Pregnancy-induced hypertension: pathogenesis and management M. A. Brown
Staff Nephrologist, Department of Renal Medicine, St George Hospital, Sydney and Senior Lecturer in Medicine, University of New South Wales.
Pregnancy-induced hypertension (PIH) is the commonest medical disorder of pregnancy and still a major cause of maternal mortality’ and a significant cause of perinatal death.’ Unfortunately this disorder remains an enigma, though increasingly its pathophysiology is being discovered, in turn leading to more rational management. This review aims to sumniarise our present understanding of the factors involved in the development of PIH and hence to discuss a rational strategy of management as well as possible future therapies.
DEFINITIONS Complex classifications of the hypertensive disorders of pregnancy have been published recently3 but these do not aid either clinical management or research into these disorders. A simple approach is to consider hypertension during pregnancy as being either pregnancy-induced hypertension (PIH), a disorder specific to pregnancy, or chronic (usually essential) hypertension. Some view PIH and pre-eclampsia as separate disorders but in this review the term PIH is used to refer to the single disorder defined as: 0 the development of a blood pressure greater than 140190 mmHg or alternatively, a rise in diastolic blood pressure of more than 25 mmHg from first trimester level^;^ 0 occurring in a primigravida; with onset after 20 weeks’ gestation; 0with no known history of hypertension or renal disease; 0whose blood pressure returns to normal within three months post-partum. Although the presence of proteinuria signifies a more severe form of this disease, neither proteinuria nor oedema are considered pre-requisites for the diagnosis of PIH. Chronic hypertension, although a condition which may affect pregnancy adversely, is not discussed here and the reader is referred to other reviews for
complete discussion of this form of hypertension during
CLINICAL FEATURES The clinical spectrum of PIH varies considerably’ (Figure 1). On the one hand a woman may present close to term with mild hypertension being the only clinical feature and this usually poses little problem to the final pregnancy outcome. Conversely, PIH may develop late in the second trimester with any combination of hypertension, proteinuria, abnormal liver function, hyperuricaemia, disseminated intravascular coagulation, renal impairment or neurological disturbances. Clearly these presentations pose an enormous challenge to physicians, obstetricians and neonatologists if the desired outcome of a healthy mother and neonate is to be achieved. Although PIH is typically a disorder of primigravidae and the appearance of hypertension in a multigravida should prompt a thorough search for a form of chronic hypertension, PIH may occur in multigravidae.8 Occasionally this is associated with a change of male partners and exposure to a new set of paternal antigens.’ I n addition, PIH can occur superimposed upon chronic hypertension, particularly when there is underlying renal disease.6 In such cases prognosis for both mother and foetus is considerably worse than if chronic hypertension alone is present during the pregnancy.s Other unusual presentations of this disorder include: (a) intra- or early post-partum onset, which should be treated carefully as all the maternal risks of this disorder are still present in such women;’O (b) postpartum eclampsia, as about one-half of such convulsions occur within 24-48 hours after delivery;’ (c) so-called ‘HELLP’ syndrome, characterised by hypertension (which is often only mild) and ‘haemolysis, elevated liver enzymes and low platelets’ (‘HELLP’).’’ This term should probably be abolished so that this
Reprinr rrqursrs ro: Dr M. A. Brown, 1st Floor, Main Building, St George Hospital, Kogarah, NSW 2217, Australia. PREGNA4KCY-INI)UCEDI I Y I’ERTENSION
Aust NZ J Med 1991; 21
257
n
The precise aetiology of PIH remains unknown but a considerable amount has been learned about the pathophysiology of this condition in recent years. It is now possible to piece together a proposed pathway through which this disorder may develop (Figure 2) and these concepts are discussed below. * Pulmonary w&ma
venepuncturesites
.Acute renal fnilure quadrant p i n
relardallon
Genetics Several lines of evidence suggest a genetic basis to PIH. Firstly, there is an increased frequency of PIH and eclampsia in both sisters and d a ~ g h t e r s 'of ~ women with these disorders. Recent analyses of cohorts of families with eclampsia suggested a single recessive gene inheritance,l4,l5though analysis of similar data from Scotland did not fit this model as well.I6 Most workers implicate the maternal genotype in this inheritanceL5but recent evidence suggests that the foetal genotype may be involved." The gene responsible for the susceptibility to PIH is not known though some have studied markers on chromosome 6 . Kilpatrick and co-workers found a higher frequency of HLA DR4 antigen in British women with PIH and their babies than in controls.'* They also observed that sisters of women with PIH, who themselves developed PIH, had a higher frequency of HLA DR4 than did sisters who had normotensive pregnancies. l9 These findings were not confirmed in a large study of primigravidae from southern USA where the incidence of HLA DR4 was higher in normotensive women than in those with PIH.20It is also possible, in view of the reported association between trisomy-13 and PIH, that chromosome 13 may be implicated.21Whichever chromosome is involved and whatever mode of inheritance ultimately
Figure I: T h e clinical spectrum of pregnancy-induced hypertension.
syndrome is not viewed as anything other than a severe form of PIH. Finally, it is important to appreciate the clinical heterogeneity of PIH, some organ systems being severely affected in one woman but completely spared in another, despite similar blood pressure readings.
