Journal of Human Hypertension (2000) 14, 705–724 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh REVIEW ARTICLE Hypertension in pregnancy F Broughton Pipkin1 and JM Roberts2 1School of Human Development, University of Nottingham, UK; 2University of Pittsburgh and Magee- Women’s Institute, USA Hypertension arising during pregnancy remains one of fetal growth restriction. Prospective studies have sug- the two most frequently-cited causes of maternal death gested a hyperdynamic circulation in early pregnancy, in the UK. In some cases, pregnancy is unmasking with cardiac output only falling in established disease. underlying hypertension, which manifests itself in later Baroreflex sensitivity is decreased in normal pregnancy, life. Pregnant women who develop de novo proteinuric and still further decreased in established PE. Activation hypertension (pre-eclampsia, PE) can share many risk of endothelial cell function antedates the clinical diag- factors with patients with the metabolic syndrome, such nosis, and has features in common with atheroscler- as obesity, dyslipidaemia and insulin resistance. How- osis. Dyslipidaemia is common in PE and, via oxidation ever, more than half the women who develop PE remain of susceptible lipids, may contribute to endothelial acti- normotensive thereafter. There is a genetic component(s) vation. Oxidative ‘stress’ is increased in PE, perhaps to the disease, but it is most improbable that there is a through a variant of the hypoxia-reperfusion phenom- ‘PE gene’. Rather, there are factors such as genetically- enon in the developing intervillous spaces. Such early determined thrombophilias which are predisposers but changes might then lead to the clinically-evident not prerequisites. Impaired placentation is a feature, syndrome in susceptible women. PE is a protean, multi- with inadequate invasion of the spiral arteries by syncy- system, multifactorial disease, the causes of which are tiotrophoblast and poor remodelling. However, similiar only slightly less enigmatic than a decade ago. features are found in association with non-hypertensive Journal of Human Hypertension (2000) 14, 705–724 Keywords: pregnancy; hypertension; pre-eclampsia; gestational hypertension Introduction collaboration with colleagues across numerous disciplines. It is a lamentable fact that, until relatively recently, However, pregnancy remains a higher-risk state there was little basic research in obstetrics. Obser- than non-pregnancy. In the most recent ‘Report on vation certainly, and consideration of management Confidential Enquiries into Maternal Deaths in the regimes, but investigations into the physiology and United Kingdom’,1 which is believed to have near- pathophysiology of pregnancy were the province of total ascertainment, pre-eclampsia/eclampsia a few dedicated individuals. Convulsions in preg- remain one of the two most frequently-cited causes nancy have been noted since at least the time of of maternal death, as they have for the last 30 years. Galen (4th century BC). As maternal death rates fell in the 20th century AD, at first slowly, then much In the United Kingdom, as in North America, the more rapidly after the introduction of antibiotics, absolute numbers of maternal deaths are relatively small1 (USA 9.2/100000 and UK 12.2/100000 and with improving antenatal and peri-partum care, 1,2 so the relative importance of the ‘toxaemias’ of preg- maternities; but in less developed countries, such nancy as causes of maternal death increased. They as Central and parts of South America and sub-Sah- have, however, always been one of the ‘Big Four’, aran Africa, rates, where available, can be 20–30 3 the others being infection, thrombosis and haemor- times higher (eg, Mungra et al, 1999; Etard et al, 4 rhage. A quick scan of Medline reveals that in 1969, 1999). a mere 22 articles with the keyword ‘pre-eclampsia’ As usual, the Greeks had a word for it. The word? or ‘preeclampsia’ were published. By 1979 this had Eclampsia, the thunderbolt, which strikes from the risen to 115 and to 285 in 1989. A scan in late 1999 blue, and can kill where it strikes. A prospective identified 468 such publications, and whereas 30 study which attempted to involve every consultant years ago, more than half of the papers were case obstetrician in the United Kingdom reported an inci- reports or related to management, those today are dence of eclampsia of 4.9/10000 maternities.5 far more likely to be concerned with basic science, Eleven percent had no recorded hypertension or utilising extremely sophisticated methodology and proteinuria at the antenatal clinic visit immediately preceding the onset of fitting, and a further 10% had proteinuria but no hypertension. Even in those who had been admitted to hospital, the highest recorded Correspondence: Professor F Broughton Pipkin, Department of diastolic pressure before the onset of convulsions Obstetrics and Gynaecology, University Hospital, Nottingham NG7 2UH, UK was 100 mm Hg or less in a third (34%). Diastolic Received and accepted 