* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Pre-eclampsia and hypertension in pregnancy
Birth control wikipedia , lookup
Epidemiology wikipedia , lookup
Women's medicine in antiquity wikipedia , lookup
HIV and pregnancy wikipedia , lookup
Maternal health wikipedia , lookup
Epidemiology of metabolic syndrome wikipedia , lookup
Prenatal nutrition wikipedia , lookup
Prenatal development wikipedia , lookup
List of medical mnemonics wikipedia , lookup
Prenatal testing wikipedia , lookup
Fetal origins hypothesis wikipedia , lookup
Maternal physiological changes in pregnancy wikipedia , lookup
HowtoTreat www.australiandoctor.com.au PULL-OUT SECTION inside COMPLETE HOW TO TREAT QUIZZES ONLINE (www.australiandoctor.com.au/cpd) to earn CPD or PDP points. Case study Definitions Aetiology and risk factors Detecting and monitoring hypertension in pregnancy Managing pre-eclampsia and hypertension The authors DR ANNEMARIE HENNESSY, foundation chair of medicine, University of Western Sydney, and the Heart Research Institute, Sydney, NSW. Pre-eclampsia and hypertension in pregnancy DR ANGELA MAKRIS, renal and obstetric physician, Liverpool Hospital, Sydney, NSW. Authors’ case study SUSAN, 38, presents to her GP with a plan for another pregnancy with her new partner. She had had a single live birth 13 years earlier, as well as two miscarriages, with her first husband. Her earlier full pregnancy with her son was complicated by early delivery at 33 weeks’ gestation, due to upper abdominal pain, headache, high BP and proteinuria. Relevant clinical issues arising from this case include: • What was the likely nature of the pregnancy complication 13 years earlier? • What was the likely cause of that complication? • What is her risk of a repeat episode in a new pregnancy, and what can be done to reduce that risk? Relevant history Susan described her first full pregnancy in 1997 as uneventful in the early stages. She had a pre-preg2 nancy BMI of 23kg/m and her medical notes reveal no personal history of hypertension. There was a positive family history of hypertension on her mother’s side of the family, including in pregnancy. She was being seen by her GP for shared care with her local hospital antenatal clinic, her antenatal tests were all normal and initially her blood pressure was low at 110/60mmHg. Her problems began at about 31 weeks, when her GP noted her BP to be 130/80. The GP noted that there was no radiofemoral delay and no epigastric bruit, and there was no hyperreflexia or clonus and no epigastric tenderness, the uterus was appropriate for 31 weeks’ gestation and there was no uterine tenderness and no proteinuria. The GP organised review at the local hospital in the same week despite the patient having no new symptoms. Notably there was no headache, no decrease in appetite and no upper abdominal pain. Her BP reading at the local clinic was 140/90 and she was assessed for pre-eclampsia. At that time, her examination was unremarkable, her urine protein dipstick was negative and her baby was appropriately grown for 32 weeks’ gestation (by fundal height). She was admitted to day-stay for assessment of her hypertension and started on a low dose of methyldopa (250mg tds) under supervision at the local hospital-based fetomaternal assessment unit. A cardiotocograph was performed, which was “reassuring” in terms of baseline fetal heart rate and baseline variability. Susan’s blood tests showed a creatinine concentration of 30μmol/L (non-pregnant reference range 6090μmol/L) and uric acid concentration of 0.30mmol/L (0.150.35mmol/L); her LFTs were normal and her platelet count was 175 × 109/L. Her BP reading was 140/90 before treatment and settled to 120/80 over the next four hours after starting methyldopa. Susan was returned to the care of her GP and the high-risk clinic, with a request to have her BP checked twice a week. She remained well until 33 weeks, when she presented to the delivery suite with headache and right upper quadrant pain. She was noted at this time to have a BP of 170/110 and brisk reflexes with www.australiandoctor.com.au clonus. Her cardiotocograph was normal and her urine had ++++ protein. She had a normal retinal fundal examination without vessel changes or haemorrhages. An urgent caesarean delivery was organised and Susan was started on intravenous hydralazine for BP control and magnesium sulfate for seizure prophylaxis. She delivered a 1050g baby boy. She was transferred to ICU for 24 hours, but her BP settled to normal over the next six days and she was discharged on no medications. No further follow-up was recommended on discharge from the hospital. Susan’s miscarriages had preceded that pregnancy and were at eight and 10 weeks’ gestation. Both pregnancies had been confirmed by ultrasound investigation after a positive pregnancy test. They were uncomplicated by bleeding or changes in BP. Susan only had her BP checked once in the intervening 12-year period and that was described as normal. She had no other medical or surgical issues. cont’d next page 14 January 2011 | Australian Doctor | 17 HOW TO TREAT Pre-eclampsia and hypertension in pregnancy Definitions of hypertension in pregnancy and pre-eclampsia WHILE prior definitions of hypertension in pregnancy had up to 23 classifications (including peripheral oedema), we now use a four-category system relevant to patient risk while pregnant and in the immediate- and long-term post-period (see box below). Pregnancy-specific diagnoses are gestational hypertension and pre-eclampsia. Other diagnoses are chronic hypertension, which includes essential hypertension and secondary hypertension (eg, renal disease, endocrine disease, renovascular disease or coarctation of the aorta [see box: ‘Causes of secondary hypertension identified in pregnancy’, right]), and preeclampsia superimposed on chronic hypertension. Hypertension in pregnancy is defined as a systolic BP of ≥140mmHg or a diastolic BP ≥90mmHg. The blood pressure must be elevated on two occasions at least four hours apart. It should be measured in the right arm, with the patient sitting in the semirecumbent position, with the cuff fitted to the bare arm deflated appropriately slowly. Too rapid deflation of the cuff can underestimate the systolic BP and overestimate the diastolic reading. On the first assessment the BP