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Gestational Hypertension and Preeclampsia: Are They the Same Disease?

      Key Words

      ABBREVIATIONS

      BP
      blood pressure
      GHTN
      gestational hypertension
      HTN
      hypertension
      PE
      preeclampsia
      PIGF
      placental growth factor
      sEng
      soluble endoglin
      sFIt
      soluble fms-like tyrosine kinase-1

      INTRODUCTION

      Preeclampsia, complicating 5% to 8% of pregnancies, has been traditionally defined by an elevated blood pressure (over 140/90 mmHg on at least 2 occasions at least 6 hours apart) and proteinuria, at or beyond 20 weeks’ gestation.
      Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.
      • ACOG
      In 2013, the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy recommended that the definition of PE should be extended to include cases without evidence of proteinuria, provided that the hypertension is accompanied by evidence of end-organ involvement.
      • ACOG
      PE is associated with an increased risk of adverse pregnancy outcome, including prematurity, placental abruption, and intrauterine growth restriction.
      • Cruz M.O.
      • Gao W.
      • Hibbard J.U.
      Obstetrical and perinatal outcomes among women with gestational hypertension, mild preeclampsia, and mild chronic hypertension.
      In contrast, gestational hypertension is defined by an elevated BP at or beyond 20 weeks’ gestation in the absence of proteinuria
      Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.
      • ACOG
      and is considered to be a transient condition (Figure 1).
      Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.
      The development of proteinuria later in pregnancy changes the final diagnosis to preeclampsia. Otherwise, the final diagnosis is determined according to a re-evaluation of BP recordings at approximately three months postpartum. For women who are then normotensive (the most common scenario
      • Reiter L.
      • Brown M.A.
      • Whitworth J.A.
      Hypertension in pregnancy: the incidence of underlying renal disease and essential hypertension.
      ), the final diagnosis is transient HTN of pregnancy (Figure 1). Persistence of GHTN for more than three months postpartum is consistent with a diagnosis of chronic hypertension.
      Figure thumbnail gr1
      Figure 1Gestational hypertension as a temporary diagnosis
      For clinicians who provide management for women with hypertension in pregnancy, several issues are of interest with respect to the importance of distinguishing between GHTN and PE. The first is the long-standing controversy of whether GHTN is an independent clinical entity or merely a mild or pre-onset form of PE. A second and more practical issue is determining the risk of progression of GHTN to PE. A third issue is quantifying the degree to which GHTN is associated with adverse pregnancy outcomes. Although GHTN is the most common form of hypertension in pregnancy,
      • Walker J.J.
      Pre-eclampsia.
      most researchers have focused their efforts on PE because of its implications for maternal–fetal health, whereas information about the implications of a diagnosis of GHTN is much more limited. Herein, we attempt to summarize the most up to date information available to address these important clinical questions.

      Is gestational hypertension an independent clinical entity or a “pre-preeclampsia” state?

