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COMMENTARY

Gestational Hypertension and Preeclampsia:


Are They the Same Disease?
Nir Melamed, MD, MSc,1 Joel G. Ray, MD, MSC, FRCPC,2 Michelle Hladunewich, MD, MSc, FRCPC,3
Brian Cox, PhD,4 John C. Kingdom, MD, FRCSC1
Maternal-Fetal Medicine Division, Department of Obstetrics and Gynaecology at Mount Sinai Hospital, University of Toronto, Toronto ON
1

Department of Medicine at St. Michaels Hospital, University of Toronto, Toronto ON


2

Department of Medicine (Division of Nephrology) at Sunnybrook Health Sciences Centre, University of Toronto, Toronto ON
3

Department of Physiology, University of Toronto, Toronto ON


4

INTRODUCTION For clinicians who provide management for women with


hypertension in pregnancy, several issues are of interest with

P reeclampsia, complicating 5% to 8% of pregnancies,


has been traditionally defined by an elevated blood
pressure (over 140/90mmHg on at least 2 occasions at
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
least 6 hours apart) and proteinuria, at or beyond 20 weeks mild or pre-onset form of PE. A second and more practical
gestation.1,2 In 2013, the American College of Obstetricians issue is determining the risk of progression of GHTN to
and Gynecologists Task Force on Hypertension in PE. A third issue is quantifying the degree to which GHTN
Pregnancy recommended that the definition of PE is associated with adverse pregnancy outcomes. Although
should be extended to include cases without evidence GHTN is the most common form of hypertension in
of proteinuria, provided that the hypertension is pregnancy,5 most researchers have focused their efforts on
accompanied by evidence of end-organ involvement.2 PE PE because of its implications for maternalfetal health,
is associated with an increased risk of adverse pregnancy whereas information about the implications of a diagnosis
outcome, including prematurity, placental abruption, and of GHTN is much more limited. Herein, we attempt to
intrauterine growth restriction.3 In contrast, gestational summarize the most up to date information available to
hypertension is defined by an elevated BP at or beyond address these important clinical questions.
20 weeks gestation in the absence of proteinuria1,2 and
is considered to be a transient condition (Figure 1).1 The 1. Is gestational hypertension an independent
development of proteinuria later in pregnancy changes clinical entity or a pre-preeclampsia state?
the final diagnosis to preeclampsia. Otherwise, the final We will approach this question by comparing the
diagnosis is determined according to a re-evaluation of BP epidemiologic, pathologic, pathogenetic, and hemodynamic
recordings at approximately three months postpartum. For characteristics of GHTN and PE.6 Several observations
women who are then normotensive (the most common indicate that GHTN and PE have distinct epidemiologic
scenario4), the final diagnosis is transient HTN of features, including some differences in their underlying
pregnancy (Figure1). Persistence of GHTN for more than risk factors. In a large Swedish population-based study,
three months postpartum is consistent with a diagnosis of several factors were common to the two conditions,
chronic hypertension. whereas multiple pregnancy and diabetes mellitus were
exclusively associated with PE.7 A secondary analysis of
the WHO Antenatal Care Trial, involving almost 40000
Key Words: Gestational, hypertension, preeclampsia women, had similar findings.8 While primiparity and
Competing Interests: None declared.
maternal respiratory disease were associated only with PE,
Received on February 25, 2014
antepartum hemorrhage (OR 1.4; 95% CI 1.1 to 1.7) and
Accepted on March 31, 2014
J Obstet Gynaecol Can 2014;36(7):642647

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Gestational Hypertension and Preeclampsia: Are They the Same Disease?