should be measured in both arms to ensure the readings are similar. Some of the basic physiological changes of pregnancy occur very early and result in a natural decrease in both systolic and diastolic BP. The cardiovascular responses to this decrease in BP include: • Activation of the renin–angiotensin system, and thus sodium and water retention and increased blood volume. • Increased heart rate (sinus tachycardia up to 120bpm). • Increased cardiac output. The increase in blood volume is further demonstrated by reduced haemoglobin concentration. The decrease in serum creatinine concentration seen in normal pregnancy (<60μmol/L) reflects the increased glomerular filtration rate due to increased renal blood flow as the renovascular resistance is lowered by the natural pregnancy vasodilators. The vasodilatory state manifests in several ways, including: BP decreasing from early pregnancy (6-8 weeks) to 24 weeks’ gestation then increasing slightly towards term; and BP being intrinsically more resistant to a ‘stress’ response than is seen outside pregnancy. This stress-resistant state means that any increase in BP in pregnancy is abnormal and should therefore be considered carefully and reviewed regularly. The tendency of chronic (ie, pre-existing) hypertension to progress to pre-eclampsia (17% of patients) is the same 18 Figure 1: Renal biopsy changes in ‘pure’ pre-eclampsia. Photomicrograph at high power (×80) demonstrating the unique feature of human pre-eclampsia — endothelial cell swelling of the renal glomerular endothelial cells. This finding explains the clinical features of proteinuria, and, when severe, the reduced renal function manifests as rising serum creatinine concentration and oliguria. ≥90mmHg occurring after 20 weeks’ gestation and which normalises by three months post-partum. There must be no prior history of hypertension or renal disease for this diagnosis to be made. A family history is not relevant here. An increase of 25mmHg in systolic BP, or of 15mmHg in diastolic BP, should be a cause for concern and should trigger maternal and fetal monitoring. This is because of the lower BP seen in a normal pregnancy compared with the BP of the non-pregnant state. Pre-eclampsia The defining features of preeclampsia are listed in the box on the opposite page. Causes of secondary hypertension identified in pregnancy Vascular causes Coarctation of the aorta Renal artery stenosis Endocrine causes Phaeochromocytoma Primary aldosteronism Cushing’s syndrome Hypothyroidism Hyperthyroidism Polycystic ovary syndrome Hyperparathyroidism Renal causes Definitions of hypertension in pregnancy Gestational hypertension as the risk of white-coat hypertension progressing to pre-eclampsia. This indicates that any increase in BP is potentially pathological in pregnancy. Pre-eclampsia/eclampsia Chronic hypertension: • Essential • Secondary • White-coat Pre-eclampsia superimposed on chronic hypertension Some of the basic physiological changes occur very early and result in a natural decrease in both systolic and diastolic blood pressure. | Australian Doctor | 14 January 2011 Gestational hypertension Gestational hypertension is defined as a systolic BP ≥140mmHg or a diastolic BP Chronic hypertension This is defined as an increase in BP before 20 weeks’ gestation, or persisting beyond three months post-partum. It can be essential hypertension, white-coat hypertension or secondary hypertension. As mentioned above, whitecoat hypertension in pregnancy has the same risk pro- Diabetic nephropathy Reflux nephropathy Polycystic kidney disease Focal sclerosing glomerulosclerosis IgA disease Renin-secreting renal tumours file of progression to superimposed pre-eclampsia as chronic hypertension and should be taken seriously and monitored carefully. However, treatment of white-coat hypertension is not usually recommended until the elevation in BP is sustained above the guideline limits of 140mmHg systolic or 90mmHg diastolic. Secondary hypertension includes all known causes such as renal disease (figure 2), diabetes, endocrine disease, renovascular disease or coarctation of the aorta (see box, left). Hypertension associated with the metabolic syndrome, oral contraceptive pill use or polycystic ovary syndrome also meets this criterion. The ‘must-not-miss’ causes include hypo- and hyperthyroidism, which also have an impact on the developmental outcomes for the baby and are easily correctable. These are relatively common. The maternal mortality associated with phaeochromocytoma is always worrying, but these women often have refractory hypertension and the periodic symptoms (flushing, tachy- Figure 2: Renal biopsies of common renal diseases presenting in young women with hypertension and urinary abnormalities (proteinuria or haematuria). A: A normal glomerulus. B: IgA disease causes mesangial expansion and is associated with hypertension and haematuria. Episodes of acute renal failure in pregnancy can be difficult to distinguish from superimposed pre-eclampsia. C: Focal sclerosis is demonstrated in the glomerulus on the right. Focal sclerosing glomerulosclerosis (FSGS) usually presents as proteinuria and hypertension with or without progressive renal failure. These women have a high likelihood of developing superimposed preeclampsia. D: PAS stain demonstrating the extent of fibrosis in a focal sclerosis lesion. E: The globally sclerosed glomerulus in this photomicrograph illustrates advanced FSGS in a woman who had significantly worse renal failure after pre-eclampsia in her first pregnancy (creatinine 55mmol/L pre-partum and 101mmol/L at three months postpartum). F: High-grade lupus nephritis with areas of focal necrosis. The glomerulus has a lobular appearance with inflammation and vasculitis. A B C D Segmental sclerosis (PAS stain) Segmental sclerosis E F www.australiandoctor.com.au Nuclear ‘dust’ cardia, acute anxiety and changes in skin colour) commonly associated with catecholamine excess. This is a very rare cause of hypertension in pregnancy. Hypertension due to lifestyle factors such as obesity, illicit drug use (cocaine and amphetamines) and caffeine intake are not traditionally considered secondary causes, but attention to lifestyle in the pre-pregnancy period can dramatically reduce the risk of escalating BP in pregnancy. Superimposed pre-eclampsia