Brief Review

Angiogenic Factors in Diagnosis, Management,

and Research in Preeclampsia
Sarosh Rana, S. Ananth Karumanchi, Marshall D. Lindheimer

O bservational studies in humans and experimental studies

in animals provide strong evidence that abnormalities in
circulating angiogenic factors play a pathogenic role in pre-
eclampsia.1 Numerous angiogenic factor abnormalities have
been noted in preeclampsia, but the factors studied most exten-
sively are the antiangiogenic protein, soluble fms-like pro-
tein kinase 1 (sFlt1), and the proangiogenic protein, placental
growth factor (PlGF).2 Placental expression of sFlt1 is strik-
ingly increased in preeclampsia, and this is associated with
increased levels of maternal circulating sFlt1 and decreased
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discuss potentially new exciting uses of these biomarkers to
guide clinical care, and postulate that analysis of angiogenic
profiles by improving classification will lead to better studies,
particularly those designed to clarify the natural history and
remote prognosis of the disorder.
Problems With Clinical Studies to Predict
Preeclampsia
Substantial resources have been allocated to preeclampsia
prediction studies. In most of these studies, however, the

levels of free bioactive PlGF,3 a finding confirmed by several
groups.1 Alterations in these angiogenic factors occur before
clinical signs and symptoms and correlate with the severity
of the disease and adverse maternal/neonatal outcomes.4–7 In
addition, basal sFlt1 levels are higher in women with multiple
gestation, trisomy 13, and molar pregnancy conditions asso-
ciated with higher preeclampsia rates.1 Other synergistic anti-
angiogenic proteins such as soluble endoglin have also been
demonstrated to contribute to preeclampsia.8 It has therefore
been hypothesized that excessive production of both antian-
giogenic proteins sFlt1 (inhibiting vascular endothelial growth
factor and PlGF signaling) and soluble endoglin (inhibiting
transforming growth factor-β signaling) may lead to endothe-
lial dysfunction, and the manifestations of human preeclamp-
sia, and that phenotypic preeclampsia is attributable to an
antiangiogenic state.9,10
During the last decade, several clinical studies were
designed to determine potential of angiogenic factors as pre-
diction tests in preeclampsia.5,7,11–16 However, their accuracy
fell far short of sensitivities and likelihood ratios required for
clinical use,17–19 although prediction was much more reliable
for early-onset (<34 weeks) preeclampsia.13,16,20–23 The mod-
est results were interpreted by some as evidence that pre-
eclampsia is a heterogeneous disease with no single pathway
to explain its spectrum24 and led to a decreased interest in the
importance of these measurements. However, important new
roles in diagnoses, and prognosis, plus their potential regard-
ing developing novel treatments, and improving classification
schema for more meaningful immediate and remote follow-
up investigations have recently emerged.1,6,25 Here, we explore
dilemmas that compromise many preeclampsia studies,
diagnostic criteria are imprecise, few using adverse outcomes
other than hypertension and proteinuria in their definitions.
We have known for decades that many patients diagnosed pre-
eclamptic by clinical criteria alone are misclassified.26 This is
particularly relevant when risk factors such as diabetes mel-
litus, chronic hypertension, and obesity are present.27–29 In a
clinical study of women diagnosed with preeclampsia, renal
biopsies revealed that diagnosis was incorrect in 15% of the
nulliparas and almost half the multiparas, glomerulonephritis
being a frequent imposter.26 Such observations are not surpris-
ing given that de novo hypertension and proteinuria are non-
specific in delineating disease. Perhaps other end points such
as adverse outcomes might better define the disorder, but few
studies use this approach. However, incorporating outcomes
would not eliminate all errors because certain conditions that
mimic preeclampsia may lead to adverse outcomes as well.
Another conclusion to consider from the 1981 report26 is the
lack of reliability of protocols that study multiparas.
Other problems arise when studying high-risk gestations.
