SCREENING FOR NEURAL-TUBE DEFECTS

373 assessed. We would be grateful to receive other patients with pineal tumours.

serum

samples from

Department of Medicine, General Hospital, Birmingham B4 6NH

S. G. BARBER

University of Bradford

J. A. SMITH

Dudley Road Hospital, Birmingham

D. H. COVE

Women’s

S. C. H. SMITH

Hospital, Birmingham

Queen Elizabeth Hospital, Birmingham

D. R. LONDON

SMOKING, OBESITY, AND THE MENOPAUSE SiR,—Two reports in The Lancet12 have confirmed

among

non-smoking women over age 50. Among the 500 studied, hysterectomy had been done, for each decade age 50, with similar frequency among non-smokers and

women

my

observations3 and those of Hammond4 that habitual cigarette

smoking is associated with an earlier natural menopause. Mattison and Thorgeirsson5 have suggested that this change may be due to chemicals absorbed from tobacco smoke, deposited in ovarian tissue and there modified by ovarian enzymes into agents known to be carcinogenic. I suggest that a different mechanism may contribute to the relation between smoking and early menopause-namely, the relative lack of obesity among smokers.

Non-smokers are more likely than smokers to be obese6-8 and obese women tend to have a later menopause.9 To determine whether early menopause was independently related to both smoking habits and lack of obesity, I analysed data for 500 consecutive women aged 40-69 interviewed in my general internal medicine practice. 236 had had a natural menopause. The other 264 women were excluded because they were premenopausal, had had ovarian or uterine surgery, or had received supplemental hormones for treatment of menopausal symptoms, thereby obscuring the onset of their natural menopause. Weights were compared with those recommended for height in standard life-insurance tables for women of medium build. A woman with a smoking history of 5 pack years before age 45 was defined as a cigarette smoker. Smoking and obesity were independently associated with age at menopause (see table). Some of the difference between the average menopausal age of smokers and non-smokers will be due to the greater tendency of non-smokers to be obese and of smokers to be underweight. In addition, however, significant differences between smokers and non-smokers similarly obese persisted, an observation compatible with the hypothesis of Mattison and Thorgeirsson. It seems likely that the delayed menopauseof obese women is related to the production of oestrogen by adipose tissue which can transform an adrenal steroid (androstenedione) with little oestrogen activity into oestrone, a potent cestrogen.10 11 The much greater production of oestrone by obese menopausal women has been offered as an explanation for the greatly prolonged presence, among them, of cestrogenic effect in vaginal smears and urinary sediment12 13 as well as their inherent protection against osteoporosis.3 This seems likely to explain the delayed menopause of obese women as well. Of additional interest is the high frequency of hysterectomy Jick, H., Porter, J., Morrison, A. S. Lancet, 1977, i, 1354. Bailey, A., Robinson, D., Vessey, M. ibid. 1977, ii, 722. Daniell, H. W. Archs intern. Med. 1976, 136, 298. 4. Hammond, E.C. Archs envir. Hlth, 1961, 3, 146. 5. Mattison, D. R., Thorgeirsson, Lancet, 1978, i, 187. 6. Higgins, M. W., Kjelsberg, M. Am. J. Epidem. 1967, 86, 60. 7. Khosla, T., Lowe, C. R. Br. med. J. 1971, iv, 10. 8. Comstock, G. W., Stone, R.W. Archs envir. Hlth. 1972, 24, 271. 9. MacMahon, B., Worcester, J. Age at Menopause: Natn. Center Hlth Stat., series 11, no. 19. Washington, D. C., 1966. 10. Schindler, A. E., Ebert, A., Friedrichs, E.J. clin. Endocr. 1972, 35, 627. 11. Grodin, J. M., Siiteri, P. K., MacDonald, P. C. J. clin. Endocr. Metab. 1973, 36, 207. 12. DeWaard F., Oettle, A. G. Cancer. 1965, 18, 450. 13. DeWard, F., Schwarz, F. Acta Cytol. 1964, 8, 449. 1. 2. 3.

AVERAGE AGE AT NATURAL MENOPAUSE ANALYSED BY HISTORY OF CIGARETTE SMOKING AND PRESENCE OF OBESITY

before smokers and for obese and non-obese. After age 50, however, while 40% of women were smokers, all but 3 of the 29 who had a hysterectomy were non-smokers, and most of these were over-weight. Most of these operations had been done because of erratic or excessive menstrual bleeding which, seems likely to reflect prolonged oestrogen effect among these women. 2020 Court Street, Redding, California 96001, U.S.A.

