Alternative to nitroprusside. Not used in heart failure or catecholamine crisis. Hydralazine Causes direct vasodilation of arterioles. Only indicated in pregnancy/eclampsia as it impro ves uterine blood \202 ow. Nitrogylcerine Preferred agent for patients with myocardial ischemia/infarction complicating hypertension. Blocks A1- and A2-adrenergic receptor sites. Intravenous treatment In general, nitroprusside is the IV drug of choice in patients withou t significant renal impairment or myocardial ischemia. In patients with these conditions la betolol or nitroglycerine are preferable. If one agent is not effective, sensible combinati ons would include nitroprusside and labetolol or nitroglycerine and labetolol. The availabl e IV antihypertensive drugs are summarized in Table 9.3.2. Phentolamine Used exclusively as \201 rst-line treatment for catecholamine crises. The BP does not need to be ideally controlled, but the patient will need regular review eve ry 2 weeks for BP measurement and adjustment of treatment if required. Further investigatio ns (see above) will need to be planned. Prior to discharge, a specialist with an interest i n HTN should ideally review the patient, or an early appointment made in a dedicated specia list clinic (within 2 weeks). In the longer term, cardiovascular risk assessment, to take i nto account primary or secondary prevention, should be undertaken. Oral treatment Oral treatment requires drug therapy of rapid onset (<12 h). Nifedipine and atenolol are the drugs of choice. ACEIs (or ARBs) are reserved for patients with sclero- de rma. These drugs are also effective in severe HTN, but their use in a nonscleroderma popula tion is cautioned especially if renovascular disease is suspected. The use of sublingual or oral liquid nifedipine is dangerous as the fast absorption of these formulations can resul t in sudden and large falls in BP. Prognosis With successful early management of malignant HTN life expectancy is similar to p atients with uncomplicated HTN. Further reading Anonymous. Treatment of hypertensive urgencies and emergen- cies. European Society of Hypertension Scienti \201 c Newsletter: Update on Hypertension Management 2006; 7(28): http://www.eshonline. org/education/newsletter/2006_28_agabiti_rosei.pdf Intravascular volume assessment After BP correction some patients may develop intravascu- l ar volume depletion and require IV \202 uid. Volume depletion can occur as a consequence of prior excessive vasoconstriction or pressure-related diuresis: high BP can lead to an in creased GFR and a reduction in renal tubular sodium reabsorption. This is particularly rele vant in the management of patients with acute pulmonary edema as a hypertensive emergency w here \201 rst-line treatment is often with a loop diuretic. Elliott WJ. Management of hypertension emergencies. Curr Hypertens Rep 2003; 5 486 \200\223492. Kaplan NM. Management of hypertensive emergencies. Lancet 1994; 344: 1335. Lip GY, Beevers M, Beevers DG. Does renal function improve after diagnosis of malignant pha se hypertension? J Hypertens 1997; 15: 1309. Murphy MB, Murray C, Shorten GD. Fenoldopam: a selective peripheral dopamine-receptor agoni st for treatment of severe hypertension. N Engl J Med 2001; 345 1548 \200\2231557. Follow-up Patients can be safely discharged once their clinical status has improved and the ir BP is stable. van den Born BJ, Honnebier UP, Koopmans RP, van Montfrans GA. Microangiopathic hemolysis an d renal failure in malignant hyper- tension. Hypertension 2005; 45: 246. CHAPTER 9.3 Malignant hypertension 303 Internet resources British Hypertension Society: London Hypertension Society (an excellent link to many of the national guidelines on manage ment of hypertension): http://www.lhs.sgul.ac.uk/links/guidelines.htm www.bhsoc.org/ NICE C G34 Hypertension guideline: See also Clinical approach to hypertension, p. 286 Renovascular disease, p. 292 Hypertensiv e children, p. 304 Hypertensive disorders in pregnancy, p. 310 www.nice.org.uk/nicemedia/pdf/Hypertension Guide.pdf Hypertension Education Foundation: http://www.hypertensionfoundation.org/ European Society of Hypertension: http://www.eshonline.org/ P. HOUTMAN 304 Hypertensive children Introduction Hypertension in childhood is an uncommon clinical prob- lem. When it occurs, i ts investigation and management is often quite protracted and requires a specialist approac h. Although it is increasingly recognized that \200\230adult \200\231 hyperten- sion often has its roots in adolescence, the assumption in children should be that it is likely to be secondary to a speci \201 c cause until shown otherwise. ated in terms of appropriate normal data obtained using comparable methods. Invasive BP monitoring In sick and premature neonates BP is often measured inva- sively usi ng umbilical or peripheral arterial catheters. This must be