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Medical Research Council/University of Natal Pregnancy Hypertension. Research Unit. DR WILLIAM HAGUE. Women's and Children's Hospital,. North Adelaide ...


Cardiovascular Profile

Hypertension in pregnancy Round-table discussion: Part I PROF. ANDRIES BRINK


Cardiovascular Journal of South Africa Durbanville, W. Cape

Department of Obstetrics and Gynaecology, Lyell McEwin Hospital, Adelaide University

PROF. WOLE AKANDE Department of Reproductive Health and Research, World Health Organisation, Geneva, Switzerland

PROF. JACK MOODLEY Department of Obstetrics and Gynaecology, King Edward VIII Hospital and University of Natal; Medical Research Council/University of Natal Pregnancy Hypertension Research Unit

DR WILLIAM HAGUE Women’s and Children’s Hospital, North Adelaide, and Department of Obstetrics, University of Adelaide, South Australia

DR DAVID HALL Department of Obstetrics and Gynaecology, Tygerberg Hospital and University of Stellenbosch; Medical Research Council Perinatal Mortality Research Unit

DR WILHELM STEYN Department of Obstetrics and Gynaecology, Tygerberg Hospital and University of Stellenbosch; Medical Research Council Perinatal Mortality Research Unit

PROF. HEIN ODENDAAL Department of Obstetrics and Gynaecology, Tygerberg Hospital and University of Stellenbosch; Medical Research Council Perinatal Mortality Research Unit PROF. BRINK: Blood pressure (BP) is a biological characteristic such as weight or height. It follows a bell curve type of distribution with an extended leg on the right for the older age groups. Normal levels are arbitrary depending on different criteria from various organisations. A single measurement is not enough to characterise hypertension. Several readings on several occasions should be obtained. It is more reliable to have 24-hour ambulatory monitoring of the BP to assess significance of the BP elevation. The mean arterial pressure is a product of total peripheral resistance and cardiac output. The renin-angiotensin-aldosterone system is important in the regulation of BP, through vasoconstriction and its effects on electrolyte and fluid balance. These factors are relevant when considering management and treatment of hypertension. BP levels can range widely among

population groups depending on age, gender, and ethnicity. The United States Joint National Committee on Detection, Evaluation and Therapy of High Blood Pressure (USNCDETHBP) puts the upper levels at 140/90 mm Hg, beyond which one should consider patients as being hypertensive. In the USA this means that about 33% of white and 38% of black men between 18 and 74 years of age have hypertension.1 The World Health Organisation (WHO) criteria puts the levels beyond 160/95 mm Hg for hypertension.2 Ethnic differences exist between black and whites in the USA. Various hypotheses for this phenomenon, none convincingly proven, relate to differences in diet, stress, cultural factors and exposure to a different way of life. In South Africa and other developing countries BP levels vary between white and black populations.3 In South Africa blacks in rural areas may have lower BPs than those in urban populations.4,5 Response to various anti-hypertensive agents may also differ between white and black patients.6 The individual daily variations that occur in BP levels relate to age, stress, exercise, emotion, or sexual intercourse. There are normal variations during 24 hours of the day (circadian rhythm). A 24hour monitoring of the BP is more appropriate for meaningful evaluation

CARDIOVASCULAR JOURNAL OF SOUTH AFRICA Vol 13, No. 1, January/February 2002 of the BP. The circadian rhythm tends to disappear or become less pronounced in certain situations such as diabetes mellitus, eclampsia, patients who have had cardiac transplants, and in old patients. Persons who have transient high BP at an early age tend to develop persistent hypertension later on. The pathogenesis of hypertension has been studied extensively and relates to many aspects of life and lifestyle such as nutrition, diet, salt potassium, magnesium and calcium intake, low birth weight, obesity, alcohol intake, social stresses, and others. It remains, however, difficult to pinpoint any single factor or combination of factors in the genesis of this condition. There is little doubt that there is a genetic component to hypertension but this too is a complex situation. It is well recognised that hypertension occurs more often in some families. There is a possibility that ongoing repetitive stress could lead to sustained high BP but proof of this is lacking. Hypertension can be secondary to other conditions, with acute and chronic renal disease, vascular renal pathology and diabetic nephropathy being the most frequent causes. Patients are not infrequently referred for evaluation of hypertension when the underlying condition is coarctation of the aorta. It is essential to remember always to palpate the pulses in both the upper and lower extremities in order not to fall into this trap. Young women who are pregnant don’t often have essential hypertension. It appears that hypertension may develop in early pregnancy and subside after the pregnancy. With repetitive pregnancies the hypertension becomes sustained. Oral contraceptives, pheochromocytoma or Conn’s syndrome, are endocrine situations in which the BP becomes elevated. Essential hypertension and secondary hypertension occur during pregnancy. Essential hypertension is the more common condition. There must, however, always be an awareness of secondary hypertension so that appropriate actions are taken. The early diagnosis of either primary or secondary hypertension is important for both mother and foetus. The back-

