Clinical management of established pre-eclampsia

5

Clinical management of established pre-eclampsia

Paul Moran BM, BS, MRCOG

Research Associate

John M. Davison BSc, MD, MSc, FRCOG

Professor of Obstetric Medicine

Department of Obstetrics and Gynaecology, 4th Floor, Leazes Wing, Royal Victoria Infirmary,Newcastle upon Tyne NE14LP, UK

This chapter summarizes the identification, assessment and management of women withestablished pre-eclampsia. Guidelines for out-patient management and in-patient treatment aregiven and are based on clinical experience and published reports. Drug treatment options arebriefly reviewed and the timing of delivery is discussed. A comprehensive regimen for the intra-partum management of severe pre-eclampsia is provided founded on protocols used in the RoyalVictoria Infirmary, Newcastle upon Tyne, over recent years. The chapter emphasizes the import-ance of medical history, clinical examination and investigations when arriving at what are oftendifficult clinical decisions. Controversial areas are highlighted with reference to recent publishedreports.

Key words: pregnancy; pre-eclampsia; therapy; diagnosis; anticonvulsants; antihypertensiveagents; therapeutic use.

Pre-eclampsia is still a leading cause of maternal and fetal morbidity and mortality.This review focuses on the key clinical issues regularly faced by the clinician, namelyin-patient versus out-patient monitoring, which investigations to perform, whom andhow to treat, when to deliver and how best to manage intrapartum care. Althoughdelivery is ultimately the only curative intervention, the build-up to this event and itstiming are rarely straightforward and the clinician must weigh the risks of infantprematurity against maternal well-being. Antenatal care may combine the approachesof obstetricians and physicians, each with different areas of interest, for instance thepharmacology of blood pressure control, the interpretation of fetal surveillance testsand/or intrapartum care issues, but both groups of physicians ultimately care aboutsafe outcomes. By distilling these approaches, we aim to provide guidance for whatare common but difficult and often controversial decisions faced when caring forpregnant women with established pre-eclampsia.

Baillière’s Clinical Obstetrics and GynaecologyVol. 13, No. 1, pp 77–93, 1999

1521–6934/99/010077 + 17 $12.00/00 © 1999, Baillière Tindall

IN-PATIENT VERSUS OUT-PATIENT CARE

Individual units must decide how best to use limited facilities to assess hypertensivewomen who can constitute up to 25% of antenatal referrals. Out-patient care can beundermined by the fact that disease progression may be rapid and unpredictable withmany women asymptomatic until an advanced stage of the disease. A day assessmentunit (DAU), however, enables women in the community to be kept under regulardetailed review and, indeed, randomized controlled trials have shown that in selectedwomen, without significant proteinuria, in-patient care can be reduced by 60–80%without compromising maternal or fetal management (Tuffnell et al, 1992; Twaddle andHarper, 1992).

ASSESSMENT OF THE MOTHER

Measuring blood pressure

At the Royal Victoria Infirmary, Newcastle upon Tyne, a blood pressure of140 mmHg systolic and 90 mmHg diastolic, sustained over 15 minutes, is thecriterion for referral to the DAU. To minimize ‘white coat hypertension’, anelevated blood pressure seen in an overtly clinical setting (Rayburn et al, 1993),mean blood pressure is calculated from readings at 30 minute intervals over 2hours in a relaxed setting. Hypertension will be over-diagnosed in obese womenunless a large cuff (bladder size 15 cm × 33 cm) is used, as discussed in Chapters1 and 2. Blood pressure is recorded in both arms for the first visit and the rightarm is used thereafter. Phase I Korotkoff sound corresponds to the systolicpressure and phase V is the closest approximation to the diastolic pressure. It isonly in a minority that phase V is never reached and, in the majority of readings,phases IV and V are within 5 mmHg (Brown and Whitworth, 1991). However, inorder to overcome this problem, the majority of trials in pregnancy refer to phaseIV Korotkoff although phase V is the standard for most non-pregnancy studies,making direct comparisons difficult. Unfortunately, as no universally agreed ‘goldstandard’ exists, what remains important is consistency within a unit with thephase used preferably being recorded. It is worth remembering that automateddevices measure phases I and V and are likely to underestimate the latter ineclampsia and shock when vascular wall flexibility is reduced and the sounds areless distinct. A detailed analysis of the controversies surrounding blood pressuremeasurements including the role of automated ambulatory blood pressuremonitoring is presented in Chapter 1.

Blood pressure interpretation

The blood pressure at the first antenatal visit represents a convenient baseline againstwhich subsequent changes can be assessed. It must be remembered that at this timereduced peripheral vascular resistance leads to a diastolic pressure averaging7–10 mmHg below non-pregnancy values with a nadir attained early in the secondtrimester and an increase in the third trimester by 10–12 mmHg to pre-pregnancylevels. Thus a single blood pressure reading of 140 mmHg systolic and 90 mmHgdiastolic defines approximately 2% of the population before 20 weeks but 21.5%

78 P. Moran and J. M. Davison

afterwards (Redman, 1995). These gestational changes can be exaggerated in womenwho are hypertensive prior to conception creating diagnostic confusion in the thirdtrimester with the development of pre-eclampsia.

