Introduction
Perinatology Research
Branch, Program for
Perinatal Research and
Obstetrics, Division of
Intramural Research,
Eunice Kennedy Shriver
National Institute of
Child Health and
Human Development,
NIH, 31 Center Drive,
Bethesda, MD 20892,
USA and 3990 John R
Street, Detroit,
MI48201, USA (T.C.,
P.C., S.J.K., L.Y., R.R.).
Competing interests
The authors declare no competing interests.
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Key points
Combinations of biomarkers perform better than single biomarkers for
predicting pre-eclampsia, but require external validation before they can be
used routinely
Potentially effective interventions to prevent pre-eclampsia in patients at risk
include early administration of low-dose aspirin or larginine in combination with
oral antioxidants (vitamins C and E)
Maternal plasma levels of angiogenic and antiangiogenic factors identify most
patients who will develop early pre-eclampsia, correlate with disease severity
and have prognostic value for maternal and/or perinatal complications
Management of pre-eclampsia includes control of hypertension, prevention of
seizures and timely delivery; steroids are administered to enhance fetal lung
maturity if induction of labour before 34weeks is contemplated
In pre-eclampsia at 37weeks of gestation, delivery effectively optimizes
pregnancy outcomes; for preterm gestations, the risk of continued pregnancy
must be balanced against that of premature birth
Women with pre-eclampsia are at increased risk of developing cardiovascular
disease, including chronic hypertension, stroke, coronary artery disease,
diabetes and end-stage renal disease later in life
0.11
m/s
0.8
0.6
0.4
0.2
0
PW: 2.5 MHz = 12
0.11
0.11
m/s
1.0
0.5
0
PW: 2.5 MHz = 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 velocityend diastolic velocity]/time averaged velocity, averaged across both
uterine arteries), above the 95th percentile for gestational age.
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Research in this area focuses not only on the identification of biomarkers that can predict pre-eclampsia, but
also on predictors of adverse perinatal outcomes after
diagnosis of pre-eclampsia. For example, the full PIERS
(pre-eclampsia integrated estimate of risk) model was
developed in 2011 to predict fatal or life-threatening
maternal complications of pre-eclampsia within 48h of
admission, using standard clinical and laboratory information.57 This model was validated using a threshold
of 10% predicted probability to define a positive test,
and predictive variables obtained within 6h and 24h of
admission. The full PIERS model identified 44% and
57% of the women who would later develop adverse
outcomes at these two respective time points, resulting
in positive predictive values (PPVs) of 24% and 26%.58
An imbalance between angiogenic and antiangiogenic factors has emerged as an important pathogenetic
mechanism in pre-eclampsia,59,60 and evidence indicates that maternal plasma levels of these factors can
identify the majority of patients who will develop early
pre-eclampsia.61,62 Moreover, levels of these biomarkers
correlate with disease severity 59,60,63,64 and have prognostic
value in identifying women who subsequently develop
maternal and/or perinatal complications, especially in
patients suspected of having pre-eclampsia at <34weeks
of gestation.1215,65,66
An emerging debate is whether pre-eclampsia is a
homogeneous disease.67 Critics argue that assessing a few
biomarkers involved in only one pathway of disease (angiogenesis) is unlikely to predict or detect all women with preeclampsia, a disease that has multiple aetiologies.68 Some
investigators counter this argument with the proposal that
the forms of pre-eclampsia associated with an angiogenic
imbalance are those that result in adverse outcomes.67,69
Furthermore, reported evidence of heterogeneity in the literature might be largely due to misclassification of other
diseases as pre-eclampsia, as the criteria for its diagnosis
(such as hypertension and proteinuria) are nonspecific.67
However, several questions should be answered prior to
concluding that pre-eclampsia is a homogenous disease.
For example, the criteria used to define angiogenic imbalance (including fixed cut-offs derived from receiver operating characteristic [ROC] curve analyses, multiples of
median values or percentile distributions of analyte levels)
have yet to be agreed. Consequently, it is difficult to ascertain what proportion of patients with pre-eclampsia truly
have an angiogenic imbalance. Most women with preterm
pre-eclampsia have abnormal profiles of angiogenic and/
or antiangiogenic factors, but this is not the case in women
with pre-eclampsia at term (37weeks of gestation).64,61
It is uncertain that patients who do not have abnormal
ratios of angiogenic to antiangiogenic factors at term have
been misclassified as having pre-eclampsia. Most patients
with pre-eclampsia are diagnosed at term, and eclampsia
is also not uncommon after 37weeks gestation. Moreover,
what causes the antiangiogenic state in the first place
remainsunclear.
