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Pregnancy induced hypertension, pre-eclampsia and chronic hypertensionAfolabi DB, Abudu 00.

Hypertension is the most common medical problem seen in pregnancy. The hypertensive disorders of pregnancyconstitute major threats to matemallife during pregnancy, labour and the immediate postpartum period. Since mostcases in the developing countries present late in pregnancy and because there are inadequate facilities forinvestigations, it is not easy to differentiate on clinical grounds between pregnancy induced hypertension (Plli),essential hypertension and chronic renal disease. Under the general title of hypertensive disorders of pregnancy thefollowing classification is acceptable:

1. Pregnancy induced hypertension (Plli).(a) Gestational hypertension or Pill alone without proteinuria or other associated features.(b) Gestational hypertension with proteinuria i.e. pre-eclampsia (PE). •

2. Chronic hypertension (Clff') of any aetiology. This includes essential hypertension and chronic renal disease.

3. cm with superimposed PE.

Pregnancy Induced Hypertension (PIH)Pill is the development of hypertension in the second half of pregnancy on two or more occasions, about 4 hoursapart, in a woman who has previously been normotensive, and in whom blood pressure (BP) returns to normal within6 weeks of delivery. Pill without proteinuria is a relatively benign condition and usually occurs in the third trimester,during labour or the puerperium. Perinatal mortality is usually not increased in this condition and it is thus importantto distinguish between it and PE.

PE is a multi-systemic disorder characterised by hypertension and proteinuria, which often develops after the 20th

week of pregnancy. In hydatidiform mole, however, it could occur before the 20th week. The occurrence of PE inmolar pregnancy suggests that the presence of a fetus is not essential to the development of the disease.

PE is essentially a disease of the primigravida and is more common in the age group of <20 and >35 years. Whenthis condition is present in the multipara it is commonly associated with multiple pregnancy, essential chronichypertension and chronic renal disease. It is also seen in multiparous women in their first pregnancy with a newpartner.

HypertensionHypertension is usually defined as a BP of 140/90 mmHg and above. This is because perinatal mortality has been found tobe significantly increased above a diastolic BP of 90 mmHg. In a normal pregnancy, however, the BP falls gradually untilthe late second trimester (22-24 weeks) whereupon it begins to rise and reaches pre-pregnant levels at term. Thus, thegestational age at which the BP is recorded should be taken into consideration. Also BP readings differ between ethnicgroups. A study done in Ile-Ife, Nigeria, showed that the figure for 2 standard deviations above the mean BP, of 189women who were monitored during the different stages of pregnancy, was 130/80 mm Hg. Different mean values andupper limits should therefore be set for different stages of pregnancy, in different populations. However, since mostpatients book late in pregnancy in Nigeria, it is necessary to have an absolute value at which monitoring of the patient canbe commenced and the figure of 140/90 is thus used.

A change in BP is also used in the defmition of PIH. Many pregnant Nigerians have relatively low BP readings and maydevelop complications of PE before their BP reaches the absolute level of 140/90 mm Hg. Since diastolic BP rises byabout 10 mm Hg at the end of pregnancy, it has been suggested that the defmition of hypertension in pregnancy shouldinclude a rise in diastolic BP of at least 25 mm Hg. The standard defmition in Nigeria:, however, has been an increase in

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eystolic BP ofJO mm Hg above the earliest recorded reading or a diastolic increase of 15 mm Hg. Using this definition ofa change in BP readings also helps differentiate between borderline essential hypertension and true PIH.

In summary, therefore, hypertension in pregnancy should be defined as a BP of 140/90 and above, or a rise in systolic BPof 30 mm Hg or diastolic of 15 mm Hg during the course of pregnancy. It is important to confirm abnormal readings byrechecking the BP 4 hours later but a single reading of 110 mm Hg diastolic BP or more is appropriate for diagnosis.

