British Journal of Obstetrics and Gynaecology September 1988, Vol. 95, pp. 877-879

Human leucocyte antigen status in African women with eclampsia

NICHOLAS JOHNSON, JACK MOODLEY, MICHAEL G. H A M M O N D

Summary. Investigation of the HLA system in 53 African eclamptic or imminently eclamptic women showed that they were significantly more likely to be heterozygous at the B locus than were normal controls. This did not apply to the A or D related loci.

The aetiology of eclampsia remains unknown, but suggestions that it may be an immunogenetic disorder date back to the beginning of the cen- tury (Beer & Need 1985). Redman et al. (1978) reported that women who had only one detect- able surface antigen determined by the HLA-B locus were at an increased risk of developing pre-eclampsia in pregnancy. This work has yet to be confirmed. To examine this association, we studied the HLA system in women who devel- oped eclampsia and compared it with that found in the normal population.

Patients and methods

The study included 53 black African women from Zululand admitted to the labour ward of King Edward VIII hospital who had systolic blood pressures greater than 160 mmHg and diastolic blood pressures greater than 115 mmHg, gross oedema and at least 2+ pro- teinuria by standard turbinometric methods in a catheter specimen of urine. Forty-two patients had already suffered at least one seizure before

Department of Obstetrics and Gynaecology, University of Natal, PO Box 17039, Congella 4013, Durban, South Africa NICHOLAS JOHNSON Registrar JACK MOODLEY Professor

Natal Blood Transfusion Services, Pinetown, South Africa MICHAEL G. HAMMOND Director of Natal Transplant Services

Correspondence: N. Johnson, Department of Obstetrics and Gynaecology, St James's University Hospital, Leeds LS9 7TF

admission and the remaining 11 all complained of headache, nausea and visual disturbances. All were either irritable or had intellectual clouding and an independent observer described those who had not had a seizure as being hyper-reflexic with clonus before therapy. Patients with a history of neuropathology, diabetes, hyper- tension, renal disease, recurrent miscarriage or a recent blood transfusion were all excluded. Patients who were still proteinuric or hyperten- sive (>140/90 mmHg) 12 days after delivery were also excluded. Three patients with eclampsia did not know their parents, but the remainder denied that they could be the product of consanguineous marriage or matings.

The control group for the A and B locus of the HLA system consisted of 1416 blood donors of the same tribe and resident within the same hos- pital catchment area and 412 of them also acted as controls for the DR locus.

The HLA, A, B and DR antigens were deter- mined by a two-stage lymphocytotoxicity test (Terasaki & McClelland 1964). Patients with only one antigen per locus were considered to be homozygous at that locus. Frequency differ- ences between the eclamptic patients and the controls were tested for significance with the X2-test. The formula given by Haldane (1956) was used to combine data from the available published series with the data presented. Rela- tive risk was defined as the number of times more often the disease occurred in women posi- tive for that antigen than in those negative for that antigen (Woolf 1955).

Results Clinical details of the subject group are recorded in Table 1. Women with eclampsia or imminent

877

878 N . Johnson et al.

Table 1. Clinical details of patients with eclampsia cant that women born of a consanguineous rela-

Variable Number

No. of patients 53 No. with previous viable pregnancy 26 (49%) Nulliparous 27 (51%) Preterm labour (< 35 weeks gestation) Age (years)

26 (49%)

< 20 16 20-24 21 25-30 11 > 30 5

Maternal deaths I*

*Intracranial haemorrhage.

tionship, and thus relatively homozygous, have some protection from developing eclampsia in pregnancy (Stevenson et aE. 1976). However, heterozygosity in eclamptics does not occur at the A or DR locus, this observation is unlikely to be related.

Our data contradict the findings of Redman et al. (1978). They studied 80 Oxfordshire women suffering from pre-eclampsia and computed a P value of 0.025 supporting an association between pre-eclampsia and homozygosity at the B locus. Simon et al. (1980) also reported that French pre-eclamptic patients were relatively homozygous, but they only recruited 26 paticnts

eclampsia were less likely to have only one (six were homozygous) and their control group detectable antigen at the B locus than were the was limited to 16 men, none of whom was homo- normal population, the difference was statis- zygous. However, Persitz et af. (1983) investi- tically significant (P < 0.01, x2 = 7.4). The rela- gated 40 women in Israel, and Scott et al. (1976) tive risk in patients in whom both antigens were studied 46 women from Iowa with eclampsia and detected at the B locus is thus increased to 2.3. pre-eclampsia and both studies failed to show This docs not apply to the A locus or at the DR such a relation. It is difficult to understand why locus (Table 2). No specific A, B or DR antigen English pre-eclamptic patients should tend occurred more commonly in eclamptic patients. towards homozygosity at the A and more par-

ticularly at the B locus yet Africans with eclampsia are more likely to be heterozygous. Discussion An immunogenetic explanation seems unlikely.

