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REFERENCES1 Rom WN. Environmental and occupational medicine. Boston:Little Brown. 1992.2 Rosenstock L, Cullen MR (eds). Textbook of clinical, occupational and environmental medicine. Philadelphia:

W.B. Saunders, 1994.3 Pickering CAe. Byssinosis. In: Parkes WR (ed). Occupational lung disorders. New Deihi:Oxford, Butterworth-

Heinemann, 1994:729-54.4 Murlidhar V, Murlidhar VJ. Kanhere V. Byssinosis in a Bombay textile mill. Natl Med J India 1995;8:204-7.5 Cullen MR, Rosenstock L. The challenge of teaching occupational and environmental medicine in internal

medicine residencies. Arch Intern Med 1988;148:2401-4.6 Christiani DC, Eisen EA, Wegman DK. Ye TT. Lu PL, Gong ZC, Dai HL. Respiratory disease in cotton

textile workers in the People's Republic of China. I: Respiratory symptoms. Scand J Work Environ Health1986;12:40-5.

7 Takam J, Nemery B. Byssinosis in a textile factory in Cameroon: A preliminary study. Br J lnd Med 1988;45:803-9.

8 Tuypens E. Byssinosis among cotton workers in Belgium. BrJ Ind Med 1961;18:117-19.9 Demedts M, Gheysens B, Nagels J, Verbeken E, Lauweryns J, van den Eeckhout A, et al. Cobalt lung

in diamond polishers. Am Rev Respir Dis 1984;130:130-5.10 Nemery B, Nagels J, Verbeken E, Dinsdale D, Demedts M. Rapidly fatal progression of cobalt lung in

a diamond polisher. Am Rev Respir Dis 1990;141:1373-8.11 Beckett WS. The epidemiology of occupational asthma. Eur Respir J 1994;7:161-4.12 Burge PS. Problems in the diagnosis of occupational asthma. Br J Dis Chest 1987;81:105-15.13 Sakula A. Ramazzini's de morbis anificum and occupational lung disease. Br J Dis Chest 1983;77:349-61.14 Bisetti AA. Bernardino Ramazzini and occupational lung medicine. Ann NY Acad Sci 1988;534:1029-37.15 Parikh JR. Byssinosis in developing countries. Br J Ind Med 1992;49:217-19.16 Markowitz G. Rosner D. The limits of thresholds: Silica and the politics of science. 1935 to 1990. Am J

Public Health 1995;8S:25~2.17 Choi BCK. Definition, sources, magnitude, effect modifiers. and strategies of reduction of the healthy

worker effect. J Occup Med 1992;34:979-88.18 Sekimpi DK; Testa Tambellini A, Van Trung L. The global economy and occupational health. lnt J Occup

Environ Health 1995;2:76-9.19 Ould Kadi F, Mohammed-Brahim B, Fyad A, Lellou S, Nemery B. Outbreak of pulmonary disease in

textile dye sprayers in Algeria. Lancet 1994;344:962-3.20 Dhara R. Dhara VR. Bhopal: A case study of international disaster. Int J Occup Environ Med 1995;1:5!Hi9.

B. NEMERYDepartment of Occupational Medicine and

Laboratory of Pneumology (Unit of Lung Toxicology)K. U. Leuven

Belgium

Pre-eclampsiaPre-eclampsia is a peculiar disorder characterized by the development ofproteinuric hypertension during pregnancy. It is an important cause of maternaland perinatal death. Pre-eclampsia is unpredictable in onset and variable inits progression; the only known cure is termination of pregnancy.

The exact cause of pre-eclampsia is still a mystery but it appears to beassociated with abnormal trophoblastic implantation. In normal pregnancies,trophoblast invasion into the uterus produces extensive changes in the spiralarteries that supply the intervillous space. The endothelium and the internalelastic lamina are replaced by trophoblast and amorphous matrix containingfibrin. These vascular changes extend to the inner third of the myometriumand increase the diameter of the spiral arteries up to four to six times of thatin the non-pregnant state. These large channels do not respond to circulatingvasopressors, thus ensuring adequate blood flow to the placenta. In contrast,such changes either do not occur in pre-eclamptic women or are limited tothe decidual portion of the vessels, with the myometrial segments retainingsmooth muscle and the blood vessels supplying the intervillous space remainingnarrow. 1 The changes during normal and deficient implantation are completeby mid-pregnancy; yet the disorder does not manifest itself until late pregnancy.