      We will approach this question by comparing the epidemiologic, pathologic, pathogenetic, and hemodynamic characteristics of GHTN and PE.
      • Hauth J.C.
      • Ewell M.G.
      • Levine R.J.
      • Esterlitz J.R.
      • Sibai B.
      • Curet L.B.
      • et al.
      Pregnancy outcomes in healthy nulliparas who developed hypertension. Calcium for Preeclampsia Prevention Study Group.
      Several observations indicate that GHTN and PE have distinct epidemiologic features, including some differences in their underlying risk factors. In a large Swedish population-based study, several factors were common to the two conditions, whereas multiple pregnancy and diabetes mellitus were exclusively associated with PE.
      • Ros H.S.
      • Cnattingius S.
      • Lipworth L.
      Comparison of risk factors for preeclampsia and gestational hypertension in a population-based cohort study.
      A secondary analysis of the WHO Antenatal Care Trial, involving almost 40 000 women, had similar findings.
      • Villar J.
      • Carroli G.
      • Wojdyla D.
      • Abalos E.
      • Giordano D.
      • Ba’aqeel H.
      • et al.
      Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions?.
      While primiparity and maternal respiratory disease were associated only with PE, antepartum hemorrhage (OR 1.4; 95% CI 1.1 to 1.7) and a history of large for gestational age newborn (OR 1.7; 95% CI 1.3 to 2.2) were limited to women with GHTN.
      Several studies have addressed the risk of recurrence of GHTN and PE in a subsequent pregnancy. Overall, the risk of recurrence is higher in women with prior GHTN (20% to 47%) than in women with prior PE (5% to 10%).
      • Hargood J.L.
      • Brown M.A.
      Pregnancy-induced hypertension: recurrence rate in second pregnancies.
      • Dukler D.
      • Porath A.
      • Bashiri A.
      • Erez O.
      • Mazor M.
      Remote prognosis of primiparous women with preeclampsia.
      Furthermore, in a large retrospective study, women with prior GHTN were more likely to experience GHTN (26%) than PE (6%) in a subsequent pregnancy, whereas women with previous PE had a similar 6% risk of recurrence of either PE or GHTN.
      • Brown M.A.
      • Mackenzie C.
      • Dunsmuir W.
      • Roberts L.
      • Ikin K.
      • Matthews J.
      • et al.
      Can we predict recurrence of pre-eclampsia or gestational hypertension?.
      Only two studies comparing placental pathology in pregnancies complicated by GHTN versus PE have been published, and both identified differences in placental pathology between the two conditions. Correa et al.
      • Correa R.R.
      • Gilio D.B.
      • Cavellani C.L.
      • Paschoini M.C.
      • Oliveira F.A.
      • Peres L.C.
      • et al.
      Placental morphometrical and histopathology changes in the different clinical presentations of hypertensive syndromes in pregnancy.
      found that GHTN and PE had some placental pathologic features in common, but women with PE had placentas characterized by a higher number of syncytial knots and by differences in the size and distribution of fibrin deposits. In a more recent retrospective study of 150 women, placentas from women with PE were characterized by a trend towards higher rates of decidual vasculopathy (47% vs. 33%; P=0.08) and villous infarction (50% vs. 38%; P=0.1),
      • Maloney K.F.
      • Heller D.
      • Baergen R.N.
      Types of maternal hypertensive disease and their association with pathologic lesions and clinical factors.
      suggesting that placental ischemia is confined to PE.
      Vascular biology studies have suggested that there is a contrasting pathophysiology between PE and GHTN. Noori et al. compared endothelial dysfunction and angiogenic markers in women with GHTN and PE.
      • Noori M.
      • Donald A.E.
      • Angelakopoulou A.
      • Hingorani A.D.
      • Williams D.J.
      Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension.
      They followed 159 women from 10 weeks’ gestation to three months postpartum. Flow-mediated dilatation (a sonographic measure of vascular endothelial function) was abnormal only in those with PE; women with GHTN had flow-mediated dilatation that was similar to non-hypertensive control subjects. Similarly, maternal blood levels of the anti-angiogenic markers sFlt1 and sEng were elevated only in women with PE.