Chronic hypertensives and the very obese frequently harbor
glomerulosclerosis,30,31 the latter also demonstrating glomeru-
lomegaly.31,32 Daily protein excretion slightly increased but still
normal in early gestation may become abnormal near term, as
proteinuria increases in all gravid women as gestation pro-
gresses.33 In such instances, the appearance of frank proteinuria
may have nothing to do with any new pathological process but
lead to an erroneous diagnosis of superimposed preeclampsia.
Of interest, prediction accuracy seems far better for early
than late preeclampsia because late disease often presents
with mild features. With advancing gestation, production and
circulating levels of sFlt1 increase in all pregnant women,

Received August 23, 2013; first decision September 9, 2013; revision accepted October 2, 2013.
From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (S.R., S.A.K.) and Division of Nephrology, Department of
Medicine (S.A.K.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; Howard Hughes Medical Institute, Chevy Chase, MD
(S.A.K.); and Department of Medicine and Obstetrics and Gynecology, University of Chicago School of Medicine, IL (M.D.L.).
Correspondence to Sarosh Rana, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center,
330 Brookline Ave, Kirstein 382 Boston, MA 02215. E-mail srana1@bidmc.harvard.edu
(Hypertension. 2014;63:198-202.)
© 2013 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.113.02293

198
 Rana et al   Angiogenic Factors and Preeclampsia   199
including those who remain normotensive.4,15 These factors
combined with the above discussed physiological increments
in protein excretion make it more difficult to discriminate
preeclampsia from controls using angiogenic factor measure-
ments when the disease presents near term. However, beyond
gestational week 37, such testing seems unnecessary as then
hypertension, whatever the cause, is considered by most as
sufficient reason to deliver.34
One argument against pursuing biomarker research has
been the absence of disease-modifying agents to make such
pursuits useful. Critics argue that angiogenic profile use differs
from those for biomarkers measured to predict aneuploidy or
diabetes mellitus where pregnancy can be terminated or blood
glucose controlled. It is therefore imperative that studies to
predict preeclampsia focus not only on identifying the disease,
but also demonstrate clinical usefulness, that is, what does the
obstetrician do if disease is predicted early?
Finally, most studies using angiogenic factors were per-
formed with manual ELISA kits, methodology often dis-
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playing high interassay coefficient of variation (10%–20%).
Automated assays, now available, are much more reliable,
(interassay coefficients of variation <5%), report the results
rapidly, and produce more robust associations with altered
factor levels and preeclampsia.35–37
An Improved Approach to Diagnosis and
Prognosis
An emerging role for angiogenic factors is risk stratification
that permits determination of the potential morbidity of the
disease when women present with diagnosed or suspected
preeclampsia.6,38–42 This approach resembles evaluation of
suspected cardiac disease, in which use of highly sensitive
cardiac troponin has revolutionized management of patients
presenting with chest pain.43,44 Rather than focusing on diag-
nostic certainty, we have suggested that angiogenic biomark-
ers can predict serious imminent adverse outcomes far better
than traditional laboratory and clinical criteria. For instance,
our published data, although still preliminary, demonstrate
that the plasma sFlt1/PlGF ratio on arrival for triage of sus-
pected preeclampsia predicts those destined to have adverse
outcomes within 2 weeks, versus those who do not, especially
when women present preterm.6 The ratio alone outperformed
currently relied on approaches, including blood pressure, pro-
teinuria, uric acid, alanine aminotransferase, platelet count,
and creatinine.6 Of further note is a report that measuring
angiogenic proteins also permits accurate risk assessment of
severe late preeclampsia, importantly identifying imminent
stillbirths (the latter, if confirmed, a major breakthrough in
prenatal care).45,46 Measurement of angiogenic proteins in the
plasma may also serve as noninvasive surrogate of placental
dysfunction.15 Circulating angiogenic factors are also useful to
differentiate preeclampsia from diseases such as chronic and
gestational hypertension, acute and chronic glomerulonephri-
tis, lupus flares, and gestational thrombocytopenia.47–50
Our data further suggest that clinical tests, signs, and symp-
toms currently used for triage lead to significant misclassifica-
tion and overtesting/treating, substantial resources and costs
erroneously allocated to low-risk patients.6 Thus increased
specificity, using the sFlt1/PlGF ratio in triage, should by