HARRY W. DANIELL

SCREENING FOR NEURAL-TUBE DEFECTS

SIR,-In their comments on our article on voluntary maternal serum-alpha-fetoprotein (A.F.P.) screening for fetal neuraltube defects, Dr Wald and colleagues (July 22, p. 216) point out that there are no material inconsistencies between our study and the U.K. collaborative study.1 Ours was the largest single group of patients with neural-tube defects contributed to the U.K. study and we certainly did not intend to imply that there were important differences of fact. The major difference relates rather to screening policy. However, we would like to clarify a misunderstanding about the classification of closed neural-tube defects which tends to give a misleadingly low estimate of the screening sensitivity for all spina-bifida pregnancies in the West of Scotland study. The 14 closed neural-tube defects encountered in phase n of our study can all be unambiguously defined as closed lesions because they were covered at birth either by full-thickness skin or by opaque fibrous tissue and keratinising squamous epithelium. There were 2 iniencephalics with closed posterior spina bifida and hydrocephalus (one of which had to be decompressed to allow delivery), 5 meningoceles, 1 encephalocele, 2 myeloceles (one of which was ruptured during delivery), and 4 fetuses with spina-bifida occulta each identified at birth because of an overlying hairy noevus. Although we included the latter 4 with the other closed defects, they would not normally be classified as spina-bifida cystica malformations and should perhaps have been excluded. If they are excluded, the sensitivity of our test for all spina-bifida pregnancies in phase n is 14 of 26 (53.8%) and not, as Wald suggests, 14 of 30 (47%). What is clear, however, is that none of the closed lesions in our series could have conceivably been classified as open and missed, so that the 81.2% sensitivity quoted for open spina bifida is a true estimate which we believe compares favourably with the 64% sensitivity estimated from the U.K. study by Wald and colleagues. Admittedly, the numbers in both series are small and the confidence limits wide, and it remains to be seen which will prove the more reliable estimate. We feel that our study may have an advantage in that particular attention has been paid to the accurate estimation of gestation by obstetric ultrasound in both patients and controls, which may not have been equally available to the other 18 centres contributing to the U.K. study. 1. U.K. Collaborative

Study

on

Alpha-fetoprotein

Defects. Lancet, 1977, i, 1323.

in

Relation

to

Neural-tube

374 Dr Wald notes that the proportion of closed in the West of Scotland series (30.0% in

spina-bifida phase i and 38.5%, after excluding the occult lesions, in phase n) is much higher than the 17% reported to the U.K. study. We believe these findings are typical of the West of Scotland; they were confirmed in an independent series of 704 pregnancies in

that similar progress could have been achieved by withholding the programme until the ancillary services were developed to a point able to cope with the screening policy suggested by the U.K. study.

which we tested the amniotic A.F.P. because the mothers had had previous children with neural-tube defects. In this series, 12 anencephalics and 13 open spina-bifida lesions were detected and the fetus was aborted, and there were 7 closed neural-tube defects among those pregnancies that continued to delivery-i.e., the proportion of closed to open spina-bifida defects was 35%. Although the West of Scotland may have a higher than average incidence of closed neural-tube defects, it also seems possible that in the U.K. study (which was mainly retrospective), closed lesions were underreported. The problem of open and closed spina bifida seems to have confused Mrs Raab (July 22, p. 217), who rightly expects a screening programme to uncover approximately similar numbers of anencephalics and spina-bifida cases. She criticises the adequacy of our follow-up on the grounds that there were more cases of anencephaly than spina bifida in phase n, but this is not so when open and closed lesions are added. There were (excluding the-occult lesions) 27 anencephalics, 16 open spina bifidas, 8 closed spina bifidas, and 2 iniencephalics with closed spina bifida in 11 585 pregnancies. This gives an incidence of 4.6per 1000 births, which is what one expects in the West of Scotland remembering that women with a previous history were excluded from the study population. Mrs Raab also criticises our estimate of the sensitivity of the test, and indicates that the true detection-rate for open spina bifida should have been 75% rather than 81.2%’, because 1 case was misreported at screening. However, we do not mention detectionrates in our study and define the sensitivity of the test in a manner comparable to that used in the U.K. study-namely, as the proportion of pregnancies with open neural-tube defects in which the first serum-A.F.P. level is above the intervention

