Professional Documents
Culture Documents
Introduction
Current management of pre-eclampsia consists of con- syndrome.23 This Review discusses the potential clinical
trolling maternal hypertension, prevention of seizures value of biomarkers, focusing on the use of angiogenic
and timely delivery of the fetus. Although understanding and antiangiogenic factors for prediction and monitoring
of the pathophysiology of this important obstetric syn- of pre-eclampsia. Current management, possible inter-
drome remains elusive,1 efforts are underway to identify ventions and long-term consequences of pre-eclampsia
biomarkers that can predict pre-eclampsia as early as the are also discussed.
first trimester.2 Subgroup findings from meta-analyses
and small randomized controlled trials of aspirin3–6 and Biomarkers that predict pre-eclampsia
combinations of nitric oxide donors (l-arginine) Considerable efforts have been made to identify bio-
and antioxidants (vitamins E and C)5 for the prevention of markers that can predict pre-eclampsia as early as the
pre-eclampsia are promising. However, these preventive first trimester,2 as some evidence suggests that patients
strategies remain investigational. An imbalance between could benefit from early (<16 weeks of gestation) admin-
angiogenic and antiangiogenic factors has emerged as an istration of aspirin or combinations of nitric oxide
important pathogenetic mechanism in pre-eclampsia.7–11 donors and antioxidants.3–6 Risk assessment of patients
Perinatology Research The levels of these proteins in maternal blood, especi with pre-eclampsia using biochemical markers25,26 (such
Branch, Program for ally when measured in patients suspected of having as pregnancy-associated plasma protein A [PAPP‑A],27
Perinatal Research and
Obstetrics, Division of
pre-eclampsia <34 weeks of gestation, have prognostic inhibin A, activin A, α‑fetoprotein [AFP] and free
Intramural Research, value in identifying patients who will develop maternal choriogonadotropin subunit β [CG‑β] 28,29), placen-
Eunice Kennedy Shriver and/or perinatal complications.12–16 Importantly, several tal morphology and/or perfusion30 and uterine artery
National Institute of
Child Health and potential interventions could ameliorate an imbalance Doppler velocimetry (UtADV) in the first or second
Human Development, between angiogenic and antiangiogenic factors17–22 and, trimesters (Figure 1), 31 has not provided encourag-
NIH, 31 Center Drive,
Bethesda, MD 20892,
hence, might provide opportunities to improve maternal ing results. Plasma levels of placental protein 13 (PP13,
USA and 3990 John R and/or perinatal outcomes. Patients with pre-eclampsia also known as galactoside-binding soluble lectin 13 or
Street, Detroit, are at increased risk of long-term complications, such as galectin‑13) in the first trimester were predictive of early
MI 48201, USA (T.C.,
P.C., S.J.K., L.Y., R.R.). cardiovascular disease,23 renal disease24 and metabolic pre-eclampsia in two studies,32,33 but these findings were
not subsequently corroborated.27,34,35
Correspondence to: T.C.
tchaiwor@ Competing interests Combinations of biomarkers generally have better diag-
med.wayne.edu The authors declare no competing interests. nostic performance than single biomarkers in predicting
a b 0.11
0.11
0.11
m/s m/s
0.8
0.6 1.0
0.4
0.2 0.5
0 0
PW: 2.5 MHz θ = 12° PW: 2.5 MHz θ = 43°
Figure 1 | Uterine artery Doppler velocimetry findings in the second trimester of pregnancy. a | Normal findings.
b | Abnormal findings, indicated by either the presence of bilateral uterine artery early diastolic notches (arrows) or a mean
pulsatility index (calculated as [peak systolic velocity – end diastolic velocity]/time averaged velocity, averaged across both
uterine arteries), above the 95th percentile for gestational age.