more accurately defining the population at risk, enable appro-
priate and reduced cost/resource expenditure.51 Most impor-
tantly this approach should permit temporization and prevent
unnecessary early deliveries.25
Quantitative proteinuria and liver function tests used rou-
tinely to assess preeclampsia’s severity are neither sensitive
nor specific in predicting maternal and fetal complications.52–54
Similarly, headache and epigastric pain lack specificity.55
Recently, a complex model (PIERS [Preeclampsia Integrated
Estimate of RiSk]) that uses clinical signs and laboratory tests
to predict adverse outcomes has been advocated. However the
model, not robust at presentation, is useful only after 48 hours
of admission.56 Thus, it is fair to conclude that, as of 2013, pro-
tocols designed to determine risk stratification for suspected or
diagnosed preeclampsia are far from ideal.57 Such assessments,
too often, are directed by expert opinion–based guidelines
that perform rather poorly as predictors of imminent adverse
maternal or fetal outcomes.58 Needed are better approaches to
predict complications and guide care. Thus, rather than rely-
ing on signs, symptoms, and nonspecific tests, biomarkers that
are reproducible and quickly obtained, pathogenically linked
to the disease, demonstrating high specificity to predict com-
plications, and requiring less expertise to interpret, should have
significant clinical usefulness.
Accurate risk stratification will help clinicians focus on
the appropriate patients whether their disease classification
is definitely apparent or not when first evaluated and should
also reduce unnecessary interventions on women at low risk
for adverse outcomes. In fact, because the latter group did not
suffer any adverse outcomes except a few iatrogenic preterm
deliveries,25 we anticipate that using angiogenic biomarkers
for evaluation of preeclampsia will help avoid unnecessary
preterm deliveries. Thus, the compelling and promising data
cited this far should be followed by larger prospective studies
to confirm whether use of angiogenic factors in clinical deci-
sion making can decrease the incidence of preterm delivery
and reduce resource utilization without increasing the risk of
adverse maternal and neonatal outcomes.
Therapeutic Studies Targeting the Angiogenic
Pathway
Studies of angiogenic pathways are helping devise specific
therapies for preeclampsia. In a pilot study limited to 3 severe
early preeclamptics (24–32 weeks of gestation), Thadhani et
al59 depleted sFlt1 30% by apheresis and prolonged pregnancy
by 2 to 4 weeks. If confirmed, this approach could lead to
targeted therapy for a specific group of patients, those with
an abnormal angiogenic profile. More recently, statin therapy
that promotes PlGF expression and angiogenesis was shown
to prevent or ameliorate disease in an animal model of pre-
eclampsia.60,61 Pilot human trial to test safety and efficacy of
statins in severe preeclampsia is ongoing.62 Relaxin increases
production of local vascular endothelial growth factor, its
therapeutic potential also being investigated.63 Finally, dietary
choline supplementation, shown to reduce placental sFlt1
expression, has been suggested as a strategy to improve pla-
cental angiogenesis.64 The future for specific therapies that
antagonize sFlt1’s action or reduce its production and those
that enhance PlGF levels are therefore promising.
 200  Hypertension  February 2014
Are There Multiple Causes of Phenotypic
Preeclampsia?
Some suggest that searching for a single biomarker to predict
or diagnose preeclampsia is fruitless because the disease has
multiple causes.24,65,66 If preeclampsia phenotypes were het-
erogeneous, both angiogenic and nonangiogenic forms24,66,67
should manifest multisystemic involvement and similar
adverse maternal and perinatal outcomes. Whether this is
true or not would require large prospective data, but in our
studies patients diagnosed with preeclampsia, without angio-
genic imbalance, showed no risk for any major preeclamp-
sia-related adverse outcomes other than what seemed to be
unnecessary decisions to deliver prematurely.25 This forms the
basis of our view that preeclampsia, or at least the form of the
disorder that should most concern us, is a single and specific
entity whose phenotypes relate to angiogenic imbalance and
that measurements of these proteins help identify the severe
form of the disease, and its management, and identify the best
populations for follow-up research. This does not mean that
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other hypertensive proteinuric diseases (at times designated
suspected preeclampsia) should not be watched carefully, but
that angiogenic factor measurements will by identifying what
we consider “true preeclampsia” not only will help caregivers
in management decisions but also improve classification, the
latter improving research on causality, prediction, and epide-
miological surveys of both immediate and remote outcomes.