Our view is that if an imbalance between angiogenic and antiangiogenic factors represents the terminal pathway of multiple aetiologies, it is possible that
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The potential clinical utility of angiogenic and anti
angiogenic factors in differentiating superimposed preeclampsia from exacerbations of pre-existing medical
conditions has been proposed in several case reports
relating to pregnant women with nephrotic syndrome,75
systemic lupus erythematosus76 or those with end-stage
renal disease undergoing haemodialysis.77 Subsequently,
in two casecontrol studies, higher serum levels of
sVEGFR1 and lower serum levels of PlGF were reported
in patients with CKD having superimposed pre-eclampsia
than in women with CKD having normal pregnancies.78,79
However, the diagnostic performance of these biomarkers
in a clinical setting has yet to be reported.
Management of pre-eclampsia
The management of pre-eclampsia focuses on the control
of acute hypertension, the prevention of seizures and
timely delivery of the fetus. In a patient with pre-eclampsia
who is near or at term (37weeks gestation), when the
fetus is mature, delivery is an effective way to treat thedisorder and optimize pregnancy outcomes (Figure2). In
preterm gestations, the risk of continuing the pregnancy
in the face of a multisystemic disorder must be balanced
against the risks of premature birth.90 Delivery is indicated
when life-threatening maternal complications are present
or impending, such as severe hypertension refractory to
treatment (which places the mother at risk of stroke), pulmonary oedema, acute renal failure, hepatic rupture or
eclampsia.90 Delivery would also be indicated if a viable
fetus is at risk of impending death. The mode of delivery
(vaginal versus caesarean) depends on obstetric indications (such as fetal distress or previous classic caesarian
deliveries). Attempted induction of labour does not seem
to increase neonatal morbidity, but is rarely successful
at <28weeks in these patients.91 Detailed discussion of
the expectant management of women who have pre-
eclampsia with severe features at <34weeks of gestation, including patient selection, treatment and delivery
indications, can be found elsewhere.90,92
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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
Pre-eclampsia without
severe features
Gestational age
37 weeks
Gestational age
<37 weeks
Induction
of labour*
Expectant management
Maternal
Daily assessment
of symptoms (vitals
signs twice daily)
Weekly laboratory
testing (platelet counts,
liver enzymes and sCr)
Fetal
Daily fetal movement
test
Twice-weekly nonstress
test
Serial fetal growth
every 3 weeks
At least once-weekly
amniotic fluid volume
assessment
Indications for delivery
Gestational age
37 weeks
Worsening of maternal
or fetal conditions
Labour or prelabour
membrane rupture
Induction of labour
Expectant management
Maternal assessment
Monitor vital signs, fluid intake, urinary output, symptoms of severe pre-eclampsia
and presence of contractions and/or membrane rupture, or bleeding at least every 8 h
Daily laboratory testing (CBC, platelet counts, liver enzymes and sCr)
Fetal assessment
Daily kick count and nonstress test with uterine contraction monitored
Twice-weekly biophysical profile
Fortnightly serial fetal growth and umbilical Doppler studies (if fetal growth restriction
suspected)
Indications for delivery
Maternal
Uncontrolled severe hypertension or persistent severe symptoms despite medications
HELLP syndrome or eclampsia develops
Pulmonary oedema
Significant renal dysfunction (sCr >1.1 mg/dl or doubling of sCr in the absence of
other renal diseases)
Suspected abruptio placentae
Eclampsia
Progressive labour or membrane rupture
Fetal
Severe fetal growth restriction (ultrasonographic estimate of fetal weight loss <5th percentile)
Persistent oligohydramnios (maximum vertical pocket estimated by ultrasonography <2 cm)
Biophysical profile 4/10 on >2 occasions 6 h apart
Reversed end diastolic flow on umbilical artery Doppler studies
Recurrent variable or late decelerations during nonstress test
Fetal death
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
at34 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 preeclampsia after 36weeks 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.130133 If preterm induction of labour is contemplated, steroids are administered between 24weeks and
34weeks of gestation to improve fetal lung maturity. Magnesium sulfate is administered during labour and the first 24h 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.
