- Email: [email protected]
Hypertension in pregnancy
ARTICLE IN PRESS Current Obstetrics & Gynaecology (2004) 14, 1–10
www.elsevier.com/cuog
Hypertension in pregnancy Richard Hayman* The Orchard Centre, Gloucester Royal Hospital, Great Western Road, Gloucester, UK
KEYWORDS Pre-eclampsia; Pregnancy; Hypertension; Proteinuria
Summary A diagnosis of hypertension may be made in 5–8% of all pregnancies. Preeclampsia, a disease associated with defective placentation, is arguably the most important cause of maternal and fetal morbidity and mortality associated with a rise in maternal blood pressure. This clinical syndrome has a complex aetiology and pathophysiology, and is possibly the result of an as yet unidentified circulating factor of placental origin that targets the maternal vascular endothelium. The multi-organ dysfunction that develops in pre-eclampsia is a result of this generalised endothelial disruption and is reflected in the clinical presentation with the haematological, renal, hepatic and cerebral systems being principally affected. & 2003 Elsevier Ltd. All rights reserved.
Introduction
Hypertension
Hypertension is a frequently encountered complication of pregnancy and has a number of possible aetiologies. Its onset may predate a pregnancy or develop during the antenatal, intrapartum or postpartum course. Arguably the most important cause of hypertension in pregnancy is pre-eclampsia. This condition remains a leading cause of maternal and perinatal mortality, and is responsible worldwide for over 200 000 maternal deaths each year. This review summarises the current understanding of the aetiology, pathophysiology and clinical management of pregnancies complicated by hypertension, concentrating specifically on the syndrome of pre-eclampsia.
The patient’s blood pressure should be measured with the woman in a semi-reclining position with a 30-degree lateral tilt, and the sphygmomanometer at the level of the heart. The selection of Korotkoff sounds have long been the subject of much controversy, although present evidence suggests that Korotkoff sound V corresponds more closely to the intra-arterial pressure and is the most reproducible end-point in pregnancy. However, where this tends towards a value of 0 mmHg, as may occur in some women, Korotkoff IV should be employed, and a record of this decision clearly documented in the records. Normal pregnancy is associated with a fall in the maternal blood pressure to a nadir in the second trimester where the diastolic blood pressure is on average 15 mmHg and the systolic blood pressure 30 mmHg, lower than before pregnancy. In the third trimester this physiological fall normally reverts to pre-pregnancy levels that may appear elevated in comparison to the values measured at the booking visit. At any point in pregnancy, the absolute blood pressure level provides the best guide to fetal and maternal prognosis. The level currently accepted as significant is a pressure greater than 140/ 90 mmHg, as a diastolic blood pressure of 90 mmHg
Definition and classification There are many definitions of the hypertensive disorders of pregnancy, the most widely accepted is the classification devised by Davey and MacGillivray. *105 St. George’s Road, Cheltenham, Gloucestershire GL50 3ED, UK. E-mail address: [email protected] (R. Hayman).
0268-0890/$ - see front matter & 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.curobgyn.2003.10.009
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corresponds to the point of the curve inflexion above which perinatal mortality is significantly increased. In all cases, these blood pressure levels must be recorded on 2 occasions more than 4 h apart.
systolic blood pressure of greater than 30 mmHg above booking values should be regarded as significant if other features of pre-eclampsia syndrome are present.
Chronic hypertension Proteinuria Healthy individuals normally excrete a small amount of protein in their urine. In pregnancy, protein excretion may increase significantly by up to 0.3 g/l of protein per 24 h (0.5 g/24 h) which is accepted as normal. In all cases a mid-stream urine specimen should be analysed for evidence of infection, as this is the most common cause for an increase in protein concentration. Proteinuria is commonly screened for by using reagent strips. However, the concentration of protein in a random urine sample is dependent on several factors and reagent strips are notoriously inaccurate at concentrations of less than 0.3 g/l ( þ ). It is therefore recommended that a 24 h measurement of urinary protein be made to confirm the diagnosis suspected from the reagent strips. However, the positive predictive value of the reagent strips increases as the severity of the proteinuria worsens, and þ þ or more on dipstix is likely to reflect a significant concentration. Should intervention be warranted on clinical grounds, a clinician should not delay the instigation of active management in order to complete a 24-h collection.
Pre-eclampsia Pre-eclampsia is classically defined as hypertension of at least 140/90 mmHg measured on 2 separate occasions at least 4 h apart and arising de novo in previously normotensive women after the twentieth week of gestation, accompanied by significant proteinuria, all of which are resolved by 6 weeks post-partum. Such a definition, whilst appropriate in the research setting, excludes the presence of symptoms, therefore many clinicians employ a diagnosis that relies upon 2 or more, of the following symptoms being present: *
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hypertension of at least 140/90 mmHg on 2 separate occasions at least 4 h apart; significant proteinuria 0.3 g/l of protein per 24 h (0.5 g/24 h); symptoms including headache, photophobia, visual disturbance, epigastric pain, alteration in the conscious state.
Also, many clinicians consider that rises in the diastolic blood pressure of 15 mmHg and the
Chronic hypertension is hypertension that is either present pre-pregnancy or is diagnosed before the twentieth week. This definition also encompasses those patients whose hypertension is diagnosed during pregnancy but does not resolve postpartum. However, the presence of chronic hypertension does not preclude pre-eclampsia occurring, and in such patients, the prognosis for the mother and fetus is less favourable.
Gestational hypertensionFpregnancy induced hypertension (PIH) Gestational hypertension is a rise in blood pressure in the absence of proteinuria, detected after mid-pregnancy. This is a non-specific diagnosis covering patients with transient pregnancy induced hypertension, those who go on to develop pre-eclampsia and those with chronic hypertension presenting for the first time in pregnancy. Often a definitive diagnosis can only be made retrospectively.
Aetiology Pre-eclampsia is associated with a defect in placentation with as yet unidentified maternal or fetal genes conferring susceptibility.
Genetics The presence of a familial factor in the development of pre-eclampsia is suggested by a 3–4fold increase in the incidence of pre-eclampsia in first-degree relatives of affected women. However, the discordance in incidence between identical twins suggests that factors other than just the maternal genotype are implicated, an observation that raises the possibility of contribution from a fetal factor. The Genetics of pre-eclampsia Collaborative Study (GOPEC) is a multi-centre British project currently being undertaken to investigate various candidate genes, using the technique of transmission disequilibria testing. Under investigation are the genes coding for: angiotensin; angiotensin II type I receptor; Factor V Leiden; and tumour necrosis factor.
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Immunology Immunological factors in pre-eclampsia are heavily implicated by epidemiological studies. The increased risk recognised in primigravid women should be extended to include primi-paternity as it has been shown that there is a raised incidence of pre-eclampsia in women who change partners after the birth of their first child. The avoidance of barrier methods of contraception, longer periods of cohabitation and practicing oral sex reduce the incidence of pre-eclampsia. These observations suggest that the incidence of pre-eclampsia may be related to the duration of prior exposure to paternal antigens in sperm. Such findings support the hypothesis that normal pregnancy is a state of tolerance to the paternally derived antigens of the fetus. In patients with preeclampsia this immunological tolerance is impaired and the abnormal placentation that is seen may reflect an abnormal response to the paternally derived fetal antigens. The greater the load of these antigens, the greater the prevalence of preeclampsia (as illustrated by an increased incidence of this disease in multiple and molar pregnancies).
Placental factors
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clinical syndrome that develops is the result of the widespread changes in endothelial cell function that occur. Whilst the intact endothelium has anticoagulant properties and modifies the vascular response to agonists, activated endothelial cells promote coagulation and increase vasopressor sensitivity, which are major features of preeclampsia. Further evidence of endothelial activation in pre-eclampsia include: characteristic changes in glomerular capillary endothelial morphology; increased capillary permeability; and elevated blood levels of molecules associated with endothelial cell activation (endothelin and cellular fibronectin).
Circulating factors Delivery of the placenta results in the resolution of pre-eclampsia. The placenta is thus implicated as the source of the factor(s) causing functional as well as structural damage to the endothelial cells. The nature of the circulating factor(s) has yet to be demonstrated. There are several properties, which the factor(s) must possess including the capacity: * *
Endovascular cytotrophoblasts invade the lumina of the spiral arteries in 2 waves, the first commencing at 10 weeks and the second occurring 4–5 weeks later. This process alters the morphology of the placental spiral arteries by disrupting the muscular and elastic wall constituents, and leads to the conversion of small muscular arteries into dilated low resistance ‘conduits’. These vessels are specifically unresponsive to circulating vasoconstrictive stimuli, and create a low-pressure, high-flow blood supply to the placenta. The process of intramural trophoblast invasion that occurs after 14 weeks is impaired in women with pre-eclampsia. The spiral arteries retain their endothelial and muscular linings, this results in a dramatic reduction in the intervillous blood flow. The result is placental hypoperfusion, which is thought to induce the release of a factor into the maternal circulation. The endothelial disruption that is seen in pre-eclampsia compounds this problem, leading to a further decrease in placental blood flow. This vicious pathway is only broken with the delivery of the placenta.