Our view of preeclampsia’s specificity, its phenotypes
explained by angiogenic imbalance, and the magnitude of
which influences the severity of adverse outcomes brings to
mind the validity of older morphological studies in which a
single pathological entity of preeclampsia seemed apparent.
Sheehan and Lynch68 in a 1973 monograph discuss 677 autop-
sies of pregnant women, often performed within 3 hours after
death, thus avoiding the confusion of postmortem changes.
The text focuses on a detailed reanalysis of material from
377 cases, 159 of whom had either preeclampsia or eclampsia
(Generally, eclampsia assures the clinical diagnosis of pre-
eclampsia was correct, whereas autopsy, of course, confirms
the disease’s severity!). The authors detail the gross and his-
tological pathology of virtually every organ, the observations
most unique to preeclampsia/eclampsia, greatest in liver and
kidney (the latter further detailed by electron microscopy in
numerous biopsy reports). These were the same lesions that
investigators produced in rodents with sFlt1 overproduction
several decades later and reversed the glomerular endothelio-
sis by administering recombinant proangiogenic proteins.3,69
We suggest that the triage studies reviewed here6,37–40,42
delineate, with a high degree of success (certainly superior
to current approaches), the “true preeclampsia” that is a dis-
ease with organ-specific histopathologies that lead to major
adverse outcomes, including hepatic and renal disease, and
fetal jeopardy, and the other outcomes classically associated
with the severest forms of preeclampsia is associated with
markedly elevated sFlt1/PlGF ratio in serum/plasma. We fur-
ther suggest that many of the patients with sFlt1/PlGF ratios
below the cutoff were misdiagnosed clinically,26 one reason
they could be managed expectantly.
In summary, we posit that altered angiogenic factors allow
clinicians to discriminate a serious from a more benign form
of hypertension and proteinuria in a manner that defines a spe-
cific and multisystemic form of preeclampsia with a definitive
organ pathology or the true preeclampsia.
Concluding Thoughts
This commentary focused on newer uses of angiogenic fac-
tors, most notably for accurately diagnosing and managing
preterm preeclampsia. We discussed pitfalls in preeclampsia
research that may underlie disputes regarding whether pre-
eclampsia phenotypes have heterogeneous causes, or our view
that they represent angiogenic factor imbalance, alone. Thus,
we conclude by suggesting that even if multiple factors lead
the placenta to produce excess amounts of antiangiogenic
factors, these proteins alone account for the disease’s major
phenotypes and therefore are extremely specific for both diag-
nosis and prognosis. Also, measuring these factors whose
results can be produced rapidly with automated platforms will
be important for triage may prevent unnecessary early deliver-
ies in preeclamptic women with normal angiogenic profile.
Based on our data, we also suggest that future screening stud-
ies should focus on prediction of angiogenic form of pre-
eclampsia rather than disease diagnosis based on nonspecific
clinical criteria. Measurement of angiogenic factors may also
aid in designing specific preventive, and therapeutic trials, and
for adequate short- and long-term follow-up studies.
Sources of Funding
S. Rana is supported by K08HD068398-01A1 (National Institute
of Child Health and Human Development) and 13CRP16130003
(American Heart Association). S.A. Karumanchi is an investigator of
the Howard Hughes Medical Institute.
Disclosures
S.K. Karumanchi is a coinventor on multiple patents for preeclamp-
sia markers and reports service as a consultant to Roche, Siemens,
Beckman Coulter, and has financial interest in Aggamin LLC. The
other authors report no conflicts.
References
1. Powe CE, Levine RJ, Karumanchi SA. Preeclampsia, a disease of the
maternal endothelium: the role of antiangiogenic factors and implications
for later cardiovascular disease. Circulation. 2011;123:2856–2869.
2. Cerdeira AS, Karumanchi SA. Angiogenic factors in preeclampsia and
related disorders. Cold Spring Harb Perspect Med. 2012;2.
3. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann
TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP,
Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1
(sFlt1) may contribute to endothelial dysfunction, hypertension, and pro-
teinuria in preeclampsia. J Clin Invest. 2003;111:649–658.
4. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF,
Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme
VP, Karumanchi SA. Circulating angiogenic factors and the risk of pre-
eclampsia. N Engl J Med. 2004;350:672–683.
5. Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza J,
Bujold E, Gonçalves L, Gomez R, Edwin S, Mazor M. Plasma soluble
vascular endothelial growth factor receptor-1 concentration is elevated
prior to the clinical diagnosis of pre-eclampsia. J Matern Fetal Neonatal
Med. 2005;17:3–18.
6. Rana S, Powe CE, Salahuddin S, Verlohren S, Perschel FH, Levine RJ,
Lim KH, Wenger JB, Thadhani R, Karumanchi SA. Angiogenic factors
and the risk of adverse outcomes in women with suspected preeclampsia.
Circulation. 2012;125:911–919.
7. Noori M, Donald AE, Angelakopoulou A, Hingorani AD, Williams DJ.
Prospective study of placental angiogenic factors and maternal vascular
function before and after preeclampsia and gestational hypertension.
Circulation. 2010;122:478–487.
 Rana et al   Angiogenic Factors and Preeclampsia   201
8. Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to
the pathogenesis of preeclampsia. Nat Med. 2006;12:642–649.
9. Agarwal I, Karumanchi SA. Preeclampsia and the Anti-Angiogenic State.
Pregnancy Hypertens. 2011;1:17–21.
10. Romero R, Chaiworapongsa T. Preeclampsia: a link between tropho-
blast dysregulation and an antiangiogenic state. J Clin Invest. 2013;123:
2775–2777.
11. Shibata E, Rajakumar A, Powers RW, Larkin RW, Gilmour C, Bodnar
LM, Crombleholme WR, Ness RB, Roberts JM, Hubel CA. Soluble
fms-like tyrosine kinase 1 is increased in preeclampsia but not in nor-
motensive pregnancies with small-for-gestational-age neonates: relation-
ship to circulating placental growth factor. J Clin Endocrinol Metab.
2005;90:4895–4903.
12. Rana S, Karumanchi SA, Levine RJ, Venkatesha S, Rauh-Hain JA, Tamez H,
Thadhani R. Sequential changes in antiangiogenic factors in early pregnancy
and risk of developing preeclampsia. Hypertension. 2007;50:137–142.
13. Stepan H, Unversucht A, Wessel N, Faber R. Predictive value of maternal
angiogenic factors in second trimester pregnancies with abnormal uterine
perfusion. Hypertension. 2007;49:818–824.
14. Erez O, Romero R, Espinoza J, Fu W, Todem D, Kusanovic JP, Gotsch
F, Edwin S, Nien JK, Chaiworapongsa T, Mittal P, Mazaki-Tovi S, Than
NG, Gomez R, Hassan SS. The change in concentrations of angiogenic
and anti-angiogenic factors in maternal plasma between the first and sec-
ond trimesters in risk assessment for the subsequent development of pre-
Downloaded from http://hyper.ahajournals.org/ by guest on July 30, 2017
eclampsia and small-for-gestational age. J Matern Fetal Neonatal Med.
2008;21:279–287.
15. Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, Kusanovic JP,
Gotsch F, Erez O, Mazaki-Tovi S, Gomez R, Edwin S, Chaiworapongsa T,
Levine RJ, Karumanchi SA. A longitudinal study of angiogenic (placental
growth factor) and anti-angiogenic (soluble endoglin and soluble vascu-
lar endothelial growth factor receptor-1) factors in normal pregnancy and
patients destined to develop preeclampsia and deliver a small for gesta-
tional age neonate. J Matern Fetal Neonatal Med. 2008;21:9–23.