      • Noori M.
      • Donald A.E.
      • Angelakopoulou A.
      • Hingorani A.D.
      • Williams D.J.
      Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension.
      In concordance with these findings, Verlohren et al. reported that the ratio of the anti-angiogenic marker sFlt1 to the pro-angiogenic marker PlGF (sFlt1/PlGF) was significantly elevated in women with PE, but not in those with GHTN, again suggesting that only PE is characterized by an anti-angiogenic milieu.
      • Verlohren S.
      • Herraiz I.
      • Lapaire O.
      • Schlembach D.
      • Moertl M.
      • Zeisler H.
      • et al.
      The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients.
      Furthermore, in a prospective study of 110 pregnant women, levels of endothelial microparticles (associated with endothelial cell damage) were found to be significantly higher in women with PE but not GHTN.
      • Gonzalez-Quintero V.H.
      • Smarkusky L.P.
      • Jimenez J.J.
      • Mauro L.M.
      • Jy W.
      • Hortsman L.L.
      • et al.
      Elevated plasma endothelial microparticles: preeclampsia versus gestational hypertension.
      Khalil et al. compared the effect of treatment with α-methyldopa on the levels of angiogenic markers in women with GHTN and PE.
      • Khalil A.
      • Muttukrishna S.
      • Harrington K.
      • Jauniaux E.
      Effect of antihypertensive therapy with alpha methyldopa on levels of angiogenic factors in pregnancies with hypertensive disorders.
      They found that α-methyldopa treatment was associated with a significant reduction (50%) in sFlt1 and sEng levels in women with PE, but not in women with GHTN (whose levels were much lower). In a recent study, Sandrim et al. found differences in the polymorphism of vascular endothelial growth factor between women with GHTN and women with PE, raising the possibility of differences in the genetic predisposition for each.
      • Sandrim V.C.
      • Palei A.C.
      • Cavalli R.C.
      • Araújo F.M.
      • Ramos E.S.
      • Duarte G.
      • et al.
      Vascular endothelial growth factor genotypes and haplotypes are associated with pre-eclampsia but not with gestational hypertension.
      Another group found that the sensitivity of platelets to prostaglandin E1 was decreased only in women with PE, suggesting that platelet activation is a characteristic specific to PE and not GHTN.
      • Torres P.J.
      • Escolar G.
      • Palacio M.
      • Gratacos E.
      • Alonso P.L.
      • Ordinas A.
      Platelet sensitivity to prostaglandin E1 inhibition is reduced in pre-eclampsia but not in nonproteinuric gestational hypertension.
      In a recent meta-analysis of the use of antiplatelet agents for the prevention of PE, it was found that these agents decreased the risk of PE in either moderate- or high-risk women, while such a beneficial effect in the prevention of GHTN was observed only among high-risk women.
      • Duley L.
      • Henderson-Smart D.J.
      • Meher S.
      • King J.F.
      Antiplatelet agents for preventing pre-eclampsia and its complications.
      Collectively, these findings suggest that endothelial dysfunction and an imbalance between pro- and anti-angiogenic factors are characteristics specific for PE but not for GHTN.
      Pathophysiologic changes are different in women with PE and those with GHTN, including decreased maternal blood volume among the former.
      • Silver H.M.
      • Seebeck M.
      • Carlson R.
      Comparison of total blood volume in normal, preeclamptic, and nonproteinuric gestational hypertensive pregnancy by simultaneous measurement of red blood cell and plasma volumes.
      In addition, there is recent evidence that non-invasive hemodynamic measures, such as changes in cardiac output and peripheral vascular resistance, precede the onset of severe PE by several weeks in high-risk women.
      • Ohashi Y.
      • Ibrahim H.
      • Furtado L.
      • Kingdom J.
      • Carvalho J.C.
      Non-invasive hemodynamic assessment of non-pregnant, healthy pregnant and preeclamptic women using bioreactance. [corrected].

