Pre-Eclampsia Toxaemia of Pregnancy

The toxaemias of pregnancy form a discrete clinical syndrome which has been recognised as a disease of pregnancy almost since the practice of medicine began. Their aetiology and pathogenesis are still unknown, and despite all the resources of modern medicine, there is no treatment more effective than termination of the pregnancy — a therapy which was discovered several centuries B .C. There is no question that the nature of the condition provides one of the most fascinating problems of contemporary medical research, but the urgency of gaining an understanding of the condition, and of evolving more effective therapy, is only seen by considering the damage actually done by the disease, and the toll it still takes of maternal and infant life. Present day maternal mortality figures are approximately 0.4 deaths per 1000 births. Of these, 18% are due to pregnancy toxaemia, which is second only to abortion as the largest single cause of maternal loss of life. For the child, the risk of stillbirth or early neonatal death is more than doubled in toxaemia, compared with normal pregnancy. It is possible to calculate that the loss of infant life in United Kingdom which can be ascribed to toxaemia is about 3,000 deaths per annum. For comparison, the total number of deaths in road accidents is about 7,000 per annum. Thus pregnancy toxaemia can be taken to be responsible for nearly half as many deaths as our much publicised traffic problem. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISSN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, Winter 1965-66, 5(1): 29-33 doi: 10.2218/resmedica.v5i1.449 PRE-ECLAMPSIA TOXAEMIA OF PREGNANCY ROBERT C. HEADING, B.Sc. Based on a dissertation read to the Royal M edical Society, on 5th Novem ber, 1965. T h e toxaemias of pregnancy form a discrete clinical syndrome which has been recognised as a disease of pregnancy almost since the practice of medicine began. T h eir aetiology and patho­ genesis are still unknown, and despite all the resources of modern m edicine, there is no treatm ent more effective than termination of the pregnancy — a therapy which was dis­ covered several centuries B .C . There is no question that the nature of the condition pro­ vides one of the most fascinating problems of contem porary m edical research, but the urgency of gaining an understanding of the condition, and of evolving more effective therapy, is onlyseen by considering the damage actually done by the disease, and the toll it still takes of maternal and infant life. Present day m aternal m ortality figures are approxim ately 0.4 deaths per 1000 births. O f these, 18 % are due to pregnancy toxaemia, which is second only to abortion as the largest single cause of maternal loss of life. For the child, the risk of stillbirth or early neonatal death is more than doubled in toxaemia, com ­ pared with normal pregnancy. It is possible to calculate that the loss of infant life in United Kingdom which can be ascribed to toxaemia is about 3,000 deaths per annum . Fo r comparison, the total num ber of deaths in road accidents is about 7,000 per annum . Thus pregnancy toxaemia can be taken to be responsible for nearly half as many deaths as our muchpublicised traffic problem. T h e actual incidence of the condition is difficult to assess, largely due to the problem of establishing a generally acceptable set of diagnostic criteria. Average figures seem to suggest an incidence of 10 % in first pregnancies, and 5% in other pregnancies, but estimates as high as 25% of all pregnancies have been quoted.1 Thus toxaemia of pregnancy is not sim ply a rare and interesting obstetric curiousity. It is a very real disease, responsible for considerable suffering, which deserves our close and critical appraisal. D efin ition o f Toxaem ia Toxaem ia of pregnancy is strictly a syndrome, not a disease. It is characterised by three fea­ tures — hypertension, oedema and album in­ uria — and these three features define the condition. However, they do not all need to be present to justify the diagnosis, since in mild cases, albuminuria may be absent or m inim al There arc also three possible origins or found­ ations for the toxaemia, and these are preeclampsia, essential hypertension and chronic


PRE-ECLAMPSIA TOXAEMIA OF PREGNANCY
ROBERT C. HEADING, B.Sc.

Based on a dissertation read to the Royal M edical Society, on 5th N ovem ber, 1965.