Two antigen types are inherited, one from each It is true, however, that some disorders are asso- parent. If only one antigen can bc detected, then ciated with an HLA type only in certain races, it can be inferred that the individual has either e.g. HLA-B54 is associated with juvenile inherited the same antigen from each parent, diabetes mellitus in Japanese, but not in Cauca- thus making her homozygous at that locus, or sians. No condition yet described is associated that she has an antigen yet to be discovered. As it with such marked polarization as demonstrated is believed that over 98% of the B locus antigens here. If the explanation of such conflicting are known to us, the finding of a single B locus results is not within the different racial study antigen is presumed to be synonymous with groups then it may be with the disease. We have homozygosity. Pregnant Zulu women suffering presumed that pre-eclamptics become eclamp- from eclampsia or imminent eclampsia are less tics and therefore the two groups are compar- likely to have only one detectable human lym- able. However, patients presenting with acute phocyte antigen at the B locus than are the eclampsia may have a different genotype com- normal, healthy population from the same tribe pared with those presenting with proteinuric and district. Our eclamptics are more likely to be hypertension in pregnancy. Finally, it must be hctcrozygous at the B locus. It is perhaps signifi- noted that 30% of our control population are

Table 2. Frequency of human leucocyte antigen (HLA) homozygosity in patients with eclampsia and in normal controls

Eclamptic patients HLA locus n (”/.)

Normal controls n (”/. 1

A 19/53 (35.8) 37411416 (26-4) B 7/53 (13.2) 43511416 (30.7)*

DR 22/53 (41.5) 2234 12 (54.1)

Significance of difference between the two groups. * P < 0.01, x* = 7 4

HLA and eclampsia 879

Haldane, J. B. S. (1956) The estimation and signifi- cancc of the logarithm of a ratio of frequencies. Ann Hum Genet 20, 309-311.

Persitz, E., Oksenberg, J., Amar, A., Margalioth, E. J., Cohen, 0. & Brautbar, C. (1983) Histocom- patibility antigens, mixed lymphocyte reactivity and severc pre-eclampsia in Israel. Gynecol Obstet lnvest 16, 283-291.

Redman, C. W. G., Bodmer, J. G., Bodmer, W. F., Beilin. L. J . & Bonnar, J. (1978) HLA antigens in severe pre-eclampsia. Lancet ii, 397-399.

Scott. J. R., Beer, A. E. C Stansty, P. (1976) Immu- nogerietic factors in preeclampsia and eclampsia: erythrocyte, histocompatibility and Y-dcpcndent antigens. JAMA 235, 402-404.

Simon, P., Fauchct, R., Mcnault, M. et 01. (1980) HLA A, H and DR antigens in pre-eclampsia: preliminary results. Kidney Int 17, 705-706.

Stevenson, A. C . , Say, R., Ustaoglu, S. & Durrnus. A. (1976) Aspects of pre-eclamptic toxaemia of preg- nancy, consanguinity and twinning in Ankara. J Med Genet 13, 1-8.

Terasaki, P. I . & McClelland, J . D. (1964) Microdrop- let assay of human serum cytotoxins. Nature

Woolf, B. (1955) On estimating the relation between blood group and disease. Ann Hum Genet 19,251- 253.

(Land) 204, 998-1000.

Received 6 April 1987 Accepted 10 February 19x8

homozygous. This remarkably high figure may be a reflection of African tribal society and the immobility of its members due to political and economic constraints. Such nuclear commu- nities are not a feature of Oxfordshire, Iowa or France.

The history of H L A associations with certain diseases has been a major breakthrough in our understanding of the genetics of many diseases. The exciting work by Redman et al. (1978) asso- ciating pre-eclampsia with homozygosity at the B locus promoted many ideas and strengthened the immunogenetic interest in the subject. I t is not clear why in African women we found a significant association between heterozygosity and eclampsia, just the opposite of what we expected If all the available literature is gathered it conflicts and when it is summated no trend emerges. Eclampsia is either independent of HLA status or the association is so compli- cated it dcfics present comprehension.

References

Beer, A. E. & Need, J. A. (1985) Immunological aspccts of pre-eclampsia/~clampsia. Birth Defects 21 (5) , 131-154.