      Doherty A, Carvalho J, Drewlo S, Khuffash A, Downey K, Dodds M, et al. Altered hemodynamics and hyper-uricemia accompany an elevated sFlt-1/PlGF ratio prior to the onset of early severe preeclampsia. J Obstet Gynaecol Can. In Press.

      Such a tool may also be useful for predicting PE in the specific group of women with new onset of isolated hypertension in pregnancy, since the detection of increased total peripheral resistance and increased cardiac output in these cases may reflect the presence of early stage PE rather than GTHN.
      Another aspect to be considered is the long-term outcome following pregnancies complicated by GTHN or PE. Most of the studies conducted to date have been focused on the long-term risks of cardiovascular morbidity and mortality. Most of these studies have found that women with either GHTN or PE are at increased risk of chronic hypertension, ischemic heart disease, cerebrovascular disease, and venous thromboembolism, although the risk was higher for women with severe PE than for women with GHTN.
      • Bellamy L.
      • Casas J.P.
      • Hingorani A.D.
      • Williams D.J.
      Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.
      • Lykke J.A.
      • Langhoff-Roos J.
      • Sibai B.M.
      • Funai E.F.
      • Triche E.W.
      • Paidas M.J.
      Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother.
      • Chen C.W.
      • Jaffe I.Z.
      • Karumanchi S.A.
      Pre-eclampsia and cardiovascular disease.
      • Ray J.G.
      • Vermeulen M.J.
      • Schull M.J.
      • Redelmeier D.A.
      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
      One important limitation of many of these studies, most of which are based on coding diagnoses, is that a considerable proportion of women with GTHN may in fact have had undetected chronic hypertension.
      In summary, it appears that there are significant differences between PE and GHTN with respect to their epidemiologic, pathologic, pathogenetic, and hemodynamic characteristics. GHTN and PE seem to be two distinct entities. Nevertheless, some pregnant women who initially present with isolated HTN do progress to develop PE, reflected by subsequent development of proteinuria and/or laboratory evidence of HELLP syndrome. How can these two apparently conflicting observations be reconciled? One potential explanation is that women who present with isolated HTN in pregnancy are a heterogeneous group, comprising some with an early stage of PE who somehow delay the development of proteinuria, and others with GHTN, a distinct disorder representing a benign regulatory imbalance between systemic vascular tone and cardiac output (Figure 2). This concept is supported by a recent study in which the levels of pro- and anti-angiogenic markers in maternal blood were compared between three groups of patients: women with GHTN, women who initially presented with isolated HTN but later developed PE, and women who presented with PE.
      • Hirashima C.
      • Ohkuchi A.
      • Takahashi K.
      • Suzuki H.
      • Yoshida M.
      • Ohmaru T.
      • et al.
      Gestational hypertension as a subclinical preeclampsia in view of serum levels of angiogenesis-related factors.
      The group that presented with isolated HTN and progressed to PE had sFlt/PlGF ratios and sEng levels that were similar to those in women with PE; both groups had significantly higher levels than women who presented with isolated HTN but had a final diagnosis of GHTN.
      • Ray J.G.
      • Vermeulen M.J.
      • Schull M.J.
      • Redelmeier D.A.
      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
      Figure thumbnail gr2
      Figure 2Women with isolated hypertension as a heterogeneous group
      Such an explanation raises several interesting and practical questions with respect to this group of women who present with isolated hypertension in pregnancy. These include:
      • 1.
        among women presenting with isolated HTN, what proportion has GHTN and what proportion will ultimately develop PE?
      • 2.
        Is it possible to distinguish between these two subgroups at the initial finding of hypertension?
      • 3.
        In those women in whom isolated HTN represents an early stage of PE, what is the lag time before the overt expression of PE?

      What is the risk of progression from gestational hypertension to preeclampsia?