T h e toxaem ias of pregnancy form a discrete clinical syndrom e which has been recognised as a disease of pregnancy alm ost since the practice o f m edicine began.T h e ir aetiology and patho genesis are still unknow n, and despite all the resources of m odern m edicine, there is no treatm ent m ore effective than term ination of the pregnancy -a therapy w hich was dis covered several centuries B .C .T h e re is no question that the nature of the condition pro vides one of the m ost fascinating problem s of contem porary m edical research, bu t the urgency of gaining an understanding of the condition, and of evolving m ore effective therapy, is onlyseen by considering the damage actually done by the disease, and the toll it still takes of m aternal and in fan t life.
Present day m aternal m ortality figures are approxim ately 0.4 deaths per 1000 births.O f these, 18 % are due to pregnancy toxaem ia, which is second only to abortion as the largest single cause of m aternal loss of life.F o r the child, the risk of stillbirth or early neonatal death is m ore than doubled in toxaem ia, com pared with norm al pregnancy.It is possible to calculate that the loss of in fan t life in U nited K ingdom which can be ascribed to toxaem ia is about 3,000 deaths per annum .F o r com parison, the total num ber of deaths in road accidents is about 7,000 per annum .T h u s pregnancy toxaem ia can be taken to be responsible for nearly half as m any deaths as our muchpublicised traffic problem .
T h e actual incidence of the condition is difficult to assess, largely due to the problem of establishing a generally acceptable set of diagnostic criteria.Average figures seem to suggest an incidence of 10 % in first pregnancies, and 5 % in other pregnancies, bu t estim ates as high as 2 5 % of all pregnancies have been quoted.1 T h u s toxaem ia o f pregnancy is not sim ply a rare and interesting obstetric curiousity.It is a very real disease, responsible for considerable suffering, which deserves our close and critical appraisal.

D efin itio n o f Toxaem ia
T oxaem ia o f pregnancy is strictly a syndrome, not a disease.It is characterised by three fea tures -hypertension, oedema and album in uria -and these three features define the condition.H ow ever, they do not all need to be present to ju stify the diagnosis, since in mild cases, album inuria m ay be absent or m inim al T h ere arc also three possible origins or found ations for the toxaem ia, and these are preeclam psia, essential hypertension and chronic nephritis.
T h e classification becom es further com plicated by the fact that quite apart from the toxaem ia deriving from essential hypertension, patients with essential hypertension suffer an increased risk of developing a superimposed pre-eclam ptie toxaemia.It is possible for a patient to have essential hypertension through out pregnancy without developing toxaemia, but the interesting question of whether the same m ay be said of pre-eclampsia cannot be answered.
T h e three conditions are com m only classed together since differentation between them, particularly in the late pregnancy, is often im possible, and since the treatm ent is largely identical, resolution is usually an academic point.T h ere is, however, som e basis for con sidering pre-eclampsia a discrete condition.In this type, the onset of toxaem ia is often asym p tom atic and usually occurs after the thirtieth week of pregnancy.It may advance slowly or rapidly, and all but the m ildest form will pro duce histological changes in the liver, kidney and placenta.Severe pre-eclampsia w ill lead to eclam psia.T h is pattern is characteristic of the pre-eclam ptic type of toxaemia, and forms the basis for the statem ent that pre-eclampsia can occur in the patient with essential hyper tension.Subsequent discussion is confined to this type of toxaemia, since it seems possible that the basic pathology underlying it is also partly responsible for the production of the other toxaemias.
H ow ever it should be emphasised that this is an assum ption w ithout solid foundation, and is not generally accepted.

Presentation o f Pre-Eclam psia
Pre-eclampsia is a condition confined to pregnancy.T h e three primary features of toxaemia have been described, and in this form , the hypertension is usually the first to appear, followed by the fluid retention.H ypertension is com m only taken to be present when the blood pressure readies 140/90, but since the B .P .during the second trim ester may norm ally be as low as 110 / 7 0 , a sudden rise from this to 130 /8 5 could well represent the onset of toxaemia.It is therefore im perative that the blood pressure is recorded under identical con ditions each tim e the patient attends for ante natal care.
Fluid retention appears as a generalised oedema not to be confused with ankle-swelling, which is often present in apparently normal pregnancy.Tightness of the wedding-ring, or puffiness of the eyes is often the patients com plaint, and although a worsening ankle oedema m ust be held to be suggestive of toxaemia, evidence of a non-dependent oedema is a much stronger clue.A lbum inira is a late sign of pre eclampsia and of little use diagnostically.Its degree does, however, carry considerable pro gnostic significance.