Superimposed pre-eclampsia is defined as chronic hypertension (as above) with the addi- tional features of pre-eclampsia outlined in the box, right. The presence of proteinuria in a patient with renal disease cannot be used to define pre-eclampsia and the additional features are required. In the case of SLE with lupus nephropathy, the diagnosis of superimposed preeclampsia can be more difficult still. Reliance is needed on additional clinical features such as intrauterine growth restriction and abnormal LFTs. Cerebral signs can only be used in the absence of cerebral lupus, and platelet counts in the absence of known antiplatelet autoantibodies in the underlying disease. Defining features of pre-eclampsia Pre-eclampsia is defined as elevation in BP as for gestational hypertension plus one or more of the following: Renal involvement (figure 1) • Significant proteinuria: dipstick proteinuria confirmed by a spot urine protein:creatinine ratio ≥30mg/mmol • Serum or plasma creatinine ≥ 90μmol/L (normal range 6090μmol/L) • Oliguria (<0.5mL/kg for three consecutive hours) Haematological involvement • Thrombocytopenia (>30% reduction compared with baseline reading) • Haemolysis (Both these indicate disseminated intravascular coagulation) Liver involvement • Raised serum transaminase levels (ALT and AST) • Severe epigastric or right upper-quadrant pain Neurological involvement • Convulsions (eclampsia) • Hyperreflexia with sustained clonus • Severe headache • Persistent visual disturbances: photopsia (flashes of light), scotomata, cortical blindness, retinal vasospasm • Stroke Pulmonary oedema Fetal growth restriction Placental abruption In the Australian guidelines for diagnosis: • Proteinuria is not mandatory to make the clinical diagnosis • Hyperuricaemia is a common but not diagnostic feature of pre-eclampsia • The HELLP syndrome (haemolysis, elevated liver enzyme levels and a low platelet count) represents a particular presentation of severe preeclampsia, and separating it as a distinct disorder is not helpful • Peripheral oedema is not a defining feature Aetiology and risk factors for pre-eclampsia Aetiology and pathology THE aetiology and pathology of preeclampsia are not well understood. Pre-eclampsia is thought to be a twostage disease. Stage one occurs early in pregnancy when there is a failure of invasion by the (placental) trophoblasts and inadequate remodelling of the uterine spiral arteries. The uterine spiral arteries do not adequately invade the inner third of the myometrium, as is normally the case. As the pregnancy progresses, this poor vascular invasion results in placental dysfunction. The dysfunctional placenta mediates stage two of the disease, in which the maternal and fetal signs and symptoms of preeclampsia are seen. The reasons why the trophoblasts fail to invade the myometrium adequately are thought to be many, including immunological disturbances, vascular disease, endothelial dysfunction and a thrombotic tendency, to name but a few. Risk factors Women with a short duration of cohabitation with their partner, those who have used only barrier methods of contraception, and those who Table 1: Recurrence rates for pre-eclampsia Risk factor Relative risk (95% confidence interval) Antiphospholipid antibodies 9.72 (4.34-21.75) Previous history of pre-eclampsia 7.19 (5.85-8.83) Pre-exisiting diabetes 3.56 (2.54-4.99) Multiple pregnancy 2.91 (2.04-4.21) Nulliparity 2.91 (1.28-6.61) Family history of pre-eclampsia 2.90 (1.7-4.93) Elevated BMI (>25kg/m ) 2.47 (1.66-3.67) Maternal age >40 years 1.96 (1.34-2.87) Diastolic BP > 80mmHg at booking 1.38 (1.01-1.87) 2 have a new partner are generally at increased risk of pre-eclampsia, which suggests that immunological factors are involved. There is an increased risk with various forms of assisted reproduction technology and with the number of fetuses (triplets > twins > singletons). An inter-pregnancy interval of more than 10 years also increases the risk, but this may also reflect the risk associated with a change in partner that may occur during that interval. Pre-eclampsia and miscarriage are associated in patients with obstetric lupus syndrome and can be a manifestation of other thrombophilias. These should be investigated in the settings of: • Recurrent (three or more) miscarriages. • Second- or third-trimester pregnancy loss. • Early severe pre-eclampsia (delivery before 34 weeks of gestation). Thrombophilic abnormalities include: • Non-pregnant protein S and protein C deficiency. • Antithrombin III deficiency. • Activated protein C resistance (usually conferred by the factor V Leiden mutation). • Hyperhomocystinaemia. Antiphospholipid syndrome is defined as multiple miscarriages (three or more) or second-trimester losses in the setting of any of the following: • Abnormal APTT. • Lupus inhibitor. • Lupus anticoagulant. • Positive Russell’s pit viper test. • The presence of moderate or high concentration of anticardiolipin autoantibodies (IgG or IgM). In some populations, dietary influences such as low calcium intake, high fat intake and soft drink consumption have been associated with an increased risk of pre-eclampsia. A dietary history for calcium and appropriate advice regarding healthy eating are essential for preventing preeclampsia as well as general wellbeing during pregnancy. Recurrent superimposed pre- eclampsia is more common in women with underlying renal or hypertensive disease, autoantibody diseases or diabetes. Recurrence rates in women without underlying disease are higher in those with previous early severe pre-eclampsia without other cause. The main risk factors for recurrence of pre-eclampsia are summarised in table 1. Summary of Susan’s case Susan’s greatest risk factor is her previous history of early severe preeclampsia, which confers a risk of recurrence of 18%. Having a new partner confers a risk of about 10% for pre-eclampsia (baseline rate 5% for normal pregnancy). The interpregnancy interval of more than 10 years doubles the risk. However, thankfully, these risks are not additive. Susan’s diet is replete in calcium, and supplements are not recommended. Her thrombophilia and anticardiolipin antibody screening tests were normal. Her BP since her first pregnancy has been normal. Her overall risk of pre-eclampsia is about 18%. Physical examination for