PATHOPHYSIOLOGY Obstetricians have long appreciated that PIH is a disorder primarily of trophoblast, and removal of the placenta is the only known cure for this disorder. It is also clear that very few of the maternal aspects of this disease are caused by hypertension. Rather, they arise from intense vasoconstriction, often with reduced intravascular volume and intravascular coagulation, leading to hypoperfusion of the uteroplacental bed and maternal organs including kidneys, liver and brain. 258
ABNORMAL PLACENTATION
$ 5
I 13
VASCULAR ENDOTHELIUM
Figure 2: Pathways for the development of foetal and maternal abnormalities in pregnancy-induced hypertension. Some of these steps are supported strongly by scientific evidence, some remain controversial and some are only speculative at this point. See text for full discussion. (Pg12= prostacyclin; T x = thromboxane; E T = endothelin; A11 = angiotensin 11; DIC = disseminated intravascular coagulation; BP = blood pressure.)
Aust NZ J Med 1991; 21
BROWN
proves to be correct, these studies have alerted us to the increased risk of developing PIH in women with a family history of this disorder, particularly if their mother has been affected.
Immunology Just how a genetic susceptibility might lead to the development of PIH remains unknown. However, electron dense deposits have been observed in renal biopsies from women with PIHZZand the original observation of Brosens and co-workersZ3 that the placental bed sometimes resembled a rejecting allograft raised the possibility that PIH was an immunemediated disorder. Many workers have since tried to define a specific derangement of the immune system in these women but data remain conflicting. Some have proposed that PIH is an immune complex disorder with complement activationz4but these studies vary depending on the type of assay Taufield and co-workers found that maternal lymphocytes from women with PIH did not demonstrate the cellular hyporesponsiveness to foetal cells which is typical of normal pregnancy.26This provided indirect support for Faulk‘s proposal that in normal pregnancy there exist TLX (trophoblast-lymphocyte cross reacting) antigens, to which ‘blocking antibodies’ are formed, thereby preventing recognition of trophoblast antigens by the m ~ t h e r . ~If’ these antibodies are lacking then a maternal-foetal immune reaction could ensue. However, proof of this hypothesis is awaited. Two other observations have promoted interest in the immunological aspects of PIH. Firstly, a change of male partners reverts the risk of developing PIH back to that of the first pregnancy and this may be associated with immunological paternal-maternal incompatibility.’ Second, in a case-control study of 110 primiparae who developed PIH, prior use of barrier contraceptive methods was associated with a two-fold greater risk of developing P I H compared with nonbarrier methods.z8 These authors proposed that barrier methods lead to PIH by preventing prior exposure of the maternal immune system to paternal antigens, though they acknowledged that other factors must also be important as many women who used non-barrier methods also developed this disorder. Thus, at present there is suggestive evidence that PIH may be immune mediated but many aspects of this hypothesis require confirmation. Placenta As the only known cure for P I H is delivery of the placenta it is likely that this disorder results directly or indirectly from abnormal placental functions or production of a substance by the placenta which somehow causes maternal organ dysfunction. In this PREGNANCY-INDUCED HYPERI‘ENSION
regard both morphological and physiological abnormalities of the placenta occur in women with PIH: (a) In normal pregnancy trophoblast invades the spiral arteries of the uteroplacental bed, converting them into capacitance vessels which carry increased blood flow under low pressure. This process, called ‘placentation’, occurs until about 10 weeks’ gestation, with a ‘second wave’ of trophoblast invasion at about 20 weeks.29 It is now apparent that in many women who develop PIH this ‘second wave’ phenomenon is lacking, leaving muscular coated spiral arteries which limit uteroplacental blood flow and may constrict in response to local or circulating vasoconstrictors. (b) A second lesion which can occur in mild or severe P I H is that of ‘acute atherosis’ whereby spiral arteries undergo fibrinoid necrosis and lipid-like infiltration of their walls.3o Whether this is an extension of the failure of normal placentation or a separate process is not known, nor is the mechanism which prevents normal placentation from occurring in the first place. It follows nevertheless that these abnormalities are capable of reducing uteroplacental blood flow and in severe cases causing placental infarction and abruption, features which may accompany severe PIH.31 (c) Other changes in the placenta include incqmplete denervation of the uterine adrenergic system around the spiral arteries, increased tissue production of n~radrenaline~’ and reduction in the ratio of placental prostacyclin and thromboxane p r o d u ~ t i o nAll . ~ ~these abnormalities promote local vasoconstriction and reversal of the prostacyc1in:thromboxane ratio also permits platelet aggregation and local intravascular coagulation. Walsh and C o ~ l t e have r ~ ~ shown that these placentae also produce more progesterone than normal and have found that progesterone inhibits invitro placental prostacyclin, but not thromboxane production. This might explain why PIH is more common in conditions such as multiple pregnancy3’ and hydatidiform where there is an increased mass of trophoblast. All the abnormalities described above set the scene for uteroplacental ischaemia and thereby provide ready explanation for the foetal problems encountered in PIH. However, none of the widespread maternal features can be explained by these abnormalities alone. It is possible that these placental abnormalities are part of a widespread process such as endothelial cell d y s f u n ~ t i o n , or ~ ~ alternatively, that the placenta releases a factor into the maternal circulation which is capable of causing endothelial damage and thereby the maternal clinical features of PIH.