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to pass freely into the maternal circulation; to increase cellular permeability and possibly cell turnover; to alter nitric oxide and prostacyclin production; to cause an alteration in the response to endothelium-dependent agonists.
Potential candidates currently being considered include: * * *
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vascular endothelial growth factor (VEGF); neurokinin B; oxidative stress and lipid peroxidases. Recent work has suggested that supplementation with the antioxidants vitamins C and E can reduce the incidence of pre-eclampsia in high-risk patients; syncytiotrophoblast microvillous membranes (STBMs). It has been suggested that STBMs are the link between abnormal placental invasion and endothelial dysfunction, as the increased circulating levels seen in pre-eclampsia could trigger the endothelial cell damage and disordered function that is observed.
Endothelial factors
Pathophysiology
The vascular endothelium appears to be the target cell for the disease process of pre-eclampsia, the
Pre-eclampsia is a multi-system disease defined by its clinical presentation. Distinguishing
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pre-eclampsia from chronic or gestational hypertension is important as its systemic manifestations may have life-threatening consequences for both mother and baby.
The haematological system Haemodynamics Normal pregnancy is a state of reduced vascular resistance accompanied by an increase in cardiac output, plasma volume and heart rate. Preeclampsia is associated with a comparative increase in the vascular resistance within the placental bed (thus contributing to the development of hypertension), and a reduction in circulating plasma volume in conjunction with a redistribution of fluid toward the extravascular compartment. Platelets Platelets are vital for haemostasis and clot formation, and in the event of endothelial damage they adhere to the damaged area. With the generalised endothelial damage that occurs in pre-eclampsia, a reduction in the platelet count may occur. Although this frequently predates the clinical signs of the disease, significant clotting abnormalities are rarely seen in the absence of a marked thrombocytopaenia. Coagulation cascade The intrinsic and extrinsic pathways combine in a succession of enzyme reactions to convert fibrinogen into fibrin, a cascade regulated by the fibrinolytic pathway. In pre-eclampsia, diffuse vascular damage in association with the laying down of fibrin is suggests activation of coagulation. Regulatory proteins These include anti-thrombin III, protein C and protein S. In pre-eclampsia the levels of all these proteins are reduced, increasing the tendency toward coagulation. Fibrinolytic system Plasminogen is converted to plasmin, which then acts on fibrinogen to form fibrin, fibrin degradation products and D-dimers. This pathway is carefully regulated with a tight balance being maintained between the formation and degradation of fibrin. In pre-eclampsia, this balance may be compromised, with the potential for a state of disseminated intravascular coagulopathy to develop.
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The liver Changes in liver function are thought to occur secondary to vasoconstriction of the hepatic vascular bed. The histological events observed include periportal fibrin deposition, haemorrhage and hepatocellular necrosis. In severe cases of hepatic involvement, complications such as hepatic rupture or infarction may be seen. The exact incidence of hepatic dysfunction in preeclampsia is unknown, as wide variations in the accepted normal range of liver function tests in pregnancy prevents systematic data collection and analysis.
The kidney The initial change observed in the kidney in pre-eclampsia is that of defective tubular function. This leads to reduced clearance of uric acid and hence hyperuricaemia. Changes that precede the impairment of glomerular filtration and the relative loss of intermediate weight proteins such as albumin and transferrin occurs. The development of proteinuria in turn causes a reduction in the plasma oncotic pressure with the subsequent complication of generalised tissue oedema. The characteristic, but not pathognomonic, lesion seen in pre-eclampsia, is glomerular endotheliosis (swelling of the endothelium and fibrin deposition causing a reduction in the capillary lumen, which resolves post-partum). Acute renal failure rarely results from acute tubular or cortical necrosis, but when either of these occur, they may lead to maternal death.
The brain The development of convulsions in a patient with pre-eclampsia is defined as eclampsia. The pathophysiology of eclampsia has not been fully elucidated. One possible explanation is that localised cerebral vasospasm results in reduced cerebral perfusion. This causes abnormal electrical activity, which has the potential to trigger an eclamptic fit. An alternative theory is that endothelial injury compounded by vascular over-distension due to hypertension overcomes the normal cerebral autoregulation capability. This results in cerebral oedema due to leakage of fluid into the interstitial spaces. Whatever the cause, in most cases the main areas affected are the occipital and parietal lobes; this correlates closely with the visual disturbances observed by patients. Such models are supported
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by the complete resolution of neurological defects seen post-recovery. Rare complications of both preeclampsia and eclampsia include cortical and retinal blindness. The most common cause of death seen in eclampsia is intracerebral haemorrhage.
Screening Many investigative procedures have been suggested as screening tests for those judged (based on their or their families past obstetric history) to be at increased risk of developing pre-eclampsia. Whilst the ‘roll over test’ is relatively harmless yet ineffective, other more reliable procedures, such as the ‘angiotensin infusion test’ are invasive, time consuming and best placed for research studies. Therefore there are, as yet, no reliable screening tests that can be routinely used to diagnose those at risk of pre-eclampsia. The use of Doppler ultrasound as both a screening and an investigative tool has been widely studied. Harrington et al reported that combining colourflow imaging, uterine artery resistance and the presence of a diastolic notch resulted in a test with a sensitivity of 76% and a specificity of 86% for the prediction of pre-eclampsia, if performed 16–24 weeks into gestation. Other studies have made it clear that abnormal Doppler findings identify a small group of fetuses, namely those that are hypoxaemic and small as a result of inadequate placental function. Although these undoubtedly include a subset of fetuses from patients with pre-eclampsia, the ability to predict how the pregnancy will proceed remains unanswered, and as yet, this modality does not provide a suitable basis for a screening test.
Clinical presentation It is imperative that a high degree of suspicion of pre-eclampsia is maintained, as many patients are asymptomatic, at least initially. Risk factors such as primiparity, a previous history of preeclampsia, diabetes, chronic renal disease, antiphospholipid syndrome, multiple pregnancy and pre-existing hypertension should be highlighted. The classic symptoms of pre-eclampsia are a frontal headache, visual disturbance and epigastric pain. A complete obstetric and neurological examination should be performed, specifically noting the presence or absence of epigastric pain, hyperreflexia, clonus and papilloedema. The presence of peripheral oedema is a common and usually favourable sign, its appearance in association with
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proteinuria and hypertension is not often significant as a prognostic indicator. Eclampsia affects 1–2% of pregnancies and can occur at any time antenatally, intrapartum or postpartum. It is important to note that convulsions occur before the onset of proteinuria and hypertension in about one third of patients. The presence of tonic-clonic seizures that are not secondary to other causes (i.e. epilepsy, subarachnoid haemorrhage, meningitis, and space occupying lesions) should lead to a diagnosis of eclampsia until proven otherwise. Another syndrome presented within the spectrum of the hypertensive disorders of pregnancy is that of HELLP (haemolysis, elevated liver enzymes, and low platelets). The HELLP syndrome occurs in 4–12% of patients with severe pre-eclampsia, although hypertension is not always initially characteristic of this condition. As a consequence it may be confused with other medical conditions such as thrombotic thrombocytopaenia purpura. The presentation of this condition is often with non-specific findings, although disseminated intravascular coagulopathy, placental abruption, and fetal demise are not infrequent accompaniments. Amongst women with severe pre-eclampsia, 6% will present with 1 abnormality suggestive of HELLP (usually elevated liver enzymes), 12% will develop 2 abnormalities and 10% will develop the classic triad. HELLP syndrome can manifest itself at any stage during pregnancy, but 30% will occur postpartum and only 80% of such patients will have had pre-eclampsia diagnosed antenatally.
Diagnosis It is imperative that a full fetal and maternal assessment is made to avoid the complications of uncontrolled maternal hypertension and to reduce the possibility of unnecessary medical intervention that may lead to iatrogenic premature fetal delivery.