hypertension in pregnancy PHYSICAL examination should be undertaken at the first pregnancy review or as part of pre-conceptual counselling. The importance of an accurate physical examination cannot be underestimated in assessing hypertension in pregnancy. In a woman such as Susan in our case study, who has a past history of pre-eclampsia and is planning another pregnancy, any evidence of underlying causes for hypertension in pregnancy should be sought, as well as looking for evidence of endorgan involvement due to hypertension. The initial assessment should include: • BP in both arms. • Identification of the apex beat and heart rate. • Identification of an S4 or systolic flow murmur, indicating left ventricular hyper- trophy or coarctation of the aorta. • Feeling for radiofemoral delay by simultaneously assessing the femoral and radial pulses. • Listening in the epigastrium for a systolic bruit, indicative of renal artery stenosis. Assessing urine has become less universal in regular antenatal practice but is essential in chronic or potentially hypertensive women to exclude the multitude of glomerular possibilities. Haematuria exists in 6.7% of the general Australian population and mostly indicates thin-membrane disease or other benign forms of glomeular abnormality. However, for haematuria in the presence of additional clinical features — proteinuria or hypertension in particular — a glomerular diagnosis should be strongly considered. The systemic features of vasculitis (rash, abdominal pain, joint swelling, neuropathy, confusion) should be obvious. The features of SLE such as malar rash, arthritis, enlarged spleen, and rash may be more subtle. Features of endocrine conditions would include purple striae and proximal muscle wasting in Cushing’s disease, which may also be associated with depression and diabetes. Thyroid disease is best assessed by thyroid function tests, but a thyroid examination should include palpation and auscultation of the gland. A retinal examination is essential to identify hypertensive changes (figure 3). Arterial bruits are very uncommon in people of childbearing age with hypertension, but a renal bruit can indicate fibromuscular disease of the renal arteries in young women. Figure 3: Retinal changes in pre-eclampsia can represent malignant hypertension. The early findings of retinal oedema (the glistening retina) is a subtle change; the dramatic changes of retinal haemorrhage, papilloedema and retinal infarction are advanced signs and indicate the need for urgent delivery, as these changes reflect microvascular injury elsewhere in the white matter and cerebral cortex. Although also uncommon, this a potentially correctable cause of refractory hypertension associated with severe www.australiandoctor.com.au superimposed pre-eclampsia. If present, consideration can be given to angioplastic or surgical correction before a planned pregnancy. Biochemical screening is not a part of routine antenatal care. In hypertensive women a baseline creatinine concentration is essential (Note: the estimated GFR [eGFR] has not been validated in pregnancy). The finding of a low serum potassium level can indicate primary hyperaldosteronism, corticosteroid excess, catecholamine excess or renovascular disease. Assessing thyroid function can exclude either hyper or hypothyroidism as a cause of elevated BP in pregnancy, and a normal calcium concentration corrected for serum albumin can exclude hyperparathyroidism from a parathyroid adenoma as a cause. Again, these are treatable, reversible causes even if they are uncommon. cont’d page 22 14 January 2011 | Australian Doctor | 19 HOW TO TREAT Pre-eclampsia and hypertension in pregnancy Monitoring MONITORING for the categories of hypertension in pregnancy should include frequent urine testing for proteinuria. This is especially the case with chronic hypertension, when BP increases alone become difficult to interpret. Whenever BP or antihypertensive medication requirements increase, urine testing, pre-eclampsia blood tests (platelet count, LFTs and serum creatinine) and fetal growth assessment are required to establish a diagnosis. Uric acid concentration is useful as a marker of disease progression, although this is not diagnostic. These investigations need to be repeated as often as required until delivery to monitor for progression to the more severe forms of the disease. Assessing urinary protein includes screening via a urinary dipstick (figure 4). Greater accuracy can be achieved with the use of a urine-protein:creatinine ratio (>30mg/mmol) but this requires a formal laboratory Figure 4: Dipstick proteinuria indicates pathological proteinuria with a high degree of certainty at 2+ or greater. The diagnostic level of >300mg/day represents + or more in a standard specimen and may need to be confirmed with a 24-hour urine collection. The picture shows the dipstick result for a pre-eclamptic patient who had 42g of proteinuria, which resolved after delivery at 34 weeks’ gestation. test. The ‘gold standard’ of 24-hour urinary protein still stands, but can be difficult to interpret due to inaccurate collection (up to 50% of collections) and patient inconvenience. Initial screening of the urine is essential in early pregnancy hypertension to exclude underlying renal disease. Screening for proteinuria at the time of any change in BP, at the time of development of new symptoms, or in the con- text of intrauterine growth restriction is an important adjunct to the diagnostic workup. Monitoring for the progression of hypertension in pregnancy usually involves high- risk obstetric services in association with general practice shared care and midwifery support. It would be usual for the high-risk service to review a stable woman at least monthly, then more frequently if the BP is unstable, and as the pregnancy advances. Adjuncts to the clinic-based assessment can include the use of day assessment units for monitoring BP and overall wellbeing, and occasionally admission to hospital to assess 24-hour BP patterns and symptoms. Given that the definition of hypertension in pregnancy requires a demonstration of sustained high BP, the use of fetal–maternal or day-stay assessment units to determine elevated BP have a proven benefit in the care of pregnant women. These units are hospital based and