ground given to development of hypertension should be regarded as a guide to management and treatment of the various factors associated with elevation of BP during pregnancy. PROF. ODENDAAL: Let us consider the aetiology of pre-eclampsia. Although we still do not know what it is we do have sounder theories now than 10 years ago. PROF. DEKKER: Pre-eclampsia is a clinical syndrome. Three characteristics are involved: (i) the degree of vasoconstriction which may or may not result in hypertension; (ii) involvement of the haemostatic system; and (iii) a degree of capillary leakage. It is important to emphasise that patients may be quite sick with only a minimal increase in BP. The pathogenesis of pre-eclampsia is characterised by shallow endovascular trophoblast invasion by the cytotrophoblasts in the spiral arteries, and inappropriate endothelial cell activation. In considering the aetiology there are two major hypotheses. According to the so-called placenta ischaemia hypothesis (Oxford model) ischaemia is the causative factor. According to this hypothesis, placental ischaemia would result in the release of a variety of inflammatory mediators, which subsequently set off endothelial cell activation of the mother. The other hypothesis is the so-called immune maladaptation hypothesis. This hypothesis is based on epidemiological data showing the effect of length of sexual relationship and change of sex partner. Pregnancy can be regarded as the most common organ transplantation in mankind and mostly it’s a successful transplant. The mechanisms that are in place ensure that the mother does not reject the fetus, which is what one would expect to happen. This process is not well understood. Several mechanisms have been proposed. One of these is that the cytotrophoblast expresses a certain HLA type, the so-called HLA-G, which is not polymorphic. The presence of this HLA-G is thought to be important to prevent activation of maternal T-cells and killer cells. We do know that there is inflammation in preeclampsia. There is even inflammation in normal pregnancy. Pre-eclampsia may be a further step in the degree


of inflammation. Increased inflammation is demonstrated by the increased neutrophil activation, free radicals and cytokines. Pre-eclampsia is characterised by a dominance of so-called TH1 cytokines, e.g. interferon gamma, and IL1, while successful pregnancy is characterised by a dominance of TH2 cytokines such as IL10 and IL4. The causative mechanism is either the hypoxia or the immune response, or both, we don’t know. Accepting the presence of a degree of inflammation, the maternal constitution must be taken into account. A variety of pre-existing conditions for each mother such as her age, obesity and a series of susceptibility genes dictate how she will cope with varying degrees of inflammation. If she is a young, healthy woman without underlying disorders she can probably cope with a fair amount of inflammatory stress. If, on the other hand, she is 41 years old, homozygous for factor V and insulin resistant, she will develop significant disease. On the one hand, a degree of inflammatory stress is present, whether caused by hypoxia or by immune mechanisms; on the other hand a certain pre-existing quality of her cardiovascular system and especially her endothelial cells exists to cope with the inflammatory stress. The balance of these factors provides a practical scheme for ways to address the problem. PROF. ODENDAAL: We don’t know exactly why pre-eclampsia develops. It may turn out to be a combination of many risk factors acting simultaneously. Another important aspect to address is hyperhomocysteinaemia. Hyperhomocysteinaemia plays an important role in various conditions that affect the complicated pregnancy, for instance early abortion, intra-uterine growth retardation and maybe abruptio placentae. It could play a role in pre-eclampsia or in the susceptibility to preeclampsia. DR HAGUE: High plasma levels of homocysteine have been associated with a tendency to increased thrombotic activity.7 In children with an inherited recessive disorder of cystathionine β-synthase deficiency widespread premature atherosclerosis has been observed.8 The significance of