compared with appropriate norma l values for mean BP. Indications for measuring BP in children In older children it is appropriate to take BP rou tinely in any medical consultation. In children younger than 3 years this is less easily r ecom- mended but certainly it should be considered if there are any relevant concerns such as renal tract problems. De \201 nitions in children The de \201 nition of hypertension in children is not simple. BP is directly related to size (both height and weight) in growing individuals. Tables and charts are available with ranges of systolic and diastolic BPs according to gender, age, h eight and weight. These are expressed as BP percentiles. They are an important resource whe n evaluating BP in both population samples (for research), and individually in clinical pra ctice. Hypertension is de \201 ned as an average systolic and/or diastolic BP above the 95 th percentile for these parame- ters of growth, with measurements on three or more sepa- ra te occasions. BP between the 90th and 95th percentiles is now known as \200\230prehyperten sion \200\231. Within the hypertensive range, severity can be categorized into two stages: signi \201 cant and severe hypertension. BP >5 mmHg above the 99th percentile requires urg ent evaluation. Table 9.4.1 gives approximate values for \200\230signi \201 cant \200\231 and \200\230severe \200\231 hypertension and may be used as a very rough guide to BP leve ls that should be investigated and managed effectively. Screening the pediatric population for hypertension cannot yet be advised, but this may be a future proposal, particularly in adolescence. Causes of hypertension Renal diseases predominate as secondary causes of hyper- tension in children. Transient hypertension Blood pressure can be transiently raised in acute neph- ropathies. C onditions relatively commonly encountered in childhood include: \200 \200 \200 postinfectious glomerulonephritis; Henoch \200\223Sch nlein purpura; hemolytic \200\223ure mic syndrome. Paradoxically BP can also be raised in hypovolemic states, such as seen in nephrotic relaps e, associated with vasocon- striction. Sustained hypertension In sustained hypertension, it is helpful to distinguish neonates fro m older age groups. Coarctation of the aorta and other vascular problems including renal ar tery stenosis and thromboses relating to umbilical arterial catheterization are important c auses in the very young. The range of conditions associated with sustained child- hood hype rtension is very broad (Table 9.4.2). These prob- lems can present at any age, but it shoul d be noted that many of the processes are developmental in origin. The most important are d iscussed below. Blood pressure measurement The principles of BP measurement are the same as those for adult s. There are major practical considerations, par- ticularly in younger children and infants . Auscultation is the standard means of taking BP, but auto- mated oscillometric devices ar e increasingly employed, some of which have been \200\230validated \200\231 by appropriate organ- izations. Several cuff sizes must be available to cope with upper arm sizes, whiche ver method is used. The inner bladder should cover \211 70% of the length and circumferenc e of the upper arm. In infants it is often necessary to use a Doppler probe to \200\230hea r \200\231 the Korotkoff sounds. Even with this method, the 5th sound (disappearance) is co mmonly absent down to zero and systolic BP is in practice a better indicator. Blood pressur e should be measured on several separate occasions to clarify that it is truly elevated. \200\230White-coat hypertension \200\231 exists in children, and children do not usually re main quiet and physically relaxed for long. \200\230Scarring \200\231 nephropathy The terminology for this group of conditions remains con- fusing, and this is mainly due to continuing uncertainty as to the fundamental cause of the processes leading to renal scarring in early life (Fig. 9.4.1). Previously, it was a ssumed that urinary tract infections in the presence of vesicoureteric re \202 ux led dire ctly to chronic pyelonephritis and permanent scarring ( \200\230re \202 ux nephropathy \200\231). This may be the case in some individuals, but more recently it has been recogniz ed that many of these patients are born with renal dysplasia or hypoplasia, without ongoing evidence of vesicoureteric re \202 ux, urinary tract infection or upper urinary tract obs truction. Ambulatory BP monitoring Ambulatory BP monitoring can be achieved even on quite small child ren, but requires appropriate devices and exper- tise to perform and interpret; the results must be evalu- CHAPTER 9.4 Hypertensive children 305 Table 9.4.1 Rough guide of hypertension values in childhood Age Signi \201 cant hypertension Severe hypertension Systolic (mmHg) Diastolic (mmHg) Systolic (mmHg) Diastolic (mmHg) 7 days 96 106 <1 month 104 110 <2 years 112 74 118 82 3 \200\2235 years 116 76 124 84 6 \200\2239 years 122 78 130 86 10 \200\22312 years 126 82 134 90 13 \200\22315 years 136 86 144 92 16 \200\22318 years 142 92 150 98 Table 9.4.2 Causes of hypertension in children Renal Acute kidney injury Acute glomerulonephritis Hemolytic uremic syndrome Chronic glomer ulonephritis Renal scarring and dysplasia Chronic kidney disease Renal transplantation Poly cystic kidney disease (recessive and dominant) Renal tumors Renovascular Endocrine Cushing \200\231s Conn \200\231s Mineralocorticoid dysregulation Pheochromocytoma Primary hypertension Others Coarctation of aorta Fig. 9.4.1 DMSA radioisotope scan from a child with a small, scarred left kidney, probably congenital in origin. Endocrine causes As well as acquired conditions including Cushing \200\231s syn- drome (oft en iatrogenic) and pheochromocytoma, there are a number of speci \201 c genetic diseases n ow recognized as responsible for hypertension in a small proportion of children including: \200 \200 \200 The condition can be familial. Abnormalities of early bladder development may be impli- cat ed in some cases, and fetal USS has been useful in delin- eating progress in utero. Althoug h the onset of renal scarring is a phenomenon of early life, it is often several years befo re clinical effects are evident, so that the associated hypertension is more likely seen in late childhood or in adults. Increased renin secretion can be detected before this stage, and hypertension usually pre-dates signi \201 cant renal impairment. Liddle syndrome; glucocorticoid-remediable hyperaldosteronism; syndrome of apparent mineral ocorticoid excess. Liddle syndrome is a disorder of epithelial sodium channel tubular transportation and respo nds to amiloride. Glucocorticoid-remediable hyperaldosteronism (GRH) and the syndrome of ap parent mineralocorticoid excess (AME) are further examples of \200\230low renin state \200 \231 inheritable conditions. Renovascular hypertension This is relatively uncommon as a cause of hypertension in childre n. Within this group, renal arterial stenosis is the commonest cause and often associated w ith \201 bromuscular dysplasia. Neuro \201 bromatosis and other genetic conditions may a lso be responsible. Worldwide, Takayasu \200\231s disease is an important cause. Primary hypertension This is increasingly being recognized as an important issue in older c hildren and adolescents. P. HOUTMAN 306 Blood pressure can be seen to \200\230track \200\231 growth percentile lines in individual s from an early age, and there is also a familial in \202 uence on BP that can be detected in childhood. It is accepted that growth in utero and early infancy affects later cardiova scular risk factors. How important these various factors are relative to morbidity and mort ality later in life is still incompletely understood. The rise of obesity in the youth of m any societies and its associated morbidity has highlighted environmental factors in the dev elopment of hypertension, particularly food and exercise. Weight has now become the major f actor in determining BP in this age group. However, the clinical recognition of primary hyp ertension in individual children is still uncommon. Assessment of the renin \200\223angiotensin system Routine biochemistry may give further cl ues, particularly whether plasma potassium is high or low, re \202 ecting the activity of the renin \200\223angiotensin system. Measurement of plasma renin activity (PRA) itself is more sensitive but the normal range is strongly age-dependent (with much higher normal acti vity in young children par- ticularly). PRA may be high in renovascular hypertension, but, when depressed, it can be especially useful indicating a possible mineralocorticoid-mediate d cause. Assessment for endocrine causes of hypertension More complex biochemistry tests are indicat ed if hormo- nal causes are suspected. The diagnosis of the various min- eralocorticoid syn dromes demands specialist steroid pro \201 ling, now also followed by genetic testing for condi- tions with known gene defects (including Liddle syndrome and GRH). Pheochromocytoma is assessed with plasma and urine catecholamines. Clinical features Often there are no symptoms or signs even in severe hypertension. If pres ent, these are mainly neurological: \200 \200 \200 \200 visual symptoms; convulsions; hemiplegia; frank hypertensive encephalopathy. Assessment for renovascular hypertension The further investigation of possible renovascular hyper- tension has traditionally been by direct angiography together with renal vein sampl ing for renin. Renal isotope scans before and after ACE inhibition have also been helpful. Newer techniques including MRI angiography and spiral computed tomography have not been ext ensively evalu- ated