      Saudan et al. determined the risk of progression from GHTN to PE in 528 women who initially presented with mild GHTN
      • Saudan P.
      • Brown M.A.
      • Buddle M.L.
      • Jones M.
      Does gestational hypertension become pre-eclampsia?.
      : the overall rate of progression to PE was 17%. The risk of progression of GHTN to PE decreased in relation to the gestational age at which the diagnosis was made. GHTN diagnosed before 34 weeks progressed to PE more frequently (36% to 42%) than GHTN diagnosed after 34 weeks of gestation (7% to 20%) (P<0.01).
      • Saudan P.
      • Brown M.A.
      • Buddle M.L.
      • Jones M.
      Does gestational hypertension become pre-eclampsia?.
      The interpretation of these findings is limited by the fact that the true natural history of women who developed GHTN late in pregnancy cannot be determined because some of these women either had labour induced or delivered spontaneously before possible progression to PE. Therefore, delivery in women with a diagnosis of GHTN could have confounded the subsequent diagnosis of PE. Nevertheless, this study reflects what happens in clinical practice with respect to the risk of progression of GHTN to PE. In a similar study, Barton et al. found that the overall risk of progression to PE among 748 women who presented with mild GHTN at 24 to 35 weeks’ gestation was 46%, and of these approximately 10% progressed to severe PE.
      • Barton J.R.
      • O’Brien J.M.
      • Bergauer N.K.
      • Jacques D.L.
      • Sibai B.M.
      Mild gestational hypertension remote from term: progression and outcome.
      In agreement with the study of Saudan et al., Barton et al. found that the risk of progression to PE was considerably higher when GHTN was diagnosed before 34 weeks of gestation. The difference between these studies in the overall risk of progression to PE (46% vs. 17%) is the result of the different distribution of gestational age at the time of presentation with GHTN.
      Tabled 1Factors associated with progression from gestational hypertension to preeclampsia
      FactorCut-offSensitivity, %Specificity, %LR+LR-Reference
      Gestational age34 weeks85.060.02.130.25Saudan et al.
      • Saudan P.
      • Brown M.A.
      • Buddle M.L.
      • Jones M.
      Does gestational hypertension become pre-eclampsia?.
      24-hour systolic BP137 mmHg61.076.02.540.51Davis et al.
      • Davis G.K.
      • Mackenzie C.
      • Brown M.A.
      • Homer C.S.
      • Holt J.
      • McHugh L.
      • et al.
      Predicting transformation from gestational hypertension to preeclampsia in clinical practice: a possible role for 24 hour ambulatory blood pressure monitoring.
      Uric acid309 umol/L87.793.313.090.13Bellomo et al.
      • Bellomo G.
      • Venanzi S.
      • Saronio P.
      • Verdura C.
      • Narducci P.L.
      Prognostic significance of serum uric acid in women with gestational hypertension.
      Uterine artery RI0.5785.790.28.740.16Florio et al.
      • Florio P.
      • D’Aniello G.
      • Sabatini L.
      • Severi F.M.
      • Fineschi D.
      • Bocchi C.
      • et al.
      Factor II: C activity and uterine artery Doppler evaluation to improve the early prediction of pre-eclampsia on women with gestational hypertension.
      sFlt/PlGF ratio8572.994.012.150.29Rana et al.
      • Rana S.
      • Powe C.E.
      • Salahuddin S.
      • Verlohren S.
      • Perschel F.H.
      • Levine R.J.
      • et al.
      Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia.
      RI: resistance index; LR+: positive likelihood ratio; LR−: negative likelihood ratio.
      Several studies have tried to identify risk factors for progression to PE among women who initially presented with GHTN (Table). As described above, the most important factor associated with progression to PE is the earlier gestational age at the time of presentation with GHTN.
      • Saudan P.
      • Brown M.A.
      • Buddle M.L.
      • Jones M.
      Does gestational hypertension become pre-eclampsia?.
      • Barton J.R.
      • O’Brien J.M.
      • Bergauer N.K.
      • Jacques D.L.
      • Sibai B.M.
      Mild gestational hypertension remote from term: progression and outcome.
      In a recent study of 75 women with GHTN, Davis et al. found that, in addition to an earlier gestational age at presentation, a higher systolic BP on 24-hour ambulatory monitoring was also associated with progression to PE.
      • Davis G.K.
      • Mackenzie C.
      • Brown M.A.
      • Homer C.S.
      • Holt J.
      • McHugh L.
      • et al.
      Predicting transformation from gestational hypertension to preeclampsia in clinical practice: a possible role for 24 hour ambulatory blood pressure monitoring.