The Korotkoff sound to be used in measuring the diastolic reading is also controversial. Phase 4 (muffling phase) has beenused in the past and is what most management strategies arc based 011. However, phase 5 (disappearance phase) is morereproducible, correlates better with intra-arterial measurements of diastolic blood pressure, and is more closely related tooutcome. Thus phase 5 is being increasingly accepted as preferable.

ProteinuriaProteinuria is usually defined as the presence of 3OOmgor more of protein in a 24-hour urine collection or a proteinmeasurement of 2+ (Jg albumin/l) or greater in a random urine specimen. Attention should be paid to the concentration ofthe urine as, in dilute urine e.g. specific gravity less than 1030, proteinuria of 1+ (O.3g albumin/l) is significant. Beforeascribing proteinuria to PE, other possible causes such as urinary tract infection, vaginal discharge and chronic renaldisease have to be excluded. Examination of a mid-stream specimen of urine obtained after cleaning the vulva with waterwould exclude urinary tract infection and vaginal discharge. Proteinuria of chronic renal disease pre-dates the pregnancyand occurs throughout its duration. This, of course, applies to patients who booked before the 20th week of pregnancy. Inunbooked patients or patients who booked late, the distinction may not be made until after pregnancy when the proteinuriabecomes persistent. Renal biopsies are only indicated in cases before 32 weeks where knowledge of the renal lesionwould affect management and a steroid-sensitive lesion is suspected. In such cases, the diagnosis of chronic renal diseasebecomes obvious. Orthostatic (,standing straight') proteinuria is an uncommon cause of proteinuria and is not peculiar topregnancy. Testing the urine before and uficr activity can make the diagnosis.

Proteinuria in PE is associated with the classic pathological finding of glomeruloendotheliosis, which is not permanent butrecovers after delivery. The occurrence of hypertension and progressive proteinuria increases the poor maternal and fetaloutcome in PE. Other causes of proteinuria in the tropics like sickle cell disease and malaria should be considered asdifferential diagnosis.

Oedema is now not generally accepted as a pathognomonic sign of PE. This is because oedema of the feet and hands arepresent in 50 - 80% of normal pregnancy. However where rapidly increasing or severe oedema of the fingers, face or legsis present, the sign of oedema should be taken seriously and other features of PE should be searched for.

PATHOPHYSIOLOGYThe aetiology of PE is still unknown almost a century after it was first termed 'the disease of theories'. However severalaspects of its pathology are clearer and can now be related to the clinical manifestation. There is now known to be aplacental trigger, which is followed by a maternal response. It is the extent of this response that determines the severityand spectrum of the disease.

Placental triggerThe central pathology to the development of PE lies in the placenta. The incidence is higher in conditions with increasedplaccntalmass like twin pregnancy, molar pregnancy, diabetic pregnancies and hydrops fetalis. In normal pregnancy,cytotrophoblasts invade the uterine spiral arteries by 4-6 weeks and reach the myometrial segments of the arteries by 15-18 weeks, converting them into low resistance, high t1ow, dilated vessels. In PE, there is a failure of this invasion of thearteries, which remains superficial and does not reach the myometrial level. Thus the spiral arteries remain as undilatedand high resistance vessels, and they respond to vasomotor substances like angiotensin II and noradrenaline.Uteroplacental blood flow is thus reduced and there is poor villous development. Fibrin deposition and thrombosis maydevelop in the placenta as a result. This failure of trophoblast invasion is also seen in other conditions where there isplacental insufficiency such as PIR, IUGR without maternal hypertension and CHT. Not all women with this placentaltrigger develop PE thus it is the extent of the maternal response that is the detenn ining factor.

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Matemal responseWidespread vascular endothelial dysfunction is responsible for most of the clinical manifestations ofPE. Hypertension,altered vascular reactivity, activation of the coagulation cascade and the general multiorgan damage can be explained byendothelial disturbance which in tum causes the release of several vasoactive compounds, resulting in generalisedvasoconstriction. These include increased production of thromboxanc A2 (a vasoconstrictor) and reduction in prostacyclin(a vasodilator) production, increased production of plasma endothclin I (a potent vasoconstrictor) and deranged nitricoxide (NO) production. The extent of development of the disease depends on v;m'..IUS modifying factors, which could begenetic or environmental.