Clotting Fulminant PIH is accompanied by disseminated intravascular coagulation (DIC), but recent research has demonstrated more subtle and chronic changes of Aust NZ J Mcd 1991; 21 2 59
platelet aggregation and coagulation during normal pregnancy and in women with PIH.'" Most workers agree that thrombocytopenia accompanies severe PIH,39 presumably reflecting platelet consumption, though some have demonstrated platelet-bound IgG raising the possibility of immune mechanisms mediating this thrombocytopenia in some patient^.^“ Although platelet life-span is reduced in women with PIH4' this is not due to an intrinsic change in platelet activity4*and these findings appear most compatible with platelet consumption even though in-vim tests of platelet aggregation have been conflicting. Morrison et ~ 2 1found . ~ ~ that platelet responsiveness to arachidonic acid was increased in women with PIH but others have found blunted platelet aggregation in response to collagen, arachidonic acid and ADP.j8 Some have suggested that the latter observations are due to the presence of 'exhausted' platelets, which have already been aggregated and degran~lated,'~ but these studies cannot yet be reconciled. Benedetto and c o - w ~ r k e r s ~ ~ have shown that serum from normal pregnant women inhibits platelet activating factor-induced platelet aggregation more so than does serum from women with PIH, though the mechanism for this could not be elucidated. As well as thrombocytopenia and reduced platelet life-span, there are changes in coagulation and fibrinolysis in women with PIH. The ratio of factor VIII related antigen to factor VIII coagulant activity is greater in women with PIH than during normal perhaps as a result of endothelial cell damage.46Reports of elevated plasma fibronectin are in keeping with this latter hyp~thesis.~'There is general agreement that plasma antithrombin I11 (AT 111) activity is reduced in PIH, suggesting increased coagulation. Weiner found that a low plasma AT I11 activity, measured near term, was moderately sensitive and highly specific for the diagnosis of P1H.j" In a recent comprehensive study, though 'muddied' by variable patient classifications, Kobayashi and Terao4' found that PIH was accompanied by decreased AT I11 activity as well as increased thrombin-AT I11 complex, reduced platelet count and increased D-dimers, compared with normal pregnancy. These changes reflect enhanced intravascular coagulation and increased fibrinolysis and, together with the slight increase in fibrin degradation products observed in these patients, can be interpreted to reflect chronic low grade DIC in women with PIH. Volume Homeostasis Normal pregnancy is accompanied by weight gain and expansion of the maternal extracellular fluid volume. Although these are normal events, maintaining volume homeostasis has remained a great challenge to the pregnant woman who has borne the brunt of therapeutic 260
fashions, being diuresed, salt-restricted and more recently given intravenous fluid loads (reviewed in reference 49). When oedema was first recognised as an accompaniment of PIH it was assumed that these women were volume overloaded and should therefore receive salt restriction5"and diuretics. However, it was later found that their plasma volume was reduced from that of normal p~egnancy,S'*~* and that the degree of maternal plasma volume expansion correlated significantly with foetal birthweight in normal pregnancy,5' in those with idiopathic intrauterine growth r e t a r d a t i ~ nand ~ ~ in pregnancies complicated by PIH,55thus implying some role for the maternal blood volume in maintaining adequate placental perfusion. They also excrete inhsed sodium slowly, a normal renal response to perceived intravascular volume depletion56and it is thus likely that this reduction in plasma volume is of physiological consequence and may be involved in the development of acute renal failure in this c~ndition.~' Although it has been more than 40 years since this reduction in plasma volume was first ~eported,~" the mechanisms producing this abnormality remain unclear. It is unlikely to result from sodium loss, as these women do not have an exaggerated natriuretic response to saline i n h ~ i o n but , ~ may ~ ~ in ~ ~part be due to a decrease in plasma colloid osmotic pressure (COP):"-63 or an increase in interstitial COP.64There is now evidence that capillary permeability is altered in women with PIH. We have recently demonstrated that there is a rapid loss of Evans Blue dye from the circulation in these women signifying an increase in their capillary permeabilitf5 (Figure 3). Factors which may potentially alter capillary permeability in women with PIH include atrial natriuretic ~ e p t i d e , 6 ~ endothelin6"and a substance in maternal serum which is cytotoxic to endothelial cells6' but changes in capillary permeability have not yet been examined in relation to these factors in pregnancy. Whatever the mechanism(s) leading to plasma volume reduction, the major effect of this abnormality is Iikely to be a fall in cardiac output with consequent organ hypoperfusion. Recent haemodynamic studies have shown that normal pregnancy is accompanied by an increase in cardiac output, a fall in COP, pulmonary and systemic vascular resistance but no change in pulmonary capillary wedge pressure (PCWP) or central venous pressure (CVP).68 Haemodynamic studies of women with PIH have been conflicting, with two main groups being identified: those with high cardiac output-low systemic vascular resistance and those with low cardiac output-high systemic vascular ~esistance."~ However, Wallenburg has shown that these differences could be accounted for by the administration of intravenous fluids before measurements were made or by undertaking studies during
Aust NZ J Med 1991; 21
BROWN
Studies have shown that the addition of enalapril (RENITEC)to established digitalis and diuretic treatment in patients with congestive heart failure (NYHA classes II to IV) produces improvements in exercise performance and reductions in fatigue.' Percentage of i m ~ ~ v e ~in ent exercise.