Maternal In patients with pre-existing hypertension, baseline laboratory tests help to formulate a diagnosis if pre-eclampsia is suspected in later pregnancy. However, most investigations need repeating on a regular basis to enable adequate monitoring of disease progression and resolution: *
haematological monitoring: sequential platelet counts are useful in monitoring severe disease
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progression rather than for initial diagnosis. In cases of reduced or falling levels, clotting studies should be performed; hepatic function monitoring: monitoring of hepatic involvement by means of liver function tests (especially lactic dehydrogenase, aspartate and alanine transaminases), may aid diagnosis and decisions regarding disease severity. Indeed, this is frequently the only way that the HELLP syndrome may be detected; renal function monitoring: if the plasma urea or creatinine is elevated, especially in the presence of a relatively normal plasma uric acid, underlying renal disease is likely. In a patient with preeclampsia however, rising plasma creatinine or urea indicates a worsening of the disease. Serum uric acid levels tend to rise before the development of proteinuria in pre-eclampsia; urine monitoring: a mid-stream urine test to exclude urinary tract infection and a 24 h collection to identify significant proteinuria should follow initial dipstick, providing the disease-state permits the time for completion of the collection; blood pressure monitoring: blood pressure may need to be monitored as often as every 15 min during the acute phase of severe disease, but more commonly it is taken every 4 h.
or intrauterine growth restriction. In contrast, the umbilical artery Doppler has not been shown to be predictive of fetal wellbeing after 36 weeks gestation. Data from controlled trials of unselected or low risk pregnancies has failed to demonstrate any significant difference between the Doppler groups and the control groups for antenatal hospitalisation, obstetric outcome or perinatal morbidity. To complicate matters further, uncertainty exists as to the management of pregnancies with Doppler findings.
In patients with chronic or newly diagnosed hypertension, investigations to exclude causes such as Cushing’s disease, Addison’s disease and phaeochromocytoma should be performed.
Most patients have mild hypertension and are at low risk of cardiovascular and neonatal complications. This is especially true when the renal function in such patients is normal. However, the major risk in this group of women is with the superimposition of pre-eclampsia. This complication occurs in up to 25% of these patients, and in a higher proportion if renal dysfunction is present from the onset. The aim of treatment is to reduce the risk of maternal complications whilst keeping the fetus safe. The drug of choice being either methyldopa or labetolol. Atenolol and ACE inhibitors are both associated with growth restriction, and the latter is also linked to oligohydramnios, neonatal renal failure and neonatal death. The use of diuretics are not recommended, as these drugs theoretically counteract the physiological plasma volume expansion seen in normal pregnancies and therefore increase the risks to the patient of developing preeclampsia. It is not uncommon for antihypertensive medication to be discontinued in the first trimester of pregnancy, as the nadir of the physiological change in maternal blood pressure occurs between 16 and 24 weeks. However, if treatment is stopped at any stage, then close monitoring must be organised,
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Fetal Ultrasonography The uses of ultrasound vary from simple measurements of fetal size, gestation and growth, to the confirmation of the presentation and calculation of the biophysical profile score and Doppler flow studies. It is clear that no definitive investigation exists but that a combination of observations enables decisions to be made on appropriate management strategies. The ultimate management depends on maternal disease severity and predicted fetal outcome. Patient management, including the use of the Doppler measurement of blood flow in the fetal umbilical artery, has been associated with a reduction in perinatal mortality. However, the absence of end diastolic flow velocity, which carries a crude perinatal mortality in excess of 40%, and a 30% chance of developing preeclampsia, has only been shown to be of benefit in clinically high-risk pregnancies, i.e. those with a gestation of less than 34 weeks with pre-eclampsia
The cardiotocograph (CTG) It must be emphasised that the CTG only provides a snapshot view of fetal health and further monitoring may be justified when other factors are considered, such as the presence of pre-eclampsia or intrauterine growth restriction. Identification of pre-existing disease enables an appropriate plan for fetal monitoring to be arranged (e.g. pre-eclampsia complicating chronic hypertension is associated with increased fetal loss).
Treatment Chronic hypertension
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and a recognised threshold for recommencing treatment clearly defined (e.g. 150–160/100– 110 mmHg or signs of end organ damage (retinal haemorrhage, nephropathy etc)). (See Fig. 1.)
Pre-eclampsia The development of proteinuric hypertension is usually managed on an in-patient basis, at least until quantification of the proteinuria has occurred. This protocol has the additional benefits of permitting a detailed fetal assessment whilst sequentially monitoring the blood pressure and enabling the speed of disease progression in each patient to be individually assessed.
In all cases, treatment consists of stabilising the mother until such a time as iatrogenic immaturity becomes insignificant or the predisposing condition necessitates delivery. The decision as to when to treat is obvious in the severely affected patient, but is less clear-cut in cases of pre-eclampsia at early gestations (o34 completed weeks). (See Fig. 2.)
Drug treatment Antihypertensives The initial aim of treatment is to lower maternal blood pressure to a safe level (i.e. one at which the patient is unlikely to develop hypertensive encephalopathy and suffer the irreversible consequences of this disease such as cerebral
MAP > 140 mm Hg
MAP 125−140 mm Hg
Recheck blood pressure every 5 min
Recheck blood pressure every 15 min
Hydralazine 5 mg IV
Recheck BP Every 15 min
MAP ≥ 125 mm Hg Confirm with mercury Sphygmomanometer
Labetolol 20 mg IV followed at 10 min intervals by 40, 80, 80 mg up to a cumulative dose of 220 mg
Maintenance Therapy
Recheck MAP after 15 min
MAP > 125 mm Hg and Heart rate > 120/min or 15 mg Hydralazine given
MAP < 125 mm Hg
Repeat Hydralazine 5mg IV every 15 min until either cumulative dose of 20 mg or side effects
Maintain MAP < 125 mm Hg with; Intermittent Hydralazine 5mg IV
Heart rate ≤ 120/min No side effects
If requiring > 10 mg/h to keep MAP < 125 mm Hg
Hydralazine Infusion Dilute 40 mg in 40 ml normal saline. Start at 10 mg/h and double every 30 min until a satisfactory response or dose of 40 mg/h reached Side Effects Headache Dizziness Flushing
Heart Rate > 120/min or side effects with Hydralazine
Labetolol Infusion Dilute 200 mg in 50 ml normal saline. Start at 40 mg/h and double every 30 min until a satisfactory response or dose of 160 mg/h is reached
MAP = mean arterial pressure = diastolic blood pressure + 1/3 (systolic−diastolic blood pressure)
Figure 1 The intrapartum management of hypertension.
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Hypertension (≥ 140/90 mm Hg) with proteinuria (≥ 300 mg/l or ≥ 2+ on urinary dipstix) And at least one of the following i) Headache, visual disturbance, epigastric pain ii) Clonus (≥ 3 beats) iii) Platelet count < 100 x 10 9 and/or falling rapidly from previous count. b) Severe hypertension (systolic ≥ 170 mm Hg, or diastolic ≥ 110 mm Hg (MAP > 125 mm Hg) with proteinuria (≥ 300 mg/l or ≥ 2+ on urinary dipstix). c) Eclampsia.
a)
In the presence of severe pre-eclampsia, or eclampsia, the duty obstetric consultant must be informed, a plan of management being decided in liaison with the on-call anesthetis+ and the paediatric teams.
Transfer to the labour ward Investigations:
Full blood count: clotting screen; group and save serum. Urea and electrolytes: liver function tests; uric acid. Mid stream urine sample.
Designate one-to-one midwifery care. Insert urinary catheter and commence fluid balance chart (hourly input vs. output). Decision to deliver to be taken after discussion with/review by duty consultant.
Or Or
Artificial rupture of membranes + syntocinon infusion. Prostaglandin E2 pessary. Elective caesarean section.
If delivery to be delayed and gestation < 34/40: dexamethasone 12 mg IM (x 2 12 h apart). Commence monitoring 1.
IV fluids
2.
Anticonvulsants
Blood pressure every 15 minutes. Fluid protocol
Monitor urine output.
Eclampsia
Eclampsia protocol
Consider seizure prophylaxis with MgSO4 .
Pre-eclampsia 3.
Antihypertensives
MAP > 125 mm Hg (over 3 consecutive readings)
MAP < 125 mm Hg 4.
Anesthesia
Monitor Plasma MgSO4 levels.
Hydralazine protocol
Monitor BP every 15 min. recheck BP every 30 min.
Insert CVP line/pulmonary artery catheter if indicated. Caesarean section Labour If no contraindication to regional block insert epidural.
Continuous fetal monitoring whilst on labour ward (CTG).
Consider Doppler/biophysical profile (if labour or delivery delay planned). Repeat investigations (FBC, U&E’s, clotting studies, LFT’s) every 12 h. Close observation after delivery is required and all parameters must be monitored for at least 24 h with the BP being checked 4 hourly for 5 days. MAP = mean arterial pressure = diastolic blood pressure + 1/3 (systolic – diastolic blood pressure).
