1370

antigen, in the form of polypeptides, as immunogens.19 20

We cannot yet evaluate the effect of booster injections in maintaining protection against hepatitis-B virus. From our first results, the fact that HBs antibodies are still present at protective levels six months after the first injection seems to indicate that a booster once a year should be enough. The work on delayed hypersensitivity to HBs antigen, already proposed as a diagnostic test for hepatitis-B infection,21 seems to point to a means for controlling postvaccinal protection. In a hsemodialysis unit where the risk of infection remains constant, the epidemiological data reinforce the evidence that vaccination protects. No vaccinated subject gave any sign of clinical or biological hepatitis, while, during the same period, 43% of non-vaccinated patients became HBsAg-positive. No significant differences in immunological responses were observed between dialysed patients and ward staff (p=0.55). We might have expected that our patients would respond less efficiently, in view of the immune deficiency which is common in chronic renal failure. It is too early to draw any conclusions, but these results encourage us to continue our work. In any extension of vaccination to persons outside the haemodialysis unit, we must consider the association of the two major subtypes ad and ay in the preparation of the vaccine. This specific vaccination against hepatitis B could be quickly extended to all the members of the hospital (clinical wards and laboratories) as well as to other patients exposed to a high risk of infection, such as those undergoing multiple transfusions.22 Many arguments favour HB virus as a cause of liver cancer, which is widely distributed in tropical Africa.23 24 By specific vaccination against hepatitis B in areas of high endemicity for hepatitis-hepatoma, it may be possible to interrupt or even eradicate this oncogenic process, whether HB virus is the direct or an indirect agent. Such vaccination could be the first example of prevention of a potentially oncogenic viral infection. We gratefully acknowledge the help of Dr C. Milhaud and Dr M. Klein (Neurophysiology Service, Aeronautics Medical Research Centre, C.R.M.A., Paris), whose chimpanzees were used for controls; Dr A. Eyquem and Dr J. Pillot (Institut Pasteur, Paris) for biochemical and immunological controls; Dr A. M. Courouce (National Centre for Blood Transfusion, Paris), who provided subtyped sera for preparation of vaccine; and Dr K. Biziere, Mr J. Y. Sizaret, Mr J. C. Turin, and Mme F. Binet.

Requests for reprints should be addressed to P. M., Institut de Virologie de Tours, 2 bis Boulevard Tonnelle, 37000 Tours, France.

REFERENCES 1.

B. S.,

Gerstley,

HYPERTENSIVE PREGNANCY C. W. G. REDMAN

Nuffield Department of Obstetrics and Gynœcology, John Radcliffe Hospital, Headington, Oxford L.

J. BEILIN Department of the Regius Professor of Medicine, Radcliffe Infirmary, Oxford

J. BONNAR Department of Obstetrics and Gynœcology, Rotunda Hospital, Dublin

R. H. WILKINSON

Nuffield Department of Clinical Biochemistry, Radcliffe Infirmary, Oxford The relation of perinatal mortality to concentrations and bloodpressure was studied in 332 pregnant patients with hypertension. Perinatal mortality was markedly increased when maternal plasma-urate concentrations were raised, generally in association with severe preeclampsia of early onset. Plasma-urate was a better indicator than blood-pressure of prognosis for the fetus. Maternal hypertension, even severe, without hyperuricæmia, was associated with an excellent prognosis for the fetus. Conversely, when maternal hypertension was mild and hyperuricæmia was severe, the prognosis for the fetus was poor. These findings suggest that, in terms of fetal health, changes in renal handling of urate may be a more important feature of pre-eclampsia than the hypertension.

Summary

plasma-urate

Introduction

hypertension during pregnancy can have It is either a long-term medical probgeneral lem during which pregnancy has supervened; or it is a specific problem of pregnancy (pre-eclampsia, toxaemia). Chronic maternal hypertension persists after delivery, whereas pre-eclamptic hypertension does not. The two MATERNAL

two

causes.

conditions may coincide because chronic maternal hypertension is a major predisposing factor to preeclampsia, so that mixed syndromes of pre-eclampsia

superimposed on pre-existing hypertension are common. Pre-eclampsia always implies an abnormal pregnancy, so that fetal health is invariably threatened to some degree, whereas chronic hypertension complicating an

B.