I
RENITEC plus diuretics and digoxin ( n = 115)
22% *
Diuretics and digoxin alone (n=l16)
Perceniuge of patients with an ~ ~ p r o ~ e weakness and fatigue.2
I
L.
RENITEC plus d i u r e t i c s and digoxin (n=73)
53%*
Tablets
RENITEC (enalapril rnaleate, MSD)
25%] Diuretics and digoxin alone (n=661
References 1. Enalapril Congestive Heart Failure Investigators. Long-term effects of enalapril in patients with congestive heart failure. A multicenter, placebo-controlledtrial. Heart Failure 3f3): 102-107, 1987. 2. Data on file Merck Sharp & Dohme Research Laboratories, Rahway, N.J.. USA. 11-91RNT 9O-AUS-16OJ RCCF 2142A d Registered Trademark of Merck & Co., Inc., Rahway, N.J., USA
Before prescribing, please review Product Information. Committed to original research for life
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Figure 3: Evans Blue disappearance rate in non-pregnant women, normal pregnant women and those with pregnancyinduced hypertension. The more rapid disappearance rate signifies capillary leakage. **@< 0.01, PIH vs normal pregnant). Adapted from reference 55.
labour (when cardiac output and systemic vascular resistance rise).’O His group made haemodynamic measurements in 44 nulliparae with severe PIH before any treatment was initiated70and all had low PCWP, low cardiac output and high systemic vascular resistance.
Vascular Reactivity Normal pregnancy is accompanied by refractoriness to infused angiotensin I1 (AII)” even in the first trimester,72but this refractoriness is reduced in women with PIH.’I Isolated omental vessels from women with PIH exhibit enhanced contraction in response to A11 and potassium, though not to n~radrenaline,’~ while epigastric arteries from women with PIH are more sensitive to both noradrenaline and calcium Several mechanisms may be involved in producing these responses: Renin-Angiotensin-Alsterone (R-A-A)System In normal pregnancy A11 is necessary for the maintenance of blood press~re’~ and plasma concentrations of renin, aldosterone and A11 are all increased from values obtained in non-pregnant ~ o m e n . ~ These ’.~~ changes in the R-A-A system are probably secondary increases in response to demands upon body sodium and a perceived under-filling of the vascular bed.77 262 Aust NZ J Med
They are not purely autonomous, ie primary increments, as these plasm components can be suppressed by dietary78*79 and intravenous sodium loadings6 and blood pressures are not elevated in .normal pregnancy. On the other hand, even the combination of intravenous saline i&sion and dietary salt loading during normal pregnancy cannot reduce plasma renin activity to values of non-pregnant womens9and there must be other factors, speculatively placental in origin, which stimulate basal release of renin from the kidneys and perhaps other sites. Maternal plasma concentrations of renin, aldosterone and angiotensin I1 are reduced in women with PIH but there has been no good explanation for these changes which seem inappropriate for a volume contracted state. We have shown that maternal plasma renin can be suppressed from this low level by saline loading56and stimulated by upright posture.60 Thus it appears that basal secretion of renin is reduced in women with PIH, but that renin can still be suppressed or stimulated appropriately around this new level. Nochy et d8’ demonstrated a paucity of renincontaining granules in renal biopsy specimens from women with PIH, suggesting ‘exhaustion’ of renal renin production but unfortunately plasma renin was not measured. Therefore it appears that basal renin secretion is reduced in women with PIH, but whether this is due to an abnormality of kidneys, uteroplacental bed or maternal vasculature remains unclear. Despite the reduced plasma concentrations of renin and AII, there is enhanced pressor sensitivity to infused A11 in women who have, or are about to develop, PIH.7’ This has formed the basis of the ‘angiotensinsensitivity’ test used in research centres to select women at risk of developing PIH in their third trimester.82 It has recently been proposed that this pressor sensitivity results from a failure to downregulate A11 but the methodology of this study has been q u e ~ t i o n e d In . ~ ~an earlier series of experiments, Gant and co-workers concluded that refractoriness to infused A11 in normal pregnancy was due to enhanced production of vasodilator prostaglandins andor 5-alphadihydroproge~terone.~~ As prostacyclin (PgI,) is both vasodilatory and stimulates renin release directly in man,86deficiency of this substance could explain both a reduced basal secretion of renin and enhanced pressor sensitivity to infused A11 in women with PIH. Thus prostacyclin deficiency has been proposed as an essential mechanism in the pathophysiology of PIH. Prostaglandins
The past decade has heralded a surge of research into the roles of prostaglandins in the development of PIH.87 Initially it was thought that PgE2 deficiency might be responsible for the vasoconstriction of this 1991; 2 1
BROWN
"A significant improvement in NYHA classification was observed in the enalapril group, together with a reduction in heart size and a reduced requirement for other medication for heart failure? Improvement in NYHA ~~nctional Classi icafion at end of 5tudy.***
Tablets
"'p
Staff Nephrologist, Department of Renal Medicine, St George Hospital, Sydney and Senior Lecturer in Medicine, University of New South Wales.