Hypertension presenting for the first time before 20 weeks warrants investigationfor an underlying cause, as discussed in Chapter 8.

After 20 weeks, hypertension without proteinuria may be a transient finding, asa result of chronic hypertension unmasked as vascular tone returns to non-pregnant levels, or it may indicate developing gestational hypertension. Thepresentation of pre-eclampsia is extremely variable, with many women remainingasymptomatic until the late stages. Elevated blood pressure is easily detected butit represents only one aspect of a multisystem disease. Other systemic conditionswhich mimic aspects of pre-eclampsia must be excluded, namely thromboticthrombocytopenic purpura, haemolytic uraemic syndrome and acute fatty liver ofpregnancy.

General maternal assessment

It is necessary to go beyond just measuring the blood pressure and testing forproteinuria. Proteinuria is a relatively late sign of renal involvement and, although itssignificance is undisputed, evidence of haematological, neurological and hepaticinvolvement must not be overlooked.

Blood is taken for urate, aspartate transaminase, creatinine and full blood count.Albustix urine testing is performed on a midstream sample, which is sent for culture ifany degree of proteinuria is present, and a 24 hour urine collection arranged if +1 ormore is measured (see below).

Women with uncomplicated hypertension are reviewed in the routine antenatalclinic. Admission is considered on maternal grounds if there are symptoms of pre-eclampsia, the blood pressure mean is greater than 150 mmHg systolic and 95 mmHgdiastolic, significant proteinuria is present (+2 on dipstick or greater than 300 mg/24hours) or the blood results are abnormal.

Fetal surveillance

Fetal risks are secondary to placental insufficiency. This may be manifest asintrauterine growth retardation (IUGR), abruptio placentae or, in extremecases, intrauterine fetal death. However, if inappropriate premature intervention isto be avoided then it is necessary to make an accurate assessment of fetal well-being.

In Newcastle upon Tyne, we use the following regimen when considering specificinvestigations of fetal well-being in the DAU setting. A cardiotocograph (non-stresstest (NST)) is performed and the symphyseal–fundal height measured. If thesymphyseal–fundal height is less than the 10th centile, ultrasound assessments ofamniotic fluid index (AFI) and fetal growth including umbilical artery Doppler analysisare performed. A biophysical profile is required if there is an abnormal cardio-tocograph, the fetal abdominal circumference is less than the 10th centile, the AFI lessthan 5 cm or the umbilical artery Doppler pulsatile index greater than the 90thcentile.

The biophysical profile score (BPS) is unique in combining acute indices (fetalbreathing, tone, gross body movements, heart rate reactivity) and chronic indices

Clinical management of established pre-eclampsia 79

(liquor volume) of fetal well-being. We advocate its use in high-risk pregnancies ontwo counts. (1) A reassuring test is strongly correlated with a low false-negative rate(for example a rate of 0.676/1000, measured as still-births within 1 week of a normaltest (Manning et al, 1987)); this outperforms the NST alone. A normal BPS,therefore, provides reliable confirmation of fetal well-being, enabling conservativemanagement and avoiding prematurity and its complications. (2) Timely interventionbased on an abnormal score has been shown to reduce perinatal mortality rate inhigh-risk populations (Manning, 1997). The lower the BPS, the closer is thecorrelation with clinically significant fetal acidaemia. At a BPS of 4/10 10% areacidotic (pH <7.20), rising to 20% at a BPS of 2/10 and 100% with a score of 0/0(Manning, 1997).

In-patient management

Close supervision of maternal and fetal well-being is only possible on an in-patientbasis. It is, however, neither practical nor desirable to admit all women with hyper-tension if the traditional ‘cut-off ’ for normality (140 mmHg systolic–90 mmHg diastolic)is used. All maternal and fetal investigations can be performed in a DAU setting andwhat differs with in-patient care is the frequency with which they can be undertaken.Once those at particular risk have been identified then in-patient management enablesmonitoring of antihypertensive treatment and disease progression with a promptresponse to any sudden deterioration. Bed rest alone is a dubious reason for admissionas it is of unproven value (Anonymous, 1992) and if too stringent holds the risk ofvenous thrombosis.

INVESTIGATIONS TO ASSESS SYSTEMIC INVOLVEMENT

Haematological tests

The platelet count decreases in pre-eclampsia because of increased peripheralconsumption due to endothelial dysfunction evoking non-immune surface-mediatedplatelet activation. The platelet count impinges on management only if it is part of anaccompanying clotting disorder. No strict guidelines can be given for an acceptable, safeplatelet count but values greater than 50 × 109/1 are associated with normal platelethaemostasis and spontaneous bleeding only becomes a risk at counts less than20 × 109/l.

The haematocrit is often overlooked but provides a measurement of the degreeof haemoconcentration seen with hypovolaemia resulting from disordered volumehomeostasis.