Research in this area focuses not only on the identifi- assessing biomarkers of angiogenesis might identify most
cation of biomarkers that can predict pre-eclampsia, but patients with pre-eclampsia, especially the forms of this
also on predictors of adverse perinatal outcomes after disorder resulting from placental abnormalities (such as
diagnosis of pre-eclampsia. For example, the full PIERS early pre-eclampsia), which have a major adverse effect
(pre-eclampsia integrated estimate of risk) model was on perinatal outcomes.61,67,70 Indeed, our research group
developed in 2011 to predict fatal or life-threatening has observed that ~80–90% of women with preterm
maternal complications of pre-eclampsia within 48 h of pre-eclampsia and 40–50% of those with pre-eclampsia
admission, using standard clinical and laboratory infor- at term have abnormal plasma PlGF:sVEGFR‑1 or
mation.57 This model was validated using a threshold PlGF:soluble endoglin ratios, (defined as being below
of ≥10% predicted probability to define a positive test, the tenth percentile for gestational age of uncompli-
and predictive variables obtained within 6 h and 24 h of cated pregnancies) within the 7 days prior to delivery
admission. The full PIERS model identified 44% and (Chaiworapongsa et al., unpublished work).
57% of the women who would later develop adverse
outcomes at these two respective time points, resulting Clinical value of biomarker assessment
in positive predictive values (PPVs) of 24% and 26%.58 Potential interventions exist to ameliorate an imbalance
An imbalance between angiogenic and antiangio- between angiogenic and antiangiogenic factors, and
genic factors has emerged as an important pathogenetic hence provide opportunities to improve maternal and/
mechanism in pre-eclampsia,59,60 and evidence indi- or perinatal outcomes in patients with pre-eclampsia.
cates that maternal plasma levels of these factors can Studies evaluating the potential clinical utility of meas-
identify the majority of patients who will develop early uring angiogenic and antiangiogenic factors in pre-
pre-eclampsia.61,62 Moreover, levels of these biomarkers eclampsia have focused on three scenarios: firstly, triage of
correlate with disease severity 59,60,63,64 and have prognostic symptomatic patients suspected of having pre-eclampsia;
value in identifying women who subsequently develop secondly, differentiation of pre-eclampsia from exacerba-
maternal and/or perinatal complications, especially in tions of pre-existing medical conditions; and thirdly, risk
patients suspected of having pre-eclampsia at <34 weeks assessment in asymptomatic women.
of gestation.12–15,65,66
An emerging debate is whether pre-eclampsia is a Triage of women with suspected pre-eclampsia
homogeneous disease.67 Critics argue that assessing a few Patients with pre-eclampsia can present with some, but
biomarkers involved in only one pathway of disease (angio- not all, of the symptoms of pre-eclampsia and/or features
genesis) is unlikely to predict or detect all women with pre- similar to other conditions. Accurate diagnosis of pre-
eclampsia, a disease that has multiple aetiologies.68 Some eclampsia by a combination of clinical symptoms and
investigators counter this argument with the proposal that biomarkers might improve the management of patients
the forms of pre-eclampsia associated with an angiogenic who are at risk of adverse outcomes. Indeed, determina-
imbalance are those that result in adverse outcomes.67,69 tion of plasma levels of angiogenic and antiangiogenic
Furthermore, reported evidence of heterogeneity in the lit- factors in combination with assessment of clinical vari-
erature might be largely due to misclassification of other ables, in patients with suspected pre-eclampsia who
diseases as pre-eclampsia, as the criteria for its diagnosis present before 34–35 weeks of gestation, improves the
(such as hypertension and proteinuria) are nonspecific.67 detection of patients who are likely to require preterm
However, several questions should be answered prior to delivery or develop adverse outcomes within 2 weeks,
concluding that pre-eclampsia is a homogenous disease. compared with standard evaluations based on clinical
For example, the criteria used to define angiogenic imbal- factors or standard laboratory tests for pre-eclampsia
ance (including fixed cut-offs derived from receiver oper- alone.12–15,65,66,71 Moreover, implementation of this strategy
ating characteristic [ROC] curve analyses, multiples of reduced costs and usage of health-care resources, accord-
median values or percentile distributions of analyte levels) ing to a cost-effectiveness analysis.72 Larger studies, using
have yet to be agreed. Consequently, it is difficult to ascer- appropriate algorithms for management of patients with
tain what proportion of patients with pre-eclampsia truly suspected pre-eclampsia according to the results of these
have an angiogenic imbalance. Most women with preterm biomarkers, are urgently needed.
