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Pre-eclampsia: pathopiiysioiogy and its management

By Anne Morley
This theory is supported by the hypothesis that normal pregnancy is a state of tolerance to paternally derived, fetal antigens. The incidence of pre-eclampsia is reduced in women who avoid barrier methods of contraception, cohabitate for longer, and practise oral sex (Koehnan et al, 2000), which suggests that a paternal factor is involved in the development of pre-eclampsia. The placental factor leads to an abnormal interaction between the invading trophoblast cells and the decidua during implantation (Roehnan et al, 2000). This complex aetiology means that research aimed at identifying a factor that will enable early diagnosis or act as a tool for screening in early pregnancy is ongoing (Bosio et al, 2001). At present there is no definitive method of predicting the development of the disease, or its severity, which would enable the administration of therapy and could reduce mortality from the disease (Vainio et al, 2002). Ineffective implantation It is the second wave of trophoblastic invasion, at 14-15 weeks gestation, and alteration in the spiral arteries that are relevant to pre-eclampsia (Duckett et al, 2001). In pregnancies affected by preeclampsia, trophoblastic invasion disrupts the muscular and elastic wall constituents of the spiral arterioles; small muscular arteries therefore become converted to dilated, lowresistant vascular vessels, which are unresponsive to vasoconstrictive stimuh. In pre-eclampsia, however, trophoblastic invasion Is impaired, and the spiral arteries retain their endothelial and muscular linings, and dilate to only 40% of that in normal pregnancy. This results in diminished uteroplacental circulation and chronic fetal hypoxia (Broughton Pipkin, 1995). This ineffective implantation has a disruptive elTect on epithehal cell integrity, causing widespread activation of endothelial cells. This adversely affects the production of cirBRmSH JOURNAL OF MIDWIFERY, JANUARY 2 0 0 4 , VOL 1 2 . NO 1

Pre-ectampsia has a sfgnificant impact on ttae mortality and morbidity of pregnant women and their neonates. It is a multisystem condition In which systemic damage occurs before symptoms become apparent. This article describes the pathophysiology, investigations and management of pre^ctampsia, especially before 34 weeks gestation, when the decision between expectant management and delivery is often difficult. The impKcations of the Magpie trial for the management of pre-eclampsia are also discussed.

ypertension complicates up to 15% of pregnancies, with pre-eclampsia affecting 2-3% (Kean, 2002; RCOG, 2003). Pre-eclampsia is a multisystem disorder and the major cause of maternal mortality and morbidity. It accounts for 15% of direct maternal deaths, while two-thirds of other maternal deaths are related to the disorder (Confidential Enquiries into Maternal Deaths, CEMD, 2001). Pre-eclampsia also accounts for 500-600 neonatal deaths and one-sixth of the cot use in neonatal intensive care (Draycott et al, 2000). Pre-eclampsia is defined as a multisystem disorder characterised by raised blood pressure (>140/90mmHg) and proteinuria (>0.3g/24h) (CEMD, 2001). However, these symptoms are late manifestations of a disease process that is initiated in early pregnancy (Broughton Pipkin, 1995).

Pre-eclampsia has a complex aetiology, mediated by an interplay of abnormal genetic, immunological and placental factors (Duckett et al, 2001). Familial factors are suggested by the three- to four-fold increase in incidence of pre-eclampsia in first-degree relatives of affected women, and immunotogical factors by the increased risk of preeclampsia in prlmigravid women and those who change their partner after the hirth of their first child (Duckett et at, 2001).

culating factors by the vascular endothelium. Production of the local vasodilator prostacyclin is decreased, and production of the vasoconstrictor thromboxane A2 and platelet activation are increased (Broughton Pipkin 1995). Epithelin is a recently discovered endothelial vasoconstrictor that activates local renin-angiotensin systems; these effects are compounded by an increased sensitivity to angiotensin II (Beevers et al, 2001). The ultimate effect of these local vasoactive agents is generahzed vasoconstriction and reduced tissue perfusion, which results in multiple organ damage. In addition, the loss of epithelial cell integrity leads to an increase in vascular permeahility. To compensate for this increase in systemic vascular resistance, the cardiac index is reduced hy 22% and the intravascular hydrostatic pressure is increased, causing oedema, reduced circulating plasma volume and haemoconcentration (Visser and Wallenburg, 1991).