Clotting parameters

The activated partial thromboplastin time and prothrombin time evaluate the intrinsicand extrinsic pathways respectively. Both provide information on the commoncoagulation pathway but are unaffected by hypofibrinogaemia until fibrin levels are verylow (approximately 0.5 g/l). The thrombin time provides the best information on theeffectiveness of the final common coagulation pathway. It is prolonged in the presenceof fibrin degradation products, heparin or reduced fibrinogen levels. These tests are


normal in pre-eclampsia unless complicated by disseminated intravascular coagulation(DIC).

Serum biochemical markers

Uric acid is one of the best markers for assessing disease severity and progression. Itincreases as gestation advances, with mean levels of 0.28, 0.29, 0.34 and 0.39 µmol/l at16, 28, 32 and 36 weeks, respectively (Redman et al, 1976). For most women itincreases with the development of hypertension and before the development ofproteinuria.

High serum urea and creatinine with a decreased creatinine clearance indicate arelatively late stage of renal involvement and are usually found in combination withsignificant proteinuria; serial determinations are useful in assessing diseaseprogression.

Proteinuria

In normal non-pregnant individuals the 24 hour urinary protein excretion averages40–80 mg (with an upper limit of 75–150 mg). This is derived from albumin (55%) andimmunoglobulins (immunoglobulin G (IgG) 5–10%, light chains 5%, IgA 3%) with theremainder largely comprising Tamm–Horsfall glycoprotein from the tubules and lowerurinary tract. Haemodynamic, electrochemical and mechanical factors limit proteinmovement across the glomerular wall with protein size, configuration, deformity andcharge being the specific determinants for glomerular handling. This selectivity isgradually lost in pre-eclampsia as proteinuria increases. It is normal to see a slightdecrease in albumin concentration in normal pregnancy but with increasing proteinuriain pre-eclampsia marked hypoalbuminaemia ensues with reduced plasma oncoticpressure and exacerbation of fluid shifts into the extravascular compartment, reducingintravascular volume.

Urinary dipstick analysis provides a convenient screening test for proteinuria butcarries high false-positive and false-negative rates. Urinalysis with an automated devicecan reduce these inaccuracies, particularly at the lower range, increasing the positivepredictive value from 24% to 47% at the +1 (0.3 g/l) concentration and from 53% to83% at the +2 (1 g/l) level without altering the false-negative rate (Saudan et al, 1997).The 24 hour urine collection remains the ‘gold standard’ for quantification of protein-uria with values over 300 mg/24 hour (in the absence of a urinary infection) represent-ing ‘significant’ proteinuria.

Most published studies (three of four) have shown that a random urineprotein:creatinine ratio gives an accurate value for the daily protein excretion (Saudanet al, 1997). This has obvious implications for out-patient monitoring and may avoidunnecessary delays when planning care. Microalbuminuria up to 30 mg/24 hour isconsidered normal in pregnancy and is not the result of hypertensively relatedstructural changes in the kidney (Erley and Risler, 1994). Once proteinuria exceedsthis level the perinatal mortality rate increases in proportion to the degree of proteinloss (Friedman and Neff, 1977). This has not been shown to be the case for maternalmortality or morbidity. For example a small study of 66 pre-eclamptic women foundthat proteinuria increases for most women managed conservatively although therewas no difference in maternal (or fetal) outcome for those who experienced amarked increase compared with those who had a modest or no increase (Schiff et al,1996).


Liver function testing

Hepatic involvement may lead to serious complications: subcapsular haematoma andrupture, hepatic infarction, and haemolysis, elevated liver enzyme and low platelet(HELLP) syndrome. Alkaline phosphatase activity increases during pregnancy andalbumin may show a slight reduction; both changes may be exaggerated in pre-eclampsia. Most other liver function tests are unchanged in normal pregnancy. Anincrease in aspartate aminotransferase (AST) and other transaminases indicateshepatocellular damage. Haemolysis may increase AST slightly but will dis-proportionately increase lactate dehydrogenase levels with serial measurementsproviding a reliable indicator of the degree of haemolysis present.

SPECIFIC THERAPY

Corticosteroids

The Royal College of Obstetricians and Gynaecologists (1996) recommends that‘every effort should be made to initiate antenatal corticosteroid therapy in womenbetween 24 and 36 weeks gestation’, with intrauterine infection or maternaltuberculosis presenting the only exclusion criteria. Controlled trials have revealed astatistically significant reduction in the incidence of neonatal respiratory distresssyndrome with the maximum effect achieved if delivery occurs between 24 hours and7 days from commencing treatment (Crowley, 1989). Betamethasone anddexamethasone remain the steroids of choice; they readily cross into the fetalcirculation and are given as 24 mg in divided doses over 48 hours by the intra-muscular or oral route. Benefit is still gained when delivery is effected before 24hours have elapsed and delivery should not be postponed if this places the mother atrisk.

Drug treatment of hypertension

All drugs are best avoided in the first trimester when safety data are limited.Fortunately the physiological decrease in blood pressure during this and the secondtrimester may make treatment unnecessary. The hypertension of pre-eclampsia iscaused by increased peripheral resistance and drug treatment is directed towardsrelieving this without compromising cardiac output. Monotherapy is the goal withagents selected for their safety record in pregnancy and episodic treatment should beavoided.