pre-eclampsia have abnormal profiles of angiogenic and/
or antiangiogenic factors, but this is not the case in women Differentiation from pre-existing conditions
with pre-eclampsia at term (≥37 weeks of gestation).64,61 The diagnosis of pre-eclampsia in patients with chronic
It is uncertain that patients who do not have abnormal kidney disease (CKD) is challenging, especially in
ratios of angiogenic to antiangiogenic factors at term have patients who have proteinuria or high blood pressure
been misclassified as having pre-eclampsia. Most patients before 20 weeks of gestation. Indeed, in nonpregnant
with pre-eclampsia are diagnosed at term, and eclampsia women, higher plasma levels of sVEGFR‑1 have been
is also not uncommon after 37 weeks gestation. Moreover, observed in patients with CKD than in healthy con-
what causes the antiangiogenic state in the first place trols.73 This elevation correlates with serum levels of
remains unclear. von Willebrand factor (a marker of endothelial dysfunc-
Our view is that if an imbalance between angio- tion), suggesting that sVEGFR‑1 might be associated with
genic and antiangiogenic factors represents the termi- endothelial dysfunction and future cardiovascular risk in
nal pathway of multiple aetiologies, it is possible that these patients.74
Pre-eclampsia
Evaluation
Maternal assessment
■ Clinical assessment of symptoms and signs that might indicate involvement of multiple organ
systems (such as severe headache, epigastric or right quadrant pain and visual disturbances)
■ Blood pressure
■ Proteinuria
■ Platelet counts, hepatic enzymes (aspartate aminotransferase and alanine aminotransferase),
renal function (BUN, sCr and creatinine clearance)
Fetal assessment
■ Nonstress test or biophysical profile when fetus is viable
■ Ultrasound biometry for fetal growth, amniotic fluid volume and Doppler interrogation of the umbilical arteries
Gestational age Gestational age Gestational age 24–34 weeks Gestational age ≥34 weeks
≥37 weeks <37 weeks
Figure 2 | Management of pre-eclampsia. Management of pre-eclampsia depends on the severity of the disease (with or
without severe features) and gestational age at diagnosis.134 For pre-eclampsia without severe features, delivery is
recommended at term (≥37 weeks). For pre-eclampsia with severe features, delivery is recommended if gestational age is
at ≥34 weeks. Before 34 weeks of gestation, the decision to deliver should be balanced between risk of maternal or fetal
complications and benefit of continuing pregnancy to fetal maturity. *Patients with gestational hypertension or mild pre-
eclampsia after 36 weeks who undergo induction of labour have a reduced rate of adverse maternal outcomes (especially the
development of severe hypertension), lower incidence of caesarean delivery and a better quality of life than those who had
expectant management.130–133 If preterm induction of labour is contemplated, steroids are administered between 24 weeks and
34 weeks of gestation to improve fetal lung maturity. Magnesium sulfate is administered during labour and the first 24 h after
delivery for seizure prophylaxis.104 Abbreviations: BUN, blood urea nitrogen; CBC, complete blood count; GA, gestational age;
HELLP, haemolysis, elevated liver transaminases, low platelets; sCr, serum creatinine.