What is responsible for this widespread endothelial dysfunction'!Circulating factorsThere is evidence to support a substance in the plasma ofPE patients that is responsible for the endothelial dysfunction.The nature of this factor is Unkn0\\11 but certain substances arc currently being investigated. These include lipidpcroxidation degradation products, cytokines like tumour necrosis factor and interleukin 6, ana placentalsyncytiotrophoblast microvillous membranes (STBM).

What makes some women more susceptible to developing these factors or PE in general?Genetic factorsDaughters of women with PE arc about 4 times more likely to develop the disease than daughters-in-law and it has beenestablished that it can be familial. There does not however appear to be a single PE gene; instead there may be somemodifier genes together with environmental factors.

Abnormal lipid metabolismWomen destined to develop PE have marked increases in serum triglyceride, free fatty acid and low density lipoprotein(LDL) concentrations, which arc evident as early as 16-18 weeks gestation. These LDL are more susceptible to oxidativemodification and it is the generation of oxidative stress that is thought to be responsible for the circle of events whichcauses the vascular endothelial damage.

CHRONIC HYPERTENSION OF ANY AETIOLOGYThe hypertension in this group of women pre-dates the pregnancy and is usualtv noted at booking if the patient was notalready being treated for hypertension. In patients seen after 20 weeks, the clinical differentiation is not easy. Most of thepatients with chronic hypertension in pregnancy would be those with essential hvpertension, The others have hypertensionsecondary to such conditions as renal artery stenosis, coarctation of the aorta, phaeochromocytoma, primaryaldosteronism, Cushing's syndrome, system ic lupus erythematosus, polycystic disease of the kidneys, diabeticnephropathy and chronic renal disease (chronic glomerulonephritis and chronic pyelonephritis).

Because of the physiological reduction in BP in early pregnancy already alluded to, patients with chronic hypertensionmay be normotensive when seen in mid-pregnancy (some may already be well controlled on antihypertensives) so thedevelopment of hypertension in late pregnancy does not always signify PIH. These patients with chronic hypertension arevery prone to superimposed PE but pregnancy docs not appear to influence adversely the course of their underlyingdisease. Fetal outcome appears more related to the severity of the superimposed PE. Phaeochromocytoma in pregnancy ishowever attended by a high maternal and fetal mortality.

CLINICAL FEATURESPE is a syndrome with various symptoms and signs. Hypertension and proteinuria are the most common clinical signs butno single feature is constantly present and the absence of these signs does not exclude the diagnosis. Patients are usuallyasymptomatic at the onset of the disease. Headache, double or blurred vision, flashing lights, nausea and vomiting,epigastric pain and rapidly increasing or severe oedema and hyperreflexia are some of the features that are associated withPE. The severity also varies and criteria like BP > 1601l1O, visual or cerebral disturbance and epigastric pain have beenfound to be associated with severe PE. However since eclampsia can occur with mild hypertension, there must be a highindex of suspicion when the other criteria occur with a little or 110 hypertension The presence of proteinuria is ominous

and is related to increased maternal and fetal morbidity. However, the exact level of proteinuria has not been shown tocorrelate with the degree of risk.

INVESTIGA TIONSThe haernatocrit and haemoglobin concentration are raised in PE becai.-. of the haemoconcentration caused by thediminished plasma volume seen in these patients. Platelet count falls due to increased intravascular destruction andincreased consumption. A low platelet count is one of the components of rhe HELLP syndrome (haemolysis, elevatedliver enzymes and low platelets), which is a severe variant of PE that carries a worse prognosis for both the mother andthe baby than PE on its own. Delivery should be effected as soon as possible although this should be preceded bycorticosteroids for the promotion of fetal lung maturity when this is feasible. A platelet count above 100 x 109/L isunlikely to be associated with other coagulation abnormalities. A clotting profile - clotting time, prothrombin time, partialthromboplastin time, fibrinogen level can be done when there is severe thrombocytopaenia or clinical suspicion ofdisscm inated intravascular coagulation (D Ie).