ters remain preferable. In a high dependency area the accuracy of the automated device should he confirmed on a regular hasis with a mercury sphygmomanometer or an intraarterial line (RCOG, 2003), The RCOG (2003) recommends treating women with elevated blood pressure according to their local protocols. Rean (2002) identifies a blood pressure of > 170/110 mmHg as the level at which the risk of maternal complications greatly increases, potentially causing hypertensive encephalopathy and irreversible cerebral haemorrhage. CMED (2001) does give a more cautious recommendation of treating the woman when her blood pressure is > 160/llOmmHg, though the general consensus in the literature is > 170/110 mmHg (Duley and Henderson-Smart, 2002). Haematological system The efTect of pre-eclampsia on the haemological system is reflected in a raised haemocrit, which results from the redistribution of extracellular fluid and a marked reduction in circulating plasma volume (Duckett et al, 2001). An additional consequence of this haemoconcentration is an elevated haemoglobin the opposite of the physiological anaemia associated with the haemodilution of normal pregnancy. Platelets are essential for haemostasis and clot formation, with endothelial damage activating platelet production (Duckett et al, 2001). Widespread endothelial damage results in excessive platelet turnover, a falling platelet level and, potentially, thromhocytopenia. Serial platelet counts are therefore used as a parameter for monitoring disease progress in mild pregnancyinduced hypertension. Platelet activation also results in activation of the fihrinolytic system, with fihrin being laid down on the areas of vascular damage. These microthromhi cause further damage to small vessels, increasing stimulation of the coagulation cascade. Clotting factors become depleted, as do the platelets, leading to no further clotting, uncontrollable bleeding and disseminated intravascular coagulation. Fibrinolysis occurs, the flhrin and fibrinogen are broken down to maintain a patent vessel, resulting in increased serum levels of fibrin degradation products such as D-dimer (Martini, 2001).

...signs and symptoms can vary enormously and may not be the same in every case. This emphasizes the importance of continuity in antenatai visits, enabiing the midwife to iinow the woman...

Clinical features and related management

Because of the multi-organ nature of preeclampsia, the presenting signs and symptoms can vary enormously and may not he the same in every case. This emphasizes the importance of continuity in antenatal visits, enahling the midwife to know the woman and he in a position to observe any significant changes, such as increased oedema. Cardiovascular system Blood pressure needs to he recorded accurately and monitored regularly, hecause of its impact on management. A raised blood pressure in pregnancy is not necessarily indicative of pre-eclampsia; it could indicate essential hypertension, which would greatly alter the management (Hartley, 1998). Measurement of diastohc hlood pressure offers plenty of scope for error, as 'white-coat' hypertension, cuff size and maternal position all influence the reading (Rubin, 1996). The pregnant woman needs to be seated, or on her left side, wearing the appropriate-sized cuff; the first and the fifth Korotkoff sounds selected for systolic and diastoHc respectively (TICOG, 2003). Automated instruments for blood pressure are not validated for use in pregnancy and mercury sphygmomanome-



JK history of headache is reievant when documenting symptoms related to raised biood % pressure. J

Renat system Protein excretion increases during pregnancy, and urinary protein concentrations of up to 0.3g/24h are normal (Kean, 2002). Proteinuria is a central feature of preeclampsia (Davies et al, 2002). The vasospasm of pre-eclampsia is associated with the renal lesion, glomerular endotheliosis, which results in an increase in vascular endothelial permeability and larger molecular weight proteins entering the glomerular nitrate (Davies et al, 2002). Excessive protein excretion is reflected in serum analysis as falling albumin level (Duckett et al, 2001). Uric acid clearance becomes impaired through defective tubular function, resulting in hyperuricaemia. Uric acid acts as a predictor of pre-eclampsia, the serum level becoming elevated before the onset of proteinuria, as renal tubular damage precedes glomerular damage. Gestational proteinuria may be caused by infection or renal disease, although urinary tract infection is rarely associated with more than 1+ of protein (Kean, 2002). Unfortunately, the routine screening test for proteinuria is flawed and subjective. This has serious implications for women with proteinuria who are placed at risk through a false-negative result and a lack of essential investigations and interventions (Davies et al, 2002). The simple effects of diurnal variation in protein excretion or levels of hydration can affect the results. Values can change from negative to as much as 3+ over a 24-hour period, as demonstrated by Meyer et al (1994) in their study of 300 hypertensive women. On urinalysis, 125 had a negative value or trace of protein; on 24-hour quantification, however, 66% (81) of these women had significant proteinuria that required investigation. The use of 24-hour urine collections eliminates subjectivity, but is inconvenient and time-consuming and causes a delay in diagnosis and management (Davies et al, 2002). An effective method of detecting proteinuria that avoids subjective visual interpretation of colours on a dipstick is needed. Saudan et al (1997) performed visual and automated dipstick analysis on samples from 103 hypertensive women. They found that the automated device significantly increased the accuracy of protein detection.