It is exceptional for a firm diagnosis of preeclampsia to be m ade on a single consultation.If the patient is attending regularly, a finding of a rise in blood pressure of 10 m m .diastolic, a com plaint of oedema, or a weight gain of 3 lb. in two weeks requires that the patient be seen again within two or three days.If the findings are confirm ed, the diagnosis of toxaem ia should be made, and therapeutic measures instituted.T h is m ay sound easy, but one m ust remember that ankle oedema is com m on in pregnancy; urinary infection (producing a trace of album in uria) is also com m on, and any anxiety will elevate the blood pressure.A ll three signs may thus co-exist without having any basis in toxaem ia.Diagnosis is thus m ade from repeated routine checking of weight, blood pressure and the urine, and provided these tests are con scientiously carried out successful early detec tion can be achieved.
In the m ore severe ease of pre-eclampsia other m anifestations of the toxaemia are addednam ely headache, visual disturbances, epigastric pain and vom iting, and the condition may pro ceed to frank eclam psia with episodes of con vulsions, coma and then further convulsions.E ven if left untreated, not every case of pre eclam psia would proceed to eclam psia, but there is no way o f predicting the course of the disease at the tim e of its onset and it is not possible to detect those destined for the severe type of toxaemia.E arly diagnosis and careful observ ation is therefore necessary in all eases.

Pathology
T h e classical pathology of eclam psia is repre sented by changes in the liver and kidney which are quite characteristic.T h e liver is said to undergo a periportal necrosis in the first instance, but this of course may extend to a massive necrosis with liver failure.A midzonal necrosis is also seen in som e cases.H ow ever it is the periportal lesion that is characteristic of eclampsia and it has been shown that it is caused by leakage of plasma into the space between the colum n of liver cells and its sheath of connective tissue, pro ducing compression and necrosis o f the cells.2T h e leakage is of blood rather than plasma in cases of haem orrhagic necrosis.M u ltiple small haemorrhages arc also present beneath the capsule of the liver, and within the organ itself.T h e kidney exhibits a characteristic glom er ular change with endothcliosis, swelling of the endothelial cells and oedema of the intcrstitium .
N o abnorm ality of the basement m em brane has been found.The placenta shows evidence of premature ageing with areas of infarction and fibrin nodes on the villi, but there are no changes characteristic of the disease.Elsew here in the body, the lesions are those of capillary throm bosis and haemorrhage, and small haemorrhages are found generally.
Investigations into blood flow have shown that the kidney in pre-eclampsia has a low blood flow as a consequence of reduction in diameter of the afferent arteriole3 and there is some evidence that the uterine and placental arterial supply is also dim inished.4Blood flow to the liver, brain and lim bs in pre-eclampsia has not been shown to differ from normal pregnancy, but in eclam psia, the cerebral blood flow is severely reduced5.T h u s the pathology of the condition, together with the clinical m anifestations appears to indicate that there is an arterial or arteriolar constriction in at least kidney and placenta which has given rise to an increase in peripheral resistance, and so to hypertension.The capillary haemorrhages and liver changes can be regarded as secondary to hypertension, and the eclam ptic convulsions arc almost certainly due to cerebral anoxia follow ing arteriolar spasm.
The renal picture of a broadened pale renal cortex and congested m edulla, with m icroscopy showing swollen glomeruli, im m ediately calls to mind the lesion of acute glom erulonephritis.T h e similarities, of course, go further-the presenting clinical signs in both conditions include hypertension, non-dependent oedema and album inuria, and in severe glom erulone phritis, convulsions also occur.It is therefore necessary to bear in mind the possibility of pre-eclampsia having a related pathogenesis, and being essentially an im m unological reaction to a sensitising agent derived from the foetus or placenta.However considerable difficulty arises when an attem pt is m ade to explain the relationship of the odcma to the hypertension, and in trying to correlate the degree of hyper tension with the extent of renal damage.Nevertheless, some support is produced for im m unological explanations of pre-eclampsia and although these do not hold widespread popularity, they should not be overlooked.6-7

Aetiology
Before considering some of the other possible causes of pre-eclampsia, it is desirable to record some of the epidem iological findings that will have to be reconciled with any acceptable theory.