Serum uric acid falls in normal pregnancy but tends to be raised in PE and a rise correlates with a poorer outcome for bothmother and baby. The rise is as a result of reduced renal excretion. Serum urea and creatinine may also be raised and areuseful for detecting renal compromise. Urinalysis should be done daily to check for proteinuria and 24 hour urine proteincould also be done to assess the progression of the proteinuria which correlates with the degree of renal damage.

Liver involvement is responsible for the epigastric pain seen in severe Pli.and could be in the fonn oflocal tissue oedemaor subcapsular hacmorrhagc. Elevated alanine and aspartate transaminascs may thus occur and are also seen in the HELLPsyndrome.

Fetal well being can be assessed by fctal kiek charts, fctal heart rate monitoring, amniotic fluid and growth monitoring,and umbilical artery Dopplers. .

MANAGEMENTThe aims of management in this disease are:

I. To prevent maternal complications from hypertension including eclampsia.2. To reduce fetal morbidity and mortality.

Pregnant patients with III ild hypertension (e.g. diastolic BP of90-95) with. >1t proteinuria or any other features of PEcan be managed on an out-patient basis but must be carefully counselled ,jll'.! followed up. The development ofproteinuria, severe hypertension or symptoms ofPE, should prompt admission to hospital for further investigation's,and if necessary, initiation of treatment.

In general, the maturity of the fetus dictates the line of action. Where pregnancy is 37 weeks and above and severehypertension or other PE features are present, immediate control of BP and delivery should be effected. For cases inwhich the baby is immature, conservative management is adopted, the idea being to gain time to achieve reasonablefetal maturity so that perinatal deaths could be minimised. However, if the BP becomes uncontrollable, or ominoussymptoms like epigastric pain or visual defects set in, with or without rising levels of uric acid or liver enzymes,conservative management must be abandoned regardless of the gestational age of the fetus.

Conservative managementBed rest is often advised although there is no clear evidence that strict bed rest has any beneficial effects. The cost isprohibitive, it disrupts family life and there is an additional risk of thromboembolic disease with total immobility.Admission into hospital however enables the patient to be monitored more closely and appropriate intervention insti-tuted as necessary. Patients on admission should be kept informed of their progress, plans and prospects, in order toget their co-operation, as they often look and feel well and fail to appreciate the gravity of the situation.

Day care is an effective alternative for patients who require close monitonnz but not more than two visits a week. Itis commonly used in developed countries. Women attend for 2-3 hours, th, If BP and urine are checked, the results of

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maternal and fetal (cardiotocography, biophysical profile, ete) investigations are reviewed, and the managementdecided before the patient leaves the unit It has been shown to be very cost effective provided well trained andmotivated staff are present

An tihypertensivesThese drugs should be used to treat hypertension whether due to non-proteinuric PIH, PE or CHT. This is so as to reducethe risk of complications of hypertension, especially that of cerebral hacmorhh age. However it is established that whilethese drugs may lower the BP and reduce maternal complications, they do not prevent the progression of the disease. Theexact level of BP at which to commence therapy remains controversial but all agree that it is mandatory to treat if the BPgoes above or equal to 170/110 mmHg. In Nigeria where blood pressure levels arc slightly lower than in Caucasians, itmay be wiser to commence treatment at lower levels.

Methyldopa is the drug of choice for hypertension in pregnancy. It acts centrally by stimulating CX-2 adrenoceptors andreducing sympathetic outflow and has been found not to have any serious side effects on the fetus or children followed upto the age of 7 years. It is the most commonly used drug for treatment of hypertension in pregnancy on a long-term basis.The dose is O.5g to 3g daily in divided doses. Side effects include sedation, depression, nightmares and posturalhypotension. The fall in BP is maximal after 4-8 hours.