Department of Medical Genetics, Royal Hospital for Sick Children, Glasgow G3 8SJ

M. A. FERGUSON-SMITH

Radioimmunoassay Unit, Biochemistry Department, Royal Infirmary, Glasgow G4 0SF

J. G. RATCLIFFE

cases

point. Although the U.K. collaborative study discusses the factors which might influence the selection of cut-off levels in antenatal screening, the reader of that report is left with the impression that the best time for detecting open spina bifida is at 16-18 weeks of pregnancy, using 2.5times the normal median serum-A.F.P. as the cut-off. It is suggested that with such a cutoff, 3% of unaffected singleton pregnancies would have falsepositive results, and a patient with a positive result would have a 1 in 10 chance of having a fetus with a neural-tube defect. The apparent recommendation is so strong that at least three screening programmes in the U.K. are believed to use a similar policy, so that about 2% of all screened patients proceed to amniocentesis after revision of gestation. We strongly believe that this is not the best way to introduce a maternal serum-A.F.P. screening programme to the U.K., because there are at present insufficient personnel experienced in obstetric ultrasound and amniocentesis to cope with such a demand. We favour a more conservative approach at the outset, using a higher cut-off point and a lower amniocentesis-rate. We have shown that this policy has led to the avoidance of 96.3% of anencephalic and 56.2% of open-spina-bifida births in our study population, with an amniocentesis-rate of 0.63% (among which 46.6% had a fetal abnormality), without the loss of one normal pregnancy which could be shown to be the direct result of screening. As expertise in obstetric ultrasound grows and as teams experienced in safe amniocentesis are established, the intervention point can be safely lowered to the theoretical optimum so that the sensitivity of the screening test is increased and an even higher proportion of open-spina-bifida births are avoided. We have found that the gradual introduction of screening in our area has been welcomed by our obstetric colleagues who have responded by rearranging their clinic bookings and by helping to develop the ancillary services such as counselling, ultrasonography, and amniocentesis. It is unlikely current

ETHICAL PROBLEMS OF SCREENING FOR NEURAL-TUBE DEFECTS

SiR,—The general spirit of the findings of the working party on the ethical problems of routine screening is very much that already considered correct and proper and practised by most caring obstetricians. Counselling is very difficult indeed on some occasions. Proper advice may be given but we mostly find that the mother concerned has already made a decision, even in the abstract, as to how she would view the birth to herself of an abnormal child. The opportunity to talk about and discuss it is almost as much as we can offer. The right to contract out is always, of course, implied or offered, provided the mother is fully aware of the implications of the decision, either way, she is making. Although an investigation is offered and a test is available the decision at all stages is still that of the mother, father, and the obstetrician, jointly. University of Obstetrics and Gynaecology, Ninewells Hospital, Dundee DD1 9SY

JAMES WALKER

RAISED AMMOTIC-FLUID ALPHA-FETOPROTEIN IN A CASE OF NUCHAL BLEB

SIR,-Several investigators have reported the association of raised concentrations of amniotic-fluid (A.F.) alpha-fetoprotein (A.F.P.) with Turner syndrome (45, XO) fetuses. The mechanism proposed to explain this rise is the leakage of fetal serum components from the fluid-filled cervical pouches (cystic hygromata) found in these fetuses. We have diagnosed a somewhat similar anomaly consisting of a familial midline nuchal bleb in a chromosomally normal 21-week fetus by ultrasonography and amniography. The concentration of A.F. A.F.P. was abnormally high, suggesting that the bleb may be the site of leakage of A.F.P. into theA.F.. A healthy 26-year-old White female was referred for amniocentesis 19-20 weeks into her fourth pregnancy. Her history included two pregnancies yielding stillborn female fetuses at 32 and 35 weeks. Both were reported to have had an occipital encephalocele although no pathological studies were done; Ultrasonographic examination revealed polyhydramnios and an approximately 21-week fetus with a saccular structure at the occiput. Amniocentesis was done for chromosome analysis and for A.F.P. measurement. Amniography clearly showed a filling defect in the occipital region, extending over the base of the neck. The results of ultrasonography and amniography were interpreted to be consistent with an encephalocele and the patient elected to terminate the pregnancy. The chromosome analysis of amniotic-fluid cells revealed a normal female karyotype, 46XX. A.F. A.F.P. concentration (Dr A. Milunsky) was in the range typical of fetuses with an open neural-tube defect (258±7.6 s.D.mg/dl). The abortus had a large midline nuchal bleb which was completely closed and skin-covered, micrognathia, short neck, and a barrel-shaped thorax and abdomen. Dissection of the abortus failed to reveal the suspected encephalocele; no defect