Control of blood pressure should be achieved before not recommended for the management of severe hyper-
delivery, even in urgent circumstances, such as eclamp- tension during pregnancy because nimodepine and ket-
sia;98 endotracheal intubation for a caesarean delivery anserin were associated with more persistent high blood
increases maternal blood pressure, sometimes to severe pressure than hydralazine and diazoxide was associated
levels.98 Hydralazine, labetalol and nifedipine are the with a higher risk of hypotension than labetalol.100 Sodium
three most commonly used agents in the acute setting nitroprusside is reserved only for the rare patients in
(Table 1).99 Nimodepine, ketanserin and diazoxide were whom hypertension is refractory to other agents, because
of concerns related to cyanide and thiocyanate toxicity in sulfate (Box 1),102 which reduces the rate of seizures by
the mother and baby, and potential worsening of cerebral 52% when compared to diazepam, and by 67% when
oedema in the mother.93 compared with phenytoin.103 Clinicians generally agree
that magnesium sulfate should be administered to
Prevention of seizures patients with pre-eclampsia who have severe features
The development of seizures and/or coma is a charac- (number needed to treat [NNT] 63–71).104 However,
teristic of eclampsia, and increases the risk of maternal whether this agent is required in the management of pre-
and perinatal death, as well as other complications (such eclampsia without severe features (NNT 109–400) is cur-
as disseminated intravascular coagulation, pulmonary rently unknown.104 Treatment with magnesium sulfate is
oedema, acute renal failure and cardiopulmonary arrest). associated with a reduced rate of eclampsia (RR 0.4) and
The onset of eclampsia can be antepartum (38–53%), placental abruption (RR 0.64), but an increased rate of
during labour (18–36%) or postpartum (11–44%).101 caesarean delivery (RR 1.05) compared with placebo or
Although most patients with postpartum eclampsia no anticonvulsant.105
present within 48 h after delivery, some can occur as late
as 23 days postpartum.101 Prevention of pre-eclampsia
The agent of choice for the prevention of seizures or A broad range of interventions has been tested for the pre-
recurrent seizure episodes in eclampsia is magnesium vention of pre-eclampsia, including low-salt diets, diuret-
ics, fish oil, calcium supplementation, antioxidants, aspirin
and heparin.106 However, most of these interventions have
Box 1 | Use of magnesium sulfate for seizure prophylaxis in pre-eclampsia not been proven effective.
Continuous intravenous infusion
■■ Loading dose of magnesium sulfate (4–6 g administered over 15–20 min) Antiplatelet agents
■■ Maintenance infusion with 1–2 g/h An imbalance between prostacyclin and thromboxane has
■■ Maintain magnesium sulfate concentration between 480 mg/l and 840 mg/l
been proposed to be one of the mechanisms mediating
■■ Monitor urinary output and if <25–30 ml over 2 consecutive hours, oliguria
is diagnosed; fluid status and magnesium level should be assessed and
pre-eclampsia;107 thus, antiplatelet agents (in particular,
magnesium infusion should be decreased or discontinued aspirin, which blocks platelet production of thrombox-
■■ Monitor magnesium toxicity by combination of assessment of deep tendon ane B2)108 have been extensively tested in randomized
reflexes and respiratory rate clinical trials to prevent pre-eclampsia. In a multicentre
■■ Discontinue infusion 24 h after delivery randomized clinical trial of low-dose aspirin for the pre-
Intermittent intramuscular injection (when intravenous administration is not possible) vention and treatment of pre-eclampsia in 9,364 pregnant
■■ 20% magnesium sulfate solution (4 g intravenously at rate not exceeding 1 g/min) women, the use of aspirin was associated with a non
■■ 50% magnesium sulfate solution (10 g, 5 g injected deeply in the upper outer significant reduction (12%) in the incidence of protein
quadrant of both buttocks). If convulsions persist after 15 min, give up to 20% uric pre-eclampsia.109 This treatment had no significant
solution of magnesium sulfate (2 g) intravenously at a rate not exceeding 1 g/min
effect on the incidence of intrauterine growth restriction,
■■ Every 4 h thereafter give 50% magnesium sulfate solution (5 g) injected deeply
in the upper outer quadrant of alternate buttocks, but only after confirming that
stillbirth or neonatal death. Aspirin did, however, signifi-
the patellar reflex is present, respiration is not depressed and urinary output cantly reduce the likelihood of preterm delivery: 19.7%
in the previous 4 h exceeds 100 ml in patients receiving aspirin versus 22.2% in controls, an
■■ Discontinue treatment 24 h after delivery absolute reduction of 2.5 events per 100 women treated
Adverse effects (P = 0.003).109 Subsequently, a meta-analysis of data from
■■ Flushing, nausea and vomiting, muscle weakness, thirst, headache, drowsiness, 32,217 women showed that patients receiving aspirin for
confusion and respiratory depression the prevention of pre-eclampsia had a significant (10%)
Adapted with permission obtained from Chesley’s Hypertensive Disorders in Pregnancy, reduction in the incidence of pre-eclampsia, preterm
Lindheimer, M. D. et al. (eds) © Elsevier (2009).