Hydralazine is the most commonly used drug for the management of severe hypertension. It lowers the BP by directaction on the vascular smooth muscle producing peripheral and central vasodilatation. It improves renal blood flow, mayimprove utero-placental blood flow, and produces a reflex tachycardia and increased cardiac output. It is given as a slowintravenous injection in doses of 5mg, repeated every 20-30 minutes as necessary. Its onset of action after intravenousadministration is 15-20 minutes. Side effects include headache, restlessness and palpitations. Oral hydralazine can also beused in moderate to severe hypertension as a second-line drug, for those patients who do not respond to monotherapy withmethyldopa alone.

Beta-blockers are useful antihypertensives in clinical practice but their safety in the fetus is not so well established. Thereis suggestion that they may cause IUGR \\hr.:n used long term in pregnancy. They are thus not recommended for use inpregnancy except in some CHT patients wh., arc poorly controlled on other medication.

Labetalol is listed as an alpha and beta-adrenergic blocking agent but in fact contains more of beta-blocking agent. Thisdrug can be used intravenously in acute cases to control BP (dose is ]00--400mg) or orally in graduated doses for lesssevere cases. It has a rapid onset of actio: but because of the concern about beta-blockers (see above), it should be.restricted to short-term therapy in the third trimester.

Calcium channel blockers cause vasodilation by inhibiting calcium influx into vascular smooth muscle cells. Nifcdipine iscommonly used and oral administration of a 10 mg tablet reduces BP within 10-15 minutes, but with the slow releasetablet, the onset of action is about 60 minutes. Side effects include headaches, tachycardia and facial flushing. They areuseful both for the management of severe hypertension and also for long-term control of moderate hypertension.

Alpha-adrenergic blocking agents such as Prazosin have the advantage of reducing peripheral resistance particularly in thevisceral vascular bed, and increasing blood volume without a decrease in cardiac output. The initial dose is lmg twicedaily, and can be increased to a total of30mg daily as required.

Diuretics should not be used because they will aggravate the already depleted plasma volume in patients with PE.They should only be used in pregnancy for the treatment of heart failure and pulmonary oedema.

Angiotensin-converting enzyme (ACE) inhibitors (e.g. Captopril, enalapril) should also not be used in pregnancybecause despite being effective hypotensive drugs, they arc very hazardous to the fetus. They causeoligohydramnios, renal failure, hypotension and there is even a risk of intrauterine death. Women with CHTpreviously on ACE inhibitors should be sw itched over to drugs like methyldopa.

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In acute severe hypertension, pre-treatment with intravenous colloids like Haemaccel or Human albumin solution is usefulfor improving renal and uteroplacental blood flow as women with PE have a reduced intravascular volume. This line ofmanagement can be pursued before hypotensive drugs are used and even help to reduce the blood pressure. However, nopatient should receive greater than 500 ml of colloid as there is a serious risk of volume overload.

There is no evidence for the use of sedatives or tranquiliscrs in the management of mild to moderate pre-eclampsia.

Fetal assessmentThis is as mentioned earlier. The symphysio-fundal measurement is done daily, the daily fetal kick chart is instituted andwhere available non-stress antenatal cardiotocography is done daily. Regular ultrasound measurements should be doneevery 2 weeks to assess fetal growth. Liquor volume and dopplers can be assessed more frequently if possible. Wherethere is evidence that the fetus is in jeopardy, the baby is best delivered. If delivery is planned before 34 weeks gestation,women should receive corticosteroids in order to induce fetal lung maturation.

Labour and deliveryThese should be well supervised and should take place in centres with facilities for recourse to Caesarean section. Labourshould be induced when it is desirable to terminate the pregnancy. If delivery is to be effected before 34 weeks thechances of success are lower and caesarean section may have to be resorted to. Even if induction is successful, emergencycaesarean section may be necessary because of fetal distress in labour. In cases of mild PE pregnancy should not beallowed 10 go past term and induction of labour should be performed any time after 38 weeks. All patients must be fullymonitored in labour. Elective caesarean section should be carried out on purely obstetric grounds.