J. S., Hungerford. D. A., et al. Ann. intern. 1967, 66, 924. 2. Krugman, S., Giles, J. P., Hammond, J. J. infect. Dis. 1970, 122, 432. 3. Soulier, J. P., Blatix, C., Courouce, A. M., et al. Am. J. Dis. Child. 1972, 123, 429. 4. Courouce, A. M., Delons, S., Soulier, J. P. Am. J. med. Sci. 1975, 270, 375. 5. Iwarson, S. Ahlmen, J., Eriksson, E., et al. ibid. p. 385. 6. Hilleman, M. R., Buynak, E. B., Roehm, R. R., et al. ibid. p. 401. 7. Purcell, R. H., Gerin, J. L. ibid. 395. 8. Zuckerman, A. J. Nature, 1975, 255, 104. 9. Zuckerman, A. J. in Liver Diseases in Infancy and Childhood (edited by S. R. Berenberg); p. 197. Leiden (in the press). 10. Millman, I., Hutanen, H., Merino, F., et al. Res. Commun. chem. Path. Pharmac. 1971, 2, 667. 11. Gerin, J. L., Holland, P. V., Purcell, R. H. J. Virol. 1971, 7, 569. 12. Goudeau, A., Houwen, B., Dankert, J. Lancet, 1974, ii, 1325.

Blumberg,

PLASMA-URATE MEASUREMENTS IN PREDICTING FETAL DEATH IN

could be attractive

Med.

13. Neurath, A. R., Prince, A. M., Lippin, A. Proc. natn. Acad. Sci. U.S.A. 1974, 71, 2663. 14. Hopf, U., Meyer zum Buschenfelde, K. H., Freudenberg, J. J. clin. exp. Immun. 1974,16, 117. 15. Lee, W. M., Reed, W. D., Mitchell, C. G., et al. Br. med. J. 1975, i, 705. 16. Houwen, B., Goudeau, A., Dankert, J. J. Immun. Methods, 1975, 8, 185. 17. Axen, R., Porath, J., Ernback, S. Nature, 1967, 214, 1302. 18. Cuatrecasas, P. J. biol. Chem. 1970. 215, 3059. 19. Zuckerman, A. J., Howard, C. R. Bull. N.Y. Acad. Med. 1974, 51, 491. 20. Howard, C. R., Zuckerman, A. J. Intervirology, 1974, 4, 31. 21. Brzosko, W. J., Kassur, B., Babiuch, L., et al. 6th International Congress of Infectious and Parasitic Diseases, Warsaw. 1974, vol. II, p. 227. 22. Tech. rep. Ser. Wld Hlth Org. 1973, no. 512, p. 30. 23. Prince, A. M., Szmuness, W., Michon, J. Int. J. Cancer, 1975, 16, 376. 24. Maupas, P., Werner, B., London, W. T., et al. Lancet, 1975, Ii, 9.

1371

otherwise normal pregnancy is associated with

prognosis for the fetus. difficult It is

clinically

very

to

separate the

a

good

two

pos-

TABLE 1--CONCENTRATIONS AT DIFFERENT STAGES OF GESTATION IN HYPERTENSIVE WOMEN

sible factors in maternal hypertension. Hyperuricaemia 2 is a characteristic biochemical feature of pre-eclampsiaz known to be caused by an early tubular retention of which occurs before any measurable decrease in the glomerular filtration-rate (G.F.R.).34 The degree of hyperuricaemia reflects .the severity of the pre-eclampsia,56as well as correlating with characteristic renal biopsy changes.This paper presents data which show that plasma-urate concentrations are a simple and reliable indicator of the prognosis for the fetus in hypertensive pregnancies. Methods urate

Hypertension was confirmed in 332 pregnant patients

when

occasions 24 hours apart the systolic or diastolic presor exceeded 140 mmHg or 90 mmHg, respectively, using a London School of Hygiene sphygmomanometer designed to minimise observer bias. Patients were studied repeatedly at monthly intervals up to 28 weeks of pregnancy then at fortnightly intervals until delivery and 6 weeks postpartum. The patients do not comprise a single cohort followed throughout pregnancy since new patients entered the study up to 32 weeks of gestation and premature delivery removed other patients from the later periods of the study. 238 patients were participating in a trial of antihypertensive treatment in pregnancy, of which 117 were randomly assigned to active treatment with methyldopa. The remaining 121 patients in the trial and 97 hypertensive patients who were not in the trial only received hypertensive treatment if severe hypertension developed. This event was defined as follows: a systolic or diastolic pressure equalling or exceeding 170 or 110 mmHg, respectively, on two occasions separated by 4 hours or longer; or 180 or 120 mm Hg, respectively, on two occasions separated by at least 5 minutes. No woman received diuretics. HyperuricaEmia was never used as an indication for early fetal delivery. If continuation of the pregnancy carried a serious maternal risk due to uncontrollable hypertension, or if impending fetal death was diagnosed from placental function tests, then the patients were electively delivered prematurely.

