Archives of Disease in Childhood 1995; 72: F139-F144 F139

OBSTETRICS FOR PAEDIATRICIANS

Hypertension in pregnancy

E Malcolm Symonds

Department ofObstetrics andGynaecology,University HospitalNottingham, Queen'sMedical Centre, EastBlock, Floor D,Nottingham NG7 2UH

Correspondence to:Professor Symonds.

The classification of high blood pressure inpregnancy is important for predicting outcomeand determining the best method of treatment.The most widely used classification is theone proposed by the American College ofObstetrics and Gynecology (ACOG) whichdivides hypertension arising during pregnancyfrom pregnancy complicating hypertensivestates. ' This classification has been furthersimplified by the International Society forthe Study of Hypertension in Pregnancy,2 butthe important feature in both classifications isthe differentiation between the occurrence ofhypertension alone and hypertension plusproteinuria or pre-eclampsia. Both maternaland perinatal mortality rates are significantlyincreased in pre-eclampsia but not withgestational hypertension. The implication ofother forms of hypertension present duringpregnancy varies according to the type ofunderlying pathology.

Gestational hypertension is the mostcommon form of hypertension complicatingpregnancy, and pre-eclampsia and eclampsiaare the most common cause of perinatal ormaternal death. In the last triennial report onConfidential Enquiries into Maternal Deathsin the United Kingdom (1988-1990),3 hyper-tensive disorders remained the highest singlecause of maternal death in England and Wales,with a rate of 8-6 deaths per million preg-nancies, compared with 8-0 deaths per millionfrom pulmonary embolism. Deaths as a resultof anaesthesia dropped from 8-7 in 1979-81 to1 0 per million in 1988-90; the correspondingfigures for hypertensive disorders were 14-2 to8-6 per million.A breakdown of immediate causes of death

shows that intracerebral haemorrhage was themost common, followed by adult respiratorydistress syndrome. In the last triennium onlythree deaths were considered to be related tothe HELLP syndrome. This syndrome repre-sents a manifestation of severe pre-eclampsiaand includes the triad of haemolysis (H) raisedliver enzymes (LE), and a low platelet count(LP). The thrombocytopenia is often severe,unlike the milder forms ofpre-eclampsia whereit occurs in less than 20% of cases. On exami-nation of the effect of hypertensive disease inpregnancy on the fetus in utero, it is clear thatthe onset of late hypertension alone has muchless effect than hypertension and proteinuriaon perinatal mortality. In a review of 13 980primigravidae in Aberdeen between 1958-72,

MacGillivray demonstrated that the perinatalmortality rate in normotensive primigravidaewas 20-7 per 1000 births; in hypertensionalone it was 18&9 per 1000 births; and in hyper-tension with proteinuria the figure was 55 0per 1000 births.4 In other words if a womandevelops hypertension alone during pregnancyshe tends to do rather better than if sheremains normotensive. If the mother developshypertension and proteinuria during preg-nancy the outcome is considerably worse thaneither of the other groups. The problem isthat such assessments can be made only inretrospect and, therefore, it is impossible topredict the likelihood of progression to pre-eclampsia in a woman who initially developshypertension alone.

The pathogenesis ofpre-eclampsiaIn normal pregnancy cardiac output increasesby 30-40% within the first 14 weeks andremains raised throughout pregnancy. Thisincrease is largely related to an increase instroke volume. At the same time plasmavolume expands by 40% but this expansionoccurs progressively until about 36 weeks'gestation. Blood pressure also decreases toreach a nadir during the second trimester andthis is inconsistent with the changes in cardiacoutput and plasma volume. The only explana-tion for this anomalous state in normal preg-nancy is that there must be a reduction in totalperipheral resistance. However, not all vas-cular beds exhibit a reduction in resistance.Studies on forearm blood flow, for example,5have demonstrated a reduction in normalpregnancy and an increase in hypertensive dis-eases in pregnancy. The predominant changesin resistance vessels seem to occur in the utero-placental circulation or in the kidney. Normalpregnancy is also associated with pronouncedveno-dilatation,6 but there is relative veno-constriction where the woman has developedpre-eclampsia or gestational hypertensionalone.The end manifestation of all these vascular

changes is to produce widespread vascularand endothelial damage in multiple organsystems, but the arguments about pathogenesisrevolve around two questions.