Bitary system Any description of 'indigestion' and discomfort in the epigastric area indicates potential vasospasm within the liver, causing small haemorrhages and hypoxic swelling. The clinical case studies described by Barry et al (1994) highhght how epigastric pain should instantly alert health professionals to possible pre-eclampsia. Deteriorating liver function is reflected in the blood analysis as an elevated aspartate transaminase level (Kean, 2002). Neurotogicat system A history of headache is relevant when documenting symptoms related to raised blood pressure. Two theories have been suggested to explain the development of headache in pre-eclampsia. The first proposes that localized cerebral vasospasm causes reduced perfusion and abnormal electrical activity. A trial by Zatik et al (2001), comparing cerebral haemodynamic changes in 22 healthy pregnant women and 26 pre-eclamptic women, provides supporting evidence for this theory. The pre-eclamptic women showed an increase in arterial blood pressure and decreased mean blood ffow velocity in the middle cerebral artery compared with healthy pregnant women. The second theory proposes that the headache is caused by cerebral oedema and leakage of fluid into the interstitial spaces, resulting from the redistribution of extracellular fluid due to a reduced circulating plasma volume (Douglas and Redman, 1994). Testing of deep tendon reffexes is performed to assess the function of sensory pathways and motor centres throughout the spinal cord and brain (Martini, 2001). The term 'brisk' signifies hyperreffexia, where the reflexes are triggered easily wdth exaggerated results. This effect is seen in compression of the spinal cord or diseases that target higher centres or descending tracts, such as the cerebral oedema associated with pre-eclampsia. Fetat wetlbeing Fetal wellbeing is assessed by ultrasound analysis of growth, weight, amniotic fluid volume, and Doppler analysis of umbilical artery blood flow. Placental insufficiency leads to intrauterine growth restriction.


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fetal hypoxia and even fetal death, while placental abruption is hazardous for both mother and baby (Kean, 2002).

Management of pre-eclampsia needs to take into consideration the stage of gestation and the associated mortahty and morbidity. Management decisions are made in light of a thorough clinical picture and the results of relevant investigations indicating any multi-organ damage and fetal compromise. Delivery or expectant management? In severe pre-eclampsia, delivery rather than expectant management, as advocated by Sibai et al (1994), is often indicated. Sibai et al (1994) advocate an expectant approach for gestations that will benefit from the administration of steroids to enhance fetal lung maturation; this involves stabilization and close maternal and fetal surveillance. Rean (2002) only advocates an expectant approach before 34 weeks' gestation, within a unit where the facilities are available for intensive monitoring and intervention in an emergency. However, the evidence for expectant management is not convincing, with only 5% (12) of the women reaching 34 weeks' gestation in a study of 340 early-onset pre-eclamptic women (Sibai et al, 1994). Acute fetal compromise due to placental abruption occurred in as many as 207o (69) of women, fetal compromise accounted for 45% (150) of urgent dehveries while maternal deterioration resulted in delivery in 30% (103) of women (Sihai et al, 1994). CEMD (2001) and the RCOG (2003) both strongly influence practice within maternity units across the countiy. CMED (2001) recommend stabilizing a blood pressure of >160/110mmHg before delivery. Hyperreflexia is a warning of impending eclampsia, and Kean (2002) maintains that the presence of hyperreflexia alongside hypertension is an absolute indication for anticonvulsant prophylaxis and delivery (Broughton Pipkin, 1995). Antihypertensives The pharmacological management of pre-eclampsia with antihypertensives is