involve assessing the mother by: • Regular (half-hourly) BP checks. • Urine testing. • Assessing diagnostic blood tests (uric acid concentra- tion, creatinine concentration, LFTs, platelet count and haemoglobin). They allow appropriate fetal monitoring, including timely fetal ultrasound looking at rates of fetal growth, wellbeing and amniotic fluid volume assessment. A cardiotocograph will commonly be done in this setting. It involves the mother having 24 hours of monitoring and review by either a member of the obstetric team or the renal and/or obstetric medicine team. Summary of Susan’s case Susan clearly had pre-eclampsia 13 years earlier, with a complete resolution of the maternal complications by three months post-partum. There was no history of renal disease and the absence of any proteinuria (or haematuria) in the post-partum follow-up would suggest that underlying glomerular (renal) disease is unlikely. Her physical examination did not reveal any endocrine or vascular causes. Management of pre-eclampsia risk in pregnancy THE potential strategies for managing the risk factors for pre-eclampsia are limited. Table 2: Low-dose aspirin therapy for prevention of pre-eclampsia High-risk patients Low-risk pregnancy 2 500 High-risk patients are women with several risk factors, as described in the ‘Causes’ box on page 18 and in table 1, page 19. The mainstay of treatment of high-risk patients is preconception counselling. For women with SLE or obstetric lupus (antiphospholipid syndrome), renal disease or endocrine hypertension, it is important to carefully manage the underlying condition with multidisciplinary care throughout pregnancy. In patients with chronic hypertension, appropriate control of BP throughout pregnancy is essential. Management of usual lifestyle issues is recommended, including a healthy Normal pregnancy 6 167 Prior severe pre-eclampsia 18 56 Renal disease 30 34 Chronic hypertension 40 25 Diagnosis Baseline event rate (%) NNT* *NNT is the number needed to treat to prevent one case of pre-eclampsia diet with adequate fruit and vegetables and limits to high-fat food, soft drinks and high salt intake. Intermediate-risk patients The intermediate-risk group should be considered for low-dose aspirin therapy to prevent progression to pre- eclampsia. The vexing question of whom to treat with aspirin has been best addressed by a recent metaanalysis of low-dose aspirin to prevent pre-eclampsia.1 Indiscriminant use in primiparous women is not supported. However, use of aspirin to prevent progression to pre-eclamp- sia in women with chronic hypertension, renal disease and those with a history of early severe pre-eclampsia (prior delivery before 34 weeks’ gestation) is supported by this study. The number needed to treat to prevent one case of pre-eclampsia is 25, 34 and 56 for these groups respectively (table 2). The greatest benefit in taking aspirin is afforded if it is started before 20 weeks’ gestation. Although the larger trials were free from bleeding complications, in individual patients common complications of aspirin such as gastric irritation, gingival bleeding or haemorrhoidal bleeding need to be monitored. Low-risk patients For patients at low risk of preeclampsia (no risk factors) there is limited support for populationbased calcium supplementation for preventing pre-eclampsia. However, an individual history of a low-calcium diet should be corrected in pregnancy by either an increase in calcium-containing foods or by supplemental calcium. There is no clear evidence to suggest that bed rest prevents pre-eclampsia and its complications in women with normal BP, although there is some evidence to recommend reducing physical and work activities. Summary of Susan’s case In view of her 18% risk, low-dose aspirin is recommended for prophylaxis from 12 weeks’ to 34 weeks’ gestation in the absence of any early pregnancy ante-partum haemorrhage. Management of hypertension in pregnancy MANAGEMENT of hypertension in pregnancy is based on two main strategies: controlling hypertension with appropriate lifestyle advice and antihypertensives; and timing the delivery based on assessment of progression of pre-eclampsia and the development of target-organ effects, such as fetal growth restriction and maternal organ involvement. A useful managment algorithm is shown in figure 5. It is not clear whether tight blood pressure control improves outcomes compared with less stringent blood pressure control. Antihypertensives Hypertension is best managed by a combination of lifestyle modification and antihypertensives. The evidence for rest is not conclusive, but continuation of full-time work or highlevel aerobic exercise in devel- 22 | Australian Doctor | 14 January 2011 oping pre-eclampsia is not recommended. Most trials in this area in the 1970s and 1980s included bed rest as part of the protocol. A meta-analysis of studies including bed rest alone confirms that this is not of proven benefit.2 However, in the setting of the need for ongoing and frequent BP monitoring by the obstetric management team, including the GP, a decrease in work commitments is recommended and bed rest should be considered an option. Hospital admission is often required when: • BP is not controlled. • Biochemistry is abnormal. • Symptoms occur. • Fetal compromise is suspected. The optimal target blood pressure in pregnancy has not been established. This is especially the case in a woman with mild-moderate hypertension. It is not clear whether tight blood pressure control improves outcomes compared with less stringent blood pressure control. The current treatment target is a BP <140mmHg systolic and <90mmHg diastolic. There is strong evidence that treating severe hypertension in pregnancy (>170mmHg systolic and/or >110mmHg diastolic) prevents episodes of extreme hypertension, intracerebral haemorrhage and placental abruption. Antihypertensive medication choice is influenced by familiarity with available agents, and fetal safety. There is no www.australiandoctor.com.au formal evidence that one agent is superior to another. Being familiar with the agent and its characteristics is the most important factor. Either a beta blocker or a centrally acting agent is used as first-line therapy. Second-line treatment is usually a vasodilator, such as hydralazine, and third-line, either