in children but are less invasive. The clinician should be particularly aware of facial palsy as a sign in severe hypertension . Skilled fundoscopy may also alert the clinician to severe hypertension. Cardiac failure i s more commonly found in very young chil- dren in whom neurological complications are relat ively rare. There may be speci \201 c clues as to the cause of the hyper- tension from the history and physical examination. Neuro \201 bromatosis is an important diagnosis not to miss \200\223 ask about family history and look for early signs including caf -au-lait sp ots. Always assess clinically for coarctation, and listen for abdominal bruits. Poor growth can indicate a chronic cause. Assessment for other cardiovascular risk factors Even when secondary causes are suspected, routine evalu- ation for the comorbidities associated with primary hyper- tension is now re commended in older children and adolescents. These include, particularly in those overweigh t: \200 \200 \200 abnormal glucose tolerance; blood lipid abnormalities; sleep disorders leading to obstructi ve sleep apnea. Investigations Once it is considered that a child has signi \201 cant hyperten- sion, usin g the principles discussed in previous sections and in particular taking the BP on several separate occasions, further evaluation focuses on: \200 \200 The presence of acanthosis nigricans on examination is also a strong marker for insulin res istance. A family history of hypertension, type 2 diabetes and car- diovascular disease wil l further in \202 uence the extent of investigation for diabetes and other comorbidities. looking for a cause; assessing the pathophysiological effects of the raised BP itself on ta rget organs. Treatment Nonpharmacological measures Lifestyle changes should be considered in the general man- agement of hypertension in all cases of secondary as well as primary hypertension, if relevant. Because of the diverse nature of the causes of secondary hypertension, a structured and sel ective approach to inves- tigation is indicated, depending on the severity of the hypertens ion. Secondary hypertension should still be con- sidered in even mild cases in children. Weight reduction is usually the most important objective. However, increasing exercise and dietary modi \201 cation are goals dif \201 cult to achieve for many individuals. Assessment of left ventricular function: echocardiography An echocardiogram to assess left ventricular function has been shown to be sensitive in children and should be rou- tine in this situation. This can also examine for coarctation as a possible cause. In adults it has long been recognized that factors such as sodium intake, healthy diet and exercise are part of the public health scope of BP modulation. This is now increasingly bei ng accepted as a priority in children. Assessment of renal structure and function First-line investigation will always include ass essment of renal function and structure. Because of the relatively high incidence of renal scarring/ dysplasia, radioisotope scanning is often performed at an early stage as well as the less-invasive renal USS. Hypertensive emergencies The principles of the management of hypertensive emer- gencies are at least as important as the speci \201 cs of the drugs used. CHAPTER 9.4 Hypertensive children 307 Consideration of the length of time over which the hyper- tension has developed is very imp ortant. Cerebral autoregulation maintains cerebral blood \202 ow relatively constant with in systemic BP limits but over time this range is altered in hypertension. If BP is lowered too rapidly there is a real danger of relative hypotensive dam- age to water-shed areas, p articularly visual cortex, cerebel- lum and end-arteries. Visual loss may be permanent. Thu s, the principle of slow reduction of severe, chronic hypertension is paramount. Assessment of \202 uid balance and renal function is critical. Beware of hypovolemia, which can cau se or exacerbate hypertension. Neurologic status (conscious level, irritability, \201 ts) will often determine the level of medical and nursing care required. Also, it can be dif \201 cult to decide whether \201 ts in the pres- ence of hypertension are the cause or an effect. Treatment must be based on the cause of the hypertension if known or suspected. In renal disease, intravascular \202 uid overload is often under- estimated. Thus, the drug of choice may be a diuretic in the infant or child whose main problem is systemic \202 u id over- load, with hypertension as part of the clinical picture. Urine output should be mo nitored. If serum creatinine is outside the normal (age-related) range, caution is needed i n the use of drugs excreted by the renal route. Hemodialysis or hemo \201 ltration may be required when renal function is severely impaired. The speci \201 c drugs most widely reco mmended