Who to treat?

Chronic hypertension represents an increased maternal risk only if there is severehypertension (blood pressure greater than 170 mmHg systolic–110 mmHg diastolic),superimposed pre-eclampsia develops (which develops in approximately 50% (Sibaiand Anderson, 1986) and/or target organ damage is present. This can be assumed tobe the case for all cases of chronic hypertension secondary to renal disease, diabetes(White (1949) White classification B–F), cardiomyopathy or collagen vasculardisease. It is in these groups that treatment of the blood pressure should be con-sidered.


Treatment reduces the risk of sudden increases in blood pressure leading to directarterial damage with the possibility of cerebral haemorrhage or hypertensiveencephalopathy. The role of treatment in cases of mild or moderate chronic hyper-tension and hypertension developing in pregnancy without proteinuria remainsuncertain as treatment does not prevent superimposed pre-eclampsia or, abruptioplacentae or influence fetal mortality. Severe pre-eclampsia will require acute orchronic treatment depending on the clinical circumstances; see Table 1. Alternatives notlisted include oral hydralazine and prazosin as second-line agents with clonidineoccasionally used as a first-line treatment.


Table 1. Drug therapy for hypertension in pregnancy.

Drug Dose Onset of action Adverse effects

Chronic treatmentMethyldopa 500–3000 mg in two Agent of choice, well

to four divided doses documented safetyrecord (after first trimester)

β-Adrenergic Specific to agent used May cause fetal bradycardia;inhibitors prolonged use of atenolol

carries a possible risk of intrauterine growthretardation (IUGR)

Nifedipine 30–120 mg p.o. in Theoretical potential forthree or four divided profound hypotension indoses as tablet or slow- combination with MgSO4

release preparation

Acute treatmentHydralazine 5 mg i.v. or i.m. i.v. 10 minutes; Agent of choice, dose may

repeated if necessary i.m. 20–30 minutes be limited by maternal or 0.5–10 mg/hour tachycardiaby infusion

Labetalol 20 mg i.v. and then 5–10 minutes Flushing, nausea20–80 mg every 20–30 minutes or infusion at 0.5 mg/minute

Nifedipine 10 mg sublingual 10–15 minutes As above, headache, nausearepeat in 30 minutesif necessary: then10–20 mg every 3–6 hours

Methyldopa

Methyldopa has been extensively studied in pregnancy and is the agent of choice forchronic blood pressure control (Redman and Roberts, 1993). Given in divided oraldoses of 1–3 g daily, its safe use in the second and third trimesters is well established.It reduces systemic vascular resistance without significantly altering heart rate orcardiac output. Peak plasma concentrations are reached after 2 hours although themaximum fall in arterial pressure occurs 4–8 hours after an oral dose. Long-termfollow-up of infants exposed in utero has shown normal development to the age of 8years (Cockburn et al, 1982). Dry mouth postural hypotension, sedation anddepression are side-effects which lead to discontinuation of treatment in about 15% of

women with the last of these making it unsuitable for continuation into the postpartumperiod.

�-blockers

The combined α- and β-adrenoreceptor blocker labetalol was the preferred oraltreatment for severe pre-eclampsia among consultants in the United Kingdom 1991(Hutton et al, 1992). The α1 blockade induces vasodilatation, with little or no changein cardiac output. With labetalol theoretical concerns over the possibility ofreduced birthweight and/or neonatal effects secondary to β blockade have not beenborne out by the majority of published data, as reviewed elsewhere (Sturgiss et al,1992).

Only one trial (using atenolol) has demonstrated a preventative effect on thedevelopment of proteinuria (Rubin et al, 1983) and proteinuria did not resolve onceestablished. No trials have yet shown that treatment with β-blockers alters theeventual timing of delivery.

Calcium channel blockers

Nifedipine can be used for acute or chronic treatment and appears to be safe inpregnancy but headache and dizziness are common side-effects. An oral 10 mgloading dose is followed by 10–30 mg six hourly. It may be given as a second-line treatment or in combination with methyldopa or a β-blocker. It is bestavoided in combination with magnesium sulphate as profound hypotension mayresult (Waisman et al, 1988). It is as effective as hydralazine when loweringsystemic vascular resistance and improving cardiac output without adversely com-promising uteroplacental blood flow (Visser and Wallenburg, 1995). Its almostimmediate onset of action makes it attractive for the treatment of acute hyper-tensive crises.

Hydralazine

Hydralazine is used for the acute management of hypertensive emergencies. Itreduces blood pressure by lowering systemic vascular resistance and has a variableeffect on uteroplacental blood flow. This has led to fetal distress in a small number ofcases (Vink et al, 1980), although this did not occur when prior volume expansionhad been used (Wallenburg, 1988). A concurrent increase in maternal heart ratemaintains cardiac output and in some instances the tachycardia produced may limitits use.