based largely on clinical experience, rather than on reliable evidence from a large clinical trial (Hartley, 1998). With the current emphasis on evidence-based care, treatment decisions based on experience rather than clinical evidence are not appropriate. As a result of this lack in supporting evidence, the RCOG (2003) recommend treatement consistent with local protocol, through hydralazine and labetalol are most commonly used (Abalos et al, 2002). Labetalol, a combined alpha- and bcta-blocker, has a good safety profile, but is associated with fetal bradycardia and intrauterinc grovrth restriction (Kean, 2002). Although antihypertensive therapy is associated with a risk of fetal distress, the risk to the mother from not stabihsing a blood pressure of >160/110mmHg is greater. Severe hypertension leads to cerebral vasospasm, cerebral ischaemia, disruption of the bloodbrain barrier and oedema. The woman is at risk of seizure and other neurological complications including coma, focal motor deficits, cortical blindness and cercbrovascular haemorrhage (Douglas and Redman, 1994). Seizure is rare in developed countries, occurring in one in 2000 deliveries, but is associated with significant morbidity. Douglas and Redman (1994) report that 38% of seizures occur in the antenatal period. Anticonvulsants Duckctt ct al (2001) advocate anticonvulsant medication for prophylaxis and treatment of pre-eclampsia, in addition to antihypertensive therapy. Until recently, there has been little adequate controlled evidence to support the use of anticonvulsants in pre-eclampsia and there has been a variation in clinical practice (Dulcy and Henderson-Smart, 2003). A quarter of obstetricians did not use anticonvulsant therapy, some used magnesium sulphate, phenytoin or diazepam (Gulnezoglu and Duley, 1998). The Magpie trial (The Magpie Trial Collaborative Group, 2002) has recently been completed and clarifies this issue by providing evidence to recommend the use of magnesium sulphate. As recommended by the Cochrane Review, the Magpie trial was an international, large, controlled, randomized study. It involved 10110 women, and was set up to evaluate the

Lx Management of preclampsia needs to take into consideration the stage of gestation and the associated mortality and morbidity.



monitoring can be achieved without serum magnesium measurement, using simple ciinical assessment of tendon reflexes, respiratory rate and urine output, with calcium gluconate available as ^ an antidote... J'

effects of magnesium sulphate on women and their babies. The size of the trial ensured that the evidence obtained and the guidelines developed are reliable. The trial provides the evidence to prevent the unethical use of unproven treatments in the management of a disease that can cause significant morbidity and mortality to both mothers and babies. It concludes that magnesium sulphate halves the risk of eclampsia, and reduces the risk of placental abruption by 27% and the risk of maternal death by 45%. There do not appear to be substantive harmful effects on mother and baby in the short-term (The Magpie Trial Collaborative Group, 2002). Magnesium sulphate is a smooth muscle relaxant, which is excreted by the kidneys; it acts primarily by relieving cerebral vasospasm through vasodilatation (Duckett et al, 2001). It is inexpensive, and any sideeffects and injection site problems are reduced by intravenous administration. However, it has a narrow therapeutic range, and magnesium toxicity leads to respiratory depression, loss of deep tendon reflexes and ultimately respiratory arrest (RCOG, 1999). Safe monitoring can be achieved without serum magnesium measurement, using simple clinical assessment of tendon reflexes, respiratory rate and urine output, with calcium gluconate available as an antidote (The Magpie TOal Collaborative Group, 2002).