for initial emergency management are: \200 sodium nitroprusside; \200 labetalol . In the second phase of management, there is a slow reduc- tion of short-acting drugs and gr adual introduction of oral longer-acting drugs. At this stage it is still important not to reduce BP too quickly. Usually more than one drug is used, for example a B-blocker, diureti c and vasodilator. Mild \200\223moderate hypertension At the other end of the spectrum are children in whom lifestyle interventions have not in \202 uenced BP suf \201 ciently to a void consideration of drug therapy. In children there is no distinction between drugs used for primary or secondary hypertension. Single drug therapy should be used if possible, and the general aim should be to reduce BP to the 95th percentile for age. However, in the pres ence of ongoing concurrent conditions, particularly CKD and diabetes, there is growing evid ence of the importance of lowering BP to well within the normal range to minimize progressi on. Data are gradually accumulating about speci \201 c drugs in children, but the evidence base, particularly regarding long- term effects, is severely lacking compared to older age groups. B-Blockers and diuretics are amongst the commoner drug classes used, as they have been available for longer than others. There has been little experience in children of the use of ARBs until recently. Within drug groups, newer drugs are usually avoided in favor of those with a greater knowledge base. Drug combination formulations are best avoided as the relative doses are not necessarily suited to children. Younger children may be particularl y compromised by the relative nonavailability of suitable drug preparations for this age gr oup. The prescribing situation is now improved with speci \201 c drug formularies being av ailable for children. Other drugs that have also been recommended include nifedipine, nicardipine and diazoxide ( Table 9.4.3). Start with the lowest dose and titrate upwards. These drugs have rapid onset, and short duration of action (except labetalol which is therefore not capable of such sens itive BP regulation as nitroprusside.). Speci \201 c situations Renovascular HTN deserves special attention, especially when unila teral. ACE inhibition may precipitate renal infarction and should be avoided at least initi ally. ACEIs are the drug class of choice in chronic glomerulone- phritis associated with si gni \201 cant proteinuria. Certain conditions respond to speci \201 c treatment: \200 \200 Table 9.4.3 Drug doses for hypertensive emergencies Drug Route Dose Sodium nitroprusside IV 0.5 \200\2238 g/kg/min amiloride for Liddle syndrome; dexamethasone for glucocorticoid-remediable hyperal- dostero nism (GRH). Labetalol IV 0.25 \200\2231.5 mg/kg/h Nifedipine Oral 0.1 \200\2230.25 mg/kg/dose Surgical management can be de \201 nitive in a number of conditions, including: \200 \200 \200 Nicardipine IV 1 \200\2233 g/kg/min Diazoxide IV 1 \200\2233 mg/kg/dose coarctation; renovascular disease; tumor-associated hypertension (including pheochromo- cyt oma and neuroblastoma). The use of nifedipine in the acute phase is controversial. In adults its use has been assoc iated with extreme hypo- tension and neurological effects, but in children this has rarely been reported and many centers use this drug in an otherwise well child in small, frequent doses. Catecholamine-driven hypertension needs specialist advice regarding both A-adrenergic and B -blockade, with particu- lar attention to problems that can occur around surgery for pheoch romocytoma. P. HOUTMAN 308 Follow-up and prognosis Children with hypertension require continuity of medical care as th ey reach adulthood, but this is a period of psy- chosocial change and growth of independenc e. Medical practice is not traditionally equipped to provide seamless provision of care at such a time, although the development of adolescent and young adult services should help to address this. Because of these factors and others, progno- sis in individual cases is ofte n dif \201 cult to assess in child- hood. More data are accumulating regarding later added cardiovascular risk from conditions in childhood such as nephrotic syndrome, as well as fr om hypertension itself. Webb NJA, Postlethwaite RJ (eds). Clinical pediatric nephrology, 3rd edn. Oxford: Oxford University Press; 2003. Houtman PN. Management of hypertensive emergencies in chil- dren. In: Jacqz-Aigrain E, Choo nara I (eds), Pediatric clinical phar- macology. London: Taylor & Francis; 2006. pp. 719 \200\223725. National High Blood Pressure Education Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation and treatment of high blood pr essure in children and adolescents. Pediatrics 2004; 114: 555 \200\223576. Internet resources The childrens British National Formulary: http://www.bnfc.org Hypertension Education Foundation: Future prospects The existence of databases containing BPs and growth parameters for large groups of children reaching adult- hood should in time lead to a greater understanding of t he possible relevance of interventions in pregnancy and child- hood for later cardiovascula r disease, but this will depend on social factors as much as on medical knowledge. In terms of treatment of hypertension in children and young adults, this has thus far been studied only to a lim- ited extent, and it is hoped that the substantial information about drug ef \201 cacy and side-effects in older age groups will in the future be mirrored by similar d irect evidence in the young. From a pediatric perspective, hypertension as a signi \201 ca nt public health problem in adults has much of its roots in early life. http://www.hypertensionfoundation.org/ European Society of Hypertension: http://www.eshonline.org/ The London Hypertension Society (an excellent link to many of the national guidelines on management of hyper- tension): http://www.lhs.sgul.ac.uk/links/guidelines.htm See also Isolated defects of tubular function, p. 200 Chronic kidney disease in children, p. 462 Ren al dysplasia, p. 646 Vesicoureteric re \202 ux and re \202 ux nephropathy, p. 648 Urinary tract infections in infancy and childhood, p. 252 Further reading Anonymous. British National Formulary for children. London: BMJ Publishing Group; 2006. This page intentionally left blank S. J. CARR 310 Hypertensive disorders in pregnancy Introduction Hypertension is the commonest medical complication of pregnancy and affects 1 0% of all pregnancies. BP may be raised before conception or become raised during pregnancy . Hypertension in pregnancy may be due to: \200 Instrument Mercury/aneroid sphygmomanometer or validated auto- mated device. Cuff size It is imperative that the appropriate cuff size is used; it is better to use one that is too big than one that is too small. chronic hypertension (essential hypertension or secondary causes); pre-eclampsia; pregnancy -induced hypertension. Setting Relaxed, quiet environment, preferably after rest. \200 Position Lying at a 45 angle or sitting (cuff at heart level). Arm Left or right (use hig her value if difference is >10 mmHg). Dependent arm, if in a lateral position. The relative incidences of each will depend on the study population. Women who were born gr owth-restricted after a normo- tensive pregnancy are more likely to develop pregnancy- indu ced HTN in later life. Hypertensive disorders of pregnancy are classified as shown in Table 9.5.1. Korotkoff sounds First (systolic) and \201 fth (diastolic). If diastolic is persistently <40 mmHg use muf \202 ing or fourth sound and make a note. De \201 nition Hypertension in pregnancy is de \201 ned as a BP >140/90 mmHg. Chronic hypertension in pregnancy This is de \201 ned as HTN diagnosed before conception o r before 20 weeks gestation. The risk of pre-eclampsia is 30% in women with chronic HTN. The kidney in normal pregnancy In normal pregnancy systemic hemodynamics are dramati- cally altered with: \200 \200 \200 increased circulating volume; increased cardiac output; reduced systemic vascular resistanc e. Advice on antihypertensives preconception Antihypertensive medication should be changed to a regime which is safe in pregnancy, ideally prior to concep- tion or as soon as pregnancy is recognized. BP should be stabilized on new medications before con- ception. ACEIs and AR Bs should be stopped (see below). This leads to a high output state with a reduction in BP in early pregnancy. The GFR increa ses progressively in the \201 rst half of preg- nancy reaching a peak of 40 \200\22360% a bove nonpregnant levels which is maintained to the end of pregnancy. This increase is due t o increased renal plasma \202 ow due to dilatation of the afferent and efferent glomerula r arterioles. The renal plasma \202 ow increases by 45 \200\22350% at 9 weeks gestation and by up to 70% later in pregnancy. Increased GFR also results in: \200 \200 \200 Combined renal \200\223obstetric care Pregnant women with chronic HTN should be managed as stated by the RCOG guidelines. Combined renal \200\223obstetric care is not required unless there is concern regarding underlying renal disease. increased sodium \201 ltration and reabsorption; increased urate reabsorption; glycosuria (due to increased \201 ltered load which exceeds the tubular reabsorbtive capacity). Pregnancy-induced hypertension This is de \201 ned as an elevation of BP >140/90 mmHg in p regnancy, detected after 20 weeks gestation in the absence of proteinuria. BP returns to no rmal postpartum (by 3 months). There is a high risk of pre-eclampsia 15 \200\22325% patien ts. There is no increase in intraglomerular pressure in normal pregnancy. Blood pressure in normal pregnancy Blood pressure falls in the early stages of normal pregn