Antihypertensive drugs to avoid

Angiotensin-converting enzyme (ACE) inhibitors are associated with IUGR, oliguria,renal failure and neonatal anuria in late pregnancy and contraindicated inpregnancy although not in the postpartum period (Rossa et al, 1989). Diureticsfurther reduce the contracted intravascular volume of pre-eclampsia and may com-promise uteroplacental perfusion. Loop diuretics, however, have a role in the acutemanagement of pulmonary oedema when this is secondary to volume overload(see below).


INDICATIONS FOR DELIVERY

After 36 weeks gestation, fetal maturity can be assumed and continuation ofconservative management of severe pre-eclampsia is rarely justified. The mode ofdelivery will be dictated by the clinical circumstances but most women will besuitable for a vaginal delivery. Although a recent study of 183 pre-eclamptic womenrevealed that induction of labour was more likely to fail in these women (8.2%compared with 1.7% of normotensive controls) the vast majority achieved a vaginaldelivery (Xenakis et al, 1997). In another study where the role of conservativemanagement was assessed in severe early pre-eclampsia (24–32 weeks), 28 womenwere managed conservatively at one centre (Oxford) and matched with 28 womenwho had early intervention after stabilization (Birmingham group). On average anadditional 9.5 days were gained prior to delivery in the conservatively managedgroup with a subsequent reduction in neonatal complications and length of stay onthe neonatal unit (Olah et al, 1993). Maternal morbidity, however, was higher in theconservative group with two cases of HELLP and two cases of ELLP syndrome. Eventhough there was also greater use of steroids in the Oxford group and there weredifferences in pre-delivery therapy between the two institutions, the study stillillustrates the trade-off between improving fetal outcome at the possible expense ofmaternal morbidity.

The concept of ‘buying time’ was also investigated by Sibai et al (1994) who random-ized 95 women with severe pre-eclampsia at 28–32 weeks gestation into expectantmanagement or prepared for delivery in the short term. Blood pressure was controlledwith nifedipine or labetolol and all were delivered once 34 weeks was reached. It waspossible to prolong the pregnancy from an average of 2.6 days (delivery afterstabilization) to 15.4 days in the expectant group. For this gestational age rangeconservative management reduced neonatal morbidity without significantly increasingin maternal morbidity. However, all patients were first observed for 24 hours excludingthose with fulminant disease, and those with renal disease, diabetes mellitus, thrombo-cytopenia and IUGR were also excluded.

A summary of indications for delivery (Australasian Society for the Study ofHypertension in Pregnancy, 1993) is given in Table 2.

INTRAPARTUM CARE

At the Royal Victoria Infirmary, Newcastle upon Tyne, the following protocol has been


Table 2. Australasian Society for the Study of Hypertension in Pregnancy (1993) indications fordelivery.

Maternal Fetal

Inability to control the blood pressure Non-reactive NST with repeated spontaneous decelarations of the fetal heart rate

Deteriorating liver function Severe IUGR, particularly if associated with oligohydramnios

Deteriorating renal functionProgressive thrombocytopeniaNeurological complications or imminent

eclampsia

successfully used for the past 5 years for severe pre-eclampsia when the decision hasbeen made to deliver.

Inclusion criteria are as follows: hypertension >170 mmHg systolic or diastolic>110 mmHg with proteinuria >0.5 g/24 hours or >+2. Hypertension >140 mmHgsystolic–90 mmHg diastolic with proteinuria also results in inclusion in the presence ofat least one of the following: headache, visual disturbances, epigastric pain, clonus(>three beats), platelet count <100 × 109/1 or AST >50 IU/1.

The protocol centres on strict fluid management and control of the blood pressureusing hydralazine or labetolol and does not advocate the use of prophylactic anti-convulsants. Figure 1 refers to management of intrapartum fluid balance and Figure 2describes intrapartum blood pressure control.


Initial CVP value

4–8 mmHg >8 mmHg<4 mmHg

Signs of pulmonary oedema?Manage expectantly, 200 ml

colloid if output remains<100 ml/4 hours

500 ml colloid over 5 minutes,repeat once if output

<100 ml/4 hours

Oliguria persists: check creatinine, potassium

Consider dopamine 1 µg/kgper minute to a maximum

5 µg/kg per minute

Chest X-ray, frusemide 40 mg, repeat ifnecessary to achieve diuresis

If no diuresis and persistent hypoxiaconsider pulmonary artery catheterization

Rapidly increasing creatinine,potassium >5.5 mmol/l

Fluid: restrict to urine output +30 ml/hourConsider haemodialysis–haemofiltration

No Yes

Figure 1. Modified intrapartum fluid regimen, Royal Victoria Infirmary, Newcastle upon Tyne (courtesy ofProfessor S. C. Robson). CVP monitoring is indicated when the urine output is less than 100 ml in thepreceding 4 hours despite crystalloid at 85 ml/hour.

Fluid regimen

It is necessary to strike a balance between overzealous administration of intravenousfluid (carrying the risk of pulmonary oedema) and underinfusion, predisposing tooliguria and renal complications. It is the aim to maintain a minimum urine output of100 ml/4 hours. Intravenous crystalloid (Hartmann’s) at 85 ml/hours is commenced, aFoley catheter inserted and fluid balance recorded at hourly intervals.