a beta blocker or centrally acting agent (depending on what was used as a firstline agent). Fetal safety is a major concern for the mother and, if this issue is not adequately addressed with her, it will result in reduced compliance. Several groups of agents have demonstrable fetal side effects. ACEIs and ARBs result in fetal renal tract anomalies and should be avoided. They have also been implicated in fetal skull ossification defects as well as an increase in the fetal anomaly rate if used in the first trimester. The long-acting, highly selective beta blockers atenolol and metoprolol have been associated with fetal growth restriction. The newer antihypertensives such as lercanidipine should also be avoided due to the lack of clinical experience and safety data. Table 3 provides a summary of antihypertensive agents in pregnancy. Seizure prophylaxis Anticonvulsant prophylaxis is reserved for cases of neurological irritability, and severe hypertension (usually >170/110mmHg). This involves the infusion of intravenous undiluted magnesium sulphate in a dedicated vein and requires at least hourly observations for signs of toxicity (most notably, depressed reflexes). The dose is adjusted according to the urine output and level of renal function. Magnesium is used at the time of patient stabilisation before delivery, then for 24 hours post-partum to prevent seizures. In cases of severe pre-eclampsia it has been shown to decrease maternal mortality. FORMERLY it was considered that once pre-eclampsia resolved, maternal cardiovascular risk returned to normal. It has become apparent that women who develop preeclampsia later in life have a significantly increased risk of developing: hypertension (odds ratio [OR] 3.7, 95% confidence interval [CI] 2.75.05), ischaemic heart disease (OR 2.16, 95% CI 1.86-2.5) or stroke (OR 2.03, 95% CI 1.64-2.67). Compared with known conventional risk factors such as smoking (relative risk 2.1, 95%CI 1.5-2.9) pre-eclampsia is a significant risk factor. What is unclear is whether vigilant monitoring and early management of known cardiovascular risk factors such as obesity, smoking, exercise levels, dietary factors, hypertension, glycaemic monitoring and lipid abnormalities, will reduce the future maternal cardiovascular risk. Until evidence is available to guide clinical practice, women who have had pre-eclampsia should be counselled to avoid smoking, exercise regularly and maintain a healthy weight, and should have their BP measured and urinalysis assessed yearly. Other cardiovascular assessments should also be undertaken, such as fasting glucose and lipids on a 3-5-yearly basis, depending on the individual profile. BP ≥140mmHg systolic or ≥90 mmHg diastolic What is the gestation of the patient? ≥20 weeks’ gestation <20 weeks’ gestation Secondary cause of hypertension evident Assessment must include a urine analysis Is there significant proteinuria on urinalysis? Yes No Seizure (eclampsia) treatment Seizures are treated with a similar protocol to that for prophylaxis, and preferably with magnesium sulfate alone. Ongoing seizure activity, which is rare on a magnesium infusion, indicates a possible structural cause (eg, intracerebral haemorrhage). If benzodiazepines are used as an adjunct to control seizures, respiratory suppression is almost guaranteed. The most common complication of a magnesium infusion is pain at the site of the intravenous cannula. Prognosis Figure 5: Treatment of chronic hypertension of <20 weeks’ gestation, and gestational hypertension and pre-eclampsia after 20 weeks’ gestation. Yes Refer for specialist review or manage as appropriate No Is the booking BP ≥130/80mmHg? Start an antihypertensive agent to reduce risk of superimposed pre-eclampsia Counselling Regular review Refer for urgent review No Yes Are there any systemic symptoms / blood abnormalities to suggest pre-eclampsia? Yes Chronic hypertension likely No Start an antihypertensive agent, frequent (twice weekly) regular review, review by specialist as soon as possible Several diagnostic possibilities — gestational or chronic hypertension but may evolve into pre-eclampsia Pre-eclampsia Refer for urgent review After delivery After delivery the BP does not immediately normalise, taking up to six weeks to return to normal. Thus, after delivery and on discharge antihypertensives usually need to be continued. In the weeks after delivery it is important not to abruptly stop the antihypertensives but to wean gradually. Uncommonly the BP can actually increase after delivery. In this instance the medication dosages will also have to be increased and titrated to control the elevated BP. NSAIDs are contraindicated in women with hypertension in the post-partum period, in which context they have been shown to exacerbate hypertension. The specific mechanism is not clear but is probably multifactorial, including reduced renal prostaglandin synthesis, increased endothelin (a potent vasoconstrictor) production, as well as sodium and water retention. If antihypertensives are still required at six weeks postpartum, consideration needs to given to whether the woman has chronic hypertension rather than pregnancyrelated hypertension. Complete resolution is expected by three months post-partum for gestational hypertension and pre-eclampsia. The urine analysis also needs to be rechecked to ensure the resolution of the proteinuria and to exclude the possibility of underlying renal disease. The proteinuria related to pre-eclampsia may take up to three months to completely resolve. Ideally a urinalysis should be performed at six weeks and in most cases the proteinuria Table 3: Antihypertensive choices in pregnancy Methyldopa Dosing Usual starting dose Max dose Side effects Notes Mechanism of action tds or qid 250mg 2000mg/ day Drowsiness, headache, increased risk of postnatal depression, postural hypotension, liver dysfunction, leukopenia, haemolytic anaemia Contraindicated in people Centrally acting taking monoamine oxidase anti-adrenergic inhibitors or lithium, and those with liver disease or positive Coomb’s test Clonidine qid 75μg 300μg qid Drowsiness, dry mouth, dry eyes, nausea, reduced fetal heart rate Avoid stopping suddenly due to pressor effect Oxprenolol tds 40mg 120mg tds Nightmares Contraindicated in people Beta blocker with asthma. Avoid in possible phaechromocytoma, in heart failure, bradycardia, peripheral vascular disease, or patients with Raynaud’s phenomenon References 1. Duley L, et al. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database of Systematic Reviews 2007; 18 Apr(2):CD004659.2. 2. Meher S, et al. Bed rest with or without hospitalisation for hypertension during pregnancy. Cochrane Database of Systematic Reviews 2005; (4):CD003514. Centrally acting sympathetic inhibitor Online resources • Preeclampsia Research Laboratories (PEARLS): www.preeclampsia.org.au • Australian Action on Preeclampsia (AAPEC): www.aapec.org.au Labetolol bd/tds 100mg 2.4g/day (no therapeutic benefit above 600mg tds) Worsening asthma, cough, nightmares, bradycardia Nifedipine tds 10mg 30mg tds Headache, Metabolised through CYT oedema, palpitations, P450-3A4 —consider nausea dizziness interaction with, eg, phenytoin and cisapride Hydralazine qid 12.5mg 50mg qid Flushing, palpitations, Should be a second- or third- Peripheral vasodilator headaches, nausea line agent to minimise side effects. Can cause autoimmune lupus will have completely resolved or at least should be considerably reduced at six weeks post-partum. A urinalysis before six weeks Contraindicated in asthmatics. Alpha- and beta Avoid in possible blocker phaechromocytoma, in heart failure, bradycardia, peripheral vascular disease or patients with Raynaud’s phenomenon is difficult to interpret because of the ongoing vaginal blood loss. Similarly, if there were any residual biochemical www.australiandoctor.com.au Calcium-channel blocker changes, such as an elevated creatinine, LFTs or haematological abnormalities, they should be repeated about one week after discharge. cont’d next page 14 January 2011 | Australian Doctor | 23 AD_ 0 2 4 _ _ _ J AN1 4 . p d f Pa ge 2 4 1 8 / 1 / 1 1 , 3 : 3 4 PM HOW TO TREAT Pre-eclampsia and hypertension in pregnancy GP’s contribution DR RENATA CHAPMAN Chatswood, NSW Case study GAYLE, 32, came to see me for confirmation of her pregnancy. She had two previous early miscarriages at six weeks. This time she was nine weeks pregnant. She was overweight, with a BMI of 29 kg/m2, and had background of mild polycystic ovary syndrome with axillary acanthosis nigricans and facial acne. Her routine examinations included BP of 110/70mmHg and blood and urine tests, which were normal. Gayle returned to me at 28 weeks for review, complaining of worsening peripheral oedema and headache. Her BP was 140/90 and there was + albumin on the urinary dipstick. I phoned my local hospital and Gayle was seen by the maternal–fetal medicine assessment unit physician the same day. She was started on oxprenolol and low-dose aspirin. When I saw her three weeks later at 31 weeks’ gestation her BP was well controlled on her medication but she was feeling sad and emotional. We discussed eventual referral to a counsellor, and Gayle was going to consider that option. She did not attend the routine follow-up but phoned me five weeks later, complaining of a sudden-onset upper-quadrant abdominal pain, nausea and vomiting. When I saw her that day her BP was 160/100 and she had significant right abdominal tenderness, bruises and hyperreflexia. There was marked albuminuria (+++) on her urine examination. Her blood tests performed later in hospital showed thrombocytopenia and elevated AST and uric acid levels. Once in hospital Gayle was given hydralazine and methyldopa (Aldomet) to control her BP and was started on IV magnesium sulfate infusion to prevent convulsions. A caesarean section was performed and a baby boy delivered. He showed mild signs of growth retardation but was in otherwise good condition, with Apgar scores 9 and 9, at one and five minutes, respectively. Eight weeks later Gayle brought her son for vaccination. Her BP had normalised and she was taking no medications at all. All biochemical abnormalities had resolved but Gayle admitted that she did not feel well — she was very emotional, crying a lot and unable to bond well with her child. Her Edinburgh Postnatal Depression Scale score was 22, indicating depression. Questions for the author It seems that pre-eclampsia and cardiovascular diseases have similar risk factors. Depression is now a wellrecognised independent risk factor for cardiovascular diseases. Could it also be an independent risk factor for preeclampsia? Depression is not currently recognised as a risk factor for pre-eclampsia. A single study from Finland showed an increased risk of pre-eclampsia in women who were identified as having anxiety or depression at 15-18 weeks’ gestation.1 A subsequent case–control How to Treat Quiz study from Peru in 2007 showed a doubling of the odds for pre-eclampsia.2 It is unclear whether this is significant in other cultural settings. Aspirin and calcium are used for prevention of pre-eclampsia in pregnant women with a past history of the condition, or the presence of risk factors for it. We know that women with a history of pre-eclampsia are at higher risk of developing hypertension and other cardiovascular diseases in the future. Would there be a place for long-term use of aspirin and calcium in Gayle, who with her PCOS has additional risk of developing CVD? A benefit for the use of calcium for prophylaxis was initially shown in developing countries, but its usefulness was not replicated in a largescale trial in the US.3 However, the meta-analysis of several smaller trials did show a benefit in pre-eclampsia prevention.4 Use of aspirin and calcium in the long term as a primary prevention strategy for CVD should be the subject of future randomised controlled trials. There are no current data to support their use in the management of pre-eclampsia. The importance of pre-eclampsia as an independent risk factor for CVD is a recent finding and work needs to be done to determine which patients would likely benefit from such an intervention. How would this recommendation relate to the recently published meta-analysis in the BMJ indicating higher risk of cardiac events in women taking calcium supplements?5 This is clearly one of the major potential detrimental effects of long-term calcium use and needs to balanced against any proven benefit in prevention of CVD. Gayle’s son was born with signs of mild growth retardation. Are there any particular problems I should be