Epidural anaesthesia should be used in these patients as it 1I0t only relieves pain but also helps control the BP and mayimprove placental blood flow. It can be used for both labour and caesarean section unless delivery is urgent in which casegeneral anaesthesia should be used for caesarean section. However, it is contraindicated if there is DIC orthrombocytopacnia ofless than J 00 x I O~IL.

Labour should be as short as possible and the second stage should be augmented with the use of vento use or forceps asprolonged pushing raises the BP even further. Ergometrine should also be avoided for the same reason and syntocinonshould be used instead. The paediatrician should be present at delivery as the baby may require intensive care afterdelivery.

COMPLICATIONSEclampsia is still one of the major causes of obstetric maternal deaths and perinatal deaths in developing countries and issignificant also in developed countries where other causes of maternal mortality such as haemorrhage, sepsis and abortionare now very uncommon. Eclampsia is thought to be caused by cerebral vasospasm leading to ischaemia and tissueoedema. The reduced plasma oncotic pressure from the loss of serum protein, and the increase in capillary permeability,lead to a decrease in plasma volume and an increase in tissue oedema which affects all organs.

Compromise of utcroplaccntal perfusion is often seen in PE and intrauterine growth retardation (IDGR) is a commoncomplication. By the time hypertension becomes clinically obvious, the disease has already progressed to a stage whereutero-placental perfusion is compromised by about 30-50%. The decrease in plasma volume and consequent highmaternal haemoglobin concentration is also associated with an increased risk of IUGR. In severe cases, intrauterine deathor neonatal death may occur. A study done at the Lagos University Teaching Hospital found that hypertensive disease ofpregnancy was responsible for 11.8% of total perinatal mortality.

Acute renal failure can occur in severe cases of PE and is often due to acute tubular necrosis. Dialysis may be required inSOJll~ cases although most recover spontaneously. Acute cortical necrosis is a more permanent cause of failure but isfortunately very uncommon in patients \\ 1Ih PE.

Pulmonary oedema is another manifestation of the generally increased tissue oedema. Injudicious use of intravenousfluids may also predispose to pulmonary oedema and as such caution must be used when administering fluids to thesepatients.

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Abruptio placentae is commonly associated with PE. This is more so in patients with chronic hypertension who havesuperimposed PE. Disseminated intravascular coagulation (DIC) complicates a few cases ofPE.

PREVENTIONAttempts to prevent PE in the past have been disappointing. However, low dose aspirin (75mg daily) started early inthe second trimester may be useful for patients at risk of developing severe early onset PE e.g. previous history ofearly onset PE, chronic hypertensives and patients with renal disease. Calcium supplementation also appears to be ofbenefit in women at high risk ofPE and in those with low dietary calcium intake.

Bibliography and suggested further reading:Abudu, O. (1988) Low birthweight and perinatal mortality in Lagos. J Obstet Gynaecol East Centr Afr 7: 68-70.Broughton Pipkin, F. (1995) Fortnightly Review: The hypertensive disorders of pregnancy. BMJ 311: 609-613.Nelson-Piercy, C. (1997) Hypertension and Pre-eclampsia. In: Nelson-Piercy, C. (ed.) Handbook of Obstetric Medicine,1st ed. Oxford: Isis Medical Media.Okonofua FE, Balogun JA, Amiengheme NA, O'Brien SP (1992) Blood pressure changes during pregnancy in Nigerianwomen. Int J CardioI37:373-9.Robson, S.c. (1999) Hypertension and renal disease in pregnancy. In: Edmonds, D.K. (ed.) Dewhurst's Textbook ofObstetrics and Gynaecology for Postgraduates. 6th ed. Oxford: Blackwell Science Ltd.Walker, r.r. (2000) Pre-eclampsia. Lancet 356: 1260-1265.

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