Oliguria

Oliguria is not uncommon in labouring pre-eclamptic patients and may represent anormal response to short-lived pre-renal causes. The reduced intravascular volume, a

poor fluid intake and vasospasm, coupled with decreased arterial pressure followingantihypertensive treatment, all predispose to oliguria. Of greater concern is pre-renalfailure presenting as oliguria after acute blood loss from postpartum haemorrhage orabruptio placentae. This is particularly dangerous if DIC supervenes. Haematuriaor haemoglobinuria leads to tubular dysfunction and profound hypotension canprecipitate acute tubular necrosis.

The role of volume expansion therapy in the clinical management of pre-eclampsiahas not yet been studied in large trials. The average deficit in the pre-eclampticintravascular volume lies between 500 and 1000 ml, the extent of the contractionbeing correlated with fetal growth retardation (Gallery et al, 1979). Several studieshave examined the short-term effects of intravenous colloid or crystalloid infusion,finding partial or complete normalization of blood pressure, cardiac output, systemicvascular resistance, central venous pressure and placental perfusion (Gallery, 1993).Volume expansion is an accepted part of fluid loading prior to epidural anaesthesiaand also has a role in preventing sudden hypotension following parental anti-hypertensive therapy. The Australasian Society for the Study of Hypertension inPregnancy (1993) also lists two further indications specifically, to help stabilize theblood pressure in women with severe pre-eclampsia and for the initial management ofoliguria.

Colloid has a theoretical advantage over crystalloid solutions for volume expansion,although there are no trials proving this in a clinical setting. Administration is notwithout a risk of hypervolaemia as the colloid may draw excessive fluid from theextravascular space. As with other conditions hypovolaemia and oliguria secondary toblood loss are best corrected by blood transfusion.

In the absence of haemolysis and signs of pulmonary oedema, an output less than100 ml/4 hours may be managed expectantly. 200 ml of colloid, gelofusine or haemaccelare given if the situation persists over the next 4 hours. We recommend invasivemonitoring with the aid of a central venous pressure (CVP) line in the antecubital fossaif further fluid manipulations are needed; see Figure 1. Extensive clinical experiencewith CVP monitoring within the delivery suite environment, its low morbidity andability to provide forewarning of pulmonary oedema recommend this form of invasivemonitoring in our unit. Pulmonary artery catheterization provides an alternative toCVP monitoring, avoiding some of its limitations (Anthony et al, 1994). Despite therelatively poor correlation between CVP and pulmonary capillary wedge pressure(PCWP), r = 0.59 (Cotton et al, 1988), differences are unlikely to be of clinical significantwith CVP readings of 6 mmHg or less (Lee and Cotton, 1997). We reserve the use ofPCWP monitoring to those women requiring an intensive care setting. Invasivemonitoring is considered in detail in Chapter 6.

With regard to persistent hypovolaemia, when the CVP <4 cm a further 400 mlof colloid is warranted, given over 30 minutes. This may be repeated if necessarybut no patient should receive more than 1000 ml in total. If oliguria persists despiteattempts to correct the intravascular volume with colloid, then intravenouscatecholamine or dopamine should be considered. At low doses (1 µg/kg per minuteincreasing to a maximum dose of 5 µg/kg per minute) dopamine is unique, actingon the renal vasculature directly, producing vasodilatation and improving renalperfusion (Mantel and Makin, 1997). Frequent checks of serum urea and electrolytesare needed to monitor progress as acute renal failure carries the risk of hyper-kalaemia. All potassium-containing fluids should be stopped; if the serum potassiumlevel is greater than 6.0 mmol/l all fluid is restricted and advice from renal physicianssought.


Diuretics are only indicated in the management of oliguria if an intrinsic renalproblem is diagnosed which is unresponsive to vasodilatation and re-expansion of theintravascular volume and confirmed by invasive monitoring. Intravenous frusemide inthese circumstances will facilitate further fluid therapy as low-output renal failurebecomes a high-output state (Anthony et al, 1994).

Pulmonary oedema

Severe pre-eclampsia predisposes to pulmonary oedema in several ways. There isincreased hydrostatic pressure secondary to raised blood pressure, hypoalbuminuriareduces oncotic pressure and capillary permeability is increased in many women,reflecting generalized endothelial dysfunction (Davison, 1997). Cardiogenic pulmonaryoedema due to impaired myocardial contractility may occur in the presence of severe


Figure 2. Modified regimen for intrapartum blood pressure control, Royal Victoria Infirmary, Newcastleupon Tyne (courtesy of Professor S. C. Robson).

MAP >140 mmHgsustained over 5 minutes

MAP 125–140 mmHgsustained over 45 minutes

MAP >125 mmHg repeatHydralazine 5 mg i.v.every 15 minutes until

MAP >125 mmHgand heart rate >120 beats/minute

or 15 mg hydralazine given

Labetalol 20 mg i.v. followed at10 minute intervals by 40, 80, 80 mg

to cumulative dose of 220 mg

Undelivered Undelivered

500 ml colloid over 20 minutes

If delivered If delivered

Hydralazine 5 mg i.v.