Firstly, does the hypertension develop as asecondary manifestation of vascular damagecaused by some initiating factors? Secondly,does the vasoconstriction occur because of a

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vasoconstrictive factor or because of the loss ofnormal vasodilatation?The search for an initiating factor has been

singularly unforthcoming and it seems likelythat pre-eclampsia represents a form ofmaladaptation rather than a disease processinitiated by a single substance. The question asto whether the focal vasoconstriction, which isa feature of pre-eclampsia and eclampsia,results from an increase in vasoconstrictoractivity or a decrease in vasodilator activity,remains unanswered. Although normal preg-nancy represents a state of vasodilatationand reduced vascular resistance, the changein angiotensin II (AII) receptor activity andthe increased concentrations of thromboxaneA2, which will be discussed later in this review,favour the dominance of a vasoconstrictoreffect in pre-eclampsia.

Predisposing factorsGestational hypertension and pre-eclampsiaoccur most frequently in primigravid womenand there are numerous studies to confirm thisobservation. The incidence of pre-eclampsia inwomen who have had a first pregnancy compli-cated by spontaneous abortion was foundto be reduced7 but more recent studies havesuggested that the incidence of pre-eclampsiain a second pregnancy after a spontaneous orinduced abortion is still much greater than theusual incidence in second pregnancies.8 Theseobservations are relevant to the possibleimmune response to fetal antigens. Parouswomen with new husbands are at increasedrisk of pre-eclampsia.9

GENETIC AND FAMILLAL FACTORSThere has always been a belief that a genetictrait might underlie the occurrence of pre-eclampsia. It has, however, been too difficult tomeasure any such claim against the effect ofparity and environmental factors. In a remark-able study extending over a period of 50 yearsChesley studied a cohort of women and theirfamilies over successive generations.10 Theincidence of pre-eclampsia and eclampsia in147 sisters, 248 daughters, 74 granddaughtersand 131 daughters in law showed an observedincidence that fitted closely with a single genecondition and with a putative gene frequencyof 0-25. The search for a specific gene suggestsa gene on chromosomes 1, 3, 9, and 18,11and recently studies have suggested that amolecular variant of angiotensinogen mightbe implicated in the development of pre-eclampsia.12 Arngrimsson and co-workers alsoidentified a genetic factor in Icelandicwomen.13 Nevertheless, it is still difficult toformulate an hypothesis that accounts forthe development of hypertension in later preg-nancies, even though the condition largelyOccurs in primigravid women.

MATERNAL AGEThe analysis of the effect of maternal agereported in the Confidential Enquiries into

Maternal Deaths in the United Kingdom3shows that the lowest incidence of maternalmortality from the effect of hypertensivedisease in pregnancy occurred in women aged25-29 years and the highest incidenceoccurred in women over the age of 40.

MULTIPLE PREGNANCYSeveral studies have shown that twinning isassociated with an increased incidence ofpre-eclampsia.7 There is, however, somedispute as to whether zygocity exerts any effecton incidence. Campbell was unable to demon-strate any differences in the incidence ofpre-eclampsia in women who had monozygoticor dizygotic twins,14 but Stevenson et alsuggested that pre-eclampsia was commonwith dizygotic twins and that women withdifferent sex twins had a higher incidence ofpre-eclampsia. 15

DIABETES, HYDATIDIFORM MOLE, ANDHYDROPS FETALISThere seems to be a higher incidence ofpre-eclampsia in women who have diabetesmellitus, although it has been suggested thatthis is largely associated with poorly controlleddiabetes. The United Kingdom survey ofdiabetic pregnancies has suggested a figure of12%.16 Diabetes is complicated by hyper-placentosis where hypertrophy of the placentaand, in particular, hyperplasia of cyto-trophoblastic tissue remains a feature asso-ciated with pre-eclampsia. This condition isalso found in hydatidiform mole and hydropsfetalis, both of which are also associated with ahigh incidence of pre-eclampsia.