ancy and subsequently climbs back to prepregnancy baseline level by term. There is a reduct ion in systemic vascular resistance in early normal pregnancy due to increased synthesis of vasodila- tory prostaglandins and resistance to vasoconstrictor effects of angiotensin II and noradrenaline. Pre-eclampsia Introduction Pre-eclampsia (PeT) is a multisystem disorder. PeT is characteri zed by: \200 vasoconstriction; \200 endothelial dysfunction; \200 metabolic changes; \200 activation of the coagulation cascade; \200 increased in \202 ammatory response. Measurement of blood pressure The Royal College of Obstetricians and Gynecologists (RCOG) g uidelines state that the following factors need to be considered when measuring BP in pregn ancy (grade A evidence): It can be very dif \201 cult to distinguish PeT from worsening renal disease in pregnancy. CHAPTER 9.5 Hypertensive disorders in pregnancy 311 Table 9.5.1 Classi \201 cation of hypertensive disorders of pregnancya Pregnancy-induced hypertension (gestational) Raised blood pressure >140/90 mmHg Detected af ter 20 weeks gestation in the absence of proteinuria Blood pressure returns to normal postp artum (by 3 months) Pre-eclampsia Raised blood pressure >140/90 mmHg and proteinuria >300 mg/L or 1+ on dipstic k Detected after 20 weeks gestation Chronic hypertension Hypertension diagnosed before conception or before 20 weeks gestation Chronic hypertension with superimposed PeT (30% of women with chronic hypertension will dev elop PeT) a National High Blood Pressure Education Program 1990 and Australasian Society for the Stud y of Hypertension in Pregnancy. An increased frequency of the M235T angiotensinogen polymorphism has been reported in women with PeT in some but not all studies. Polymorphisms in the lipoprotein lipase gene have al so been associated with an increased risk of PeT. 15 \200\22325% of women with gestational HTN will develop PeT. PeT may occasionally occur w ith HTN in the absence of proteinuria but with other features such as eclampsia, renal impa irment, thrombocytopenia, liver dysfunction or fetal compromise. Occasionally PeT may prese nt with proteinuria without HTN. Etiology There are several factors which are recognized to increase the risk of developing PeT in pregnancy (Table 9.5.2). PeT is characterized by: \200 Epidemiology PeT complicates 2 \200\2233% of all pregnancies and 5 \200\2237% of \201 rst pregnancies. PeT is a major cause of maternal and perinatal morbidity and mortality worldw ide with >4 million women develop- ing PeT each year, mainly in developing countries. vasoconstriction (increased peripheral vascular resist- ance); maternal volume contraction; platelet activation and intravascular coagulation; generalized dysfunction of the endothel ium (the hall- mark of the systemic syndrome of PeT). \200 \200 Maternal morbidity and mortality PeT is responsible for 25% of maternal deaths in the USA a lthough in developed countries the absolute rate of maternal death is quite small. In the U K, PeT accounts for 12 per 100 000 maternal deaths but the risk is up to 20 times higher in developing countries. 2% of women with PeT will develop eclampsia. Women with PeT have a d oubling of risk of death from cardiovascular disease in later life. This risk is highest in women with PeT who deliver preterm and those with recurrent PeT. PeT can be considered as a two-stage disorder. Stage I: There is placental hypoperfusion du e to inadequate tro- phoblast invasion leading to reduced placental blood \202 ow. Stage II: In some but not all women this progresses to the multisys- tem disorder of PeT and HELL P syndrome. The clinical presentation of PeT depends upon the extent of involvement of diff erent organ systems. Perinatal morbidity and mortality Fetal mortality and morbidity is considerable and related to the effects of the disease on the fetus and associated early delivery and prematurity P eT accounts for 15% all preterm births. Table 9.5.2 Factors associated with an increased risk of pre-eclampsia (PeT) Genetics There is some evidence to support the role of maternal and paternal genetic factor s in the pathogenesis of PeT. A number of genetic polymorphisms have been reported to be mo re common in women with PeT. Genes involved include those related to: \200 Primigravida Previous PeT Family history of PeT (mother or sister) High body mass index (>3 5 kg/m2 at booking) Older maternal age >40 years >10 years since previous pregnancy Multipl e pregnancy Underlying medical conditions: \200 diabetes \200 renal disease \200 chro nic hypertension \200 connective tissue diseases (SLE, especially in presence of coagulation (5,10-methylene-tetrahydrofolate reductase and factor V); folate metabolism; ox idative stress; components of RAS system. However, \201 ndings are inconsistent. \200 \200 antiphospholipid antibodies) Smoking: reduced