Barry C, Fox R, Stirrat G (t994) Upper abdominal pain in pregnancy may indicate preeelampsia. BM/308: t562-3 Reevers G, Lip GY, O'Rrien E (2001) The pathophysiology of hypertension. BMJ 522: 9t2-6 Bosio PM, Cannon S, McKenna PJ, O'Herlihy C, Conroy B, Rrady H (2001) Plasma P-seleetin is elevated in the first trimester in women who subsequently develop pre-eclampsia. Br J Obstet Gynaecol 108(7): 709-15 Rroughton Pipkin F (1995) The hypertensive disorders of pregnancy. BMJ 5li: 609-13 CEMD (Confidential Enquiries into Maternal Deaths)(2001) miy Mothers Die 1991-1999. BCOG Press, London Davies L, Waugh J, Kilby M (2002) Assessing proteinuria in hypertensive pregnancy. British Journal of Midwifery 10(7): 44t-5 Douglas KA, Redman CW (1994) Eclampsia in the United Kingdom. British Eclampsia Survey Team. 5M/309: 1395^00 Draycott T, Rroad G, Chile K (2000) The development of an eclampsia box and 'fire drill'. British Journal of Midwifery 8(1): 26-30 Duckett RA, Kenny L, Raker PN (2001) Hypertension in pregnancy. Current Obstetrics and Gynaecology 11(1): 7-14 Duley L, Gulmezoglu AM, Henderson-Smart DJ (2002) Magnesium sulphate and other anticunvulsants for women with preeclampsia (Cochrane Review). In: The Cochrane Library: Issue 4. John Wiley and Sons, Chichester Duley L, Henderson-Smart D (2002) Drugs for treatment of very high blood pressure during pregnancy (Cochrane Review). IN: The Cochrane Library: Issue 4. John Wiley and Sons, Chichester Duley L, Henderson-Smart D (2003) Magnesium sulphate and other anticunvulsants for women with pre-eclampsia (Cochrane Review). In: The Cochrane Library: Issue 4. John Wiley and Sons, Chichester Gulmezoglu AM, Duley L (1998) Use of anticonvulsants in eclampsia and preeclampsia: a survey of obstetricians in the United Kingdom and Republic of Ireland. BMJ 316: 975-6 Hartley J (1998) Diagnosis, treatment and care of the pre-eelamptic woman. RCM Midwives Journal 1(1): 17-20 Kean L (2002) Managing hypertension in pregnancy. Current Obstetrics and Gynaecology 12(2): 104-10 Koelman C, Coumans A, Nijman H, Doxiadis I, Dekker GA, Class F (2000) Correlation between oral sex and a low incidence of preeelampsia: a role for soluble HLA in seminal fluid. J Reprod Immunol 46(2): 155-66 Martini FH (2001) Application Manual: Fundamentals of Anatomy and Physiology. Prentice Hall Inc, Upper Saddle River, NJ Meyer NL, Mercer BM, Friedman SA, Sibai BM (1994) Urinary dipstick protein: a poor predictor of absent or severe proteinuria. Am J Obstet Gynecol 170(1): 157-41 RCOG (1999) Management of eclampsia. Availaljle from: http://www. reog.org.uk/guidelines/eclampsia.html (Accessed 29 August 2002) RCOG (2003) Pre-eclampsia study group recommendations. Available from:

It is important to understand the pathophysiology of pre-eclampsia, because of its relevance to investigation and management of the disorder. Despite continued research, there is still no test or tool to aid the early diagnosis of pre-eclampsia or identify women at risk of developing the condition. Consequently, pregnant women will continue to present with severe pre-eclampsia and require quick and effective management. It is therefore crucial that midwives understand the pathophysiology, investigations, and pharmacological management of pre-eclampsia, including the administration of magnesium sulphate. EBSI

Abalos E et al (2000) Antihyprtensive drug therapy for mild to moderate hypertension during pregnancy (Cochrane Review). In: The Cochrane ibrary: Issue 4. Jobn Wiley and Sons, Chichester