this observation was not fully recognised until the last 10–15 years. Homocysteine is an intermediate amino acid which is critical for two biochemical pathways – methylation and sulphuration. Homocysteine is methylated into the essential amino acid methionine, which is then demethylated, and the cycle goes around. The process is governed by a number of co-factors including vitamin B12 and vitamin B6. Folic acid and its tetrahydro compounds, tetrahydrofolic acid and methyltetrahydrofolic acid, provide the methyl groups for this process, one of the enzymes being 5,10 methylenetetrahydrofolate reductase (MTHFR). The sulphuration pathway is controlled by cystathionine β-synthase, and is irreversible. There are a number of important polymorphisms affecting the genes for these enzymes. Cystathionine β-synthase has a polymorphism that is fairly rare, but which in the homozygous state leads to classic homocystinuria. The polymorphisms for MTHFR are, however, much more common, in particular, the C→T thermolabile polymorphism at position 677, which in the homozygous state leads to mild to moderate hyperhomocysteinaemia, especially in conditions of folate deficiency. In addition, there is an A→C polymorphism at position 1298. Compound heterozygotes for these two polymorphisms show a similar degree of mild to moderate hyperhomocysteinaemia as do those homozygous for the 677 polymorphism. (Of interest, but perhaps not so relevant to this discussion, is that although in the adult the two polymorphisms appear to be in linkage disequilibrium, in the foetus crossover and multiple compound heterozygosity has been observed in non-viable embryos, which may be telling us something important about the role of this enzyme and its variants in relation to folic acid metabolism and methylation of DNA in the embryo.) Why should homocysteine be relevant to pre-eclampsia? Utero-placental thrombosis has been associated with pre-eclampsia. Animal and in vitro experiments have shown that oxidation of homocysteine is an important factor in producing atherothrombosis, whether directly through endothelial

dysfunction, through proliferation of vascular smooth muscle cells, through lipid peroxidation, or through oxidation of low-density lipoprotein (LDL) cholesterol. High concentrations of homocysteine promote both atherosclerosis and vascular thrombosis.9 Being homozygous for the thermolabile polymorphism of MTHFR, and therefore prone to hyperhomocysteinaemia, increases the risk for various vascular disorders including preeclampsia, particularly in the European and North American populations.10 The prevalence of these polymorphisms is relatively high in the European population, between 8 and 10%, whereas in a black African population it is less than 1%.11 There are various clinical conditions, not only genetic ones, that cause hyperhomocysteinaemia. Deficiencies of the various co-factors (folic acid, vitamin B12, vitamin B6) cause plasma homocysteine to rise. Renal failure causes a rise in plasma homocysteine, as to a lesser extent does hypothyroidism. Pregnancy, on the other hand, causes a decrease in plasma homocysteine and in our own work we have shown a significant fall in plasma homocysteine in the second trimester. Other workers have shown this to be the case throughout pregnancy compared with the non-pregnant range.12 In our laboratory the normal range during pregnancy in the second trimester is between 3.5 and 10.9 µmol/l, with a median of 4.9 µmol/l, whereas the non-pregnant range is between 5 and 15 µmol/l, which is a significant difference. The important thing, however, as far as hyperhomocysteinaemia is concerned, is that it is the phenotype and not the genotype which is the more important determinant of outcome. Various studies13-16 have shown that mild to moderate hyperhomocysteinaemia is associated with placental infarction, recurrent pregnancy loss, fetal growth restriction, pre-eclampsia and abruptio placentae. A study of 101 women with severe early onset preeclamptic disease some three months or more after pregnancy showed an incidence of hyperhomocysteinaemia (confirmed by a high response of homocysteine to methionine loading) of around 17–18%.17 In our own smaller study, we investigated the incidence