Numbers in

parentheses indicate numbers of women studied in each period.

on two sure

equalled

TABLE II-EVENTUAL PERINATAL

Plasma-urate was assayed by the routine automated hydroxylamine method (SMA 12/60). The mean coefficient of variation in our laboratory is a little below 3% for urate concentrations of 0-2-0-4 mmo1/1. The correlation between plasma-urate concentrations and stillbirths and first-week neonatal deaths was investigated. Stillbirths were defined as fetuses born dead after the 24th week of gestation. The data were examined during six gestational periods from 20-36 weeks (table i) and 6 weeks after delivery. The mean of all plasma-urate readings for any one patient available for each period was taken as the individual urate concentration for that patient. For each period the total number of undelivered patients was divided into four groups according to their plasma-urate concentrations at that time. In each subdivision the stillbirths and neonatal deaths occurring subsequently are listed. The number of pregnancies ending within each period is also given. Plasma-urate concentrations were also compared with diastolic blood-pressure readings in relation to perinatal mortality. In this second analysis the 117 treated patients of the trial of antihypertensive treatment were excluded since treatment did not relate to the severity of the hypertension but was randomly allocated for the purposes of the trial. The remaining patients MORTALITY* BY PLASMA-URATE

All stillbirths and neonatal deaths after 24 weeks., tTotal perinatal mortality summarised includes 2 deaths occurring at 38 weeks.

*

1372 TABLE III-PERINATAL MORTALITY ANALYSED IN RELATION TO DIASTOLIC BLOOD-PRESSURE AND PLASMA-URATE CONCENTRATIONS

in mortality between groups 2 and 3 are before 32 weeks but become so thereafter.

not

significant

Discussion

hypertension in pregnancy plasmaclearly reflects the fetal prognosis. This is entirely consistent with reports that hyperuricaemia correlates with the severity of pre-eclampsia5-’ and distinguishes reliably between pre-eclampsia and simple chronic hypertension .7-9 The data also indicate that in pregnant women with hypertension, measurement of plasma-urate is a better indication of the fetal consequences of pre-eclampsia than the measurement of blood-pressure itself. In established severe pre-eclampsia the diagnosis is usually clinically evident and the elevation of plasma-urate will simply confirm the diagnosis. But since urate retention is an early feature of the disorder, plasma-urate measurement is of the greatest value where the diagnosis of pre-eclampsia is in doubt or hypertension of unknown aetiology is present. If plasmaIn the

urate

Comparison of mortality in groups 2 and 3: 20, 24, and 28 weeks no significat difference; 32 weeks p=0.002; 34 weeks p=0.005; 36 weeks p=0.02 (Fishe: exact

test).

were divided into two groups. A more hypertensive group wa defined whose diastolic pressure equalled or exceeded 110 mn Hg at any time at or preceding the period under study, or wh4 received hypotensive therapy according to the above criteria The remaining patients comprised a group with less severe

hypertension. Results rose with length of gestation anc further 6 weeks after delivery (table I). In al six antenatal periods a very high perinatal mortality wa! associated with maternal hyperuricsemia exceeding 0.3 mmol/1 (table n). Both stillbirths and neonatal death: increased to a similar extent. Conversely, particular!) after 28 weeks of pregnancy a low maternal plasma urate concentration was associated with an exceedingl) low perinatal mortality in infants of hypertensive mothers. At 28 and 32 weeks the dividing line for identifying this low-risk group was 0-24 mmo1/1; after 32 weeks it was 0.36 mmol/l. Postnatally, the only tendency for outcome to be related to plasma-urate levels was in a small group of women with very low levels and

Mean

plasma-urate

rose even

no

perinatal mortality.

After excluding those patients who were treated as part of the trial of antihypertensive treatment the patients were divided into four subgroups: by diastolic pressures above or below 110 mmHg and by plasmaurate concentrations above or below 036 mmo1/1 (table III). The highest perinatal mortality was consistently found in group i with severe hypertension combined with hyperuricaemia-the maternal group with the most severe clinical pre-eclampsia. The next highest mortality was in those with a moderate maternal diastolic pressure combined with hyperuricsemia (group 3). In contrast, group 2 with a high diastolic pressure but without extreme hyperuricaemia carried a perinatal mortality slightly above the group average at 20 and 24 weeks gestation and considerably less than the group average from 32 weeks’ gestation onwards, with no mortality at 34 and 36 weeks’ gestation. Group 4 with lower plasmaurate concentrations and less increased diastolic pressures had a relatively low mortality up to 32 weeks and an absolutely low mortality thereafter. The differences