1. Pre-eclampsia appears more often in first pregnancies than in subsequent pregnancies.2. Essential hypertension predisposes to it, and conversely, pre-eclampsia predisposes to the developm ent of essential hypertension in later life.3. M u ltiple pregnancies carry a higher risk of pre-eclampsia than normal pregnancies.4. H ydatiform mole predisposes to preeclampsia.Death of the foetus in utero is usually associated with im provem ent in the con dition.but eclampsia can occur after delivery of the foetus and expulsion of the placenta.
T h ere is no justification for assum ing auto m atically that since pre-eclampsia is a disease of pregnancy alone, its origins will be found in the products of conception.G ross changes occur in m any organs during pregnancy, and these m ust be regarded with every bit as much suspicion as the uterine contents.N evertheless, with som e grounds, m any workers believe in the production of a pressor substance by the placenta, and the liberation of this material into the m aternal circulation, causing the hypertension.B y analogy with the kidney, the concept of the " G o ld b latt placenta" has arisen, but positive evidence of a humoral vasopressor m aterial liberated as a result of uterine or placental ischaemia is sadly lacking.It is known that the plasm a renin level is elevated during pregnancy, but there is no evidence that the uterus or placenta is responsible for this, nor that the elevation is greater in toxaem ic patients than in norm al pregnancy.8Investigation of the steroid hormones in toxaemia has given conflicting results, but the general feeling seems to support an elevation of the 17 -hydroxysteroid output, with a reduction in the adreno cortical response to A .C .T .H .even low er than in normal pregnancy.910 It has been suggested that the ratio of m ineralocorticoid/glucocorticoid hormones is elevated in toxaem ia11 but current work all seems to refute the proposal that aldosterone production in toxaemia is higher than in normal pregnancy12'13 A n elevation of aldosterone output would, of course, be an excellent prelim inary to rational ising the salt and water retention.
T h ere are also published works on the presence of an anti-diuretic material found in pre-eclamptic patients sera, suggesting a posterior pituitary-like horm one as the causative agent, but in spite of the natural tendency to think of the posterior pituitary when concerned with a problem o f vasoconstriction and water retention, this too has led now here.14-15R ecently, great interest has centred on the m onoam ines, and in particular 5 -hydroxytryptam ine.T h e discovery o f reduced m onoam ine oxidase activity in the placentae of pre eclam ptic patients led to the theory that ; -hydroxytryptam ine accum ulated in these patients, producing vasoconstriction.16 Since m onoam ine oxidase activity is known to be related to oxygen tension17 this vasoconstriction, by lowering placental oxygen tension, would reduce m onoam ine oxidase activity still further and so a vicious circle would be set up.However the m onoam ine oxidase inhibitor drugs do not appear to precipitate pre-eclampsia, as they m ight be expected to do if this theory were valid, and there is no positive evidence to support the contention that these drugs are unable to cross the " placental barrier" .In any case, a paper published recently failed to con firm the basic finding of reduced m onoam ine oxidase levels.18 A lthough pre-eclampsia am ply justifies its title of " the disease of theories" there is no question that current thought is focused on a humoral origin of the hypertension, related to ischaemia of the uterus or its contents.H ow ever, although the idea is not new 1920 the im portance of variation in sensitivity of the blood vessels to the known pressor agents does not seem to have received the intense experi mental investigation that it warrants.T h ere are two possibilities.
1. T h a t the blood vessels in the pre-eclam ptic patient are inherently more sensitive to a pressor m aterial produced by the uterus or its contents in all pregnancies.
2. T h a t the uterus in pre-eclampsia is liber ating into the maternal circulation a material which is not in itself a pressor substance, but increases the sensitivity of the blood vessels to the known pressor materials.T h e possible im plication of m onoam ine oxidase in the aetiology of pre-eclampsia renders one very conscious of the precedent pro vided by the action of the anti cholinesterase drugs at the neuromuscular junction.