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Pre-eclampsia is more common in the daughters of women who have hadthis disease than in their daughters-in-law, thus suggesting a familial tendency. 2

The risk of pre-eclampsia increases when formation of blocking antibodies toantigenic sites on the placenta is impaired.' This disorder is more commonin primigravidae. The shorter the duration of sexual cohabitation before con-ception, the greater is the risk of developing pre-eclampsia.' Pre-eclampsiais also common when there is an abundance of trophoblastic tissue as inmultifoetal and molar pregnancies, or there is underlying vascular disease asin diabetes. If the mother had been normotensive in her first pregnancy, theoccurrence of pre-eclampsia is rare in subsequent pregnancies. It may occurin a later pregnancy if the pregnancy is by a different partner, or because ofunderlying vascular disease.

The increase in maternal blood pressure may be considered to be the maternalresponse to poor placental perfusion. Unfortunately, this process may go wrongfor both mother and foetus. Vasospasm in pre-eclampsia is widespread andaffects every organ system. Endothelial cell dysfunction has been postulatedas an important factor in the disease process.> Besides vasospasm and theresultant underperfusion of organs, there is activation of the coagulationcascade. Pre-eclampsia could lead to dangerous maternal complications suchas eclampsia, cerebral haemorrhage, coagulopathy including the HELLP(haemolysis, elevated liver enzyme activity, low platelets) syndrome and evenmaternal death. Poor utero-placental circulation leads to retardation of foetalgrowth, foetal distress and perinatal death.

Most affected women are free of symptoms during the prodromal phase ofthe disease. Once the disease sets in, it may quickly progress to a terminalcrisis. However, its speed of progression is variable and clinical presentationsdiffer. Removal of the placenta is the only cure.

Perinatal prognosis is poor in those with early onset pre-eclampsia whenpregnancy has to be terminated for worsening maternal health remote fromterm. Hospitalization and strict bed rest have been advocated on the assump-tion that these reduce maternal blood pressure and improve utero-placentalperfusion. This advice is no longer valid in cases of non-proteinuric hyperten-sion in pregnancy. Also there is no good evidence from randomized trials fora beneficial role of strict bed rest even in proteinuric hypertension."

Antihypertensive drugs may prevent maternal complications whenpregnancy is remote from term and should be given when the diastolic bloodpressure is above 110 mmHg. These do not improve utero-placental bloodflow, nor do they prevent the onset of proteinuria." They cause sudden andsevere reduction in maternal blood pressure to 'normal' levels which maydecrease utero-placental circulation. The aim of therapy should be to keepthe diastolic blood pressure between 90 and 100 mmHg. In the absence ofmajor maternal complications, pregnancy may be allowed to continue so thatthe foetus matures with better chances of survival.

Methyldopa is the most widely used antihypertensive drug in pre-eclampsia.Other drugs include beta-blockers and calcium channel blockers. Parenteralantihypertensive drugs include hydralazine, labetotol and diazoxide. Thechoice of a drug is essentially dependent on its availability and on personalpreferences. Diazoxide may produce a precipitous fall in maternal and foetalblood pressure and should be used with caution. Angiotensin-convertingenzyme inhibitors are harmful to the foetus and should be avoided. Diureticshave no place in the prevention or treatment of pre-eclampsia. However,there is no satisfactory long term follow up of babies born following maternalantihypertensive therapy. 7

Termination of pregnancy, the only definitive treatment of pre-eclampsia,is indicated either when the foetus is mature enough to survive outside thewomb (varies between centres) or when the maternal condition deteriorates tosuch an extent (the blood pressure is not under control, symptoms and signs

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of imminent eclampsia, or proteinuria) that continuation of pregnancy wouldbe of greater harm to the mother. Proteinuria is a definite indication that thedisease has progressed to affect the kidneys.