context of concentration

urate is found to be low the outlook for the fetus is excellent. These results are contrary to reports that hyperuricxmia is not related to an unfavourable prognosis for the fetus in hypertensive pregnancies.1O 11 The reason for this discrepancy is almost certainly that in these investigations pregnancies were studied at or near full term. But the time of onset of pre-eclampsia is of great importance in determining the final outcome in the fetus because the only treatment for the disorder is delivery. Since pre-eclampsia is usually a relentlessly progressive disorder, if it starts between 24 and 30 weeks’ gestation it may readily progress either to intrauterine death or to a dangerous illness demanding delivery at a time when neonatal survival is unlikely. It is in this difficult situation of early onset of pre-eclampsia that raised plasmaurate levels correlate most closely with fetal outcome. That inappropriate intervention may be the cause of the observed perinatal mortality is unlikely because the stillbirth-rate shows similar patterns to the neonatal deathrates in relation to hyperuriceemia. Where the pregnancy has reached 36 weeks’ gestation or later the prognosis for the fetus should be excellent given appropriately timed intervention, and this has been the mainstay of obstetric management for over 30 years. In advanced pre-eclampsia the maternal G.F.R. falls, causing uraemia and aggravating pre-existing hyperuricsemia. We determined plasma-urate concentrations because increases have repeatedly been shown to precede changes in blood-urea’2 and the onset of proteinuria,13 and are therefore likely to have greater pre-

dictive value. The underlying mechanism of the hyperuricaemia and its relation to impaired fetal wellbeing has not been determined. The two events may be a completely separate expression of pre-eclampsia. The effects of pre-eclampsia in the fetus are probably secondary to the vascular abnormality within the uteroplacental circulation. 14 Handler suggested that the fetal condition and hyperuricsemia were directly related15 and he correlated the arterial lactate concentrations in pre-eclampsia and eclampsia with reduced urate clearances. The lactate acidosis was thought to result from anoxia in the uteroplacental circulation with increasing anaerobic metabolism by the placenta. Other maternal changes of pre-

1373

eclampsia include vasoconstriction, plasma volume

depletion, and excessive salt retention.16 The consequence of these changes with respect to the circulation in the kidney may provide an alternative explanation for urate retention. The undiscovered factor or factors that cause pre-eclamptic vasospasm may exert an effect on renal tubular function similar to that of angiotensin ii which is known to depress urate clearance without lowering G.F.R. 17 Further work needs to be completed before these relations can be clarified. The value of measuring plasma-urate concentrations in hypertensive pregnancy is greatest between 24 and 32 weeks’ gestation. Low values indicate a good prognosis for the fetus. Rising or high values at this time define a small number of very high-risk cases which are better managed and treated in hospital. Early bed-rest, monitoring of fetal wellbeing in utero, and anticipation of maternal problems related to pre-eclampsia then ensure the best chances for bringing the pregnancy to a stage where planned delivery both prevents serious maternal complications and gives the best possible chance of fetal survival. The measurement is thus of great diagnostic value. There is however no evidence from these data that there is a particular plasma-urate concentration above which fetal death becomes immediately imminent. Therefore the prediction of impending fetal death and the exact timing of delivery must rely on other measures of placental and fetal function. Requests for reprints should be addressed to C. W. G. R. REFERENCES 1.

Butler,

N.

R., Bonham,

D. G.

(editors)

in Perinatal

Mortality; p. 87,

Edin

burgh, 1963. 2. Slemons, J. M., Bogert, L. J. J. biol. Chem. 1917, 32, 63. 3. Chesley, L. C., Williams, L. O. Am. J. Obstet. Gynec. 1945, 50, 367. 4. Seitchik, J. ibid. 1953, 65, 981. 5. Lancet, M., Fisher, I. L. J. Obstet. Gynœc. Br. Commonw. 1956, 63, 116 6. Stander, H. J., Cadden, J. F. Am. J. Obstet. Gynec. 1934, 28, 856. 7. Pollak, V. E., Nettles, J. B. Medicine, 1960, 39, 469. 8. Connon, A. F., Wadsworth, R. J. Aust. N. Z. J. Obstet. Gynœc. 1968, 8, 197 9. McFarlane, C. N. J. Obstet. Gynœc. Br. Commonw. 1970, 70, 63. 10. Pritchard, J. A., Stone, S. R. Am. J. Obstet. Gynec. 1967, 99, 754. 11. Suonio, S., Nummi, S., Jouppila, P., Reinila, M. Ann. chir. gynœc. fenn 1972, 61, 202. 12. Beilin, L. J., Redman, C. W. G., Bonnar, J. in Tenth Symposium on Advanced Medicine. (edited by J. G. Ledingham), p.1, London, 1974. 13. Redman, C. W. G., Beilin, L. J., Bonnar, J. J. clin. Path. (in the press). 14. Little, W. Obstet. Gynec., N.Y. 1960, 15, 109. 15. Handler, J. S. J. clin. Invest. 1960, 39, 1526. 16. Sims, E. A. Am. J. Obstet. Gynec. 1970, 107, 154. 17. Ferris, T. F., Gordon, P. Am. J. Med. 1968, 44, 359.