MAP < 125 mmHgrecheck every 15 minutes

Maintain MAP <125 mmHg withintermittent hydralazine 5 mg i.v.

Heart rate <120 beats/min,no side-effects

If >10 mg/hourhydralazine

Heart rate >120 beats/minor side-effects

Hydralazine infusion: 10 mg/hour,double at 30 minute interval to

40 mg/hour maximum

Labetalol infusion: 40 mg/hour,double at 30 minute interval to

160 mg/hour maximum

hypertension due to an increased after-load or in patients with underlying cardiacdisease. Before diagnosing pulmonary oedema other causes of respiratory distress mustbe considered, ranging from lower respiratory tract infections to pulmonary thrombo-embolism, valvular heart disease or amniotic fluid embolism.

Rapid intravascular expansion leading to a CVP reading greater than 10 cm indicatesa risk of developing pulmonary oedema. It may, however, also develop in the presenceof a normal CVP, if systemic vascular resistance rises suddenly in combination with lowintravascular oncotic pressure. The diagnosis is suspected on clinical grounds; short-ness of breath with difficulty maintaining oxygen saturation. Blood gas analysis andchest radiography are indicated while facial oxygen is administered with the mothersat up in the bed. Depending on its aetiology, treatment with either a vasodilator(reducing systemic vascular resistance) or an intravenous frusemide bolus (wherehypervolaemia is suspected secondary to excessive intravenous fluid administration) isindicated.

Intrapartum blood pressure control

An automated sphygmomanometer measures mean arterial pressure (MAP) at 15minute intervals. Values between 125 and 140 mmHg sustained over 45 minutes aretreated with 500 ml colloid over 20 minutes if this has not previously been given; seeFigure 2. A MAP reading of 140 mmHg sustained over 15 minutes also requires anti-hypertensive treatment and we use hydralazine 5 mg intravenously as a first choice. It isthe aim to reduce blood pressure smoothly, avoiding profound hypotension. If the MAPis unresponsive to the first dose then it may be repeated after 15 minutes. Labetalol issubstituted if the MAP remains above 125 mmHg after three doses of hydralazine or ifthis induces a tachycardia (>120 beats/min). Maintenance therapy may be required if>10 mg/hour hydralazine is needed to achieve adequate blood pressure control.Hydralazine (40 mg) is diluted in 40 ml normal saline and infused at 10 mg/hour, doublingafter 30 minutes if necessary to a maximum of 40 mg/hour. If there is tachycardia,headache, flushing or dizziness, then 200 mg of labetalol in 50 ml normal saline can beinitiated, infusing at 40 mg/hour, doubling after 30 minutes up to a maximum rate of160 mg/hour. It is rarely necessary to use continuous infusions after 24 hour post-delivery when oral treatment can be re-introduced.

In the management of the third stage of labour syntocinon is used in preference tosyntometrine or ergometrine as these may produce a sudden increase in bloodpressure.

Anticonvulsant therapy

One in 200 cases of severe pre-eclampsia progress to eclampsia with an overallincidence of 4.9/10 000 maternities in the UK (Douglas and Redman, 1994). Large trialsare therefore required to address whether prophylactic anticonvulsants have a role.The MAGPIE trial (magnesium sulphate (MgSO4) versus placebo for women with pre-eclampsia) aims to recruit 14 000 women to provide reliable data on the benefits andhazards of MgSO4. It will also offer the opportunity to evaluate the long-term effectson the children exposed to MgSO4 in utero. With the current state of knowledge andconsidering the attendant side-effects of any anticonvulsant we do not advocate theirprophylactic use as even if an agent was 100% effective there would still be a need totreat 200 women with severe pre-eclampsia to prevent one fit.


Why magnesium sulphate?

While MgSO4 has long been the anticonvulsant of choice in the United States, in 1991only 2% of consultants in the United Kingdom considered it their agent of choice(Hutton et al, 1992). The results of the Collaborative Eclampsia Trial have now shownthat MgSO4 is superior to either diazepam or phenytoin for preventing subsequent fits(Duley et al, 1995). Results appertain to 1680 women from the developing world: theincidence of recurrent fits was 52% and 67% with intravenous MgSO4 compared withdiazepam and phenytoin, respectively. There were also statistically significantly lowerrates of maternal ventilation and pneumonia and fewer neonatal intensive careadmissions in the MgSO4 group. It was further evident that MgSO4 was an effectiveanticonvulsant at doses which do not impair maternal consciousness and where coughand gag reflexes are retained. It acts as a membrane stabilizer and vasodilator reducingintracerebral ischaemia.

MgSO4 regimen

A 2 g (20 ml) 10% MgSO4 intravenous loading dose infused over 5 minutes is followedby a further 4 g dose over 15 minutes. A low infusion rate avoids the attainment oftoxic levels. Maintenance intravenous therapy (2 g/hour) is continued until 24–48hours after delivery. This volume is deducted from the fluid maintenance. Recurrentseizures are treated with a further 2 g bolus over 5 minutes.

