis media in the U.K., U.S.A., and elsewhere. Mightit not be worth-while for a group of paediatricians, ENT sur-geons, epidemiologists, bacteriologists, and historians to com-

bine to explain why, in two neighbouring countries like theNetherlands and the U.K., we find such a fundamental differ-ence in the treatment of such a common and serious condition?The usual treatment in the Netherlands consists of myringo-

tomy where there is an abnormal (not necessarily bulging)drum in a child with either earache, dyspepsia, fever, or men-ingeal symptoms, or a combination of them, and with no clearmiddle-ear discharge. Is that adequate or not? I can assure

paediatricians and general practitioners that myringotomy isno more difficult or risky than venepuncture, and that withlocal anaesthesia it is less painful than intramuscular penicillin.

Medical Faculty,Free University,Amsterdam, Netherlands J. WIND

CELLULAR EXPRESSION OF WISKOTT-ALDRICHALLELE

SIR,-Gealy et al.’ concluded that selection against the Wis-kott-Aldrich allele took place among platelets and T-lympho-cytes only, and not among other peripheral blood cell types in

. their patient. They found hemizygous expression of glucose-6-phosphate dehydrogenase (G6PD) isoenzyme B in plateletsand T-lymphocytes and heterozygous expression of G6PD iso-enzymes A and B in erythrocytes, granulocytes, monocyte/macrophages, and non-T-lymphocytes of the WAS carrier. Theratio of isoenzyme A to B in these latter cell types was approxi-mately 15:85, a result ascribed by Gealy et al. to extreme

lyonisation or to "WAS-dependent selection during earlyembryogenesis which caused non-random X-inactivation".

Extreme lyonisation is thought to be rare in man.2 Non-ran-dom X-inactivation is also unlikely, as Gealy et al. point outin their discussion, and they go on to conclude that "The moststraightforward explanation for the findings in this WAS car-rier is that normal random X-inactivation is followed by separ-ate WAS-defect-dependent selection events occurring in post-thymus lymphocytes and platelets or platelet precursors". Ifthis were so, normal random X-inactivation would be expectedto affect all the patient’s cell types, including her erythrocytes,granulocytes, monocyte/macrophages, and non-T-lympho-cytes. How, then, can we account for the skewing of A:B iso-enzyme ratios observed within these cell types?We feel that a more likely explanation is -that, after random

X-inactivation, selection against cells expressing the WASallele took place among all periperal blood cell types investi- _

gated. This selection seems to have been more pronouncedamong platelets and T-lymphocytes than among other peri-pheral blood cell types; however, selection need not invariablybe absolute among all cell types in an individual. Indeed,among females heterozygous for Lesch-Nyhan syndrome,3,4 in-continentia pigmenti,4 or WAS,5.6 selection, although substan-tial, does not always result in the complete elimination of cellsof mutant phenotype. Furthermore non-haemopoietic tissueswere not examined in this patient. Consequently, we feel that

1. Gealy WJ, Dwyer JM, Harley JB. Allelic exclusion of glucose-6-phosphatedehydrogenase in platelets and T-lymphocytes from a Wiskott-Aldrichsyndrome carrier. Lancet 1980; i: 63-65.

2. Gartler SM. X chromosome inactivation and selection in somatic cells. FedProc 1976; 35: 2191-94.

3. Albertini RJ, DeMars R. Mosaicism of peripheral blood lymphocyte popula-tions in females heterozygous for the Lesch-Nyhan mutation. BiochemGenet 1974; 11: 397-411.

4. Migeon BR. Selection and cell communication as determinants of femalephenotype. In: Russell LB, ed. Genetic mosaics and chimeras in mammals.New York: Plenum, 1978.

5. Carroll AJ, Prchal JT, Prchal JF, et al. Hemizygous expression of glucose-6-phosphate dehydrogenase in leukocytes and platelets of a heterozygote forthe Wiskott-Aldrich syndrome. Am J Hum Genet 1979; 31: 41A.

6. Prchal JF, Prchal JT, Carroll AJ, et al. Wiskott-Aldrich syndrome (WAS)..An effect of WAS abnormalities on proliferation of hematopoietic precur-sors sludied by G-6-PD cell markers. Blood 1979; 54: suppl 1,159A.