birth (<34 weeks of gestation) and a composite of serious
adverse pregnancy outcomes (pre-eclampsia, small for production of PlGF, improving endothelial function,
gestational age infant, fetal death or maternal death).3 upregulating haeme oxygenase 1, decreasing oxidative
In another meta-analysis, the incidence of early pre- stress or inflammation and inhibiting complement as
eclampsia was reduced by 50% (RR 0.47, 95% CI 0.34– well as tissue factor activation.120 Statins might, therefore,
0.65) in women considered to be at risk of pre-eclampsia represent a suitable intervention for patients at risk of pre-
owing to a history of pre-eclampsia or abnormal UtADV eclampsia or those with an imbalance between angiogenic
findings, who started taking low-dose aspirin ≤16 weeks and antiangiogenic factors. Pravastatin (as opposed to
of gestation. 4 Expanded meta-analyses have confirmed other statins with lipophilic properties) is a water-soluble
these findings, and also suggest that this intervention agent that crosses the placenta slowly and, consequently,
is associated with a decrease in the rate of severe pre- might have fewer adverse effects for the fetus than do the
eclampsia.6,110,111 However, these findings were obtained lipophilic statins.121 The reported congenital anomalies
in subgroup analyses, and remain to be confirmed by of statins include isolated anomalies, such as central
randomized controlled trials. nervous system or limb defects and the VACTERL associ
ation.122 However, abnormal pregnancy outcomes were
Antioxidants not reported following exposure to pravastatin or fluva
Although oxidative stress has been implicated in the statin.122 In an experiment conducted in a dually perfused
pathophysiology of pre-eclampsia, a meta-analysis of at-term human placental lobule, 14% of pravastatin was
randomized controlled trials of vitamins C and E failed retained in placental tissue, 68% remained in the mater-
to show a beneficial effect for preventing pre-eclamp- nal circulation and only 18% was transferred to the fetal
sia and might increase risk of gestational hypertension circulation.123 These favourable findings support the use
and prelabour rupture of membranes.112 However, pre- of pravastatin during pregnancy.
eclampsia was reduced by 63% in patients considered to Other proposed therapeutic interventions to reverse
be at risk of developing the condition (owing to a per- an antiangiogenic state in pregnant women at risk of pre-
sonal or family history of pre-eclampsia) who received eclampsia include the administration of VEGF12117,18,21
l‑arginine (5.4 g daily) in combination with vitamin C or extracorporeal removal of soluble VEGFR‑1
(500 mg daily) and vitamin E (400 IU daily) before (sVEGFR‑1).20 Supplemental choline intake during the
24 weeks of gestation.5 Treatment after 24 weeks of ges- third trimester of pregnancy can reduce maternal serum
tation with antioxidant or vitamins alone was ineffective levels of sVEGFR‑1 and placental expression of total
in preventing pre-eclampsia.5 The results from this study (soluble and membrane-bound) VEGFR‑1. However,
are promising, and further investigation is warranted to whether this approach can reduce the incidence of pre-
confirm these interesting findings. eclampsia remains to be determined.22 These preven-
tive interventions probably will not reverse established
Calcium supplementation pre-eclampsia, as the antiangiogenic state is an adaptive
As calcium deficiency has been implicated in the patho- response to various insults, rather than being the primary
genesis of pre-eclampsia,113 several randomized controlled abnormality leading to pre-eclampsia. However, as deliv-
trials have examined whether calcium supplementation ery of the placenta remains the only therapeutic option
can prevent its development.114–116 One such trial in the available for women with established pre-eclampsia,
USA included 4,589 pregnant women who received either any interventions that enable the safe prolongation of
calcium supplementation (2 g daily) or placebo.117 The pregnancy might result in improved perinatal outcomes.