a history of large for gestational age newborn (OR 1.7; milieu.15 Furthermore, in a prospective study of 110 pregnant
95% CI 1.3 to 2.2) were limited to women with GHTN. women, levels of endothelial microparticles (associated with
endothelial cell damage) were found to be significantly higher
Several studies have addressed the risk of recurrence of in women with PE but not GHTN.16 Khalil et al. compared
GHTN and PE in a subsequent pregnancy. Overall, the risk the effect of treatment with -methyldopa on the levels of
of recurrence is higher in women with prior GHTN (20% angiogenic markers in women with GHTN and PE.17 They
to 47%) than in women with prior PE (5% to 10%).9,10
found that -methyldopa treatment was associated with a
Furthermore, in a large retrospective study, women with
significant reduction (50%) in sFlt1 and sEng levels in women
prior GHTN were more likely to experience GHTN (26%)
with PE, but not in women with GHTN (whose levels were
than PE (6%) in a subsequent pregnancy, whereas women
much lower). In a recent study, Sandrim et al. found differences
with previous PE had a similar 6% risk of recurrence of
in the polymorphism of vascular endothelial growth factor
either PE or GHTN.11
between women with GHTN and women with PE, raising
Only two studies comparing placental pathology in the possibility of differences in the genetic predisposition for
pregnancies complicated by GHTN versus PE have been each.18 Another group found that the sensitivity of platelets
published, and both identified differences in placental to prostaglandin E1 was decreased only in women with PE,
pathology between the two conditions. Correa et al.12 found suggesting that platelet activation is a characteristic specific
that GHTN and PE had some placental pathologic features to PE and not GHTN.19 In a recent meta-analysis of the
in common, but women with PE had placentas characterized use of antiplatelet agents for the prevention of PE, it was
by a higher number of syncytial knots and by differences in found that these agents decreased the risk of PE in either
the size and distribution of fibrin deposits. In a more recent moderate- or high-risk women, while such a beneficial effect
retrospective study of 150 women, placentas from women in the prevention of GHTN was observed only among
with PE were characterized by a trend towards higher rates high-risk women.20 Collectively, these findings suggest that
of decidual vasculopathy (47% vs. 33%; P=0.08) and endothelial dysfunction and an imbalance between pro- and
villous infarction (50% vs. 38%; P=0.1),13 suggesting that anti-angiogenic factors are characteristics specific for PE but
placental ischemia is confined to PE. not for GHTN.
Vascular biology studies have suggested that there is a Pathophysiologic changes are different in women with PE
contrasting pathophysiology between PE and GHTN. Noori and those with GHTN, including decreased maternal blood
et al. compared endothelial dysfunction and angiogenic volume among the former.21 In addition, there is recent
markers in women with GHTN and PE.14 They followed 159 evidence that non-invasive hemodynamic measures, such as
women from 10 weeks gestation to three months postpartum. changes in cardiac output and peripheral vascular resistance,
Flow-mediated dilatation (a sonographic measure of vascular precede the onset of severe PE by several weeks in high-risk
endothelial function) was abnormal only in those with PE; women.22,23 Such a tool may also be useful for predicting PE
women with GHTN had flow-mediated dilatation that in the specific group of women with new onset of isolated
was similar to non-hypertensive control subjects. Similarly, hypertension in pregnancy, since the detection of increased
maternal blood levels of the anti-angiogenic markers sFlt1 and total peripheral resistance and increased cardiac output in
sEng were elevated only in women with PE.14 In concordance these cases may reflect the presence of early stage PE rather
with these findings, Verlohren et al. reported that the ratio than GTHN.
of the anti-angiogenic marker sFlt1 to the pro-angiogenic
marker PlGF (sFlt1/PlGF) was significantly elevated in Another aspect to be considered is the long-term outcome
women with PE, but not in those with GHTN, again following pregnancies complicated by GTHN or PE.
suggesting that only PE is characterized by an anti-angiogenic 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
ABBREVIATIONS
with either GHTN or PE are at increased risk of chronic
BP blood pressure
hypertension, ischemic heart disease, cerebrovascular
GHTN gestational hypertension
disease, and venous thromboembolism, although the risk
HTN hypertension was higher for women with severe PE than for women with
PE preeclampsia GHTN.2427 One important limitation of many of these
PlGF placental growth factor studies, most of which are based on coding diagnoses, is
sEng soluble endoglin that a considerable proportion of women with GTHN
sFlt soluble fms-like tyrosine kinase-1 may in fact have had undetected chronic hypertension.

JULY JOGC JUILLET 2014 l 643


Commentary

Figure 1. Gestational hypertension as a temporary In summary, it appears that there are significant
diagnosis 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
Figure 2. Women with isolated hypertension as a
heterogeneous group
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.28 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.27

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?
Figure 3. The relation between gestational age at 3. In those women in whom isolated HTN represents an
presentation with gestational hypertension and the
early stage of PE, what is the lag time before the overt
risk and lag time for progression to preeclampsia
expression of PE?

2. 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 GHTN29: 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).29 The
interpretation of these findings is limited by the fact that
the true natural history of women who developed GHTN
Data are derived from Saudan et al.29 late in pregnancy cannot be determined because some

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Gestational Hypertension and Preeclampsia: Are They the Same Disease?