CIGARETTE SMOKINGSeveral studies have now demonstrated thatthe incidence of pre-eclampsia in primi-gravidae falls from 5-2% in smokers to 2-4% innon-smokers.17 If the woman does acquirepre-eclampsia and is a smoker, then thechances ofher having fetal compromise or fetaldeath are substantially increased.

Vasoactive substances and the regulationofblood pressureThere are a large number of vasoactivesubstances produced within the placentalbed which have always been a source ofinterest when studying the pathogenesis ofpre-eclampsia. Some systems produce potentvasoconstrictors and others produce vaso-dilators.

THE RENIN-ANGIOTENSIN SYSTEMRenin is a proteolytic enzyme which isproduced in its active form by cleavage of a436 amino acid prosignal from a proreninprecursor. Although the enzyme was first iden-tified in the kidney, it has since been shownto be produced in the human chorion,18myometrium, brain and smooth muscle. Renin

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acts on angiotensinogen to cleave an inertdecapeptide, angiotensin I, which is thenbroken down to angiotensin II (AII)which, among other things, is a potentvasoconstrictor. The system is hyperactiveduring normal pregnancy, but it is of particularinterest in pregnancy because the normalpregnant woman becomes notably insensitiveto infused AII, whereas the women who aredestined to develop pre-eclampsia and thosewho have acquired the disease exhibit anincreased sensitivity to AII, reaching levelsof response that are similar to those ofnon-pregnant women.

Using platelets as a model of smoothmuscle function, it has been possible toshow that binding site density for AIIfalls during pregnancy in parallel with thefall in AII sensitivity, and those womenwho develop pre-eclampsia also show anincrease in platelet AII binding sites. 19Furthermore, platelet AII binding site densityseems to be a better predictor of pre-eclamp-sia than the angiotensin sensitivity test. Thereduction in AII sensitivity may be a directresult of inhibition of platelet AII receptoractivity.

THE EICOSANOID SYSTEMThere have been numerous studies on thissystem and on the balance between thevasodilator effects of prostacyclin and thevasoconstrictor effect of thromboxane AII.Studies on uterine venous blood in pre-eclamptic patients and normal controlsshowed increased concentrations of throm-boxane AII and decreased concentrations of6-keto-PGF, a in pre-eclamptic women with aratio of 5 6 compared with 2O0 in normotensivewomen (Mortensson L, et al. Abstract pre-sented at Annual Meeting of Society ofGynaecologists, 1984). PGI2 has an anti-aggregatory effect on platelets; thromboxaneAII causes platelet aggregation which probablyresults in the release of serotonin from theplatelets,20 thus resulting in the increasedconcentrations of circulating serotonin whichcan be found in pre-eclamptic women.2'

LIPID PEROXIDATION AND OXYGEN RADICALSIn a recent review of lipid peroxides andoxygen free radicals in normal and hyper-tensive pregnancies, Walsh concluded thatthe production of antioxidants in normalpregnancy limits the damaging effects of lipidperoxides which are normally increased inpregnancy.22 In women who developed pre-eclampsia net antioxidant activity is decreasedand hence cell damage may result. Glutathioneperoxidase is a primary antioxidant and limitsthe production of lipid peroxides; the activityof this enzyme is significantly below normal inthe placental tissue of pre-eclamptic women.

ENDOTHELINSA great deal of research activity is currentlytaking place in the field of endothelial damage

and in endothelially derived hormones suchas endothelin. There are four isoforms ofendothelin, each encoded by a differentgene. They are potent vasoconstrictors withsecondary effects on the renin-angiotensinsystem. So far, most studies have failed toshow any differences in the plasma measure-ments between normal and pre-eclampticwomen.

