PROGESTAGENS IN THREATENED ABORTION

1242 ANTI-HAV ANTIBODIES IN NON-HUMAN PRIMATES

PROGESTAGENS IN THREATENED ABORTION

SIR,-Double-blind trialsl-5 have proved that hormonal (progestagen) treatment of threatened abortion in early pregnancy is no more effective than placebo. Nor is hormonal treatment biologically plausible for a condition where genetic factors play the major role. Even so, market data show that threatened abortion still has an important place as an indication (table I), and drug companies (personal communication) have seen no changes in the use of these preparations over the past 5 years despite warnings of possible associations between hormonal exposure and congenital malforma-

tions.6-8

9

During a two-year series of seminars on drug use in pregnancy9 obstetricians, gynaecologists, and general practitioners in various Italian regions displayed marked resistance when we discouraged hormonal treatment of early threatened abortion. However, a controlled trial was welcomed as an acceptable means of checking the validity of the information which went against personal beliefs and practices and drug representatives’ pressures.

i

*Number of animals

positive per number of animals tested.

primates become infected shortly after capture as a result of contact with man or other infected animals6 because no evidence of naturally acquired infection of non-human primates in nature has yet been presented and because human contacts are subsequently infected. Serological evidence and the length of the incubation period in man suggest that hepatitis A virus (HAV) is invariably res-

ponsible. The possibility of transmission of viral hepatitis, both type A and type B,7 from non-human primates led to this study of the sera from 27 animals of thirteen species held at the Bloemfontein Municipal Zoo as well as two groups of Cape or chacma baboons (Papio ursinus) held at the University of the Orange Free State Experimental Animal Centre (UOFSEAC). One group of 8 animals had been captured in nature on the farm "Tuinfontein", District of Petrusville, Northern Cape Province (30° 10’E, 24°45’S) 18 months before blood was taken and the second group of 4 animals were captured at the same location 2 weeks before bleeding. Sera were examined by radioimmunoassay kits (Abbott Laboratories) for hepatitis B surface antigen (HBsAg), anti-HBs antibodies, and antiHAV antibodies. All the animals’ sera were non-reactive for HBsAg and anti-HBs antibodies. The accompanying table lists the primates positive for anti-HAV antibodies. Anti-HAV antibodies, and hence HAV infections, have never before been reported in certain of these species-notably, the vervet monkey and the Cape baboon. More important, all 4 Cape baboons in the second UOFSEAC group were positive for anti-HAV antibodies. Sucrose density gradient analysis proved that these antibodies were of the IgG class. This fact, the fact that the animals were bled 2 weeks after capture, and the knowledge that the incubation period of experimental HAV infection in susceptible non-human primates is seldom less than 21 days, is strong evidence that these animals acquired infection in nature. As far as can be ascertained this is the first report of infection of nonhuman primates with HAV in nature. Whether or not these animals play a role in HAV maintenance in nature, or may serve as a suitable laboratory model for human HAV infections, remains to be determined. We thank the City of Bloemfontein for permission to bleed primates held at the Bloemfontein Zoo, and the curator of the Zoo, Mr S. J. van der Merwe, and his staff for their cooperation. Department of Medical Microbiology (Virology), University of the Orange Free State

Women with clinically diagnosed threatened abortion during the first 14 weeks of pregnancy were allocated at random, having given their informed consent, to oral (allyloestrenol, 10 mg/day) or intramuscular (hydroxyprogesterone caproate, 25 mg every 5 days) hormonal treatment or placebo. The duration of treatment was set at 8 weeks. These treatment schedules accorded with the practice prevalent in the participating centres. Twelve hospitals providing reliable data in a pilot phase took part in the trial. Clinical and biochemical (HCG) tests were required on days 1, 7, 15 and 21. Radioimmunoassay of HCG was done at a central laboratory under strict quality control. The HCG results were used to confirm pregnancy and to identify women who had already aborted. 10 The 74 women who received hormonal preparations and the 71

controls were closely comparable in respect of age, parity, previous abortions, week of gestation, medical history, previous oral con-

traceptive use, and concomitant treatments (mainly antiemetics and vitamins). There was no difference in pregnancy outcome (table n). Controlled trials of drugs are especially important when the indications are not clear or when doubtful treatment could be associated with some risk. In these situations the physician may often be uneasy about what to prescribe, and be vulnerable to unfounded advertising claims, especially in countries with no strong tradition of unbiased, independent information. While the European Economic Community is trying to set common guidelines for

1. Goldzieher JW. Double-blind trial of a progestin in habitual abortion. JAMA 1964; 188: 651-54. 2. Klopper A, MacNaughton M. Hormones in recurrent abortion. J Obstet Gynaecol Br Commonw 1965; 72: 1022-28. 3. Alling Møller KJ, Fuchs F. Double-blind controlled trial of 6-methyl, 17-acetoxyprogesterone in threatened abortion. J Obstet Gynaecol Br Commonw

1965, 72: 1042-44. 4. 5.