Factors associated with progression from gestational hypertension to preeclampsia


Factor Cut-off Sensitivity, % Specificity, % LR+ LR- Reference
Gestational age 34 weeks 85.0 60.0 2.13 0.25 Saudan et al.29
24-hour systolic BP 137 mmHg 61.0 76.0 2.54 0.51 Davis et al.31
Uric acid 309 umol/L 87.7 93.3 13.09 0.13 Bellomo et al.32
Uterine artery RI 0.57 85.7 90.2 8.74 0.16 Florio et al.33
sFlt/PlGF ratio 85 72.9 94.0 12.15 0.29 Rana et al.34
RI: resistance index; LR+: positive likelihood ratio; LR: negative likelihood ratio.

of these women either had labour induced or delivered circulating levels of angiogenic markers can also be used
spontaneously before possible progression to PE. to identify women with isolated HTN who are at risk of
Therefore, delivery in women with a diagnosis of GHTN progression to PE. In a prospective study of 616 women
could have confounded the subsequent diagnosis of PE. with suspected PE, the sFlt1/PlGF ratio was elevated only
Nevertheless, this study reflects what happens in clinical in women in whom the diagnosis of PE was confirmed
practice with respect to the risk of progression of GHTN within two weeks from the time of presentation, while the
to PE. In a similar study, Barton et al. found that the sFlt1/PlGF ratio in women in whom the final diagnosis
overall risk of progression to PE among 748 women who was GHTN was similar to that of control subjects (Table).34
presented with mild GHTN at 24 to 35 weeks gestation
was 46%, and of these approximately 10% progressed to There are limited data with respect to the lag time for
severe PE.30 In agreement with the study of Saudan et al., progression to PE in women with isolated HTN. In the
Barton et al. found that the risk of progression to PE was study of Saudan et al.,29 of the 528 women who initially
considerably higher when GHTN was diagnosed before 34 presented with mild GHTN, the subset eventually
weeks of gestation. The difference between these studies progressing to PE did so within a mean of one to five
in the overall risk of progression to PE (46% vs. 17%) is weeks from presentation. In addition, this lag period was
the result of the different distribution of gestational age at inversely related to gestational age at diagnosis. Thus,
the time of presentation with GHTN. of the women who presented with GHTN before 32
weeks gestation, almost 40% progressed to PE within a
Several studies have tried to identify risk factors for median time of approximately five weeks. Of the women
progression to PE among women who initially presented who presented with GHTN between 32 and 35 weeks
with GHTN (Table). As described above, the most gestation, 25% progressed to PE within a median time
important factor associated with progression to PE is of approximately two weeks. Finally, of the women who
the earlier gestational age at the time of presentation presented with GHTN at 36 weeks of gestation and
with GHTN.29,30 In a recent study of 75 women with beyond, approximately 10% progressed to PE within a
GHTN, Davis et al. found that, in addition to an earlier median time of approximately one week (Figure 3).
gestational age at presentation, a higher systolic BP on
24-hour ambulatory monitoring was also associated with In summary, the overall risk of progression to PE among
progression to PE.31 In another recent prospective study women who present with isolated HTN in pregnancy
of 206 women with GHTN, serum uric acid levels at the ranges from 10% to 50% and is mainly related to
time of presentation were strongly associated with the risk gestational age at the time of presentation with isolated
of progression to PE; each increase in serum uric acid HTN (Figures 2 & 3). Other factors associated with
of 1 mg/dL (59.5 mol/L) was associated with a seven- risk of PE include higher BP values and higher serum
fold increase in the risk of progression to PE.32 Using uric acid levels at presentation, abnormal uterine artery
ROC analysis, the optimal uric acid level cut-off for the Doppler velocimetry, and abnormal levels of angiogenic
prediction of progression to PE was 309 mol/L, with a markers (e.g., elevated sFlt1/PlGF ratio) (Figure 2). Since
sensitivity of 87.7% and a specificity of 93.3% (Table).32 these factors are derived from different studies, it is not
In a study of 65 women who presented with GHTN at 24 possible to combine them into a single prediction model.
to 26 weeks of gestation, Florio et al. found that abnormal Nevertheless, as an example it can be estimated that in
uterine artery Doppler velocimetry (using a resistance women with GHTN beyond 34 weeks and normal uterine
index cut-off of >0.57) was associated with positive- and artery Doppler velocimetry, the risk of progression to PE
negative-predictive values of 80% and 90%, respectively, would be only 0.7% compared with the overall risk of
for progression to PE (Table).33 Finally, it appears that the 17% (based on the negative likelihood ratios presented