VASODILATORSNitric oxide (NO) or endothelium derivedrelaxing factor (EDRF) is a potent vasodilator.Inhibition of nitric oxide synthetase increasesblood pressure in non-pregnant women.In recent studies in pregnancy where NO syn-thesis was assessed indirectly by measurementof urinary nitrate or nitrite secretion, the find-ings showed that nitrate or nitrite excretion isreduced in women with pre-eclampsia.24These changes may be related to impairedrenal production of nitric oxide production inpre-eclamptic women.The kallikrein-kinin system is also a candi-

date for vasodilation in normal pregnancy; itsabsence may result in vasoconstriction. Kininis formed by the action of kallikrein on asubstrate of kininogen. There are differencesbetween the kallikrein-kinin system in plasmaand in tissues. The kidneys produce tissuekallikrein and urinary kallikrein is purely renalin origin.

In normal pregnancy maximum concentra-tions of active urinary kallikrein occur towardsthe end of the first trimester, with levels fallingin advancing pregnancy.24 Several groups25 26have shown that kallikrein concentrations aresignificantly lower in hypertensive pregnantwomen, compared with normal pregnancy.Furthermore, the same differences occur ininactive urinary kallikrein and these differencescan be seen in the first trimester.24 Subsequentreports have shown that the inactive urinarykallikrein to creatinine ratio, measured at 14 to20 weeks' gestation, can be used to predict thedevelopment of pre-eclampsia (Kyle P M, et al.Abstract presented at International Society forStudy of Hypertension in Pregnancy, BuenosAires, 1992).

In summary, the mechanism ofhypertensiondeveloping during pregnancy seems to berelated to the balance between vasodilator andvasoconstrictor substances produced duringpregnancy, but the situation is complex andmultifactorial.

CHANGES IN THE COAGULATION SYSTEMSevere pre-eclampsia is associated withabnormalities of the coagulation system andobservations related to this subject date back tothe last century. There has always been adebate about whether these changes involvingdisseminated intravascular coagulation areprimary or secondary in nature. The bulk ofevidence now available very much suggeststhat the changes are likely to be secondary andnot causative.

Platelet function and numbers are both

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altered during normal and pre-eclampticpregnancies. There is no doubt that theplatelet count is reduced in women with severepre-eclampsia, but severe changes occur inonly about 15% of women with severedisease.27 Platelet lifespan is reduced inwomen with established pre-eclampsia.28Factor VIII clotting activity is increased abovenormal for the accepted range in pregnancyand factor VIII consumption is increased inboth pre-eclampsia and intrauterine growthretardation.29

Antithrombin III activity30 remains constantin normal pregnancy but shows a significantdecline in pre-eclampsia.32 This is directlyrelated to the severity of the disease processand may predate the onset of clinical disease.

Fibrin metabolism is significantly alteredin normal pregnancy with a rise in plasmafibrinogen. There is increased generation offibrin during normal pregnancy but wide-spread deposition of fibrin does not occur. Inpre-eclampsia, fibrinolytic activity seems to bereduced whereas fibrin generation increases.31Deposits of fibrin or fibrin-like material arewidespread and fibrin degradation productsare increased in women with severe pre-eclampsia.32

Finally, the deposition of fibrin is oftenassociated with fibronectin and laminin33 andit is not surprising that plasma concentrationsof fibronectin and laminin are increased inwomen with pre-eclampsia.

PLACENTATIONThe changes that occur in early placentationin normal pregnancy have been well docu-mented. During the first trimester, extravillouscytotrophoblast moves from the tip of anchor-ing villi to the spiral arteries in the placentalbed and migrates down the intima of the ves-sels destroying the normal musculo-elastictissue and creating flaccid sinusoidal channels.However, Brosens and his colleagues demon-strated that the second wave of invasion failedin women who developed pre-eclampsia andthe conversion of spiral arteries to a flaccidstructure did not occur.34 Thus from theearly second trimester, the impairment of thedevelopment of normal uteroplacental bloodflow and consequent fetal growth impairmentseems to be inevitable. There has been muchspeculation as to why the invasion is defectiveand whether it has an immunological basis,and also whether it plays a critical part inthe development of hypertensive disease inpregnancy.