T h ere is no question that the influencesnotably endocrine influences -on the sensi tivity of blood vessels to substances such as the catechol amines, serotorin, angiatensin and the posterior pituitary hormones are w orthy of intense investigation.Progress in research into essential hypertension m ust be closely followed by those interested in pre-eclampsia, and it could be that the two conditions have much in com m on.

Management of Pre-Eclam psia
A wom an adm itted to hospital with m ild or m oderate pre-eclampsia is usually confined to bed, given a sedative such as phenobarbitone or am ytal, and nothing more.Some obstetricians also restrict the patient's salt intake.Com plete bed rest and sedation arc designed to provide the best environm ent for peace of mind and a general absence of the em otional strains of daily life, but of course, steps must also be taken to isolate the patient from any sources of personal worry if these exist.In severe cases a check on urinary output is necessary, but in the m ajority observation of blood pressure and weight will show the success of these measures.Bed rest alone, b y virtue of being a horizontal position, w ill reduce ankle oedema, so this m ust not be regarded as an index of the response to treat m ent.
F o r the m inority of patients in w hom this regim e is unsatisfactory, the use of hypotensive drugs m ay be necessary.T h e rauwolfia and veratrum alkaloids have been used -reserpine in particular is a good drug for the m ilder degrees of hypertension.Severe cases will require the use o f guanethidine in conjunction w ith a thiazide diuretic, since it is im perative to bring the blood pressure down to less dangerous levels.O ne hopes that the risk of eclam psia is correspondingly dim inished.H ow ever the effect of the m ore potent anti-hypertensive and diuretic drugs on the prognosis for the child has been disappointing, and it appears that this is largely due to their small effect on uterine blood flow and therefore on placental supply.
T h e obstetric m anagem ent of pre-eclampsia can dem and agonising decisions.It m ay be said that as pregnancy advances to term, preeclam psia w ill tend to becom e m ore severe, and the ageing placenta will fail to m eet the require ments of the foetus.On the other hand, the foetus in pre-eclampsia is com m only smaller than average, and early induction of labour is liable to produce a very small baby, exposed to all the risks of prem aturity.T h e problem is therefore one of when to induce, and no hard and fast rules are available.Assessm ent of the baby's size is usually carried out clinically and som e idea o f placental function m ay be gained from the urinary pregnanediol output, but experience remains the best foundation for m aking the decision.Induction before 36 weeks w ill be necessary in patients w ith severe hyper tension and album inuria, since here the prognosis for the infant is better than that for the foetus in utero.T h e correlation between album inuria and prognosis has been m entioned earlier.N evertheless, the great m ajority o f cases can be left to 38 or 39 weeks, when induction should usually be carried out.T h e conventional m ethods o f induction are used, and this is not the place to discuss the relative m erits of these.B u t it is not out of place to add that the general rule of failed oxytocin induction being an indication for Caesarian section is in n o way invalidated by toxaem ia.
T h e m anagem ent o f im m inent or frank eclam psia is a standard procedure and there is little to be gained from reiterating it here.It is obvious that pre-eclampsia is a condition where it is vital under present circum stances to con centrate on early diagnosis and the prevention of eclam psia, rather than the treatm ent of eclam psia itself.Surveys of maternal m ortality in toxaem ia indicate that nearly 50% o f the deaths could have been avoided w ith early diagnosis and treatm ent.T h e size of this avoidable m ortality is in part due to patients who, for one reason or another, have failed to seek m edical attention, but it still represents an unnecessary loss o f life, and the im portance of every pregnant woman receiving anti-natal care m ust be firm ly impressed on the general popul ation.N evertheless, even w ith the best care available, the treatm ent of toxaem ia seems inadequate for the m id-twentieth century, and it looks as if perm utations and m odifications of present m ethods will provide nothing but trivial im provem ent.It is likely that the solution will eventually com e from the endocrinologist who is investigating the problem at the fundam ental level, and one would hope that from this, an efficient therapy will be developed to banish this disease of theories from our m aternity hospitals.
Liver In Eclampsia showing periportal necrosis (by courtesy of Mr. L. P. Mackenzie).