Pregnancy-induced hypertension (PIH) is the commonest medical disorder of pregnancy and still a major cause of maternal mortality’ and a significant cause of perinatal death.’ Unfortunately this disorder remains an enigma, though increasingly its pathophysiology is being discovered, in turn leading to more rational management. This review aims to sumniarise our present understanding of the factors involved in the development of PIH and hence to discuss a rational strategy of management as well as possible future therapies.
DEFINITIONS Complex classifications of the hypertensive disorders of pregnancy have been published recently3 but these do not aid either clinical management or research into these disorders. A simple approach is to consider hypertension during pregnancy as being either pregnancy-induced hypertension (PIH), a disorder specific to pregnancy, or chronic (usually essential) hypertension. Some view PIH and pre-eclampsia as separate disorders but in this review the term PIH is used to refer to the single disorder defined as: 0 the development of a blood pressure greater than 140190 mmHg or alternatively, a rise in diastolic blood pressure of more than 25 mmHg from first trimester level^;^ 0 occurring in a primigravida; with onset after 20 weeks’ gestation; 0with no known history of hypertension or renal disease; 0whose blood pressure returns to normal within three months post-partum. Although the presence of proteinuria signifies a more severe form of this disease, neither proteinuria nor oedema are considered pre-requisites for the diagnosis of PIH. Chronic hypertension, although a condition which may affect pregnancy adversely, is not discussed here and the reader is referred to other reviews for
complete discussion of this form of hypertension during
CLINICAL FEATURES The clinical spectrum of PIH varies considerably’ (Figure 1). On the one hand a woman may present close to term with mild hypertension being the only clinical feature and this usually poses little problem to the final pregnancy outcome. Conversely, PIH may develop late in the second trimester with any combination of hypertension, proteinuria, abnormal liver function, hyperuricaemia, disseminated intravascular coagulation, renal impairment or neurological disturbances. Clearly these presentations pose an enormous challenge to physicians, obstetricians and neonatologists if the desired outcome of a healthy mother and neonate is to be achieved. Although PIH is typically a disorder of primigravidae and the appearance of hypertension in a multigravida should prompt a thorough search for a form of chronic hypertension, PIH may occur in multigravidae.8 Occasionally this is associated with a change of male partners and exposure to a new set of paternal antigens.’ I n addition, PIH can occur superimposed upon chronic hypertension, particularly when there is underlying renal disease.6 In such cases prognosis for both mother and foetus is considerably worse than if chronic hypertension alone is present during the pregnancy.s Other unusual presentations of this disorder include: (a) intra- or early post-partum onset, which should be treated carefully as all the maternal risks of this disorder are still present in such women;’O (b) postpartum eclampsia, as about one-half of such convulsions occur within 24-48 hours after delivery;’ (c) so-called ‘HELLP’ syndrome, characterised by hypertension (which is often only mild) and ‘haemolysis, elevated liver enzymes and low platelets’ (‘HELLP’).’’ This term should probably be abolished so that this
Reprinr rrqursrs ro: Dr M. A. Brown, 1st Floor, Main Building, St George Hospital, Kogarah, NSW 2217, Australia. PREGNA4KCY-INI)UCEDI I Y I’ERTENSION
Aust NZ J Med 1991; 21
257
n
The precise aetiology of PIH remains unknown but a considerable amount has been learned about the pathophysiology of this condition in recent years. It is now possible to piece together a proposed pathway through which this disorder may develop (Figure 2) and these concepts are discussed below. * Pulmonary w&ma
venepuncturesites
.Acute renal fnilure quadrant p i n
relardallon
Genetics Several lines of evidence suggest a genetic basis to PIH. Firstly, there is an increased frequency of PIH and eclampsia in both sisters and d a ~ g h t e r s 'of ~ women with these disorders. Recent analyses of cohorts of families with eclampsia suggested a single recessive gene inheritance,l4,l5though analysis of similar data from Scotland did not fit this model as well.I6 Most workers implicate the maternal genotype in this inheritanceL5but recent evidence suggests that the foetal genotype may be involved." The gene responsible for the susceptibility to PIH is not known though some have studied markers on chromosome 6 . Kilpatrick and co-workers found a higher frequency of HLA DR4 antigen in British women with PIH and their babies than in controls.'* They also observed that sisters of women with PIH, who themselves developed PIH, had a higher frequency of HLA DR4 than did sisters who had normotensive pregnancies. l9 These findings were not confirmed in a large study of primigravidae from southern USA where the incidence of HLA DR4 was higher in normotensive women than in those with PIH.20It is also possible, in view of the reported association between trisomy-13 and PIH, that chromosome 13 may be implicated.21Whichever chromosome is involved and whatever mode of inheritance ultimately
Figure I: T h e clinical spectrum of pregnancy-induced hypertension.
syndrome is not viewed as anything other than a severe form of PIH. Finally, it is important to appreciate the clinical heterogeneity of PIH, some organ systems being severely affected in one woman but completely spared in another, despite similar blood pressure readings.