      In another recent prospective study of 206 women with GHTN, serum uric acid levels at the time of presentation were strongly associated with the risk of progression to PE; each increase in serum uric acid of 1 mg/dL (59.5 μmol/L) was associated with a seven-fold increase in the risk of progression to PE.
      • Bellomo G.
      • Venanzi S.
      • Saronio P.
      • Verdura C.
      • Narducci P.L.
      Prognostic significance of serum uric acid in women with gestational hypertension.
      Using ROC analysis, the optimal uric acid level cut-off for the prediction of progression to PE was 309 μmol/L, with a sensitivity of 87.7% and a specificity of 93.3% (Table).
      • Bellomo G.
      • Venanzi S.
      • Saronio P.
      • Verdura C.
      • Narducci P.L.
      Prognostic significance of serum uric acid in women with gestational hypertension.
      In a study of 65 women who presented with GHTN at 24 to 26 weeks of gestation, Florio et al. found that abnormal uterine artery Doppler velocimetry (using a resistance index cut-off of>0.57) was associated with positive- and negative-predictive values of 80% and 90%, respectively, for progression to PE (Table).
      • Florio P.
      • D’Aniello G.
      • Sabatini L.
      • Severi F.M.
      • Fineschi D.
      • Bocchi C.
      • et al.
      Factor II: C activity and uterine artery Doppler evaluation to improve the early prediction of pre-eclampsia on women with gestational hypertension.
      Finally, it appears that the circulating levels of angiogenic markers can also be used to identify women with isolated HTN who are at risk of progression to PE. In a prospective study of 616 women with suspected PE, the sFlt1/PlGF ratio was elevated only in women in whom the diagnosis of PE was confirmed within two weeks from the time of presentation, while the sFlt1/PlGF ratio in women in whom the final diagnosis was GHTN was similar to that of control subjects (Table).
      • Rana S.
      • Powe C.E.
      • Salahuddin S.
      • Verlohren S.
      • Perschel F.H.
      • Levine R.J.
      • et al.
      Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia.
      There are limited data with respect to the lag time for progression to PE in women with isolated HTN. In the study of Saudan et al.,
      • Saudan P.
      • Brown M.A.
      • Buddle M.L.
      • Jones M.
      Does gestational hypertension become pre-eclampsia?.
      of the 528 women who initially presented with mild GHTN, the subset eventually progressing to PE did so within a mean of one to five weeks from presentation. In addition, this lag period was inversely related to gestational age at diagnosis. Thus, of the women who presented with GHTN before 32 weeks’ gestation, almost 40% progressed to PE within a median time of approximately five weeks. Of the women who presented with GHTN between 32 and 35 weeks’ gestation, 25% progressed to PE within a median time of approximately two weeks. Finally, of the women who presented with GHTN at 36 weeks of gestation and beyond, approximately 10% progressed to PE within a median time of approximately one week (Figure 3).
      Figure thumbnail gr3
      Figure 3The relation between gestational age at presentation with gestational hypertension and the risk and lag time for progression to preeclampsia
      Data are derived from Saudan et al.
      • Saudan P.
      • Brown M.A.
      • Buddle M.L.
      • Jones M.
      Does gestational hypertension become pre-eclampsia?.
      In summary, the overall risk of progression to PE among women who present with isolated HTN in pregnancy ranges from 10% to 50% and is mainly related to gestational age at the time of presentation with isolated HTN (Figure 2, Figure 3). Other factors associated with risk of PE include higher BP values and higher serum uric acid levels at presentation, abnormal uterine artery Doppler velocimetry, and abnormal levels of angiogenic markers (e.g., elevated sFlt1/PlGF ratio) (Figure 2). Since these factors are derived from different studies, it is not possible to combine them into a single prediction model. Nevertheless, as an example it can be estimated that in women with GHTN beyond 34 weeks and normal uterine artery Doppler velocimetry, the risk of progression to PE would be only 0.7% compared with the overall risk of 17% (based on the negative likelihood ratios presented in Table). Similarly, the risk of progression to PE among women with GHTN, low levels of uric acid, and normal uterine artery Doppler velocimetry would be 0.4% (Table). Finally, it appears that women with isolated HTN who will eventually develop PE do so within a period of one to five weeks, and this lag is inversely related to gestational age at the time of presentation (Figure 3).