There has been interest in the use of anti-platelet medications for preventionof pre-eclampsia because it is associated with deficient intravascular productionof prostacyclin (a vasodilator) and with excessive production of thromboxane(a vasoconstrictor and a platelet aggregator produced by platelets). Low dosesof aspirin block platelet cyclo-oxygenase activity irreversibly without alteringlevels of endothelium-derived prostacyclin. These theoretical considerationsled to several small clinical trials on the role of low-dose aspirin in theprophylaxis of pre-eclampsia. Some of these trials showed promising results.However, the CLASP trial (the largest randomized trial to date on aspirin inthe prevention of pre-eclampsia) showed that the drug had a very limited rolein the prevention of pre-eclampsia." In contrast, routine calcium supplemen-tation in pregnancy has been shown to reduce pre-eclampsia and pretermdelivery."

How does one manage severe pre-eclampsia remote from term in India?Since neonatal survival remote from term is poor in most centres, womenwho have early onset pre-eclampsia should ideally be transferred to centreswhere there are adequate facilities for the management of the mother andher very low birth-weight baby. The maternal condition should be stabilizedbefore the in utero transfer. Expectant management with close monitoring ofmaternal and foetal health has been shown to be better than aggressivemanagement when pre-eclampsia occurs remote from term. 10 When deliveryis indicated, antenatal administration of corticosteroids to the mother mayhelp improve foetal lung maturity. However, if the chances of neonatal survivalare considered low-even if the severe pre-eclampsia is managed expectantlyfor another 10-15 days-the pregnancy should be terminated.

REFERENCES1 Robertson WB, Brosens I. Landells WN. Abnormal placentation. Obstet Gynecol AnnIl1985;14:411-26.2 Cooper OW. Hill JA. Chesley LC. BryansCI. Genetic control of susceptibility to eclampsia and miscarriage.

Br] Obstet Gynaecol 1988;95:644-53.3 Hypertensive disorders of pregnancy. In: Cunningham FG. MacDonald PC. Gant NF. LevenoKT, Gilstrap

III LC (eds). Williams Obstetrics. New Jersey.Prentice-Hall, 1993:763-817.4 Robillard P-Y. Hulsey TC. Perianin J. Janky E. Miri EH. Papiernik E. Association of pregnancy-induced

hypertension with duration of sexual cohabitation before conception. Lancet 1994;344:973-5.5 Roberts JM. Redman CWG. Pre-eclampsia: More than pregnancy-induced hypertension. Lancet 1993;

341:1447-51.6 Duley L. Strict bed rest for protein uric hypertension in pregnancy. In: Enkin MW. Kierse MJNC. Renfrew

MJ. Neilson JP (eds). Pregnancy and childbirth module: Cochrane database of systematic reviews. ReviewNo. 03373. 21 May 1993. Oxford: Cochrane Database of Sysemic Reviews. Update Software. 1994. DiskIssue I.

7 Collins R. Duley L. Any antihypertensive therapy for pregnancy hypertension. In: Enkin MW. KierseMJNC. Renfrew MJ. Neilson JP (eds). Pregnancy and childbirth module: Cochrane database of systematicreviews. Review No.04426. 21 April 1993. Oxford: Cochrane Update on Disk. Update Software. 1994.Disk Issue I.

8 CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. CLASP: A randomizedtrial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women.Lancet 1994;343:619-29.

9 Carroli G. Duley L. Belizan JM, Villar J. Calcium supplementation during pregnancy: A systematic reviewof randomised controlled trials. Br I Obstet GynaecoI.1994;lOl:753-8.

10 Sibai BM. Mercer BM. Schiff E. Friedman SA. Aggressive versus expectant management of severe pre-eclampsia at 28 to 32 weeksgestation: A randomized controlled trial. Am] Obstet Gynecoll994;171:818-22.

MATHEWS MATHAIDepartment of Obstetrics and Gynaecology

Christian Medical College HospitalVellore

Tamil Nadu