Figure 2 A protocol for the management of pre-eclampsia.
haemorrhage). In severe disease antihypertensive medication is often required to maintain a mean arterial pressure below 125 mmHg. Above this level a loss of cerebral autoregulation is observed. Iatrogenically induced normotension must not be
confused with cure but simply regarded as a means of stabilising and, or prolonging the pregnancy if clinically justified. Many different agents exist but all have their own specific drawbacks and therapy should not be instigated without due care. The
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most commonly used treatments are currently hydralazine, labetolol, methyldopa and nifedipine. A plethora of agents exist, all of which have different pharmacokinetic and dynamic properties, and routes of administration. The most commonly employed are: methyldopa, a centrally acting a adrenergic inhibitor; hydralazine, which reduces vascular resistance via a direct relaxation of arteriolar smooth muscle affecting the pre-capillary resistance vessels more than the post capillary resistance vessels; labetolol, which through its combined a and b adrenoceptor agonist action induces a rapid, controlled decrease in the systemic vascular resistance; nifedipine, a calcium channel-blocking agent, which relaxes predominantly venous, but also arterial, vascular smooth muscle, causing a decrease in pre-load at low doses, and afterload at high doses, glycerol tri-nitrate, which predominantly relaxes arterial smooth muscle, but also has some dilatory effect on the vascular compartment, decreasing pre-load at low doses and afterload in high doses; and ketanserin, a 5-hydroxytryptamine 2 serotonergic receptor agonist, which is thought to act peripherally via the prevention of vaso-spasm. All these drugs cross the placenta and may therefore affect the fetus. Labetolol can trigger a fetal bradycardia, and the combination of nifedipine with magnesium sulphate may cause a severe drop in blood pressure. Anticonvulsants In cases of severe pre-eclampsia and eclampsia, the drug of choice is magnesium sulphate (as illustrated by the Magpie Study, and the Collaborative Eclampsia Trial). This drug should be used to prevent and treat convulsions and hence prevent their sequaelae. It acts as a cerebral vasodilator and membrane stabiliser, reducing ischaemia and the ensuing neuronal damage. It may also act as a central anticonvulsant blocking the N-methyl-D-aspartate receptor. Magnesium sulphate has a broad therapeutic range and clinical monitoring by the observation of respiratory rate, PO2 saturations (pulse oximetry) and peripheral reflexes will suffice. Close monitoring of serum levels is especially important in the presence of reduced renal excretion, as magnesium sulphate in excess can cause profound respiratory depression and even cardiorespiratory arrest. Fortunately there is a rapidly acting antidote–calcium gluconate. Steroids Antenatal administration of corticosteroids prior to anticipated preterm delivery significantly reduces neonatal morbidity and mortality. Guidelines from the Royal College of Obstetricians and Gynaecolo-
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gists state that ‘every effort should be made to initiate antenatal corticosteroid therapy in women between 24 and 36 weeks of gestation..... providing there is no evidence of tuberculosis or intrauterine infection’. (Fig. 2.)
Supportive management Pre-eclampsia is a state of intense vasoconstriction, reduced circulating plasma volume and extracellular fluid redistribution. This is compounded by the associated low colloid osmotic pressure, a result in part of the excess loss of protein via the kidneys. This combination of factors makes fluid management extremely difficult, and the injudicious administration of fluid can have serious consequences, with the rapid development of pulmonary or cerebral oedema. It is imperative that an accurate measurement of input vs. output is charted on an hourly basis, and that the blood loss at the time of delivery is properly measured (oxytocic drugs are anti-diuretic and their use to stimulate labour and prevent post-partum haemorrhage influences urine output). Unless specific blood products are required, crystalloids are the fluid of choice and should be given whilst monitoring the urine output hourly via an indwelling catheter. Whilst the absolute volume to be replaced must be based on clinical observations, an appropriate volume for maintenance purposes is a maximum of 100 ml/hour (oral þ iv). Renal failure is a rare occurrence and the injudicious use of diuretics (e.g. frusemide) to improve the measured urine output, may further compromise an already reduced circulating volume. Should oliguria (o 20 ml/hr over a 4 h period) be noted then additional information from central venous monitoring (a CVP line) may provide valuable guidance. This management dilemma is often more of a problem antenatally than postnatally, as during the recovery period a profound diuresis is frequently seen. Indeed, a patient experiencing anuria antenatally indicates a worsening of the clinical condition, and suggests that delivery should be expedited.
Decision for delivery The aim of management is to stabilise the patient and enable appropriate decisions to be made regarding the timing and mode of delivery. The route of delivery is influenced by such factors as gestation, the presence of other
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complications (such as malpresentation), and the urgency that progression to delivery must be made. All pregnancies affected by pre-eclampsia must be classified as high-risk regardless of whether fetal compromise has been demonstrated, and as such, a low threshold for intervention should exist if the mother is allowed to continue into labour. Consultation with a senior anaesthetist is essential so that an appropriate choice of analgesia is made. Spinal, epidural and general anaesthesia all have their own individual benefits and disadvantages and the decision as to which is used depends on the clinical condition and time scale for delivery. Immediate post-partum treatment is essentially supportive with the aim of preventing complications. Forty-four percent of fits occur in the postpartum period, so vigilance should be maintained, with the blood pressure being monitored every 4 h for at least 5 days.
Postnatal follow-up In most cases of pre-eclampsia, delivery results in complete disease resolution. Patients requiring antihypertensives can usually be weaned off these by the end of the puerperium whilst gestational hypertension tends to resolve more rapidly. Those patients requiring medication antenatally are at increased risk of needing it postnatally. If pregestation values were normal or unknown then a drug free trial is reasonable in association with close monitoring and a low threshold for drug reintroduction. Counseling regarding future pregnancies plays an important role in postnatal management and psychological recovery. Patients have a 10–25% chance of developing pre-eclampsia in subsequent pregnancies; the risk is higher if other factors such as antiphospholipid syndrome are present, and also depends on the gestational age at presentation.
Conclusion Hypertension in pregnancy in association with the development of proteinuria has serious consequences for both the mother and the fetus. The aetiology and pathophysiology are incompletely understood. However, the multisystemic nature of pre-eclampsia is thought to be due to a combination of endothelial damage, vasoconstriction and hypoperfusion. These events being
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mediated by an interplay of genetic, immunological, placental and circulating factors. Diagnosis is often made at a routine visit, as symptoms are often absent, at least initially. Treatment is aimed at reducing the maternal and fetal complications, whilst minimising the risk of iatrogenic immaturity to the fetus. Delivery of the placenta results in disease resolution, although careful management is required in the initial post-delivery period. Follow-up should include counselling regarding future pregnancies and monitoring of blood pressure to identify those women with chronic hypertension.
Acknowledgements This review was revised and updated from an earlier article in this journal by R.A. Duckett, L. Kenny and P.N. Baker from the Academic Division of Obstetrics and Gynaecology, City Hospital, Hucknall Road, Nottingham NG5 1PB, UK.
Further reading Hibbard B, Milner D. Reports on the confidential enquiries into maternal deaths: audit of previous recommendations. Health Trends 1994;26:26–8. Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy (see comments). Am J Obstet Gynecol 1988;158(4):892–8. Roberts JM, Taylor RN, Musci TJ et al. Pre-eclampsia: an endothelial cell disorder (see comments). Am J Obstet Gynecol 1989;161(5):1200–4. Roberts JM, Edep ME, Goldfien A, Taylor RN. Sera from preeclamptic women specifically activate human umbilical vein endothelial cells in vitro: morphological and biochemical evidence. Am J Reprod Immunol 1992;27(3–4):101–8. Brockelsby J, Hayman R, Ahmed A et al. VEGF via VEGF receptorI (Flt-1) mimics pre-eclamptic plasma in inhibiting uterine blood vessel relaxation in pregnancy: implications in the pathogenesis of pre-eclampsia. Lab Invest 1999;79(9): 1101–11. Page NM, Woods RJ, Gardiner SM et al. Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia. Nature 2000;405(6788):797–800. Hubel CA. Oxidative stress and pre-eclampsia. Fetal Matern Med Rev 1997;9:73–101. Smarson Ak, Sargent IL, Starkey PM, Redman CW. The effect of placental syncytiotrophoblast microvillous membranes from normal and pre-eclamptic women on the growth of endothelial cells in vitro. Br J Obstet Gynaecol 1993;100(10):943–9. Douglas K, Redman C. Eclampsia in the United Kingdom. British Eclampsia Survey Team. BMJ 1994;309:1395–400. Hayman RG, Baker PN. The hypertensive disorders of pregnancy. Antenatal and intrapartum management. R Coll Obstet Gynaecol. PACE Review no. 97.
www.elsevier.com/cuog
Hypertension in pregnancy Richard Hayman* The Orchard Centre, Gloucester Royal Hospital, Great Western Road, Gloucester, UK
KEYWORDS Pre-eclampsia; Pregnancy; Hypertension; Proteinuria
Summary A diagnosis of hypertension may be made in 5–8% of all pregnancies. Preeclampsia, a disease associated with defective placentation, is arguably the most important cause of maternal and fetal morbidity and mortality associated with a rise in maternal blood pressure. This clinical syndrome has a complex aetiology and pathophysiology, and is possibly the result of an as yet unidentified circulating factor of placental origin that targets the maternal vascular endothelium. The multi-organ dysfunction that develops in pre-eclampsia is a result of this generalised endothelial disruption and is reflected in the clinical presentation with the haematological, renal, hepatic and cerebral systems being principally affected. & 2003 Elsevier Ltd. All rights reserved.