not recommended for the management of severe hypertension during pregnancy because nimodepine and ketanserin were associated with more persistent high blood
pressure than hydralazine and diazoxide was associated
with a higher risk of hypotension than labetalol.100 Sodium
nitroprusside is reserved only for the rare patients in
whom hypertension is refractory to other agents, because
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Table 1 | Therapeutic agents for control of severe hypertension in pregnancy
Agent
Mechanism
Dose
Adverse effects
Comments
Hydralazine
Vasodilator
Substantial experience of
safety and efficacy
Labetalol
- and
blocker
Nifedipine
Calcium
channel
antagonist
*Blood pressure falls within 510min of a capsule being bitten and swallowed, and 1030min with oral administration.133 All agents are FDA category C.
Information in this Table is used with permission and was partly obtained from Chesleys Hypertensive Disorders in Pregnancy, Lindheimer, M.D. etal. (eds)
Elsevier (2009).
Prevention of seizures
The development of seizures and/or coma is a characteristic of eclampsia, and increases the risk of maternal
and perinatal death, as well as other complications (such
as disseminated intravascular coagulation, pulmonary
oedema, acute renal failure and cardiopulmonary arrest).
The onset of eclampsia can be antepartum (3853%),
during labour (1836%) or postpartum (1144%).101
Although most patients with postpartum eclampsia
present within 48h after delivery, some can occur as late
as 23days postpartum.101
The agent of choice for the prevention of seizures or
recurrent seizure episodes in eclampsia is magnesium
Box 1 | Use of magnesium sulfate for seizure prophylaxis in pre-eclampsia
Continuous intravenous infusion
Loading dose of magnesium sulfate (46g administered over 1520min)
Maintenance infusion with 12g/h
Maintain magnesium sulfate concentration between 480mg/l and 840mg/l
Monitor urinary output and if <2530ml over 2 consecutive hours, oliguria
is diagnosed; fluid status and magnesium level should be assessed and
magnesium infusion should be decreased or discontinued
Monitor magnesium toxicity by combination of assessment of deep tendon
reflexes and respiratory rate
Discontinue infusion 24h after delivery
Intermittent intramuscular injection (when intravenous administration is not possible)
20% magnesium sulfate solution (4g intravenously at rate not exceeding 1g/min)
50% magnesium sulfate solution (10g, 5g injected deeply in the upper outer
quadrant of both buttocks). If convulsions persist after 15min, give up to 20%
solution of magnesium sulfate (2g) intravenously at a rate not exceeding 1g/min
Every 4h thereafter give 50% magnesium sulfate solution (5g) injected deeply
in the upper outer quadrant of alternate buttocks, but only after confirming that
the patellar reflex is present, respiration is not depressed and urinary output
intheprevious 4h exceeds 100ml
Discontinue treatment 24h after delivery
Adverse effects
Flushing, nausea and vomiting, muscle weakness, thirst, headache, drowsiness,
confusion and respiratory depression
Adapted with permission obtained from Chesleys Hypertensive Disorders in Pregnancy,
Lindheimer, M.D. etal. (eds) Elsevier (2009).
Prevention of pre-eclampsia
A broad range of interventions has been tested for the prevention of pre-eclampsia, including low-salt diets, diuretics, fish oil, calcium supplementation, antioxidants, aspirin
and heparin.106 However, most of these interventions have
not been proven effective.
Antiplatelet agents
An imbalance between prostacyclin and thromboxane has
been proposed to be one of the mechanisms mediating
pre-eclampsia;107 thus, antiplatelet agents (in particular,
aspirin, which blocks platelet production of thromboxaneB2)108 have been extensively tested in randomized
clinical trials to prevent pre-eclampsia. In a multicentre
randomized clinical trial of low-dose aspirin for the prevention and treatment of pre-eclampsia in 9,364 pregnant
women, the use of aspirin was associated with a non
significant reduction (12%) in the incidence of protein
uric pre-eclampsia.109 This treatment had no significant
effect on the incidence of intrauterine growth restriction,
stillbirth or neonatal death. Aspirin did, however, significantly reduce the likelihood of preterm delivery: 19.7%
in patients receiving aspirin versus 22.2% in controls, an
absolute reduction of 2.5 events per 100 women treated
(P=0.003).109 Subsequently, a meta-analysis of data from
32,217 women showed that patients receiving aspirin for
the prevention of pre-eclampsia had a significant (10%)
reduction in the incidence of pre-eclampsia, preterm
birth (<34weeks of gestation) and a composite of serious
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adverse pregnancy outcomes (pre-eclampsia, small for
gestational age infant, fetal death or maternal death).3
In another meta-analysis, the incidence of early preeclampsia was reduced by 50% (RR 0.47, 95% CI 0.34
0.65) in women considered to be at risk of pre-eclampsia
owing to a history of pre-eclampsia or abnormal UtADV
findings, who started taking low-dose aspirin 16weeks
of gestation. 4 Expanded meta-analyses have confirmed
these findings, and also suggest that this intervention
is associated with a decrease in the rate of severe preeclampsia.6,110,111 However, these findings were obtained
in subgroup analyses, and remain to be confirmed by
randomized controlled trials.