of hyperhomocysteinaemia in patients with early onset eclampsia or severe pre-eclampsia at or shortly after the time of delivery, and showed an incidence of 36%. The nutritionist’s response to this is that everybody needs to have folic acid supplements because we know that a small dose of folic acid can reduce plasma homocysteine quite consistently.18 But is this in fact the right response? We don’t really know, as far as pre-eclampsia is concerned, whether the homocysteine is a predisposing factor causing pre-eclampsia or whether it is a factor that comes as a result of preeclampsia.19 We are not yet able to determine that. We are running a randomised trial to see whether folic acid supplementation will indeed reduce the frequency of recurrent pre-eclampsia in women shown to be hyperhomocysteinaemic. More such trials are needed before we will know whether homocysteine is or is not an important factor in the aetiology of pre-eclampsia. PROF. ODENDAAL: Hypertension in pregnancy, especially in Africa, is a major aspect for discussion. PROF. AKANDE: Maternal mortality in Africa is very high, with hypertension and eclampsia representing a good proportion of all the causes of death. Apart from the pathology, which is well known (being the same everywhere), these conditions become very severe in Africa because of a number of associated factors. These patients are commonly unattended, in communities with poor access to healthcare facilities. Most of the time the patient is admitted to hospital in extremis. In Africa, many patients present with severe fulminating pre-eclampsia and eclampsia. Social and economic situations also underlie this syndrome. Girls often marry very early, as early as 12 years old or even younger, and have a first pregnancy at an early age. Young primigravidas, especially those aged 15 years and under, have a high risk of pregnancy-related hypertension and toxaemia.20 At such early ages they present with a considerable proportion of hypertensive disorders. Patients are frequently malnourished and subjected to harmful traditional practices. It is not hypertension alone but the interaction

CARDIOVASCULAR JOURNAL OF SOUTH AFRICA Vol 13, No. 1, January/February 2002 of these associated factors, which have to be taken into account as far as Africa is concerned. To reduce maternal mortality in Africa concerted efforts should focus on a number of areas. These include discouraging early marriage and pregnancy. This will decrease the incidence of childhood pregnancies complicated by hypertension. Access to medical care should be improved. A sufficient number of health workers who have midwifery skills must be trained. Essential supplies and equipment should be provided. In rural and poor communities in particular, pregnant patients with hypertension or preeclampsia arrive at hospitals for care and there is nothing to treat them with. Transportation should be readily available in cases of emergency. We have seen patients with severe pre-eclampsia, many in extremis, who have not been able to reach the hospital because transportation was not available. PROF. MOODLEY: I would like to outline the process of confidential inquiries into maternal deaths in South Africa. In 1997 the National Government took the step of setting up a National Committee on Confidential Inquiries into Maternal Deaths (NCCEMD). This is the only confidential inquiry committee in a poor country and probably the second only in the world. The pattern of the confidential enquiries into maternal deaths in the UK is followed.21 All maternal deaths are notifiable by law and therefore reported to central government via the provincial governments. Populationbased data rather than hospital-based data are therefore collated. Although all deaths are probably not reported, the number of deaths occurring is so large that trends can be observed. All hypertensive deaths that occurred in pregnancy, including preeclampsia, eclampsia and deaths due to chronic hypertension, accounted for 23% of all maternal deaths in this country in 1998. They’re the commonest cause of death, others being obstetric haemorrhage, sepsis, and other medical complications. Almost two-thirds of deaths related to hypertension in pregnancy are due to eclampsia, the other third is due to

chronic hypertension. This implies that both young women and women over the age of 35 years are dying from hypertensive disorders in pregnancy. The commonest cause of their deaths relates to cerebral haemorrhage. This indicates that we may not be treating high BP effectively. A further cause of death in hypertensive pregnant women is pulmonary oedema, possibly because medical care is not adequate. A third frequent cause of maternal mortality is cardiorespiratory failure. This could be the consequence of hypertension being treated successfully, saving mothers from cerebrovascular accidents but losing them in the ICU to acute respiratory distress syndrome (ARDS). Another cause of maternal death is rupture of the liver. The NCCIMD considered these deaths in relation to avoidable factors. For practical purposes avoidable factors are broken down into factors related to patients, administration, and to medical and nursing care. Patient-related factors are: 1. Lack of antenatal care or infrequent attendance for antenatal care, despite the fact that free antenatal services have been provided for the last six years. 2. Concealment of pregnancy. 3. Delay in seeking medical aid. These situations relate particularly to women in rural areas or where there is lack of transport. Administrative factors include: 1. Poor ambulance services from communities to health facilities and from one level of health facility to another. 2. Lack of ICU facilities. Many patients have to travel to tertiary hospitals because of shortage of ICU beds in the country. Women may be saved by ICU care, but the existing ICU facilities are often occupied by trauma patients. 3. Inappropriate staffing. Labour wards and obstetric high-care units should be staffed according to the norms of an ICU. There are no such resources. 4. Nursing administration. Many deaths occur following delivery. The perception exists that once the patient has delivered the problems are solved and the hypertension will settle.