24 February 2000 pressures of 120 mm Hg or more before fitting were Hypertension in pregnancy F Broughton Pipkin et al 706 only recorded in 19% of patients. Thus it is unsafe supported by epidemiological observations that to consider eclampsia as being the end-point of sev- indicate a greater risk of recurrence and essential ere pre-eclampsia, although it can be associated. hypertension in later life for women with GH than Interestingly, a careful follow-up of 65 patients 6– those with PE. Additionally, many of the character- 42 months after eclampsia found that none of the istic markers of physiological abnormalities of PE women had neurological deficits after 6 months or such as increased cellular fibronectin concentrations repeated convulsions,6 emphasising that it is a preg- are not present in GH.12 If one imagines that GH may nancy-related condition. Of the 38 who sub- be a physiological mechanism to compensate for sequently had one or more pregnancies, none had a impaired utero-placental perfusion (see recurrence of fitting. ‘Conclusion’), and PE a pathological breakdown of The relatively low incidence of eclampsia, and its such a system, then the different outcomes become diversity of presentation, make systematic study of more comprehensible. It certainly seems improbable its pathogenesis very difficult indeed. This being so, that a condition should occur with such frequency the remainder of this paper will not consider it (GH ෂ10% in first pregnancy) at such a physiologi- further, and will focus on the several hypertensive cally important time of life if it were wholly malign. conditions found in pregnancy. Problems Definitions The fact that the defining symptoms of hypertension The question of the definition of the various forms and significant proteinuria arising de novo only of hypertension found in pregnancy has exercised become apparent late in the disease process, and are numerous groups, and serious attempts are being secondary, not primary, phenomena is a further made in 1999/2000 to arrive at an agreed definition obstacle to research. The seeds of PE are sown very for research purposes, which may be used world- early indeed in pregnancy. To compound the prob- wide. For purposes of this paper, gestational hyper- lem still further, the actual measurement of the tension (GH; also referred to as ‘pregnancy-induced blood pressure is notoriously unreliable, and hypertension’, PIH) is defined as the occurrence of inclusion criteria have differed from study to study. an increase of at least 30/15 mm Hg in the blood Worse still, the determination of the level of the pressure from pre- or early-pregnancy levels or an blood pressure even in normotension is itself multi- absolute value of at least 140/90 mm Hg or more on factorial. at least two occasions not less than 4–6 h apart in a woman known to have been normotensive before Heterogeneity of study groups 20 weeks of gestation and in whom the blood press- ure has returned to normal by, at the latest, the Apparent PE occurring in a second or subsequent twelfth week post-partum.7 Korotkov sound V has pregnancy is associated with a considerably higher now been accepted as preferable for recording the incidence of hypertension in later life than if the diastolic pressure in pregnancy (eg, Shennan et al8). condition occurs only in the first pregnancy.13 Par- When this is accompanied by de novo significant ous women who develop PE or eclampsia are twice proteinuria (Ͼ300 mg/l or 500 mg/day in a 24-h as likely to die from ischaemic heart disease in later urine sample, or a minimum of two ‘pluses’ of pro- life than are women who develop PE or eclampsia tein on dipstick test), which also resolves after deliv- in their first pregnancy.14 Furthermore, renal biopsy ery, the condition is known as pre-eclampsia (PE). performed in primiparous and multiparous women Pre-eclampsia may also be accompanied by any/all diagnosed as having PE showed that while 84% of of haemolysis, elevated liver enzymes and a platelet primiparae did have diagnostic glomerular endo- count below 100 × 109 cells/l (thrombocytopaenia). theliosis, only 28% of multiparae did so.15 Thus When all are present, the condition is known as pathophysiological studies should logically concen- HELLP. Any of these conditions may be superim- trate on women who develop PE in their first preg- posed upon pre-existing essential hypertension. nancy. There is discussion as to whether GH and PE are Another problem is that the diagnosis undoubt- indeed part of the same spectrum of disease. This is edly encompasses more than one condition. For enhanced by the observation that GH at term is usu- example, in a prospective study of 212 primigravi- ally associated with normally-grown, or even dae, it was noted that 50 had had an isolated ‘spike’ slightly large, babies, particularly when centiles of systolic blood pressure of 140 mm Hg or more defined for the specific population are used during their first antenatal visit to their general prac- (reviewed in MacGillivray, 19839).