PATHOPHYSIOLOGY Obstetricians have long appreciated that PIH is a disorder primarily of trophoblast, and removal of the placenta is the only known cure for this disorder. It is also clear that very few of the maternal aspects of this disease are caused by hypertension. Rather, they arise from intense vasoconstriction, often with reduced intravascular volume and intravascular coagulation, leading to hypoperfusion of the uteroplacental bed and maternal organs including kidneys, liver and brain. 258
ABNORMAL PLACENTATION
$ 5
I 13
VASCULAR ENDOTHELIUM
Figure 2: Pathways for the development of foetal and maternal abnormalities in pregnancy-induced hypertension. Some of these steps are supported strongly by scientific evidence, some remain controversial and some are only speculative at this point. See text for full discussion. (Pg12= prostacyclin; T x = thromboxane; E T = endothelin; A11 = angiotensin 11; DIC = disseminated intravascular coagulation; BP = blood pressure.)
Aust NZ J Med 1991; 21
BROWN
proves to be correct, these studies have alerted us to the increased risk of developing PIH in women with a family history of this disorder, particularly if their mother has been affected.
Immunology Just how a genetic susceptibility might lead to the development of PIH remains unknown. However, electron dense deposits have been observed in renal biopsies from women with PIHZZand the original observation of Brosens and co-workersZ3 that the placental bed sometimes resembled a rejecting allograft raised the possibility that PIH was an immunemediated disorder. Many workers have since tried to define a specific derangement of the immune system in these women but data remain conflicting. Some have proposed that PIH is an immune complex disorder with complement activationz4but these studies vary depending on the type of assay Taufield and co-workers found that maternal lymphocytes from women with PIH did not demonstrate the cellular hyporesponsiveness to foetal cells which is typical of normal pregnancy.26This provided indirect support for Faulk‘s proposal that in normal pregnancy there exist TLX (trophoblast-lymphocyte cross reacting) antigens, to which ‘blocking antibodies’ are formed, thereby preventing recognition of trophoblast antigens by the m ~ t h e r . ~If’ these antibodies are lacking then a maternal-foetal immune reaction could ensue. However, proof of this hypothesis is awaited. Two other observations have promoted interest in the immunological aspects of PIH. Firstly, a change of male partners reverts the risk of developing PIH back to that of the first pregnancy and this may be associated with immunological paternal-maternal incompatibility.’ Second, in a case-control study of 110 primiparae who developed PIH, prior use of barrier contraceptive methods was associated with a two-fold greater risk of developing P I H compared with nonbarrier methods.z8 These authors proposed that barrier methods lead to PIH by preventing prior exposure of the maternal immune system to paternal antigens, though they acknowledged that other factors must also be important as many women who used non-barrier methods also developed this disorder. Thus, at present there is suggestive evidence that PIH may be immune mediated but many aspects of this hypothesis require confirmation. Placenta As the only known cure for P I H is delivery of the placenta it is likely that this disorder results directly or indirectly from abnormal placental functions or production of a substance by the placenta which somehow causes maternal organ dysfunction. In this PREGNANCY-INDUCED HYPERI‘ENSION
regard both morphological and physiological abnormalities of the placenta occur in women with PIH: (a) In normal pregnancy trophoblast invades the spiral arteries of the uteroplacental bed, converting them into capacitance vessels which carry increased blood flow under low pressure. This process, called ‘placentation’, occurs until about 10 weeks’ gestation, with a ‘second wave’ of trophoblast invasion at about 20 weeks.29 It is now apparent that in many women who develop PIH this ‘second wave’ phenomenon is lacking, leaving muscular coated spiral arteries which limit uteroplacental blood flow and may constrict in response to local or circulating vasoconstrictors. (b) A second lesion which can occur in mild or severe P I H is that of ‘acute atherosis’ whereby spiral arteries undergo fibrinoid necrosis and lipid-like infiltration of their walls.3o Whether this is an extension of the failure of normal placentation or a separate process is not known, nor is the mechanism which prevents normal placentation from occurring in the first place. It follows nevertheless that these abnormalities are capable of reducing uteroplacental blood flow and in severe cases causing placental infarction and abruption, features which may accompany severe PIH.31 (c) Other changes in the placenta include incqmplete denervation of the uterine adrenergic system around the spiral arteries, increased tissue production of n~radrenaline~’ and reduction in the ratio of placental prostacyclin and thromboxane p r o d u ~ t i o nAll . ~ ~these abnormalities promote local vasoconstriction and reversal of the prostacyc1in:thromboxane ratio also permits platelet aggregation and local intravascular coagulation. Walsh and C o ~ l t e have r ~ ~ shown that these placentae also produce more progesterone than normal and have found that progesterone inhibits invitro placental prostacyclin, but not thromboxane production. This might explain why PIH is more common in conditions such as multiple pregnancy3’ and hydatidiform where there is an increased mass of trophoblast. All the abnormalities described above set the scene for uteroplacental ischaemia and thereby provide ready explanation for the foetal problems encountered in PIH. However, none of the widespread maternal features can be explained by these abnormalities alone. It is possible that these placental abnormalities are part of a widespread process such as endothelial cell d y s f u n ~ t i o n , or ~ ~ alternatively, that the placenta releases a factor into the maternal circulation which is capable of causing endothelial damage and thereby the maternal clinical features of PIH.