Introduction
Hypertension
Hypertension is a frequently encountered complication of pregnancy and has a number of possible aetiologies. Its onset may predate a pregnancy or develop during the antenatal, intrapartum or postpartum course. Arguably the most important cause of hypertension in pregnancy is pre-eclampsia. This condition remains a leading cause of maternal and perinatal mortality, and is responsible worldwide for over 200 000 maternal deaths each year. This review summarises the current understanding of the aetiology, pathophysiology and clinical management of pregnancies complicated by hypertension, concentrating specifically on the syndrome of pre-eclampsia.
The patient’s blood pressure should be measured with the woman in a semi-reclining position with a 30-degree lateral tilt, and the sphygmomanometer at the level of the heart. The selection of Korotkoff sounds have long been the subject of much controversy, although present evidence suggests that Korotkoff sound V corresponds more closely to the intra-arterial pressure and is the most reproducible end-point in pregnancy. However, where this tends towards a value of 0 mmHg, as may occur in some women, Korotkoff IV should be employed, and a record of this decision clearly documented in the records. Normal pregnancy is associated with a fall in the maternal blood pressure to a nadir in the second trimester where the diastolic blood pressure is on average 15 mmHg and the systolic blood pressure 30 mmHg, lower than before pregnancy. In the third trimester this physiological fall normally reverts to pre-pregnancy levels that may appear elevated in comparison to the values measured at the booking visit. At any point in pregnancy, the absolute blood pressure level provides the best guide to fetal and maternal prognosis. The level currently accepted as significant is a pressure greater than 140/ 90 mmHg, as a diastolic blood pressure of 90 mmHg
Definition and classification There are many definitions of the hypertensive disorders of pregnancy, the most widely accepted is the classification devised by Davey and MacGillivray. *105 St. George’s Road, Cheltenham, Gloucestershire GL50 3ED, UK. E-mail address: [email protected] (R. Hayman).
0268-0890/$ - see front matter & 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.curobgyn.2003.10.009
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R. Hayman
corresponds to the point of the curve inflexion above which perinatal mortality is significantly increased. In all cases, these blood pressure levels must be recorded on 2 occasions more than 4 h apart.
systolic blood pressure of greater than 30 mmHg above booking values should be regarded as significant if other features of pre-eclampsia syndrome are present.
Chronic hypertension Proteinuria Healthy individuals normally excrete a small amount of protein in their urine. In pregnancy, protein excretion may increase significantly by up to 0.3 g/l of protein per 24 h (0.5 g/24 h) which is accepted as normal. In all cases a mid-stream urine specimen should be analysed for evidence of infection, as this is the most common cause for an increase in protein concentration. Proteinuria is commonly screened for by using reagent strips. However, the concentration of protein in a random urine sample is dependent on several factors and reagent strips are notoriously inaccurate at concentrations of less than 0.3 g/l ( þ ). It is therefore recommended that a 24 h measurement of urinary protein be made to confirm the diagnosis suspected from the reagent strips. However, the positive predictive value of the reagent strips increases as the severity of the proteinuria worsens, and þ þ or more on dipstix is likely to reflect a significant concentration. Should intervention be warranted on clinical grounds, a clinician should not delay the instigation of active management in order to complete a 24-h collection.
Pre-eclampsia Pre-eclampsia is classically defined as hypertension of at least 140/90 mmHg measured on 2 separate occasions at least 4 h apart and arising de novo in previously normotensive women after the twentieth week of gestation, accompanied by significant proteinuria, all of which are resolved by 6 weeks post-partum. Such a definition, whilst appropriate in the research setting, excludes the presence of symptoms, therefore many clinicians employ a diagnosis that relies upon 2 or more, of the following symptoms being present: *
*
*
hypertension of at least 140/90 mmHg on 2 separate occasions at least 4 h apart; significant proteinuria 0.3 g/l of protein per 24 h (0.5 g/24 h); symptoms including headache, photophobia, visual disturbance, epigastric pain, alteration in the conscious state.
Also, many clinicians consider that rises in the diastolic blood pressure of 15 mmHg and the
Chronic hypertension is hypertension that is either present pre-pregnancy or is diagnosed before the twentieth week. This definition also encompasses those patients whose hypertension is diagnosed during pregnancy but does not resolve postpartum. However, the presence of chronic hypertension does not preclude pre-eclampsia occurring, and in such patients, the prognosis for the mother and fetus is less favourable.
Gestational hypertensionFpregnancy induced hypertension (PIH) Gestational hypertension is a rise in blood pressure in the absence of proteinuria, detected after mid-pregnancy. This is a non-specific diagnosis covering patients with transient pregnancy induced hypertension, those who go on to develop pre-eclampsia and those with chronic hypertension presenting for the first time in pregnancy. Often a definitive diagnosis can only be made retrospectively.
Aetiology Pre-eclampsia is associated with a defect in placentation with as yet unidentified maternal or fetal genes conferring susceptibility.
Genetics The presence of a familial factor in the development of pre-eclampsia is suggested by a 3–4fold increase in the incidence of pre-eclampsia in first-degree relatives of affected women. However, the discordance in incidence between identical twins suggests that factors other than just the maternal genotype are implicated, an observation that raises the possibility of contribution from a fetal factor. The Genetics of pre-eclampsia Collaborative Study (GOPEC) is a multi-centre British project currently being undertaken to investigate various candidate genes, using the technique of transmission disequilibria testing. Under investigation are the genes coding for: angiotensin; angiotensin II type I receptor; Factor V Leiden; and tumour necrosis factor.
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Immunology Immunological factors in pre-eclampsia are heavily implicated by epidemiological studies. The increased risk recognised in primigravid women should be extended to include primi-paternity as it has been shown that there is a raised incidence of pre-eclampsia in women who change partners after the birth of their first child. The avoidance of barrier methods of contraception, longer periods of cohabitation and practicing oral sex reduce the incidence of pre-eclampsia. These observations suggest that the incidence of pre-eclampsia may be related to the duration of prior exposure to paternal antigens in sperm. Such findings support the hypothesis that normal pregnancy is a state of tolerance to the paternally derived antigens of the fetus. In patients with preeclampsia this immunological tolerance is impaired and the abnormal placentation that is seen may reflect an abnormal response to the paternally derived fetal antigens. The greater the load of these antigens, the greater the prevalence of preeclampsia (as illustrated by an increased incidence of this disease in multiple and molar pregnancies).
Placental factors
3
clinical syndrome that develops is the result of the widespread changes in endothelial cell function that occur. Whilst the intact endothelium has anticoagulant properties and modifies the vascular response to agonists, activated endothelial cells promote coagulation and increase vasopressor sensitivity, which are major features of preeclampsia. Further evidence of endothelial activation in pre-eclampsia include: characteristic changes in glomerular capillary endothelial morphology; increased capillary permeability; and elevated blood levels of molecules associated with endothelial cell activation (endothelin and cellular fibronectin).
Circulating factors Delivery of the placenta results in the resolution of pre-eclampsia. The placenta is thus implicated as the source of the factor(s) causing functional as well as structural damage to the endothelial cells. The nature of the circulating factor(s) has yet to be demonstrated. There are several properties, which the factor(s) must possess including the capacity: * *
Endovascular cytotrophoblasts invade the lumina of the spiral arteries in 2 waves, the first commencing at 10 weeks and the second occurring 4–5 weeks later. This process alters the morphology of the placental spiral arteries by disrupting the muscular and elastic wall constituents, and leads to the conversion of small muscular arteries into dilated low resistance ‘conduits’. These vessels are specifically unresponsive to circulating vasoconstrictive stimuli, and create a low-pressure, high-flow blood supply to the placenta. The process of intramural trophoblast invasion that occurs after 14 weeks is impaired in women with pre-eclampsia. The spiral arteries retain their endothelial and muscular linings, this results in a dramatic reduction in the intervillous blood flow. The result is placental hypoperfusion, which is thought to induce the release of a factor into the maternal circulation. The endothelial disruption that is seen in pre-eclampsia compounds this problem, leading to a further decrease in placental blood flow. This vicious pathway is only broken with the delivery of the placenta.