results showed no significant reduction in the incidence
or severity of pre-eclampsia, or delay in its onset, in the Long-term sequelae of pre-eclampsia
women receiving supplemental calcium.117 By contrast, a Although pre-eclampsia is a pregnancy-specific disorder
Cochrane systematic review and meta-analysis concluded that resolves on delivery of the placenta, women with
that women who received calcium supplementation (≥1 g pre-eclampsia are at increased risk of subsequent cardio-
daily) had a reduced incidence of pre-eclampsia (RR 0.45, vascular disease. The results of a systematic review and
95% CI 0.31–0.65).118,119 The beneficial effect was great- meta-analysis support prior observations that women
est for patients with low baseline calcium intake (RR with pre-eclampsia are more likely than those without
0.36, 95% CI 0.20–0.65), and those with a high risk of pre-eclampsia to develop long-term sequelae, including
pre-eclampsia (RR 0.22, 95% CI 0.12–0.42).118 Currently, chronic hypertension (OR 3.13), cardiovascular disease
calcium supplementation for prevention of pre-eclampsia (OR 2.28), stroke (OR 1.76), diabetes (OR 1.80)23 and
is only considered in pregnant women from populations end-stage renal disease (RR 4.70).24 The risk of end-
with low calcium intake (<600 mg daily).90 stage renal disease seems to increase progressively with
the number of pregnancies affected by pre-eclampsia.24
Other potential interventions Moreover, women with pre-eclampsia are more likely
Considerable efforts are underway to identify treatments to have microalbuminuria 3–5 years after delivery than
that can reverse the imbalance of angiogenic and anti women with a normal pregnancy.124 These findings might
angiogenic factors associated with pre-eclampsia. Statins reflect undiagnosed renal disease,125 which is common
are cholesterol-lowing agents that have the potential to in patients with pre-eclampsia,126 or, alternatively, might
reverse this angiogenic imbalance through their pleio- suggest that pre-eclampsia compromises renal function.
tropic effects, which include stimulating trophoblast Glomerular endotheliosis, a typical renal lesion observed
in pre-eclampsia and previously thought to resolve after antioxidant vitamins—remain to be fully investigated.
delivery, can be detected long after p
regnancy in some Potential interventions exist to ameliorate the imbal-
women affected by pre-eclampsia.127 ance between angiogenic and antiangiogenic factors
Receiving a diagnosis of pre-eclampsia could have pro- observed in some patients with pre-eclampsia, and hence
found long-term health-care implications, as it identifies might provide opportunities to improve maternal and/
a group of women at risk of adverse health outcomes and or perinatal outcomes. The diagnosis of pre-eclampsia
potentially enables the early implementation of preven- can have profound long-term health-care implications,
tative interventions (for example diet, exercise and/or as it identifies a subgroup of women at increased risk of
pharmacological treatment).128,129 adverse health outcomes. Further studies are required to
improve screening strategies to identify women at risk of
Conclusions pre-eclampsia who could benefit from targeted preven-
Current management of pre-eclampsia consists of con- tive interventions. Evaluation of the cost-effectiveness of
trolling hypertension, preventing seizures and timely any intervention should also be considered.
delivery of the fetus. Considerable effort has been made to
identify biomarkers that can predict pre-eclampsia. In the Review criteria
absence of safe and effective interventions, however, A search for original research and review articles published
the low prevalence of pre-eclampsia (which necessarily in English between 1840 and 2013 focusing on pre-
results in low PPVs for identified biomarkers) means eclampsia was performed in PubMed using the following
that establishing the clinical utility of any biomarker as a search terms alone or in combination: “pre-eclampsia”,
screening test for pre-eclampsia is difficult. A few preven- “toxaemia”, “pregnancy-induced hypertension” and
tive interventions for pre-eclampsia—such as low-dose “eclampsia”. The bibliographies of pertinent articles were
also examined to identify further relevant papers.
aspirin or the combination of nitric oxide donors and
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