Clotting Fulminant PIH is accompanied by disseminated intravascular coagulation (DIC), but recent research has demonstrated more subtle and chronic changes of Aust NZ J Mcd 1991; 21 2 59
platelet aggregation and coagulation during normal pregnancy and in women with PIH.'" Most workers agree that thrombocytopenia accompanies severe PIH,39 presumably reflecting platelet consumption, though some have demonstrated platelet-bound IgG raising the possibility of immune mechanisms mediating this thrombocytopenia in some patient^.^“ Although platelet life-span is reduced in women with PIH4' this is not due to an intrinsic change in platelet activity4*and these findings appear most compatible with platelet consumption even though in-vim tests of platelet aggregation have been conflicting. Morrison et ~ 2 1found . ~ ~ that platelet responsiveness to arachidonic acid was increased in women with PIH but others have found blunted platelet aggregation in response to collagen, arachidonic acid and ADP.j8 Some have suggested that the latter observations are due to the presence of 'exhausted' platelets, which have already been aggregated and degran~lated,'~ but these studies cannot yet be reconciled. Benedetto and c o - w ~ r k e r s ~ ~ have shown that serum from normal pregnant women inhibits platelet activating factor-induced platelet aggregation more so than does serum from women with PIH, though the mechanism for this could not be elucidated. As well as thrombocytopenia and reduced platelet life-span, there are changes in coagulation and fibrinolysis in women with PIH. The ratio of factor VIII related antigen to factor VIII coagulant activity is greater in women with PIH than during normal perhaps as a result of endothelial cell damage.46Reports of elevated plasma fibronectin are in keeping with this latter hyp~thesis.~'There is general agreement that plasma antithrombin I11 (AT 111) activity is reduced in PIH, suggesting increased coagulation. Weiner found that a low plasma AT I11 activity, measured near term, was moderately sensitive and highly specific for the diagnosis of P1H.j" In a recent comprehensive study, though 'muddied' by variable patient classifications, Kobayashi and Terao4' found that PIH was accompanied by decreased AT I11 activity as well as increased thrombin-AT I11 complex, reduced platelet count and increased D-dimers, compared with normal pregnancy. These changes reflect enhanced intravascular coagulation and increased fibrinolysis and, together with the slight increase in fibrin degradation products observed in these patients, can be interpreted to reflect chronic low grade DIC in women with PIH. Volume Homeostasis Normal pregnancy is accompanied by weight gain and expansion of the maternal extracellular fluid volume. Although these are normal events, maintaining volume homeostasis has remained a great challenge to the pregnant woman who has borne the brunt of therapeutic 260
fashions, being diuresed, salt-restricted and more recently given intravenous fluid loads (reviewed in reference 49). When oedema was first recognised as an accompaniment of PIH it was assumed that these women were volume overloaded and should therefore receive salt restriction5"and diuretics. However, it was later found that their plasma volume was reduced from that of normal p~egnancy,S'*~* and that the degree of maternal plasma volume expansion correlated significantly with foetal birthweight in normal pregnancy,5' in those with idiopathic intrauterine growth r e t a r d a t i ~ nand ~ ~ in pregnancies complicated by PIH,55thus implying some role for the maternal blood volume in maintaining adequate placental perfusion. They also excrete inhsed sodium slowly, a normal renal response to perceived intravascular volume depletion56and it is thus likely that this reduction in plasma volume is of physiological consequence and may be involved in the development of acute renal failure in this c~ndition.~' Although it has been more than 40 years since this reduction in plasma volume was first ~eported,~" the mechanisms producing this abnormality remain unclear. It is unlikely to result from sodium loss, as these women do not have an exaggerated natriuretic response to saline i n h ~ i o n but , ~ may ~ ~ in ~ ~part be due to a decrease in plasma colloid osmotic pressure (COP):"-63 or an increase in interstitial COP.64There is now evidence that capillary permeability is altered in women with PIH. We have recently demonstrated that there is a rapid loss of Evans Blue dye from the circulation in these women signifying an increase in their capillary permeabilitf5 (Figure 3). Factors which may potentially alter capillary permeability in women with PIH include atrial natriuretic ~ e p t i d e , 6 ~ endothelin6"and a substance in maternal serum which is cytotoxic to endothelial cells6' but changes in capillary permeability have not yet been examined in relation to these factors in pregnancy. Whatever the mechanism(s) leading to plasma volume reduction, the major effect of this abnormality is Iikely to be a fall in cardiac output with consequent organ hypoperfusion. Recent haemodynamic studies have shown that normal pregnancy is accompanied by an increase in cardiac output, a fall in COP, pulmonary and systemic vascular resistance but no change in pulmonary capillary wedge pressure (PCWP) or central venous pressure (CVP).68 Haemodynamic studies of women with PIH have been conflicting, with two main groups being identified: those with high cardiac output-low systemic vascular resistance and those with low cardiac output-high systemic vascular ~esistance."~ However, Wallenburg has shown that these differences could be accounted for by the administration of intravenous fluids before measurements were made or by undertaking studies during
Aust NZ J Med 1991; 21
BROWN
Studies have shown that the addition of enalapril (RENITEC)to established digitalis and diuretic treatment in patients with congestive heart failure (NYHA classes II to IV) produces improvements in exercise performance and reductions in fatigue.' Percentage of i m ~ ~ v e ~in ent exercise.