16. Kusanovic JP, Romero R, Chaiworapongsa T, Erez O, Mittal P, Vaisbuch
E, Mazaki-Tovi S, Gotsch F, Edwin SS, Gomez R, Yeo L, Conde-Agudelo
A, Hassan SS. A prospective cohort study of the value of maternal plasma
concentrations of angiogenic and anti-angiogenic factors in early preg-
nancy and midtrimester in the identification of patients destined to develop
preeclampsia. J Matern Fetal Neonatal Med. 2009;22:1021–1038.
17. Powers RW, Jeyabalan A, Clifton RG, Van Dorsten P, Hauth JC, Klebanoff
MA, Lindheimer MD, Sibai B, Landon M, Miodovnik M; Eunice Kennedy
Shriver National Institute of Child Health Human Development Maternal-
Fetal Medicine Units Network. Soluble fms-Like tyrosine kinase 1 (sFlt1),
endoglin and placental growth factor (PlGF) in preeclampsia among high
risk pregnancies. PLoS One. 2010;5:e13263.
18. McElrath TF, Lim KH, Pare E, Rich-Edwards J, Pucci D, Troisi R, Parry
S. Longitudinal evaluation of predictive value for preeclampsia of cir-
culating angiogenic factors through pregnancy. Am J Obstet Gynecol.
2012;207:407.e1–407.e7.
19. Kleinrouweler CE, Wiegerinck MM, Ris-Stalpers C, Bossuyt PM, van
der Post JA, von Dadelszen P, Mol BW, Pajkrt E; EBM CONNECT
Collaboration. Accuracy of circulating placental growth factor, vascular
endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble
endoglin in the prediction of pre-eclampsia: a systematic review and meta-
analysis. BJOG. 2012;119:778–787.
20. Stepan H, Geipel A, Schwarz F, Krämer T, Wessel N, Faber R. Circulatory
soluble endoglin and its predictive value for preeclampsia in second-
trimester pregnancies with abnormal uterine perfusion. Am J Obstet
Gynecol. 2008;198:175.e1–175.e6.
21. Diab AE, El-Behery MM, Ebrahiem MA, Shehata AE. Angiogenic
factors for the prediction of pre-eclampsia in women with abnormal
midtrimester uterine artery Doppler velocimetry. Int J Gynaecol Obstet.
2008;102:146–151.
22. Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-
trimester prediction of hypertensive disorders in pregnancy. Hypertension.
2009;53:812–818.
23. Myatt L, Clifton R, Roberts J, Spong C, Wapner R, Thorp J Jr, Mercer
B, Peaceman A, Ramin S, Carpenter M, Sciscione A, Tolosa J, Saade G,
Sorokin Y, Anderson G; Eunice Kennedy Shriver National Institute of
Child Health and Human Development Maternal-Fetal Medicine Units
Network. Can changes in angiogenic biomarkers between the first and
second trimesters of pregnancy predict development of pre-eclampsia in a
low-risk nulliparous patient population? BJOG. 2013;120:1183–1191.
24. Roberts JM, Bell MJ. If we know so much about preeclampsia, why
haven’t we cured the disease? J Reprod Immunol. 2013;99:1–9.
25. Rana S, Schnettler WT, Powe C, Wenger J, Salahuddin S, Cerdeira AS,
Verlohren S, Perschel FH, Arany Z, Lim KH, Thadhani R, Karumanchi
SA. Clinical characterization and outcomes of preeclampsia with normal
angiogenic profile. Hypertens Pregnancy. 2013;32:189–201.
26. Fisher KA, Luger A, Spargo BH, Lindheimer MD. Hypertension in preg-
nancy: clinical-pathological correlations and remote prognosis. Medicine
(Baltimore). 1981;60:267–276.
27. Germain S, Nelson-Piercy C. Lupus nephritis and renal disease in preg-
nancy. Lupus. 2006;15:148–155.
28. Catalano PM. Management of obesity in pregnancy. Obstet Gynecol.
2007;109(2 pt 1):419–433.
29. Powe CE, Thadhani R. Diabetes and the kidney in pregnancy. Semin
Nephrol. 2011;31:59–69.
30. Marcantoni C, Fogo AB. A perspective on arterionephrosclerosis: from
pathology to potential pathogenesis. J Nephrol. 2007;20:518–524.
31. Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD.