looking for in children of mothers who experienced pre-eclampsia? The Barker hypothesis, now known as the developmental origins of health and disease theory, indicates that growth restriction is a risk factor for future (later-life) CVD. In the Raine cohort from Perth, being born small was strongly influenced by the pattern of growth in early neonatal life and predicted both BMI and risk of hypertension. Despite these theoretical links, there is no current recommendation to screen these children for cardiovascular risk factors in childhood, other than that which would be undertaken due to their prematurity. Is there any evidence of the benefit of heparin in the management of pre-eclampsia? Heparin benefit in pregnancy for prevention of preeclampsia is indicated in women with antiphospholipid syndrome and other thrombophilias. There is no current recommendation for its global use in the prevention or treatment of pre-eclampsia. References 1. Obstetrics and Gynecology 2000; 95:487-90. 2. BMC Women’s Health 2007; 7:15. 3. New England Journal of Medicine 1997; 337:69-77. 4. Cochrane Database of Systematic Reviews 2006; Issue 3, CD001059. 5. BMJ 2010; 341:c3586. INSTRUCTIONS Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes by post or fax. The mark required to obtain points is 80%. Please note that some questions have more than one correct answer. Pre-eclampsia and hypertension in pregnancy — 14 January 2011 1. Which TWO of the following are regarded as relating to elevated blood pressure only in pregnancy? a) Gestational hypertension b) Pre-eclampsia c) Chronic hypertension d) Pre-eclampsia superimposed on chronic hypertension 2. Which TWO statements are correct? a) Hypertension in pregnancy is defined as a systolic blood pressure ≥140mmHg or a diastolic blood pressure ≥90mmHg b) Too rapid deflation of the cuff can overestimate the systolic blood pressure and underestimate the diastolic reading c) Normally blood pressure decreases from early pregnancy (6-8 weeks) to 24 weeks’ gestation then increases slightly towards term d) In a normal pregnancy, the BP response to ‘stress’ is augmented 3. Which TWO statements are correct? a) The decrease in the concentrations of haemoglobin and creatinine in a normal pregnancy reflect an increase in blood volume b) Gestational hypertension occurs within the first trimester c) An increase of 25mmHg systolic or 15mmHg ONLINE ONLY www.australiandoctor.com.au/cpd/ for immediate feedback diastolic from baseline BP should trigger maternal and fetal monitoring, even if the BP is <140/90mmHg d) Proteinuria is mandatory for a diagnosis of pre-eclampsia in a pregnant patient with hypertension 4. Which TWO statements are correct regarding pre-eclampsia? a) Thrombocytopenia and haemolysis reflect disseminated intravascular coagulation b) Peripheral oedema is a defining feature c) Hyperreflexia, severe headache or visual disturbances are some of the neurological manifestations d) Hyperuricaemia is a common diagnostic feature 5. Which TWO statements are correct? a) Chronic hypertension presents after 20 weeks’ gestation b) Chronic hypertension in pregnancy includes essential hypertension and secondary hypertension c) Hypothyroidism and hyperthyroidism are correctable causes of hypertension that also have an impact on developmental outcomes for the baby d) White-coat hypertension in pregnancy is benign and not associated with an increased risk of pre-eclampsia 6. Which TWO statements are correct? a) Antenatal urine assessment is essential in women with chronic hypertension or with risk factors for hypertension b) In a hypertensive pregnant woman, a baseline creatinine concentration is inaccurate and unhelpful in monitoring renal function c) Calcium, potassium and thyroid function tests may identify treatable secondary causes of hypertension d) Uric acid concentration is not useful as a marker of pre-eclampsia disease progression 7. Which THREE statements are correct regarding monitoring for the development of pre-eclampsia? a) An increase in blood pressure should trigger a platelet count, LFTs and a serum creatinine test b) Fetal ultrasound monitors fetal growth rate, wellbeing and amniotic fluid volume c) Urine assessment by dipstick is unhelpful d) Monitoring ideally should involve high-risk obstetric services at least monthly 8. Which THREE statements are correct? a) In pre-eclampsia there is placental dysfunction due to failure of the placental trophoblast to invade the uterine spiral arteries in the myometrium normally b) Definitive treatment of pre-eclampsia is delivery c) Risk factors for pre-eclampsia include barrier methods of contraception, a new partner and multiple-fetus pregnancy d) High calcium intake is a risk factor for preeclampsia 9. Which TWO statements are correct? a) Use of aspirin for prophylaxis against preeclampsia is appropriate for women with prior severe pre-eclampsia, renal disease or chronic hypertension b) Aspirin prophylaxis against pre-eclampsia is appropriate in all primiparous women c) Aspirin prophylaxis for pre-eclampsia should be started after 20 weeks’ gestation d) Continuation of full-time work or high-level aerobic exercise in women developing preeclampsia is not recommended 10. Which TWO statements are correct? a) Centrally acting agents or certain beta blockers are first-line therapy for hypertension in pregnancy b) ACEIs or ARBs are second-line therapy for hypertension in pregnancy c) Seizure prophylaxis with IV magnesium sulfate is used where there is neurological irritability or severe hypertension. d) Once pre-eclampsia has resolved, the maternal cardiovascular risk returns to normal CPD QUIZ UPDATE The RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2011-13 triennium. You can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online. HOW TO TREAT Editor: Dr Giovanna Zingarelli Co-ordinator: Julian McAllan Quiz: Dr Giovanna Zingarelli NEXT WEEK The next How to Treat confronts the anxiety-producing, real or perceived abnormalities in the head shape of an infant or child. The author is Professor David John David, clinical professor of craniomaxillofacial surgery, University of Adelaide, and head of the Australian craniofacial unit at the Women’s and Children’s Hospital, North Adelaide, SA. 24 | Australian Doctor | 14 January 2011 www.australiandoctor.com.au