I
RENITEC plus diuretics and digoxin ( n = 115)
22% *
Diuretics and digoxin alone (n=l16)
Perceniuge of patients with an ~ ~ p r o ~ e weakness and fatigue.2
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53%*
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References 1. Enalapril Congestive Heart Failure Investigators. Long-term effects of enalapril in patients with congestive heart failure. A multicenter, placebo-controlledtrial. Heart Failure 3f3): 102-107, 1987. 2. Data on file Merck Sharp & Dohme Research Laboratories, Rahway, N.J.. USA. 11-91RNT 9O-AUS-16OJ RCCF 2142A d Registered Trademark of Merck & Co., Inc., Rahway, N.J., USA
Before prescribing, please review Product Information. Committed to original research for life
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Figure 3: Evans Blue disappearance rate in non-pregnant women, normal pregnant women and those with pregnancyinduced hypertension. The more rapid disappearance rate signifies capillary leakage. **@< 0.01, PIH vs normal pregnant). Adapted from reference 55.
labour (when cardiac output and systemic vascular resistance rise).’O His group made haemodynamic measurements in 44 nulliparae with severe PIH before any treatment was initiated70and all had low PCWP, low cardiac output and high systemic vascular resistance.
Vascular Reactivity Normal pregnancy is accompanied by refractoriness to infused angiotensin I1 (AII)” even in the first trimester,72but this refractoriness is reduced in women with PIH.’I Isolated omental vessels from women with PIH exhibit enhanced contraction in response to A11 and potassium, though not to n~radrenaline,’~ while epigastric arteries from women with PIH are more sensitive to both noradrenaline and calcium Several mechanisms may be involved in producing these responses: Renin-Angiotensin-Alsterone (R-A-A)System In normal pregnancy A11 is necessary for the maintenance of blood press~re’~ and plasma concentrations of renin, aldosterone and A11 are all increased from values obtained in non-pregnant ~ o m e n . ~ These ’.~~ changes in the R-A-A system are probably secondary increases in response to demands upon body sodium and a perceived under-filling of the vascular bed.77 262 Aust NZ J Med
They are not purely autonomous, ie primary increments, as these plasm components can be suppressed by dietary78*79 and intravenous sodium loadings6 and blood pressures are not elevated in .normal pregnancy. On the other hand, even the combination of intravenous saline i&sion and dietary salt loading during normal pregnancy cannot reduce plasma renin activity to values of non-pregnant womens9and there must be other factors, speculatively placental in origin, which stimulate basal release of renin from the kidneys and perhaps other sites. Maternal plasma concentrations of renin, aldosterone and angiotensin I1 are reduced in women with PIH but there has been no good explanation for these changes which seem inappropriate for a volume contracted state. We have shown that maternal plasma renin can be suppressed from this low level by saline loading56and stimulated by upright posture.60 Thus it appears that basal secretion of renin is reduced in women with PIH, but that renin can still be suppressed or stimulated appropriately around this new level. Nochy et d8’ demonstrated a paucity of renincontaining granules in renal biopsy specimens from women with PIH, suggesting ‘exhaustion’ of renal renin production but unfortunately plasma renin was not measured. Therefore it appears that basal renin secretion is reduced in women with PIH, but whether this is due to an abnormality of kidneys, uteroplacental bed or maternal vasculature remains unclear. Despite the reduced plasma concentrations of renin and AII, there is enhanced pressor sensitivity to infused A11 in women who have, or are about to develop, PIH.7’ This has formed the basis of the ‘angiotensinsensitivity’ test used in research centres to select women at risk of developing PIH in their third trimester.82 It has recently been proposed that this pressor sensitivity results from a failure to downregulate A11 but the methodology of this study has been q u e ~ t i o n e d In . ~ ~an earlier series of experiments, Gant and co-workers concluded that refractoriness to infused A11 in normal pregnancy was due to enhanced production of vasodilator prostaglandins andor 5-alphadihydroproge~terone.~~ As prostacyclin (PgI,) is both vasodilatory and stimulates renin release directly in man,86deficiency of this substance could explain both a reduced basal secretion of renin and enhanced pressor sensitivity to infused A11 in women with PIH. Thus prostacyclin deficiency has been proposed as an essential mechanism in the pathophysiology of PIH. Prostaglandins
The past decade has heralded a surge of research into the roles of prostaglandins in the development of PIH.87 Initially it was thought that PgE2 deficiency might be responsible for the vasoconstriction of this 1991; 2 1
BROWN
"A significant improvement in NYHA classification was observed in the enalapril group, together with a reduction in heart size and a reduced requirement for other medication for heart failure? Improvement in NYHA ~~nctional Classi icafion at end of 5tudy.***
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