risk of PeT S. J. CARR 312 Pathogenesis of reduced placental perfusion \200 Clinical observations: Table 9.5.3 Factors implicated in the pathogenesis of pre-eclampsia Reduced placental perfusion and placental hypoxia are important early features of pregnanci es complicated by PeT and intrauterine growth retardation. PeT is more common in conditions associated with larger placentas, e.g. twin pregnancies. There is an increased incidence o f PeT in women with medical diseases associated with microvascular disease (e.g. diabetes). Increased activity of the sympathetic nervous system Increased responsiveness to angiotensi n II and noradrenaline Decreased activity of the nitric oxide system Increased levels of: \200 endothelin \200 proin \202 ammatory cytokines \200 circulating microparticles \200 circulating antiangiogenic proteins Reduced levels of: \200 relaxin \200 antioxid ants Increased ratio of thromboxane : prostacyclin (increased urinary thromboxane B2 in pre gnancy-induced hypertension) Abnormalities in the coagulation cascade with thrombophilia Hy pocalciuria and abnormalities in PTH Remodeling of spiral arteries: Normally, the spiral arteries in the intervillous space reduce their muscular coat and beco me capacitance ves- sels, thereby enabling greater blood \202 ow in pregnancy. This remod eling of spiral arteries fails to occur in PeT and consequently there is increased resistan ce in these intervillous space vessels. The physiological control of trophoblast endovascul ar invasion depends on interactions between maternal decidua and fetal trophoblast. In PeT a number of abnor- malities in trophoblast invasion have been described. These changes invo lve both ambient local oxygen ten- sions and local immune reactions. The oxygen tension inc reases in the intervillous space at 10 \200\22312 weeks and is associated with an increase in con- centration of reactive oxygen species. The maternal antioxidant capacity is believe d to be an important factor in the regulation of trophoblast inva- sion and defects in anti oxidant capacity may impair remodeling of intervillous space vessels. Many factors have been suggested as potential triggers for this endothelial dysfunction inc luding: \200 \200 \200 \200 the renin \200\223angiotensin system; circulating antiangiogenic proteins; circulating micr oparticles; oxidative stress. The renin \200\223angiotensin system (RAS): There are changes in the decidual and maternal RAS in pregnancy. Progesterone regulates the RAS and is increased in PeT which may stimulate activation of decidual RAS. In PeT there i s a reduction in plasma renin levels and to a lesser degree aldosterone levels suggesting i ncreased adrenal gland sensitivity to angiotensin II. This increased sensitivity to angiote nsin II is important in generating the increased tendency to vasoconstriction in PeT. Incre ased heterodimerization of the angiotensin I recep- tor AT1 and bradykinin B2 receptor has been proposed as a mechanism for the increased sensitivity to angi- otensin II in PeT. In a ddition, antibodies may develop against the AT1 receptor in PeT. These antibodies may play a role in enhancing vascular sensitivity to angiotensin II. Uterine natural killer cells: Uterine natural killer cells (uNK) reside within the decidua and interact with fetal tropho blasts through spe- ci \201 c receptor \200\223ligand interactions and in \202 uence trop hob- last invasion. Normal placentation requires a balance of inhibition and activation of uNK cells that is mediated by maternal and fetal factors. It has been suggested that this b alance is defective in PeT. Pathogenesis of the maternal systemic disorder of PeT Numerous factors have been implicated in the pathogene- sis of PeT (Table 9.5.3). Several of the more recently reported factors are consid- ered in more detail below. \200 Endothelial dysfunction: Circulating antiangiogenic proteins: Normal placentation involves both angiogenesis and vas- culogenesis. There are several rece ptor \200\223ligand systems that are vital to this process including: vascular endothelial growth factor (VEGF); placental growth factor (PGF). VEGF and PGF are proangiogenic growth factors and bind to the receptor Flt-1 (fms-like tyrosine kinase 1) in target tissues. Inte raction of VEGF and PGF with Flt-1 can be antago- nized by the presence of a soluble form o f the Flt-1 receptor, sFlt-1. In PeT there is generalized dysfunction of the endo- thelium. Alteration in the normal func tions of the endothelium in pregnancy can lead to: vasoconstriction; \200 \200 increase d sensitivity to pressor agents including angi- otensin II; activation of the coagulation c ascade. The activated endothelium also induces the production of in \202 ammatory mediators, growt h factors and cytokines which can in \202 uence vascular tone. CHAPTER 9.5 Hypertensive disorders in pregnancy 313