* *
to pass freely into the maternal circulation; to increase cellular permeability and possibly cell turnover; to alter nitric oxide and prostacyclin production; to cause an alteration in the response to endothelium-dependent agonists.
Potential candidates currently being considered include: * * *
*
vascular endothelial growth factor (VEGF); neurokinin B; oxidative stress and lipid peroxidases. Recent work has suggested that supplementation with the antioxidants vitamins C and E can reduce the incidence of pre-eclampsia in high-risk patients; syncytiotrophoblast microvillous membranes (STBMs). It has been suggested that STBMs are the link between abnormal placental invasion and endothelial dysfunction, as the increased circulating levels seen in pre-eclampsia could trigger the endothelial cell damage and disordered function that is observed.
Endothelial factors
Pathophysiology
The vascular endothelium appears to be the target cell for the disease process of pre-eclampsia, the
Pre-eclampsia is a multi-system disease defined by its clinical presentation. Distinguishing
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pre-eclampsia from chronic or gestational hypertension is important as its systemic manifestations may have life-threatening consequences for both mother and baby.
The haematological system Haemodynamics Normal pregnancy is a state of reduced vascular resistance accompanied by an increase in cardiac output, plasma volume and heart rate. Preeclampsia is associated with a comparative increase in the vascular resistance within the placental bed (thus contributing to the development of hypertension), and a reduction in circulating plasma volume in conjunction with a redistribution of fluid toward the extravascular compartment. Platelets Platelets are vital for haemostasis and clot formation, and in the event of endothelial damage they adhere to the damaged area. With the generalised endothelial damage that occurs in pre-eclampsia, a reduction in the platelet count may occur. Although this frequently predates the clinical signs of the disease, significant clotting abnormalities are rarely seen in the absence of a marked thrombocytopaenia. Coagulation cascade The intrinsic and extrinsic pathways combine in a succession of enzyme reactions to convert fibrinogen into fibrin, a cascade regulated by the fibrinolytic pathway. In pre-eclampsia, diffuse vascular damage in association with the laying down of fibrin is suggests activation of coagulation. Regulatory proteins These include anti-thrombin III, protein C and protein S. In pre-eclampsia the levels of all these proteins are reduced, increasing the tendency toward coagulation. Fibrinolytic system Plasminogen is converted to plasmin, which then acts on fibrinogen to form fibrin, fibrin degradation products and D-dimers. This pathway is carefully regulated with a tight balance being maintained between the formation and degradation of fibrin. In pre-eclampsia, this balance may be compromised, with the potential for a state of disseminated intravascular coagulopathy to develop.
R. Hayman
The liver Changes in liver function are thought to occur secondary to vasoconstriction of the hepatic vascular bed. The histological events observed include periportal fibrin deposition, haemorrhage and hepatocellular necrosis. In severe cases of hepatic involvement, complications such as hepatic rupture or infarction may be seen. The exact incidence of hepatic dysfunction in preeclampsia is unknown, as wide variations in the accepted normal range of liver function tests in pregnancy prevents systematic data collection and analysis.
The kidney The initial change observed in the kidney in pre-eclampsia is that of defective tubular function. This leads to reduced clearance of uric acid and hence hyperuricaemia. Changes that precede the impairment of glomerular filtration and the relative loss of intermediate weight proteins such as albumin and transferrin occurs. The development of proteinuria in turn causes a reduction in the plasma oncotic pressure with the subsequent complication of generalised tissue oedema. The characteristic, but not pathognomonic, lesion seen in pre-eclampsia, is glomerular endotheliosis (swelling of the endothelium and fibrin deposition causing a reduction in the capillary lumen, which resolves post-partum). Acute renal failure rarely results from acute tubular or cortical necrosis, but when either of these occur, they may lead to maternal death.
The brain The development of convulsions in a patient with pre-eclampsia is defined as eclampsia. The pathophysiology of eclampsia has not been fully elucidated. One possible explanation is that localised cerebral vasospasm results in reduced cerebral perfusion. This causes abnormal electrical activity, which has the potential to trigger an eclamptic fit. An alternative theory is that endothelial injury compounded by vascular over-distension due to hypertension overcomes the normal cerebral autoregulation capability. This results in cerebral oedema due to leakage of fluid into the interstitial spaces. Whatever the cause, in most cases the main areas affected are the occipital and parietal lobes; this correlates closely with the visual disturbances observed by patients. Such models are supported
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by the complete resolution of neurological defects seen post-recovery. Rare complications of both preeclampsia and eclampsia include cortical and retinal blindness. The most common cause of death seen in eclampsia is intracerebral haemorrhage.
Screening Many investigative procedures have been suggested as screening tests for those judged (based on their or their families past obstetric history) to be at increased risk of developing pre-eclampsia. Whilst the ‘roll over test’ is relatively harmless yet ineffective, other more reliable procedures, such as the ‘angiotensin infusion test’ are invasive, time consuming and best placed for research studies. Therefore there are, as yet, no reliable screening tests that can be routinely used to diagnose those at risk of pre-eclampsia. The use of Doppler ultrasound as both a screening and an investigative tool has been widely studied. Harrington et al reported that combining colourflow imaging, uterine artery resistance and the presence of a diastolic notch resulted in a test with a sensitivity of 76% and a specificity of 86% for the prediction of pre-eclampsia, if performed 16–24 weeks into gestation. Other studies have made it clear that abnormal Doppler findings identify a small group of fetuses, namely those that are hypoxaemic and small as a result of inadequate placental function. Although these undoubtedly include a subset of fetuses from patients with pre-eclampsia, the ability to predict how the pregnancy will proceed remains unanswered, and as yet, this modality does not provide a suitable basis for a screening test.
Clinical presentation It is imperative that a high degree of suspicion of pre-eclampsia is maintained, as many patients are asymptomatic, at least initially. Risk factors such as primiparity, a previous history of preeclampsia, diabetes, chronic renal disease, antiphospholipid syndrome, multiple pregnancy and pre-existing hypertension should be highlighted. The classic symptoms of pre-eclampsia are a frontal headache, visual disturbance and epigastric pain. A complete obstetric and neurological examination should be performed, specifically noting the presence or absence of epigastric pain, hyperreflexia, clonus and papilloedema. The presence of peripheral oedema is a common and usually favourable sign, its appearance in association with
5
proteinuria and hypertension is not often significant as a prognostic indicator. Eclampsia affects 1–2% of pregnancies and can occur at any time antenatally, intrapartum or postpartum. It is important to note that convulsions occur before the onset of proteinuria and hypertension in about one third of patients. The presence of tonic-clonic seizures that are not secondary to other causes (i.e. epilepsy, subarachnoid haemorrhage, meningitis, and space occupying lesions) should lead to a diagnosis of eclampsia until proven otherwise. Another syndrome presented within the spectrum of the hypertensive disorders of pregnancy is that of HELLP (haemolysis, elevated liver enzymes, and low platelets). The HELLP syndrome occurs in 4–12% of patients with severe pre-eclampsia, although hypertension is not always initially characteristic of this condition. As a consequence it may be confused with other medical conditions such as thrombotic thrombocytopaenia purpura. The presentation of this condition is often with non-specific findings, although disseminated intravascular coagulopathy, placental abruption, and fetal demise are not infrequent accompaniments. Amongst women with severe pre-eclampsia, 6% will present with 1 abnormality suggestive of HELLP (usually elevated liver enzymes), 12% will develop 2 abnormalities and 10% will develop the classic triad. HELLP syndrome can manifest itself at any stage during pregnancy, but 30% will occur postpartum and only 80% of such patients will have had pre-eclampsia diagnosed antenatally.
Diagnosis It is imperative that a full fetal and maternal assessment is made to avoid the complications of uncontrolled maternal hypertension and to reduce the possibility of unnecessary medical intervention that may lead to iatrogenic premature fetal delivery.