Antioxidants
Although oxidative stress has been implicated in the
pathophysiology of pre-eclampsia, a meta-analysis of
randomized controlled trials of vitamins C and E failed
to show a beneficial effect for preventing pre-eclampsia and might increase risk of gestational hypertension
and prelabour rupture of membranes.112 However, preeclampsia was reduced by 63% in patients considered to
be at risk of developing the condition (owing to a personal or family history of pre-eclampsia) who received
larginine (5.4g daily) in combination with vitaminC
(500mg daily) and vitamin E (400IU daily) before
24weeks of gestation.5 Treatment after 24weeks of gestation with antioxidant or vitamins alone was ineffective
in preventing pre-eclampsia.5 The results from this study
are promising, and further investigation is warranted to
confirm these interesting findings.
Calcium supplementation
As calcium deficiency has been implicated in the pathogenesis of pre-eclampsia,113 several randomized controlled
trials have examined whether calcium supplementation
can prevent its development.114116 One such trial in the
USA included 4,589 pregnant women who received either
calcium supplementation (2g daily) or placebo.117 The
results showed no significant reduction in the incidence
or severity of pre-eclampsia, or delay in its onset, in the
women receiving supplemental calcium.117 By contrast, a
Cochrane systematic review and meta-analysis concluded
that women who received calcium supplementation (1g
daily) had a reduced incidence of pre-eclampsia (RR 0.45,
95% CI 0.310.65).118,119 The beneficial effect was greatest for patients with low baseline calcium intake (RR
0.36, 95% CI 0.200.65), and those with a high risk of
pre-eclampsia (RR 0.22, 95% CI 0.120.42).118 Currently,
calcium supplementation for prevention of pre-eclampsia
is only considered in pregnant women from populations
with low calcium intake (<600mg daily).90
Other potential interventions
Considerable efforts are underway to identify treatments
that can reverse the imbalance of angiogenic and anti
angiogenic factors associated with pre-eclampsia. Statins
are cholesterol-lowing agents that have the potential to
reverse this angiogenic imbalance through their pleiotropic effects, which include stimulating trophoblast
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in pre-eclampsia and previously thought to resolve after
delivery, can be detected long after pregnancy in some
women affected by pre-eclampsia.127
Receiving a diagnosis of pre-eclampsia could have profound long-term health-care implications, as it identifies
a group of women at risk of adverse health outcomes and
potentially enables the early implementation of preventative interventions (for example diet, exercise and/or
pharmacological treatment).128,129
Conclusions
Current management of pre-eclampsia consists of controlling hypertension, preventing seizures and timely
delivery of the fetus. Considerable effort has been made to
identify biomarkers that can predict pre-eclampsia. Inthe
absence of safe and effective interventions, however,
the low prevalence of pre-eclampsia (which necessarily
results in low PPVs for identified biomarkers) means
that establishing the clinical utility of any biomarker as a
screening test for pre-eclampsia is difficult. A few preventive interventions for pre-eclampsiasuch as low-dose
aspirin or the combination of nitric oxide donors and
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Acknowledgements
The authors research is supported partly by the
Perinatology Research Branch, Division of
IntramuralResearch, Eunice Kennedy Shriver
NationalInstitute of Child Health and Human
Development, NIH, Department of Health and Human
Services (NICHD/NIH/DHHS) and partly with Federal
funding from the NICHD and NIH under contract
no.HHSN275201300006C.
Author contributions
All authors researched data for the article, made
substantial contribution to discussion of the
content,wrote, reviewed and edited the manuscript
before submission.
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