Even eclamptics are not sent to highrisk care areas. They may be sent to the routine care ward, their BPs are not taken or monitored and a patient may be found to be in extremis the next morning. Medical and nursing care factors include the following: 1. Cerebral haemorrhage is a major cause of death. The majority of obstetricians and general practitioners use magnesium sulphate believing that it is an antihypertensive agent. Magnesium sulphate is valuable, but it must be brought home that high BP must be lowered. 2. Pulmonary oedema must be avoided by appropriate fluid management. Pulmonary oedema is frequently caused by fluid overload. Clinical evidence must be sought for post delivery, particularly during anaesthesia for caesarean section. 3. Level of care. Patients can die at all levels of care. Complicated eclamptic patients should not be treated at primary and secondary levels. Clinics may not be following the prescribed referral protocols, or protocols for management may not be available. Lessons have been learnt from the confidential inquiries into maternal deaths as far as hypertension is concerned. Public health education is essential. Women have to be taught to start antenatal care early, not to use the facility as a device for booking for delivery; to attend antenatal clinics frequently; and to learn and be informed of the early signs of pre-eclampsia and other hypertensive disorders. Women who are 35 years and older constitute a significant proportion of the deaths that occur, therefore contraceptive services and tubal ligation for women 35 years and above should be strongly advocated and provided for. Many young women conceal their pregnancies and delay going to hospital. The Termination of Pregnancy Bill was instituted in 1997, but the service is not provided generally. There is an imbalance between provision in rural areas and urban centres. Management protocols must be instituted and implemented. If we have fire drills based on these protocols, the management of hypertensive pregnant patients would improve.



Ongoing clinical professional development (CPD) must be pursued. In addition, the institution of regional advisers on pregnancy hypertension would be helpful. We need to institute appropriate medical education such as teaching medical students practical things about management in small hospitals, which will help to decrease maternal deaths due to hypertension. PROF. ODENDAAL: Protocols have been completed and circulated to all obstetricians. Guidelines are structured for different regions. Each area can establish its own protocol, which will probably differ from place to place. We have also considered publishing the guidelines widely. PROF. BRINK: What does a confidential inquiry imply? PROF. MOODLEY: It’s confidential in relation to the identity of individual persons managing a particular case. PROF. BRINK: Do the data not come from the Central National Statistical Services? PROF. MOODLEY: No. When a death occurs, the hospital superintendent or representative reports the death to the directorate of maternal and child health of the Provincial Health Authority. Once the death is reported, it receives a unique number, after which an assessment of that death is done by assessors, trained by the National Committee. The assessment is based on the notes. Interviews are not held with nurses or doctors. Doctors fill in the appropriate form, from which assessments are made at yearly intervals. Annual reports are submitted with the intention of producing an expanded more comprehensive report every three years. DR HAGUE: In Australia and the UK these reports have privilege from the Courts, and the discussions have privilege so there is no possibility of any litigation arising as a result of the inquiry. PROF. MOODLEY: We follow the British system. PROF. ODENDAAL: The early recognition of hypertension in pregnancy should receive some attention, including views on when to start with treatment of hypertension in early pregnancy. DR STEYN: Hypertension occurring before 20 weeks’ gestation is usually due to pre-existing chronic hyperten-

sion. Pregnant women with chronic hypertension are at increased risk for complications such as superimposed pre-eclampsia and abruptio placentae, while perinatal morbidity and mortality are also increased. Most of the increased risk associated with chronic hypertension occurs if superimposed pre-eclampsia develops. It was concluded in the latest South African Confidential Report that intracranial haemorrhage was the most likely cause of death in pregnant women who died of hypertension. The report confirmed that the majority of these deaths were due to pre-eclampsia or its complications.22 Two earlier studies23,24 reported that perinatal outcome was significantly worse when pre-eclampsia developed in 44 patients with severe early hypertension, as well as in 212 patients with mild hypertension in early pregnancy. These complications included decreased gestational age at delivery, lower birth weight, as well as an increase in incidence of small-for-gestational-age babies, abruptio placentae and perinatal mortality. The majority of cases of chronic hypertension in pregnancy will be due to essential hypertension, but secondary hypertension occurs in approximately 10% of cases and may have implications for the pregnancies unrelated to BP level. It is important to keep this in mind when assessing patients with chronic hypertension. The managing obstetrician should consider further investigations in patients without a family history of hypertension and those with atypical features such as an abrupt onset of hypertension, resistance to standard treatment and target organ damage. During follow-up visits BP should be accurately measured, urine tested at each visit and fetal growth should be carefully monitored. There is agreement that severe hypertension, usually defined as a diastolic BP persistently above 110 mm Hg, should be treated in order to prevent or decrease the possibility of intracranial haemorrhage. No verification of this statement or controlled study is available or ever likely to become available. It is, however, supported by circumstantial evidence. The role of continued administration of antihypertensive drugs to pregnant women with less than severe chronic