Maternal In patients with pre-existing hypertension, baseline laboratory tests help to formulate a diagnosis if pre-eclampsia is suspected in later pregnancy. However, most investigations need repeating on a regular basis to enable adequate monitoring of disease progression and resolution: *
haematological monitoring: sequential platelet counts are useful in monitoring severe disease
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R. Hayman
progression rather than for initial diagnosis. In cases of reduced or falling levels, clotting studies should be performed; hepatic function monitoring: monitoring of hepatic involvement by means of liver function tests (especially lactic dehydrogenase, aspartate and alanine transaminases), may aid diagnosis and decisions regarding disease severity. Indeed, this is frequently the only way that the HELLP syndrome may be detected; renal function monitoring: if the plasma urea or creatinine is elevated, especially in the presence of a relatively normal plasma uric acid, underlying renal disease is likely. In a patient with preeclampsia however, rising plasma creatinine or urea indicates a worsening of the disease. Serum uric acid levels tend to rise before the development of proteinuria in pre-eclampsia; urine monitoring: a mid-stream urine test to exclude urinary tract infection and a 24 h collection to identify significant proteinuria should follow initial dipstick, providing the disease-state permits the time for completion of the collection; blood pressure monitoring: blood pressure may need to be monitored as often as every 15 min during the acute phase of severe disease, but more commonly it is taken every 4 h.
or intrauterine growth restriction. In contrast, the umbilical artery Doppler has not been shown to be predictive of fetal wellbeing after 36 weeks gestation. Data from controlled trials of unselected or low risk pregnancies has failed to demonstrate any significant difference between the Doppler groups and the control groups for antenatal hospitalisation, obstetric outcome or perinatal morbidity. To complicate matters further, uncertainty exists as to the management of pregnancies with Doppler findings.
In patients with chronic or newly diagnosed hypertension, investigations to exclude causes such as Cushing’s disease, Addison’s disease and phaeochromocytoma should be performed.
Most patients have mild hypertension and are at low risk of cardiovascular and neonatal complications. This is especially true when the renal function in such patients is normal. However, the major risk in this group of women is with the superimposition of pre-eclampsia. This complication occurs in up to 25% of these patients, and in a higher proportion if renal dysfunction is present from the onset. The aim of treatment is to reduce the risk of maternal complications whilst keeping the fetus safe. The drug of choice being either methyldopa or labetolol. Atenolol and ACE inhibitors are both associated with growth restriction, and the latter is also linked to oligohydramnios, neonatal renal failure and neonatal death. The use of diuretics are not recommended, as these drugs theoretically counteract the physiological plasma volume expansion seen in normal pregnancies and therefore increase the risks to the patient of developing preeclampsia. It is not uncommon for antihypertensive medication to be discontinued in the first trimester of pregnancy, as the nadir of the physiological change in maternal blood pressure occurs between 16 and 24 weeks. However, if treatment is stopped at any stage, then close monitoring must be organised,
*
*
*
*
Fetal Ultrasonography The uses of ultrasound vary from simple measurements of fetal size, gestation and growth, to the confirmation of the presentation and calculation of the biophysical profile score and Doppler flow studies. It is clear that no definitive investigation exists but that a combination of observations enables decisions to be made on appropriate management strategies. The ultimate management depends on maternal disease severity and predicted fetal outcome. Patient management, including the use of the Doppler measurement of blood flow in the fetal umbilical artery, has been associated with a reduction in perinatal mortality. However, the absence of end diastolic flow velocity, which carries a crude perinatal mortality in excess of 40%, and a 30% chance of developing preeclampsia, has only been shown to be of benefit in clinically high-risk pregnancies, i.e. those with a gestation of less than 34 weeks with pre-eclampsia
The cardiotocograph (CTG) It must be emphasised that the CTG only provides a snapshot view of fetal health and further monitoring may be justified when other factors are considered, such as the presence of pre-eclampsia or intrauterine growth restriction. Identification of pre-existing disease enables an appropriate plan for fetal monitoring to be arranged (e.g. pre-eclampsia complicating chronic hypertension is associated with increased fetal loss).
Treatment Chronic hypertension
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7
and a recognised threshold for recommencing treatment clearly defined (e.g. 150–160/100– 110 mmHg or signs of end organ damage (retinal haemorrhage, nephropathy etc)). (See Fig. 1.)
Pre-eclampsia The development of proteinuric hypertension is usually managed on an in-patient basis, at least until quantification of the proteinuria has occurred. This protocol has the additional benefits of permitting a detailed fetal assessment whilst sequentially monitoring the blood pressure and enabling the speed of disease progression in each patient to be individually assessed.
In all cases, treatment consists of stabilising the mother until such a time as iatrogenic immaturity becomes insignificant or the predisposing condition necessitates delivery. The decision as to when to treat is obvious in the severely affected patient, but is less clear-cut in cases of pre-eclampsia at early gestations (o34 completed weeks). (See Fig. 2.)
Drug treatment Antihypertensives The initial aim of treatment is to lower maternal blood pressure to a safe level (i.e. one at which the patient is unlikely to develop hypertensive encephalopathy and suffer the irreversible consequences of this disease such as cerebral
MAP > 140 mm Hg
MAP 125−140 mm Hg
Recheck blood pressure every 5 min
Recheck blood pressure every 15 min
Hydralazine 5 mg IV
Recheck BP Every 15 min
MAP ≥ 125 mm Hg Confirm with mercury Sphygmomanometer
Labetolol 20 mg IV followed at 10 min intervals by 40, 80, 80 mg up to a cumulative dose of 220 mg
Maintenance Therapy
Recheck MAP after 15 min
MAP > 125 mm Hg and Heart rate > 120/min or 15 mg Hydralazine given
MAP < 125 mm Hg
Repeat Hydralazine 5mg IV every 15 min until either cumulative dose of 20 mg or side effects
Maintain MAP < 125 mm Hg with; Intermittent Hydralazine 5mg IV
Heart rate ≤ 120/min No side effects
If requiring > 10 mg/h to keep MAP < 125 mm Hg
Hydralazine Infusion Dilute 40 mg in 40 ml normal saline. Start at 10 mg/h and double every 30 min until a satisfactory response or dose of 40 mg/h reached Side Effects Headache Dizziness Flushing
Heart Rate > 120/min or side effects with Hydralazine
Labetolol Infusion Dilute 200 mg in 50 ml normal saline. Start at 40 mg/h and double every 30 min until a satisfactory response or dose of 160 mg/h is reached
MAP = mean arterial pressure = diastolic blood pressure + 1/3 (systolic−diastolic blood pressure)
Figure 1 The intrapartum management of hypertension.
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R. Hayman
Hypertension (≥ 140/90 mm Hg) with proteinuria (≥ 300 mg/l or ≥ 2+ on urinary dipstix) And at least one of the following i) Headache, visual disturbance, epigastric pain ii) Clonus (≥ 3 beats) iii) Platelet count < 100 x 10 9 and/or falling rapidly from previous count. b) Severe hypertension (systolic ≥ 170 mm Hg, or diastolic ≥ 110 mm Hg (MAP > 125 mm Hg) with proteinuria (≥ 300 mg/l or ≥ 2+ on urinary dipstix). c) Eclampsia.
a)
In the presence of severe pre-eclampsia, or eclampsia, the duty obstetric consultant must be informed, a plan of management being decided in liaison with the on-call anesthetis+ and the paediatric teams.
Transfer to the labour ward Investigations:
Full blood count: clotting screen; group and save serum. Urea and electrolytes: liver function tests; uric acid. Mid stream urine sample.
Designate one-to-one midwifery care. Insert urinary catheter and commence fluid balance chart (hourly input vs. output). Decision to deliver to be taken after discussion with/review by duty consultant.
Or Or
Artificial rupture of membranes + syntocinon infusion. Prostaglandin E2 pessary. Elective caesarean section.
If delivery to be delayed and gestation < 34/40: dexamethasone 12 mg IM (x 2 12 h apart). Commence monitoring 1.
IV fluids
2.
Anticonvulsants
Blood pressure every 15 minutes. Fluid protocol
Monitor urine output.
Eclampsia
Eclampsia protocol
Consider seizure prophylaxis with MgSO4 .
Pre-eclampsia 3.
Antihypertensives
MAP > 125 mm Hg (over 3 consecutive readings)
MAP < 125 mm Hg 4.
Anesthesia
Monitor Plasma MgSO4 levels.
Hydralazine protocol
Monitor BP every 15 min. recheck BP every 30 min.
Insert CVP line/pulmonary artery catheter if indicated. Caesarean section Labour If no contraindication to regional block insert epidural.
Continuous fetal monitoring whilst on labour ward (CTG).
Consider Doppler/biophysical profile (if labour or delivery delay planned). Repeat investigations (FBC, U&E’s, clotting studies, LFT’s) every 12 h. Close observation after delivery is required and all parameters must be monitored for at least 24 h with the BP being checked 4 hourly for 5 days. MAP = mean arterial pressure = diastolic blood pressure + 1/3 (systolic – diastolic blood pressure).