The prevention ofpre-eclampsiaThe concept that it may be possible to preventpre-eclampsia presents the most favourableoption in any therapeutic proposal and agreat deal of effort has therefore beendirected at developing methods for selectingindividuals at high risk of pre-eclampsiaand giving them prophylaxis. Numeroustechniques for the prediction of pre-eclampsiahave been explored and these have recently

been reviewed.35 The methods includemid-trimester blood pressure measurements,the detection of microalbuminuria, cold pres-sor tests, isometric exercise tests, roll-overtests, angiotensin infusion tests, and themeasurement of platelet AII receptors.Biochemical markers such as uric acid,calcium excretion, and the excretion ofprostacyclin metabolites, urinary kallikreinmeasurements, and certain coagulationfactors, particularly in relation to fibronectinand antithrombin III concentrations, have allbeen explored. It is reasonable to concludethat, at this stage, none of these tests has beenideal. However, the two tests with the highestpredictive accuracy at present are angiotensinsensitivity tests and mid-trimester platelet AIIreceptor measurements.

LOW DOSE ASPIRINAspirin, or acetylsalicylic acid, acts as aninhibitor of cyclo-oxygenase activity and ofplatelet aggregation when used in low doses. Ithas been extensively studied in relatively highdoses taken during pregnancy but no realproblems in terms of ductus closure have beendemonstrated in the fetus. Ylikorkala and hisgroup have shown in studies on umbilicalarteries that a single dose of 500 mg of aspiriningested by the mother significantly reducedprostacyclin and thromboxane synthesis,whereas 100 mg aspirin did not affect prosta-cyclin synthesis.36 The first clinical trial of pro-phylaxis with low dose aspirin in pregnancyinduced hypertension was reported by Beaufilset al,37 and the following year Wallenburg38and colleagues produced the results of a ran-domised, placebo-controlled, double blindstudy using 60 mg of aspirin daily and selectingpatients by using the angiotensin sensitivitytest at 28 weeks' gestation. The study wasperformed on 24 women. Two of the 21women developed mild hypertension, whereas12 of the placebo group developed hyper-tension of varying degrees of severity.

Since that study, several trials have started.The largest of the multicentre trials has beenthe Collaborative Low-dose Aspirin Study inPregnancy (CLASP) trial39 which admittedonly those women in whom there was signifi-cant doubt as to whether they would benefitfrom aspirin. The results generally indicatedonly very marginal value in preventing pre-eclampsia and, therefore, the implication isthat low dose aspirin carries very little benefit.It must, however, be remembered that theDutch study was subject to meticulous selec-tion procedures and it is likely that there is aselected group within this large cohort ofpatients that would benefit from aspirin. Thereis a case for a study on primigravid womenselected as high risk and subjecting them to arandomised, double blind controlled trial.

The management ofpre-eclampsiaBetween 1-15% of British women develophypertension during pregnancy and about 10%of them develop proteinuria as well. Most

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definitions state that hypertension in preg-nancy is defined as 'the occurrence of a bloodpressure of 140/90 mm Hg or more on two ormore occasions at least six hours apart in awoman shown to be normotensive before theonset of pregnancy'. Clinically importantproteinuria is defined as 300 mg/l in a 24 hourspecimen.The management of mild gestational hyper-

tension has been based on the premise thatmild hypertension in likely to progress to pre-eclampsia and eclampsia and, therefore, it wasadvantageous to keep to women resting inhospital. However, it is now well establishedthat those women who develop gestationalhypertension alone do not exhibit increasedmaternal or perinatal loss and therefore homemanagement with day case attendances atpregnancy assessment units is becoming thefavoured option. Women can be taught toassess their own blood pressure and urine andto report to the centre should abnormal signsdevelop. The assessment of fetal growth andwelfare is essential.

THE ROLE OF DRUG TREATMENTAs mild or moderate hypertension withoutproteinuria have little adverse effect on fetalor maternal welfare, the justification for con-trolling blood pressure has to be based on theprotection of the mother's cerebrovascularcirculation and in preventing progressionto proteinuric hypertensive disease. Suchobjectives must be achieved without detrimentto the fetus as a result of side effects that thedrug may have on the fetus or neonate. Thusantihypertensive treatment is indicated wherehypertension persists and where it is desirableto prolong gestation. Many obstetricians takethe view that if it is possible to keep the infantalive in the special care baby unit (SCBU) witha good chance of survival then early delivery ispreferable. However, if the fetus can be safelykept in utero and requires minimal time in aSCBU, this must be the preferred option.