      Does gestational hypertension affect pregnancy outcome?

      While there is a considerable amount of data showing that PE is associated with an increased risk of adverse pregnancy outcomes,
      • Sibai B.M.
      • Spinnato J.A.
      • Watson D.L.
      • Hill G.A.
      • Anderson G.D.
      Pregnancy outcome in 303 cases with severe preeclampsia.
      the risks in women with GHTN are less clear.
      In a large multicentre study involving 2413 nulliparous women,
      • Knuist M.
      • Bonsel G.J.
      • Zondervan H.A.
      • Treffers P.E.
      Intensification of fetal and maternal surveillance in pregnant women with hypertensive disorders.
      the outcome of pregnancies complicated by either PE or GHTN was compared with that of uncomplicated pregnancies. Overall, the rate of perinatal complications including prematurity, low birth weight, intrauterine growth restriction, placental abruption, and perinatal mortality was higher only in the PE group, while the rate of these complications in the GHTN group was similar to that observed in uncomplicated pregnancies. Similarly, in another recent retrospective study of nulliparous women with GHTN or mild PE,
      • Cruz M.O.
      • Gao W.
      • Hibbard J.U.
      Obstetrical and perinatal outcomes among women with gestational hypertension, mild preeclampsia, and mild chronic hypertension.
      the rates of intrauterine growth restriction, placental abruption, and low five-minute Apgar score were higher only in the mild PE group and not in the GHTN group.
      Is the risk of adverse pregnancy outcome in pregnancies complicated by GHTN related to the severity of HTN? In a secondary analysis of a large randomized controlled trial on the use of calcium in the prevention of PE,
      • Hauth J.C.
      • Ewell M.G.
      • Levine R.J.
      • Esterlitz J.R.
      • Sibai B.
      • Curet L.B.
      • et al.
      Pregnancy outcomes in healthy nulliparas who developed hypertension. Calcium for Preeclampsia Prevention Study Group.
      Hauth et al.
      • Hauth J.C.
      • Ewell M.G.
      • Levine R.J.
      • Esterlitz J.R.
      • Sibai B.
      • Curet L.B.
      • et al.
      Pregnancy outcomes in healthy nulliparas who developed hypertension. Calcium for Preeclampsia Prevention Study Group.
      compared the outcomes of pregnancy in women with mild and severe HTN. While the outcomes in women with mild HTN were similar to those of uncomplicated pregnancies, women with severe HTN had significantly higher rates of several clinical complications, including placental abruption, fetal growth restriction, neonatal morbidity, and maternal renal dysfunction.
      • Walker J.J.
      Pre-eclampsia.
      The study of Hauth et al.
      • Hauth J.C.
      • Ewell M.G.
      • Levine R.J.
      • Esterlitz J.R.
      • Sibai B.
      • Curet L.B.
      • et al.
      Pregnancy outcomes in healthy nulliparas who developed hypertension. Calcium for Preeclampsia Prevention Study Group.
      supports the concept that the risk of adverse outcome is related to the severity of GHTN. However, it is unclear whether there is a critical threshold of HTN above which the risk of adverse pregnancy outcome is incurred, or if there is a continuous relation between the severity of HTN and the risk of pregnancy complications. In a large multicentre study from the United Kingdom, Steer et al. assessed the relationship between diastolic BP as a continuous variable and pregnancy outcome measures such as birth weight and perinatal mortality in otherwise uncomplicated pregnancies, excluding women with known chronic HTN or PE.
      • Steer P.J.
      • Little M.P.
      • Kold-Jensen T.
      • Chapple J.
      • Elliott P.
      Maternal blood pressure in pregnancy, birth weight, and perinatal mortality in first births: prospective study.
      These authors identified a continuous decrease in birth weight and a continuous increase in perinatal mortality in cases in which diastolic BP exceeded 90 mmHg. Thus, it appears that the risk of pregnancy complications in women with GHTN is related to the severity of the HTN in a continuous manner.

      SUMMARY

      The contemporary evidence suggests that GHTN and PE are distinct entities with different clinical characteristics. Therefore, women who present with isolated HTN in pregnancy are a heterogeneous group. Most of these women have true GHTN, but between 10% and 50% of women with isolated HTN will subsequently develop PE later in pregnancy. The proportion of women in the latter group (at risk of developing PE) is higher in women with lower gestational age at diagnosis, elevated systolic BP and serum uric acid levels at presentation, abnormal uterine artery Doppler velocimetry, elevated serum levels of anti-angiogenic markers such as sFlt-1, and reduced levels of the pro-angiogenic placental growth factor. Those who eventually progress to PE do so within a period of one to five weeks from the time of diagnosis with isolated HTN, and this lag period is inversely related to gestational age at the time of diagnosis with GHTN. Those women who have GHTN and do not progress to PE still have an increased risk for pregnancy complications, a risk that is proportional to the severity of GHTN. Although the recent recommendations regarding the definition of PE (i.e., that PE should also include cases without proteinuria if the hypertension is associated with end-organ involvement) may shed more light on the question at the centre of the current review, we believe that this is unlikely to be the case because most women with hypertension and significant end-organ disease have likely been given a diagnosis of PE even before these new recommendations.
      The practical implications of these findings are that women who present with isolated HTN in pregnancy should be evaluated for the risk of progression to PE, with those at highest risk being offered education about the symptoms and signs of PE and then monitored more closely. In the absence of risk factors for the development of PE, women can be reassured that they most likely have GHTN and consequently the risk of adverse maternal–infant outcomes is low (Figure 2).

      ACKNOWLEDGEMENTS

      Dr Kingdom is supported by the Rose Torno Chair at Mount Sinai Hospital. Dr Ray is supported by an Applied Research Chair in Reproductive and Child Health Services and Policy Research from the Canadian Institutes for Health Research.

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