hypertension is uncertain. In a doubleblind randomised placebo-controlled trial we showed that ketanserin, a serotonin 2 receptor antagonist, significantly decreased the incidence of preeclampsia and severe hypertension. Gestational age and birth weight were significantly higher in the patients receiving ketanserin, while there were trends towards a decrease of perinatal mortality and abruptio placentae.25,26 Two meta-analyses indicated some significant advantages for the mother if mild to moderate hypertension is treated early during pregnancy. These advantages include decrease in the incidence of later onset of severe hypertension and the need for hospitalisation before delivery, and also the need for additional antihypertensive treatment during the pregnancy. Although treatment to reduce BP may be beneficial for the mother, a lower BP may impair the placental perfusion and jeopardise fetal growth. Both these meta-analyses found trends towards improved perinatal mortality, but these were not statistically significant. In this area more research is needed to decide at which level one should start treatment in patients with less than severe degrees of hypertension in pregnancy. In the ketanserin study it is unclear whether the advantages that we could demonstrate were owing to the antihypertensive effect per se, or whether they were due to the antiserotonin effect of the drug. This type of study should be repeated using other drugs. PROF. ODENDAAL: We should also discuss other drugs used for the control of hypertension in pregnancy.27 DR HALL: The established place of antihypertensive therapy during pregnancy is for patients with severe hypertension. Methyldopa is widely accepted as the first-line agent among obstetricians. Although it is not a particularly potent agent, it has been proved to be safe for both the mother and the fetus.28 The effects have been studied in children up to the age of 7 years.29 Increasingly, however, more than one agent is required for adequate control of BP. Among the groups of agents that have been considered, beta-blocking agents have been widely investigated. There are concerns regarding the effects of these agents, not so much on maternal

CARDIOVASCULAR JOURNAL OF SOUTH AFRICA Vol 13, No. 1, January/February 2002 BP control, but rather on the effects on the fetus. Diuretics and alpha-blocking agents such as prazosin (on which very little research has been done) have been used. Agents combining alphaand beta-blocking properties, of which labetalol is the most widely known, have also been considered. In the case of labetalol too though, a randomised controlled trial has linked the agent with impaired fetal growth.30 Currently nifedipine, a dihydropyridine calcium channel blocker, is a promising agent. Nifedipine blocks the influx of calcium into smooth muscle cells, interfering with excitation-contraction coupling. A useful characteristic of this agent is that its degree of BP reduction is directly proportional to pre-treatment pressure. This characteristic allows nifedipine to be used for other indications beside hypertension. Therefore, a relatively large loading dose can be given to normotensive patients to suppress pre-term labour. Nifedipine has a rapid onset of action after oral administration. It has been shown to inhibit platelet aggregation,31 which is a very useful characteristic in pre-eclampsia, decrease erythrocyte aggregation32 and improve renal function.33 The vasodilatation that it causes seldom results in a problematic tachycardia. It does have some common minor side-effects such as transient facial flushing, headache and warm, sweaty extremities. Initially, data from animal studies (pregnant ewes) caused concern about fetal reactions to treatment with nifedipine.34,35 Clinicians now have extensive experience with nifedipine in hypertensive disorders of pregnancy and pre-term labour, and have not found the same associated adverse perinatal outcomes.36 Nifedipine has no significant teratogenicity in patients exposed during the first trimester of pregnancy.37 Studies of older, non-pregnant patients have found that shortacting calcium channel blockers were associated with increased cardiovascular mortality, malignancy and gastro-intestinal haemorrhage.38 In their review of the subject, the previously mentioned authors found no clear reasons for clinicians dealing with pregnant patients to alter their indications for these agents. A small risk of fatal aplastic anaemia in aged patients,