Figure 2 A protocol for the management of pre-eclampsia.
haemorrhage). In severe disease antihypertensive medication is often required to maintain a mean arterial pressure below 125 mmHg. Above this level a loss of cerebral autoregulation is observed. Iatrogenically induced normotension must not be
confused with cure but simply regarded as a means of stabilising and, or prolonging the pregnancy if clinically justified. Many different agents exist but all have their own specific drawbacks and therapy should not be instigated without due care. The
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most commonly used treatments are currently hydralazine, labetolol, methyldopa and nifedipine. A plethora of agents exist, all of which have different pharmacokinetic and dynamic properties, and routes of administration. The most commonly employed are: methyldopa, a centrally acting a adrenergic inhibitor; hydralazine, which reduces vascular resistance via a direct relaxation of arteriolar smooth muscle affecting the pre-capillary resistance vessels more than the post capillary resistance vessels; labetolol, which through its combined a and b adrenoceptor agonist action induces a rapid, controlled decrease in the systemic vascular resistance; nifedipine, a calcium channel-blocking agent, which relaxes predominantly venous, but also arterial, vascular smooth muscle, causing a decrease in pre-load at low doses, and afterload at high doses, glycerol tri-nitrate, which predominantly relaxes arterial smooth muscle, but also has some dilatory effect on the vascular compartment, decreasing pre-load at low doses and afterload in high doses; and ketanserin, a 5-hydroxytryptamine 2 serotonergic receptor agonist, which is thought to act peripherally via the prevention of vaso-spasm. All these drugs cross the placenta and may therefore affect the fetus. Labetolol can trigger a fetal bradycardia, and the combination of nifedipine with magnesium sulphate may cause a severe drop in blood pressure. Anticonvulsants In cases of severe pre-eclampsia and eclampsia, the drug of choice is magnesium sulphate (as illustrated by the Magpie Study, and the Collaborative Eclampsia Trial). This drug should be used to prevent and treat convulsions and hence prevent their sequaelae. It acts as a cerebral vasodilator and membrane stabiliser, reducing ischaemia and the ensuing neuronal damage. It may also act as a central anticonvulsant blocking the N-methyl-D-aspartate receptor. Magnesium sulphate has a broad therapeutic range and clinical monitoring by the observation of respiratory rate, PO2 saturations (pulse oximetry) and peripheral reflexes will suffice. Close monitoring of serum levels is especially important in the presence of reduced renal excretion, as magnesium sulphate in excess can cause profound respiratory depression and even cardiorespiratory arrest. Fortunately there is a rapidly acting antidote–calcium gluconate. Steroids Antenatal administration of corticosteroids prior to anticipated preterm delivery significantly reduces neonatal morbidity and mortality. Guidelines from the Royal College of Obstetricians and Gynaecolo-
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gists state that ‘every effort should be made to initiate antenatal corticosteroid therapy in women between 24 and 36 weeks of gestation..... providing there is no evidence of tuberculosis or intrauterine infection’. (Fig. 2.)
Supportive management Pre-eclampsia is a state of intense vasoconstriction, reduced circulating plasma volume and extracellular fluid redistribution. This is compounded by the associated low colloid osmotic pressure, a result in part of the excess loss of protein via the kidneys. This combination of factors makes fluid management extremely difficult, and the injudicious administration of fluid can have serious consequences, with the rapid development of pulmonary or cerebral oedema. It is imperative that an accurate measurement of input vs. output is charted on an hourly basis, and that the blood loss at the time of delivery is properly measured (oxytocic drugs are anti-diuretic and their use to stimulate labour and prevent post-partum haemorrhage influences urine output). Unless specific blood products are required, crystalloids are the fluid of choice and should be given whilst monitoring the urine output hourly via an indwelling catheter. Whilst the absolute volume to be replaced must be based on clinical observations, an appropriate volume for maintenance purposes is a maximum of 100 ml/hour (oral þ iv). Renal failure is a rare occurrence and the injudicious use of diuretics (e.g. frusemide) to improve the measured urine output, may further compromise an already reduced circulating volume. Should oliguria (o 20 ml/hr over a 4 h period) be noted then additional information from central venous monitoring (a CVP line) may provide valuable guidance. This management dilemma is often more of a problem antenatally than postnatally, as during the recovery period a profound diuresis is frequently seen. Indeed, a patient experiencing anuria antenatally indicates a worsening of the clinical condition, and suggests that delivery should be expedited.
Decision for delivery The aim of management is to stabilise the patient and enable appropriate decisions to be made regarding the timing and mode of delivery. The route of delivery is influenced by such factors as gestation, the presence of other
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complications (such as malpresentation), and the urgency that progression to delivery must be made. All pregnancies affected by pre-eclampsia must be classified as high-risk regardless of whether fetal compromise has been demonstrated, and as such, a low threshold for intervention should exist if the mother is allowed to continue into labour. Consultation with a senior anaesthetist is essential so that an appropriate choice of analgesia is made. Spinal, epidural and general anaesthesia all have their own individual benefits and disadvantages and the decision as to which is used depends on the clinical condition and time scale for delivery. Immediate post-partum treatment is essentially supportive with the aim of preventing complications. Forty-four percent of fits occur in the postpartum period, so vigilance should be maintained, with the blood pressure being monitored every 4 h for at least 5 days.
Postnatal follow-up In most cases of pre-eclampsia, delivery results in complete disease resolution. Patients requiring antihypertensives can usually be weaned off these by the end of the puerperium whilst gestational hypertension tends to resolve more rapidly. Those patients requiring medication antenatally are at increased risk of needing it postnatally. If pregestation values were normal or unknown then a drug free trial is reasonable in association with close monitoring and a low threshold for drug reintroduction. Counseling regarding future pregnancies plays an important role in postnatal management and psychological recovery. Patients have a 10–25% chance of developing pre-eclampsia in subsequent pregnancies; the risk is higher if other factors such as antiphospholipid syndrome are present, and also depends on the gestational age at presentation.
Conclusion Hypertension in pregnancy in association with the development of proteinuria has serious consequences for both the mother and the fetus. The aetiology and pathophysiology are incompletely understood. However, the multisystemic nature of pre-eclampsia is thought to be due to a combination of endothelial damage, vasoconstriction and hypoperfusion. These events being
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mediated by an interplay of genetic, immunological, placental and circulating factors. Diagnosis is often made at a routine visit, as symptoms are often absent, at least initially. Treatment is aimed at reducing the maternal and fetal complications, whilst minimising the risk of iatrogenic immaturity to the fetus. Delivery of the placenta results in disease resolution, although careful management is required in the initial post-delivery period. Follow-up should include counselling regarding future pregnancies and monitoring of blood pressure to identify those women with chronic hypertension.
Acknowledgements This review was revised and updated from an earlier article in this journal by R.A. Duckett, L. Kenny and P.N. Baker from the Academic Division of Obstetrics and Gynaecology, City Hospital, Hucknall Road, Nottingham NG5 1PB, UK.
Further reading Hibbard B, Milner D. Reports on the confidential enquiries into maternal deaths: audit of previous recommendations. Health Trends 1994;26:26–8. Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy (see comments). Am J Obstet Gynecol 1988;158(4):892–8. Roberts JM, Taylor RN, Musci TJ et al. Pre-eclampsia: an endothelial cell disorder (see comments). Am J Obstet Gynecol 1989;161(5):1200–4. Roberts JM, Edep ME, Goldfien A, Taylor RN. Sera from preeclamptic women specifically activate human umbilical vein endothelial cells in vitro: morphological and biochemical evidence. Am J Reprod Immunol 1992;27(3–4):101–8. Brockelsby J, Hayman R, Ahmed A et al. VEGF via VEGF receptorI (Flt-1) mimics pre-eclamptic plasma in inhibiting uterine blood vessel relaxation in pregnancy: implications in the pathogenesis of pre-eclampsia. Lab Invest 1999;79(9): 1101–11. Page NM, Woods RJ, Gardiner SM et al. Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia. Nature 2000;405(6788):797–800. Hubel CA. Oxidative stress and pre-eclampsia. Fetal Matern Med Rev 1997;9:73–101. Smarson Ak, Sargent IL, Starkey PM, Redman CW. The effect of placental syncytiotrophoblast microvillous membranes from normal and pre-eclamptic women on the growth of endothelial cells in vitro. Br J Obstet Gynaecol 1993;100(10):943–9. Douglas K, Redman C. Eclampsia in the United Kingdom. British Eclampsia Survey Team. BMJ 1994;309:1395–400. Hayman RG, Baker PN. The hypertensive disorders of pregnancy. Antenatal and intrapartum management. R Coll Obstet Gynaecol. PACE Review no. 97.