Govaerts-Videtzky M, Martin L, Hubinont PO. A double-blind study of progestogen treatment in spontaneous abortion. Obstet J Gynaecol Br Commonw 1965, 73: 1034. Berle P, Behnke K. Uber Behandlungserfolge der drohenden Fehlgeburt. Geburtsh Frauenheilk 1977; 37: 139-42.

6.

Greenberg G, Inman WHW, Weatherall JAC, Adelstein AM. Hormonal pregnancy tests and congenital malformations. Br Med J 1975; ii: 191-92. 7. Janerich DT, Dugan JM, Standfast SJ, Strite L. Congenital heart disease and prenatal exposure to exogenous sex hormones. Br Med J 1977; 1: 1058-060. 8. Heinonen OP, Slone D, Monson RR, Hook EB, Shapiro S. Cardiovascular birth defects and antenatal exposure to femal sex hormones. N Engl J Med 1977; 296: 67-70. 9.

Tognoni G, Bellantuono C, Colombo F et al. Drug utilization strategies within regional programs on drug control and evaluation. In: Duchêne-Marullaz P, ed. Advances in pharmacology and therapeutics: Vol 6, clinical pharmacology. Oxford: Pergamon

10.

Crosignani PG, Trojsi L, Attanasio AEM, Lombroso Finzi GC. Value of HCG and HCS measurement in clinical practice. Obstet Gynecol 1974; 44: 673-81.

Press, 1978: 101-112.

M. S. SMITH P. J. SWANEPOEL TABLE I-INDICATIONS FOR PROGESTAGEN USE

Department of Nature Conservation, Provincial Administration of the Orange Free State Bloemfontein 9300, South Africa

1979)

M. BOOTSMA

6. Koff RS. Viral hepatitis. In. Dietschy JM, ed. Clinical gastroenterology monograph series New York: John Wiley & Sons, 1978: 60. 7. Zuckerman AJ, Thornton A, Howard CR, Tsiquaye KN. Hepatitis B outbreak among chimpanzees at the London Zoo. Lancet 1978, ii: 652-54

(% OF MARKET SHARE

1243 of acute malaria in children. In one case fansidar failed to clear the parasitaemia and in three cases parasitaemia reappeared a few days after initial clearance.

TABLE II-PREGNANCY OUTCOME

treatment

-

I

I

* HCG figures relate to 82 patients only. 19 samples were not assayed under central quality control, 17 were not properly stored, and 10 were not clearly identifiable; the remaining 17 samples had plasma HCG values below normal, (normal range defined by mean ±2SD). tOutcome not specified in medical records.

drug assessment, it would be interesting to check the yield of trials with an explicit educational role, aimed at "old" concepts and at doctors likely to be outside the mainstream of information. Such trials might not seem very creative scientifically. Nevertheless, they’ could well be part of "what doctors should be doing" . 11 The following clinicians took part in the trial: A. Tomassini, C. De Nigris, A. Vecchione, M. Vignali, M. Luerti, G. Fontana, E. Manenti, A. Valsecchi, G. Mattioli, A. Teatini, E. Tucci, G. Variati, D. Gentile, F. Revelli, A. Patnarca, E. Imparato, R. Durola, C. Radaelli, A. Mazzoleni, and F. Balacco. The work was supported by a C.N.R. contract on biology and reproduction and by the

Department of Obstetrics and Gynaecology, University of Milan

all male, with initial parasite counts between 1760 and 44 400 were treated with fansidar on a dose/kg basis. Asexual parasites disappeared from the peripheral blood on day 3 or 4 and reappeared on day 7 or 8. All three were treated with chloroquine, in two cases successfuly, there being no asexual parasites noted in the subsequent 28 days. The third case showed RII chloroquine resistance and was subsequently successfully treated within 7 days of quinine together with fansidar on the fifth day. ’

Lombardy Regional Centre for Drug Information. Lombardy Regional Centre for Drug Information, Istituto di Ricerche Farmacologiche "Mario Negri", 20157 Milan, Italy

Case-report Male, aged 15 months, weight 7 - 4 kg. Presenting symptoms were fever and cough for 3 days. On examination, temperature was 38-2°C, spleen grade 4. Initial blood film (day 0) showed P. falciparum: 50 00011. He was treated with half a tablet fansidar given under observation. The fever subsided by 60 h. On day 2 the parasite count (per JlI) was 4080 and gametocytes were noted. The parasite count was 10 400/1 on day 3, 8000 on day 4, and 67 000 on day 5 when fever returned. On day 6 he was given 7 ml of chloroquine elixir (50 mg chloroquine base per 5 ml) and this was repeated on day 7 and day 8, when the parasite count was 320 with plentiful gametocytes. On day 9 no asexual forms were noted in 200 high power fields in a thick blood film, and no further asexual parasitaemia occurred in the next 28 days. Three other patients aged between 3 years 6 months and 5 years,