A total MgSO4 dose of more than 8 g (possibly 6 g for smaller women) to control theinitial seizure carries a risk of acute respiratory arrest and is not recommended(Pritchard et al, 1984). Diazepam is therefore used (10 mg and then 2.5 mg/hour) if thesecond MgSO4 bolus fails to control the seizures and is the agent of first choice in acuterenal failure or pre-existing cardiac disease.

MgSO4 monitoring

The MgSO4 plasma therapeutic range is narrow, 2–4 mmol/l (4–8 mg/dl), and hourlyclinical monitoring of patellar reflexes in conjunction with respiratory rate, electro-cardiography and pulse oximetry measurements is necessary. Magnesium (Mg) levelsare taken 1 hour after the start of the maintenance dose and repeated at six-hourlyintervals.

Because it is excreted by the kidneys a reduction to 1 g/hour is needed if oliguriapersists (output <100 ml/4 hours), if the serum urea is greater than 10 mmol/l or ifserum Mg level is above 4 mmol/l. Mg levels less than 1.7 mmol/l are consideredsubtherapeutic with the need to consider a further 2 g i.v. dose and increased main-tenance dose to 2.5 g/hour.

Toxicity is manifest as a loss of patella reflexes,weakness, nausea, flushes, somnolence,double vision and slurred speech. Respiratory arrest and muscle paralysis occur at levelsabove 6–7.5 mmol/l with cardiac arrest at values greater than 12 mmol/l. Clinical signs oftoxicity require immediate cessation of the infusion, facial oxygen and urgent measure-ments of plasma levels. Plasma levels are used to monitor current Mg concentrationsand to plan future treatment; it is not necessary to wait for the results of serummeasurements before administering calcium gluconate in order to reverse the clinicalsigns of magnesium toxicity. Calcium is a competitive inhibitor of magnesium sulphate atthe neuromuscular junction. Calcium gluconate (10 ml of 10% solution) slowly givenintravenously will reverse signs of toxicity although the effect may wear off beforemagnesium levels return to safe levels.


Important clinical considerations

Eclampsia is an absolute indication for delivery but not until stabilization of the mother.The first priority is protection of the airway; then facial oxygen is administered andsuction used if necessary, the back of the throat being avoided as this may stimulatevomiting. The majority of eclamptic seizures last for approximately 60 seconds and it israre for a convulsion to persist after 90 seconds.

For a woman presenting for the first time with a depressed level of consciousnessnon-eclamptic convulsions should always be borne in mind. There may be a knownhistory of epilepsy or more rarely intracerebral haemorrhage, sagittal sinus venousthrombosis, thrombotic thrombocytic purpura and systemic lupus erythematous can allpresent with neurological symptoms.

Anaesthesia

Regional blockade

This is the preferred method of analgesia for both labour and operative deliveries. Itsuse is limited in coagulopathy states and, while there is a paucity of evidence as to theexact level of thrombocytopenia contraindicating its use, we use a cut-off of 80 × 109/1.Marked arterial hypotension may result from the vasodilatation produced so a fluidpre-load, typically 500 ml Hartmann’s over 15 minutes prior to blockade, is usuallygiven. Epidural blockade will not control the blood pressure of a severely hypertensivewoman and should not be relied on to do so (DHSS, 1991).

General anaesthesia

Remember that intubation may precipitate a hypertensive crisis and laryngeal oedemamay make the procedure hazardous. In addition to the standard procedure, alfentanyl2 mg and labetolol 15 mg are given prior to intubation and the labetolol repeatedbefore extubation.

These issues are discussed in detail in Chapter 6.

POSTPARTUM CARE

In severe pre-eclampsia, intensive monitoring should continue for 24–48 hours afterdelivery. It should not be forgotten that one-third of eclamptic fits occur after delivery,usually within the first 24 hours (DHSS, 1991). If anticonvulsant therapy has been givenit must be continued for 24 hours, post-delivery. The onset of a postpartum diuresisusually represents the turning point in patient care.

Antihypertensive treatment is usually continued into the postpartum period as theblood pressure often remains elevated and can reach its peak 3–4 days after delivery.Methyldopa is less suitable in the postpartum period because of its depressive side-effects.

POSTNATAL REVIEW

This provides an opportunity to answer any questions arising from the pregnancy careand a discussion of future implications. The blood pressure is measured, renal function


assessed and urine tested for proteinuria. If the blood pressure remains elevated 6–12weeks post-delivery then the diagnosis of chronic hypertension is made in retrospectand further treatment or blood pressure monitoring planned. Developing pre-eclampsia or pregnancy-induced hypertension without serious complications is notthought to worsen maternal long-term health. Persistent proteinuria warrants furtherinvestigation for an underlying renal cause.

SUMMARY

It is clear that the very nature of pre-eclampsia, with its wide range of symptoms andsigns, rapidly changing degrees of severity and multisystem involvement, lends itself tomanagement based on a multidisciplinary approach. Co-ordinating care between healthcare professionals in the community and hospital environment facilitates continuity andindividualization of care. It is only by combining experience based on knowledge of theindividual woman’s circumstances,obstetric management, anaesthetic, neonatal,medicaland midwifery considerations that the highest standards of care can be achieved.

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Clinical management of established pre-eclampsia

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