JULY JOGC JUILLET 2014 l 645


Commentary

in Table). Similarly, the risk of progression to PE among a continuous decrease in birth weight and a continuous
women with GHTN, low levels of uric acid, and normal increase in perinatal mortality in cases in which diastolic
uterine artery Doppler velocimetry would be 0.4% (Table). BP exceeded 90 mmHg. Thus, it appears that the risk of
Finally, it appears that women with isolated HTN who will pregnancy complications in women with GHTN is related
eventually develop PE do so within a period of one to five to the severity of the HTN in a continuous manner.
weeks, and this lag is inversely related to gestational age at
the time of presentation (Figure 3). SUMMARY

3. Does gestational hypertension affect The contemporary evidence suggests that GHTN and PE
pregnancy outcome? are distinct entities with different clinical characteristics.
While there is a considerable amount of data showing that Therefore, women who present with isolated HTN in
PE is associated with an increased risk of adverse pregnancy pregnancy are a heterogeneous group. Most of these women
outcomes,35 the risks in women with GHTN are less clear. have true GHTN, but between 10% and 50% of women with
isolated HTN will subsequently develop PE later in pregnancy.
In a large multicentre study involving 2413 nulliparous The proportion of women in the latter group (at risk of
women,36 the outcome of pregnancies complicated by either developing PE) is higher in women with lower gestational age
PE or GHTN was compared with that of uncomplicated at diagnosis, elevated systolic BP and serum uric acid levels
pregnancies. Overall, the rate of perinatal complications at presentation, abnormal uterine artery Doppler velocimetry,
including prematurity, low birth weight, intrauterine elevated serum levels of anti-angiogenic markers such as sFlt-
growth restriction, placental abruption, and perinatal 1, and reduced levels of the pro-angiogenic placental growth
mortality was higher only in the PE group, while the rate factor. Those who eventually progress to PE do so within
of these complications in the GHTN group was similar to a period of one to five weeks from the time of diagnosis
that observed in uncomplicated pregnancies. Similarly, in with isolated HTN, and this lag period is inversely related to
another recent retrospective study of nulliparous women gestational age at the time of diagnosis with GHTN. Those
with GHTN or mild PE,3 the rates of intrauterine growth women who have GHTN and do not progress to PE still
restriction, placental abruption, and low five-minute Apgar have an increased risk for pregnancy complications, a risk
score were higher only in the mild PE group and not in the that is proportional to the severity of GHTN. Although the
GHTN group. recent recommendations regarding the definition of PE (i.e.,
that PE should also include cases without proteinuria if the
Is the risk of adverse pregnancy outcome in pregnancies hypertension is associated with end-organ involvement) may
complicated by GHTN related to the severity of HTN? In shed more light on the question at the centre of the current
a secondary analysis of a large randomized controlled trial review, we believe that this is unlikely to be the case because
on the use of calcium in the prevention of PE,6 Hauth most women with hypertension and significant end-organ
et al.6 compared the outcomes of pregnancy in women disease have likely been given a diagnosis of PE even before
with mild and severe HTN. While the outcomes in women these new recommendations.
with mild HTN were similar to those of uncomplicated
pregnancies, women with severe HTN had significantly The practical implications of these findings are that
higher rates of several clinical complications, including women who present with isolated HTN in pregnancy
placental abruption, fetal growth restriction, neonatal should be evaluated for the risk of progression to PE,
morbidity, and maternal renal dysfunction.5 with those at highest risk being offered education about
the symptoms and signs of PE and then monitored more
The study of Hauth et al.6 supports the concept that the closely. In the absence of risk factors for the development
risk of adverse outcome is related to the severity of GHTN. of PE, women can be reassured that they most likely have
However, it is unclear whether there is a critical threshold of GHTN and consequently the risk of adverse maternal
HTN above which the risk of adverse pregnancy outcome infant outcomes is low (Figure 2).
is incurred, or if there is a continuous relation between the
severity of HTN and the risk of pregnancy complications. ACKNOWLEDGEMENTS
In a large multicentre study from the United Kingdom,
Steer et al. assessed the relationship between diastolic BP Dr Kingdom is supported by the Rose Torno Chair at
as a continuous variable and pregnancy outcome measures Mount Sinai Hospital. Dr Ray is supported by an Applied
such as birth weight and perinatal mortality in otherwise Research Chair in Reproductive and Child Health Services
uncomplicated pregnancies, excluding women with and Policy Research from the Canadian Institutes for
known chronic HTN or PE.37 These authors identified Health Research.

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Gestational Hypertension and Preeclampsia: Are They the Same Disease?

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