CENTRALLY ACTING ANTIHYPERTENSIVEAGENTSThe drugs most commonly used in clinicalpractice in mild hypertension are centrallyacting antihypertensive agents such as ot

methyldopa. This drug has been usedextensively. It often has unpleasant side effectsfor the mother, but apart from occasionalhypoglycaemia and mild hypertension, it hassingularly little adverse effect on the neonate.

SYMPATHOLYTIC AGENTSA wide range of c blockers and some combinedot and c sympathetic blocking agents have beenused in pregnancy, but the most widely usedcompounds in the United Kingdom arelabetalol and atenolol. Other compounds usedinclude sotalol, metoprolol, acebutolol andoxprenalol. All of these compounds maycause neonatal bradycardia, hypotension, andhypoglycaemia when used in high doses and

their various actions have been described in acomprehensive review by Broughton Pipkin.40

CALCIUM CHANNEL INHIBITORSThese compounds act by preventing theingress of calcium to the smooth muscle cell.Although they have not been widely usedin pregnancy hypertension, drugs such asnifedipine have been shown to be very effec-tive in controlling blood pressure in severelyhypertensive women,41 but their use has beenlimited because of theoretical concerns aboutteratogenic effects. Any teratogenic effectsare of limited relevance as treatment forpre-eclampsia is required in the second andthird trimester of pregnancy. However, thereare no controlled studies of the use of thesecompounds in pregnancy and caution shouldstill be exercised in their use. Concurrentuse of calcium antagonists and magnesiumsulphate should be avoided.

ANGIOTENSIN CONVERTING ENZYMEINHIBITORSCaptopril administered to pregnant sheepand rabbits42 severely compromises fetal andneonatal survival. In a study of 12 humanpregnancies oligohydramnios and neonatalanuria were noted in four cases and inthree cases there were perinatal deaths.43This drug should be avoided where possiblein pregnancy.

Mild to moderate hypertension shouldbe managed by careful observation of bothmother and fetus and by timely interventionwhen a reasonable gestation age is achieved.This objective can sometimes be achieved bythe use of antihypertensive drugs.

Severe pre-eclampsia and eclampsiaThe principal objectives of management inthis condition are to control the fits and bloodpressure and to deliver a live infant. It is rarelypossible to prolong such pregnancy more thana few days without the risk of developingthe HELLP syndrome in the mother, withsubsequent fetal or neonatal death.

Severe pre-eclampsia and eclampsia consti-tute an obstetric emergency and it is essentialto prevent convulsions by early intervention ifthere are signs of hyperreflexia and symptomsof frontal headache and epigastric pain.Convulsions can be controlled by slow intra-venous infusion of 20 mg of diazepam, buturgent transfer to hospital is essential whereintensive care facilities are available.

Hydralazine is still the drug of choice foracute control of blood pressure. Initial intra-venous administration with a continuousinfusion with subsequent intramuscular injec-tions should stabilise the blood pressure at90 mm Hg diastolic pressure so that deliverycan be planned.

Probably the most important change inmanagement regimens has been the introduc-tion of careful regulation of blood volume andthe monitoring of pulmonary capillary wedge

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pressures. The expansion of blood volumeshould be undertaken with monitoring ofcentral venous pressure or by monitoringcapillary wedge pressure.

1 Hughes EC. Obstetric-gynecologic terminology. Philadelphia:Davis, 1972.

2 Davey DA, MacGillivray I. The classification and definitionof the hypertensive disorders of pregnancy. Clin ExpHypertens 1986; B5: 97-133.