ASPIRIN AND CONGENITAL MALFORMATIONS DENNIS SLONE OLLI P. HEINONEN DAVID W. KAUFMAN

VICTOR SISKIND RICHARD R. MONSON SAMUEL SHAPIRO

Drug Epidemiology Unit, Boston University Medical Center, Cambridge, Massachusetts 02138, U.S.A.

Summary

cohort of 50 282 gravidas and their offspring in the U.S.A., malformation rates were similar in the children of 35 418 women not exposed to aspirin, 9736 with intermediate exposure, and 5128 women heavily exposed during the first four lunar months of pregnancy. After controlling a wide range of potential confounding factors using multivariate analysis, the observed and expected numbers for In

a

a variety of malformation categories were similar in all three comparison groups. The data suggest that aspirin is not teratogenic.

Introduction ASSOCIATIONS between aspirin taken during pregnancy and congenital malformations, 1low birthweight,34 and a high perinatal mortality-rate3 4 have been reported. The widespread use and availability of the drug gives rise to particular concern over these findings. Here we report on the possible teratogenicity of aspirin. The accompanying report5 evaluates aspirin use ;n relation to birth-weight and perinatal mortality.

Methods The data described here were obtained from a prospective cohort study, the Collaborative Perinatal Project, which has been described elsewhere.6-8 A cohort of 50 282 mother-child pairs, seen in 12 hospitals throughout the U.S.A., was selected for study. Before the birth of the child, information was collected on drugs taken during pregnancy, maternal illnesses, complications of pregnancy, and other factors. Data on drug use were recorded at each antenatal visit, and were confirmed, with few exceptions, by the attending physician or by review of the hospital or clinic record. Full details of dosage were not collected; the heaviest exposure category recorded was for 8 or more days in any lunar month. Aspirin was the most commonly used drug, being taken at some time during pregnancy by 32 164 women. In evaluating aspirin in relation to congenital malformations, attention was confined to the first four lunar months of pregnancy-i.e., the period covering early embryogenesis. Aspirin was taken by 14 864 women during this period. Because of the way in which the data were collected, "heavy exposure" was defined as aspirin taken for at least eight days during at least one of the first four lunar months. There were 5128 heavily exposed mother-child pairs. 3248 children (6.5%), including survivors and those who died, had one or more congenital malformations identified before the first birthday or at death before the fourth birthday. Of these, 1128 had one or more of six malformations (inguinal hernia, 683 children; clubfoot, 192; cleft gum, 110; pectus excavatum, 92; urethral obstruction, 68; abnormal hands and fingers, 10) which showed considerable variability in the rates among the 12 hospitals (non-uniform malformations). Rates among the hospitals were reasonably uniform for all other malformations, which affected 2277 children (uniform malformations) ; 157 children had both uniform and non-uniform malformations and were includedin the uniform group. Of the 2277 children with uniform malformations, 1393 had malformations of "major" severity (2.8%).9 All 2277 children and the subgroup of 1393 with major malformations were independently evaluated, as were ten further subgroups, eight of which were based on the anatomical location of the deformity (e.g., central nervous, cardiovascular, respiratory); the two remaining subgroups were syndromes and tumours. Many of the children had multiple lesions, and the subgroups were not mutually exclusive. Of the children with non-uniform malformations, only those with inguinal hernia and clubfoot are considered here. Data concerning the remaining four non-uniform outcomes will be reported elsewhere.8 In order to control possible confounding, risk-factors for each of the outcomes were identified. A detailed description of the risk-factors and of the methods used to identify them will be presented elsewhere.8 Briefly, comparisons were made between children with and without each of the outcomes in terms of certain factors. These factors included: administrative data, such as the number of antenatal visits; personal characteristics of the mothers, such as age; characteristics of the offspring, such as birth-weight; reproductive history, such as