Comment G. TOGNONI L. FERRARIO M. INZALACO

IV

P. G. CROSIGNANI

FANSIDAR-RESISTANT FALCIPARUM MALARIA IN PAPUA NEW GUINEA

SIR,-Chloroquine-resistant falciparum malaria was first reported from Papua New Guinea in 1976., By 1980, in in vivo chloroquine sensitivity tests in schoolchildren with asymptomatic parasitaemia, type I resistance (RI) was found in approximately 60% of children and cases of RII and RIII resistance were also noted.3 In areas of the world where there is a high prevalence of chloroquine-resistant falciparum malaria, a short course of quinine followed by a single dose of’Fansidar’ (pyrimethamine 25mg plus sulfadoxine 500 mg) has been recommended for the treatment of acute falciparum malaria.4 The exigencies of treatment in tropical countries mean that a single dose drug is desirable, and fansidar is one of the few commercially available preparations. However, treatment failures with the pyrimethamine-sulfadoxine combination have been reported from a number of areas in South East Asia 5,6 and elsewhere and recently from Irian Jaya.7 We report here four cases of Plasmodium falciparum malaria clinically resistant to fansidar observed in the Madang Province of Papua New Guinea during a clinical and field trial offansidar for the 11. Black D. What should doctors be doing? Lancet 1980; ii: 304-06. 1. Grimmond TR, Riley I, Donovon KO. Chloroquine resistant malaria in Papua New Guinea. Papua New Guinea Med J 1976; 19: 184-85. 2. Han CM. Studies on the occurrence of a strain of chloroquine-resistant Plasmodium falciparum in Papua New Guinea. Papua New Guinea Med J. 1978; 21: 306-16. 3. Gibson FD. Chloroquine resistance studies in Papua New Guinea. In: Eighth SouthWest Pacific Malaria Conference. (Port Moresby, Papua New Guinea, Aug. 4-8,

1980). 4. Hall AP. The treatment of malaria. Br Med J 1976; i: 323-28. 5. Doberstyn EB, Phintuyothin P, Noeypatimanondh S, Teerakiartkamjorn C.

Single-

dose therapy offalciparum malaria with mefloquine or pyrimethamine-sulfadoxine. Bull WHO 1979; 57: 275-79. 6. Schmidt LH, Harnson J, Rossan RN, Vaughan D, Crosby R. Quantitative aspects of pyrimethamine-sulphonamide synergism. Am J Trop Med Hyg 1977; 26: 837-49. 7. Rumens LW, Dennis DT, Atmosoedjono S. Fansidar resistant falciparum malaria in Indonesia. Lancet 1979; ii. 580-81

In the first patient the parasitaemia persisted for 8 days. We are satisfied that the patient was observed to have taken the prescribed treatment (and parasitaemia did initially fall with the subsidence of fever) and the evidence for parasite resistance to the drug combination in this case is firm. In the other three patients the parasitaemia disappeared only to reappear a few days later and the time course of events makes it likely that these were cases of recrudescence rather than second infections (although this cannot be entirely excluded). In the face of the increased prevalence of chloroquine-resistant falciparum malaria in Papua New Guinea, there is obviously a need for an alternative to chloroquine for the treatment of presumptive cases. Unfortunately fansidar would not appear to be that alternative, at least in the Madang area of Papua New Guinea, although it is undoubtedly a useful drug with which to treat inpatients who do not respond to standard therapy. It seems on preliminary evidence (P. Chen, G. Lamont, T. Elliott, C. Kidson, G. Brown, G. Mitchell, J. S., and M. A., unpublished) that pyrimethamine resistance in Papua New Guinean strains of P. falciparum may be several orders higher than that in African strains, and it is likely that widespread use of fansidar would rapidly lead to increased numbers6 of resistant strains to the pyrimethamine-sulfadoxine combination. This letter draws attention to this danger and to the need for careful evaluation of the drug wherever it is being used. We thank Roche Products Pty Ltd, Australia, for supplies offansidar tablets.

Papua New Guinea Institute of Medical Research, P.O. Box 378, Madang; and

Department of Public Health, Madang Hospital, Papua New Guinea

BRIAN DARLOW HELENA VRBOVA JOHN STACE PETER HEYWOOD MICHAEL AALPERS

FEBRILE CONVULSIONS

SiR,-Your Sept. 27 editorial supports the prevailing concept that febrile seizures, which are usually benign, are due entirely to the height of the fever. However, these seizures usually occur at the very onset of the febrile illness, often before the extent of the temperature rise is known; they do not recur if, during the illness, the temperature again rises. Livingston states: "... we have never observed a simple febrile seizure as the initial convulsive reaction to an elevation of temperature later than 24 hours after the onset of an acute febrile-