3 Report on Confidential Enquiries into Maternal Deaths inthe United Kingdom. 1988-1990. London: HMSO,1994, 22-6.

4 MacGillivray I. Pre-eclampsia. In: The hypertensive disease ofpregnancy. London: WB Saunders, 1983:181-2.

5 Macpherson MBA. A study of vascular adaptation inhuman pregnancy. Thesis. University of Nottingham,1988.

6 Stainer K, Pickles C, Cowley AJ. The effects of posture onabnormalities of forearm venous tone in women withpregnancy induced hypertension. Clin Sci 1987; 73:267-9.

7 MacGillivray I. Some observations on the incidence of pre-eclampsia. Journal of Obstetrics and Gynaecology of theBritish Commonwealth 1958; 65: 536-9.

8 Campbell DM, MacGillivray I, Carrhill R. Pre-eclampsia insecond pregnancy. Bry Obstet Gynaecol 1985; 92: 131-40.

9 Need JA. Pre-eclampsia in pregnancies by different fathers:immunological studies. BMJ 1975; i: 548.

10 Chesley LC, Cooper DW. Genetics ofhypertension in preg-nancy: possible single gene control of pre-eclampsia andeclampsia in the descendants of eclamptic women. Br YObstet Gynaecol 1986; 93: 898-908.

11 Hayward C, Livingstone J, Holloway S, Liston WA, BrockDJH. An exclusion map for pre-eclampsia: assumingautosomal recessive inheritance. Am J7 Hum Genet 1992;50: 749-57.

12 Ward K, Hata A, Jeunemaitre X, Helin C, Nelson L,Namikawa C, et al. A molecular variant of angiotensino-gen associated with pre-eclampsia. Nature Genetics 1993;4: 59-61.

13 Arngrimsson R, Bjornsson S, Giersson RT, Bjornsson H,Walker JJ, Snaedal G. Genetics and familial predisposi-tion to eclampsia and pre-eclampsia in a defined popula-tion. Bry Obstet Gynaecol 1990; 97: 762-9.

14 Campbell DM, MacGillivray I, Thompson B. Twin zygo-sity and pre-eclampsia. Lancet 1977; ii: 97.

15 Stevenson AC, Davison BCC, Say T, Usutoplus LD, EinenMA, Toppozata HK. Contribution of fetal/maternalincompatibility to aetiology of pre-eclamptic toxaemia.Lancet 1971; ii: 1286.

16 Howy C, Beard RW. Report to the meeting on results of the UKsurvey of diabetic pregnancies. London: Royal College ofObstetricians and Gynaecologists, 1982.

17 Duffus GM, MacGillivray I. The incidence ofpre-eclamptictoxaemia in smokers and non-smokers. Lancet 1968; i:994.

18 Symonds EM, Stanley MA, Skinner SL. Production ofrenin by in vitro of human chorion and uterine muscle.Nature 1968; 217: 1152-3.

19 Baker PN, Broughton Pipkin F, Symonds EM. A com-parative study of platelet angiotensin II binding andthe angiotensin II sensitivity test as predictors ofpregnancy induced hypertension. Clin Sci 1992; 83:89-95.

20 Wallenburg HCS, Rotmans N. Prevention of recurrent idio-pathic growth retardation by low-dose aspirin and dipyri-damole. AmJ7 Obstet Gynecol 1987; 157: 1230-5.

21 Filshie GM, Maynard PV, Hutter C, Cooper JC, RobinsonG, Rubin P. Urinary 5-hydroxindole acetic acid concen-tration in pregnancy induced hypertension. BMJ 1992;304: 1223.

22 Walsh CW. Lipid peroxidation in pregnancy. Hypertensionin Pregnancy 1994; 13: 1-32.

23 Brown MA, Tibben E. Nitric oxide in pre-eclampsia. In:Proceedings of the IXth International Congress of theInternational Society for the Study of Hypertension inPregnancy, 1994: 298.

24 Campbell SK, Farrer A, Albano JDM, Steel PJ, Millar JGB.The renal kallikrein system in pregnancy. In: Sharp F,Symonds EM, eds. Hypertension in pregnancy. New York:Perinatology Press Ithica, 1987: 201-19.