60 years and older who are on longterm nifedipine therapy has been recorded.39 In the field of obstetrics, nifedipine has been evaluated for acute BP control and oral maintenance control. It has been used in moderate and severe grades of hypertension. In pregnancy associated with hypertension, a number of randomised controlled trials have shown it to be effective and not to have detrimental effects on the uteroplacental blood flow.40-42 We recently performed a randomised controlled trial where we compared nifedipine with prazosin as a second-line agent in patients with early severe hypertension or early severe pre-eclampsia. Nifedipine was found to be safe and allowed a mean gain of 15 days as a second agent. When we used it as a third agent a mean gain of 11 days was obtained. These results confirm its safety profile in accordance with the rest of the literature.43 PROF. ODENDAAL: By mean gain you mean prolongation of the pregnancy? DR HALL: Yes, it’s important to prolong pregnancy. Very often the severe hypertension occurs in pregnancies remote from term. Early delivery of those fetuses would diminish their chance of survival.











References 1.









Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood pressure. The sixth report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure (JNC VI). Arch Intern Med 1997; 157: 2413–2446. World Health Organisation Expert Committee on Hypertension Control. World Health Organ Tech Rep Ser 1996; No 862. Nissenen A, Böthig S, Granroth H, Lopez AD. Hypertension in developing countries. World Health Stat Q 1988; 41: 141–154. Seedat YK, Seedat MA. An interracial study of the prevalence of hypertension in an urban South African population. Trans R Soc Trop Med Hyg 1982; 72: 62–71. Seedat YK, Seedat MA, Hackland DBT. Prevalence of hypertension in urban and rural Zulu. J Epidemiol Community Health 1982; 36: 256–261. Seedat YK. Varying responses to hypotensive agents in different racial groups: black versus white differences. J Hypertens 1989; 7: 515–518. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinaemia: an independent risk for vascular disease. N Engl J Med 1991; 324: 1149–1155. McCully K, Wilson R. Homocysteine theory of arteriosclerosis. Arteriosclerosis 1975; 22: 215–227. Hankey G, Eikelboom J. Homocysteine and









vascular disease. Lancet 1999; 354: 407–413. Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 9–13. Chikosi AB, Moodley J, Pegoraro RJ, Lanning PA, Rom L. 5,10 methylenetetrahydrofolate reductase polymorphism in black South African women with pre-eclampsia. Brit J Obstet Gynaecol 1999; 106: 1219–1220. Walker MC, Smith GN, Perkins SL, Keely EJ, Garner PR. Changes in homocysteine levels during normal pregnancy. Am J Obstet Gynecol 1999; 180: Part 1, 660–664. Goddijn-Wessel T, Wouters M, Vandermolen E, et al. Hyperhomocysteinaemia – a risk factor for placental abruption or infarction. Eur J Obstet Gynecol Reprod Biol 1996; 66: 23–29. Van Pampus MG, Dekker GA, Wolf H, et al. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia. Am J Obstet Gynecol 1999; 180: 1146–1150. Wang J, Trudinger B, Duarte N, Wilcken D, Wang X. Elevated circulating homocyst(e)ine levels in placental vascular disease and associated pre-eclampsia. Br J Obstet Gynaecol 2000; 107: 935–938. Wouters M, Boers G, Blom H, et al. Hyperhomocysteinaemia: a risk factor in women with unexplained recurrent pregnancy loss. Fertil Steril 1993; 60: 820–825. Dekker G, de Vries J, Doelitzsch P, et al. Underlying disorders associated with severe early-onset pre-eclampsia. Am J Obstet Gynecol 1995; 173: 1042–1048. Collaboration HLT. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 1998; 316: 894–898. Dudman N. An alternative view of homocysteine. Lancet 1999; 354: 2072–2074. Harrison KA, Rossiter CE, Chong H, et al. The influence of maternal age and parity on childbearing with special reference to primigravidae aged 15 years and under. Brit J Obstet Gynaecol 92 (supplement): 23–31. Enquiries Into Maternal Deaths. Why Mothers Die: Report on Confidential Enquiries into Maternal Deaths in the United Kingdom, 1994–1996. BOH. Sibai BM, Abdella TN, Anderson GD. Pregnancy outcome in 211 patients with mild chronic hypertension. Obstet Gynecol 1983; 61: 571–576. Sibai BM, Anderson GD. Pregnancy outcome of intensive therapy in severe hypertension in first trimester. Obstet Gynecol 1986; 67: 517–522. Steyn DW, Odendaal HJ. Ketanserin and aspirin in the prevention of pre-eclampsia – a randomised controlled trial. Lancet 1997; 350: 1267–1271. Collins R, Wallenburg HCS. Pharmacological prevention and treatment of hypertensive disorders in pregnancy. In: Chalmers I, Enkin M, Keirse M, eds. Effective Care in Pregnancy and Childbirth. Oxford: Oxford University Press, 1989: 512–533. Duley L. Any antihypertensive therapy in chronic hypertension. In: Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, eds. Pregnancy and Childbirth Module. Cochrane database of systematic reviews: Review No 05733, 2 June 1992. Published through ‘Cochrane updates on disk’. Oxford: Update software 1994, disk issue 1.