vvww.rcog.org.uk/mainpages.asp?PageID=l 21 5 (Accessed on 5 December 2003) Rubin P (1996) Measuring diaslolic blood pressure in pregnancy. BMJ 515: 4-5 Saudan PJ, Brown MA, Farrell T, Shaw L (1997) Improved methods of assessing proleinuria in hypertensive pregnancy. Br J Obstet Gynaecol 104(10): 1159-64 Sihai BM, Mercer BM, SchifT E, Friedman SA (1994) Aggressive versus expectant management of severe pre-eclampsia at 28 to 32 weeks gestation: a randomised control trial. Am J Obstet Gynecol 171: 818-22 The Magpie Trial Collaborative Group (2002) Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebocontrolled trial. Lancet 359: 1877-90 Vainio M, Kujansuu E, lso-Ktijansuu M, Maenpiia J (2002) Low dose acetylsalieylic acid in prevention of pregnaney-induced hypertension and intrauterine growth restriction in women with hilateral uterine artery notches. Br J Obslet Gynaecol 109(2): 161-7 Visser W, Wallenburg HCS (1991) Central haemodynamic ohservations in untreated preeclamptic patients. Hypertension 17: 1072-7 Zatik J, Major T, Aranjosi J, Molnar C, Limburg M, Eulesdi B (2001) Assessment of cerebral haemodynamics during roll over test in healthy pregnant women and those with preeclampsia BrJ Obstet Gynaecot 108(4): 353-8 FURTHER READING Anim-Nyame N, Sooranna SR, Jones J, Alaghband-Zadeh J, Steer PJ, Johnson MR (2002) A longitudinal study of biochemical markers of jjone turnover during normal pregnancy and pregnancies complicated by pre-eclampsia. Br J Obstet Gynaecot 109(6): 70a-13 Anim-Nyame N, Sooranna SR, Jones J, Alaghband-Zadeh J, Steer PJ, Johnson MR (2001) Biochemical markers of maternal bone turnover are elevated in pre-eclampsia. Br J Obstet Gynaecol 108(3): 258-62 Clausen T, Djurovic S, Henriksen T (2001) Dyslipidaemia in early second trimester is

mainly a feature of women with early onset pre-eclampsia. Br J Obstet Gynaecot 108(10): 1081-7 Currie L, Peek M, McNiven M, Prosser 1, Mansour J, Ridgeway J (2002) Is there an increased maternal-infant prevalence of factor V Leiden in association with severe preeclampsia. BrJ Obstet Gynaecol 109(2): 191-6 Djuovic S, Clausen T, Wergeland R, Brosstad F, Berg K, Henriksen T (2002) Absence of enhanced systemic inflammatory response at 18 weeks of gestation in women with suhsequent pre-eclampsia. Br J Obstet Gynaecot 109(7): 759-64 GofTmet F, Aboulker D, Paris-Llado J et al (2001) Screening with uterine Doppler in low risk pregnant women followed by low aspirin in women with abnormal results: a multi-centre randomised controlled trial. Br J Obstet Gynaecol 108(5): 510-8 Hall DR, Odendaal HJ, Steyn DW, Grove D (2002) Urinary protein excretion and expectant management of early onset, severe preeclampsia. Int J Gynaecot Obstet 77(1): 1-6 Johnson MR, Anim-Nyame N, Johnson P, Sooranna SR, Steer PJ (2002). Does epithelial cell activation occur with intrauterine growth restriction? Br 7 Obstet Gynaecol 109(7): 836-9 Martin A, O'Sullivan AJ, Brown M (2001) Body composition and energy metabolism in nomiotensive and hypertensive pregnancy. Br J Obstet Gynaecol 108(12): 1263-71 Sattar N, Greer IA (2002) Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening? BMJ 325: 157-60 Sawidou MD, Lees GG, Parra M, Hingorani AD, Nicolaides KJI (2002) Levels of C-reactive protein in pregnant women who subsequently develop pre-eclampsia. Br J Obstet Gynaecot 109(3): 297-301 Suzuki Y, Vamamoto T, Suzumri K, Kajikuri J, Itoh T (2000) Modined histamine-induced NOmediated relaxation in resistance arteries in pre-eclampsia. Eur J Pharmacol 410(1): 7-13 von Dadelszen P, Ornstein MP, Bull SB (2000) Fall in mean arterial pressure and fetal growth restriction in pregnancy in pregnancy hypertension: a meta-analysis. Lancet 355: 87-92

^ Despite ^ continued research, there is stili no test or tool to aid the eariy diagnosis of pre-eciampsia or identify women at risk of deveioping | the condition. 4

Pre-eclampsia accounts for 15% of direct maternal deaths. Presentation of pre-eclampsia is not the same in every case. Continuity In midwifery visits is littportant for early detection. Blood pressure needs to be recorded accurately and monitored regularly. The routine screening test for proteinuria is flawed and subjective. Epigastric pain should alert the health professional to the possibility of pre eclampsia. Magnesium sulphate halves the risk of eclampsia, and reduces the risk of placental abruption by 27% and maternal death by 45%.