25 Valdes G, Espinoza P, Moore R, Croxatto HR. Urinarykallikrein and plasma renin activity in normal humanpregnancy. Hypertension 1981; 6 (supple II): 55.

26 Kovatz S, Arber I, Korzets Z, Rathaus M, Aderet NB,Bernheim J. Urinary kallikrein in normal pregnancy, preg-nancy with hypertension and toxaemia. Nephron 1985: 40:48-51.

27 Pritchard JA, Cunningham FG, Mason RT. Coagulationchanges in eclampsia, their frequency and pathogenesis.Am J Obstet Gynecol 1976; 124: 855-64.

28 Rakoczi I, Tallian F, Bagdany S, Gati I. Platelet life-span innormal pregnancy and pre-eclampsia as determined by anon-radioisotope. Thromb Res 1979; 15: 553.

29 Weiner CP. Clotting alterations associated with thepre-eclampsia/eclampsia syndrome. In: Rubin PC,ed. Handbook of hypertension. Vol 10. Hypertension duringpregnancy. Amsterdam: Elsevier Science Publishers, 1988:241-56.

30 Weiner CP, Brandt J. Plasma antithrombin III activity: anaid in the diagnosis of pre-eclampsia-eclampsia. Am YObstet Gynecol 1982; 12: 275.

31 McKillop CA, Howie PW, Forbes CD. Sequential studiesin pre-eclampsia using plasma fibrinogin chromatography.BrJ Obstet Gynaecol 1977; 84: 909.

32 Howie PW, Prentice CRM, McNicol GP. Coagulation fib-rinolysis and platelet function in pre-eclampsia essentialhypertension and placental insufficiency. Journal ofObstetrics and Gynaecology of the British Commonwealth1971; 78: 992-1003.

33 Stubbs TM, Lazarchick J, Horger EO. Plasma fibronectinlevels in pre-eclampsia: a possible biochemical marker forvascular endothelial damage. Am J Obstet Gynecol 1984;150: 885.

34 Brosens J, Robertson WB, Dixon HG. The role of spiralarteries in the pathogenesis of pre-eclampsia. ObstetGynecolAnn 1972; 1: 177-91.

35 Baker PN. The prediction of pre-eclampsia. CurrentObstetrics and Gynaecology 1992; 3: 69-74.

36 Ylikorkala 0, Mikila VM, Kaapa P, Viinikka L. Maternalingestion of acetylsalicylic acid inhibits fetal and neonatalprostacyclin and thromboxane in humans. Am J ObstetGynecol 1986; 155: 345-9.

37 Beaufils M, Uzan S, Donsimoni R, Colau JC. Prevention ofpre-eclampsia by early antiplatelet therapy. Lancet 1985; i:840-2.

38 Wallenburg HCS, Makovitz JW, Dekker GA, Rotmans P.Low dose aspirin prevents pregnancy-induced hyperten-sion and pre-eclampsia in angiotensin-sensitive primi-gravidae. Lancet 1986; i: 1-3.

39 CLASP (Collaborative low-dose aspirin study in preg-nancy) Collaborative Group, CLASP: a randomised trialof low-dose aspirin for the prevention and treatment ofpre-eclampsia among 9364 pregnant women. Lancet1994: 343: 619-29.

40 Broughton Pipkin F. The effect of maternal drug therapy onthe fetus. In: Sharp F, Symonds EM, eds. Hypertensionin pregnancy. New York: Perinatology Press, 1986:305-22.

41 Walters BNJ, Redman CWG. Treatment of severepregnancy-associated hypertension with the calcium-antagonist nifedipine. Br J Obstet Gynaecol 1984; 91:330-6.

42 Broughton Pipkin F, Symonds EM, Turner SR. The effectof SQ14, 225 (Captopril) upon mother and fetus in thechronically cannulated ewe and in the pregnant rabbit.YPhysiol 1982; 323: 415-22.

43 Mochizuki M, Maruo T, Motoyama S. Treatment of hyper-tension in pregnancy by a combined drug regime includ-ing captopril. Clin Exp Hyp 1986; B5: 69-78.

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