27. Saving Mothers. Report on Confidential Enquiries Into Maternal Deaths in South Africa. Pretoria: Government Printers, 1998. 28. Redman C. Hypertension in pregnancy. In: De Swiet M, ed. Medical Disorders in Obstetric Practice. 3rd edn. Oxford: Blackwell Scientific Publications, 1996: 182–225. 29. Cockburn J, Moar VA, Ounsted M, Redman CW. Final report of study on hypertension during pregnancy: the effects of specific treatment on the growth and development of the children. Lancet 1982; 1: 647–649. 30. Cruickshank DJ, Campbell DM, Robertson AA, MacGillivray I. Intra-uterine growth retardation and maternal labetalol treatment in a random allocation controlled study. J Obstet Gynaecol 1992; 12: 223–227. 31. Rubin PC, Butters L, McCabe R. Nifedipine and platelets in pregnancy. Am J Hypertens 1988; 1: 175–177. 32. Tranquilli AL, Garzetti GG, De Tommaso G, et al. Nifedipine treatment in preeclampsia reverts the increased erythrocyte aggregation to normal. Am J Obstet Gynecol 1992; 167: 942–945.

33. Ismail AA, Medhat I, Tawfic TA, Kholeif A. Evaluation of calcium-antagonist (nifedipine) in the treatment of pre-eclampsia. Int J Gynaecol Obstet 1993; 40: 39–43. 34. Harake B, Gilbert RD, Ashwal S, Power GG. Nifedipine: Effects on fetal and maternal hemodynamics in pregnant sheep. Am J Obstet Gynecol 1987; 157: 1003–1008. 35. Blea CW, Barnard JM, Magness RR, et al. Effect of nifedipine on fetal and maternal hemodynamics and blood gases in the pregnant ewe. Am J Obstet Gynecol 1997; 176: 922–930. 36. Moretti MM, Fairlie FM, Akl S, et al. The effect of nifedipine therapy on fetal and placental Doppler waveforms in preeclampsia remote from term. Am J Obstet Gynecol 1990; 163: 1844–1848. 37. Magee LA, Schick B, Donnenfeld AE, et al. The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study. Am J Obstet Gynecol 1996; 174: 823–828. 38. Davis WB, Wells SR, Kuller JA, Thorp JM. Analysis of the risks associated with






calcium channel blockade: implications for the obstetrician-gynecologist. Obstet Gynecol Surv 1997; 52: 198–201. Laporte J, Ibanez L, Ballarin E, et al. Fatal aplastic anaemia associated with nifedipine. Lancet 1998; 352: 619–620. Lindow SW, Davies N, Davey DA, Smith JA. The effect of sublingual nifedipine on uteroplacental blood flow in hypertensive pregnancy. Br J Obstet Gynaecol 1988; 95: 1276–1281. Puzey MS, Ackovic KL, Lindow SW, Gonin R. The effect of nifedipine on fetal umbilical artery Doppler waveforms in pregnancies complicated by hypertension. S Afr Med J 1991; 79: 192–194. Fenakel J, Fenakel G, Appleman ZV, et al. Nifedipine in the treatment of severe preeclampsia. Obstet Gynecol 1991; 77: 331–337. Hall DR, Odendaal HJ, Steyn DW, Smith M. Nifedipine or prazosin as a second agent to control early severe hypertension in pregnancy: a randomised controlled trial. Br J Obstet Gynaecol 2000; 107: 759–765.