Obesity-related glomerulopathy: an emerging epidemic. Kidney Int.
2001;59:1498–1509.
32. Kasiske BL, Napier J. Glomerular sclerosis in patients with massive obe-
sity. Am J Nephrol. 1985;5:45–50.
33. Lindheimer MD, Kanter D. Interpreting abnormal proteinuria in preg-
nancy: the need for a more pathophysiological approach. Obstet Gynecol.
2010;115(2 pt 1):365–375.
34. Koopmans CM, Bijlenga D, Groen H, et al; HYPITAT study group.
Induction of labour versus expectant monitoring for gestational hyperten-
sion or mild pre-eclampsia after 36 weeks’ gestation (HYPITAT): a multi-
centre, open-label randomised controlled trial. Lancet. 2009;374:979–988.
35. Sunderji S, Gaziano E, Wothe D, Rogers LC, Sibai B, Karumanchi SA,
Hodges-Savola C. Automated assays for sVEGF R1 and PlGF as an aid in
the diagnosis of preterm preeclampsia: a prospective clinical study. Am J
Obstet Gynecol. 2010;202:40.e1–40.e7.
36. Verlohren S, Galindo A, Schlembach D, Zeisler H, Herraiz I, Moertl MG,
Pape J, Dudenhausen JW, Denk B, Stepan H. An automated method for
the determination of the sFlt-1/PIGF ratio in the assessment of preeclamp-
sia. Am J Obstet Gynecol. 2010;202:161.e1–161.e11.
37. Gullai N, Stenczer B, Molvarec A, Fügedi G, Veresh Z, Nagy B, Rigó J Jr.
Evaluation of a rapid and simple placental growth factor test in hyperten-
sive disorders of pregnancy. Hypertens Res. 2013;36:457–462.
38. Chaiworapongsa T, Romero R, Savasan ZA, Kusanovic JP, Ogge G, Soto
E, Dong Z, Tarca A, Gaurav B, Hassan SS. Maternal plasma concentra-
tions of angiogenic/anti-angiogenic factors are of prognostic value in
patients presenting to the obstetrical triage area with the suspicion of pre-
eclampsia. J Matern Fetal Neonatal Med. 2011;24:1187–1207.
39. Moore AG, Young H, Keller JM, Ojo LR, Yan J, Simas TA, Maynard SE.
Angiogenic biomarkers for prediction of maternal and neonatal com-
plications in suspected preeclampsia. J Matern Fetal Neonatal Med.
2012;25:2651–2657.
40. Sibiude J, Guibourdenche J, Dionne MD, Le Ray C, Anselem O, Serreau
R, Goffinet F, Tsatsaris V. Placental growth factor for the prediction of
adverse outcomes in patients with suspected preeclampsia or intrauterine
growth restriction. PLoS One. 2012;7:e50208.
41. Chaiworapongsa T, Romero R, Whitten A, Tarca AL, Bhatti G, Draghici
S, Chaemsaithong P, Miranda J, Hassan SS. Differences and similarities
in the transcriptional profile of peripheral whole blood in early and late-
onset preeclampsia: insights into the molecular basis of the phenotype of
preeclampsiaa. J Perinat Med. 2013;41:485–504.
42. Moore AG, Young H, Keller JM, Ojo LR, Yan J, Simas TA, Maynard SE.
Angiogenic biomarkers for prediction of maternal and neonatal com-
plications in suspected preeclampsia. J Matern Fetal Neonatal Med.
2012;25:2651–2657.
43. Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of myocar-
dial infarction with sensitive cardiac troponin assays. N Engl J Med.
2009;361:858–867.
44. Reichlin T, Irfan A, Twerenbold R, et al. Utility of absolute and relative
changes in cardiac troponin concentrations in the early diagnosis of acute
myocardial infarction. Circulation. 2011;124:136–145.
45. Chaiworapongsa T, Romero R, Korzeniewski SJ, Kusanovic JP, Soto E,
Lam J, Dong Z, Than NG, Yeo L, Hernandez-Andrade E, Conde-Agudelo
A, Hassan SS. Maternal plasma concentrations of angiogenic/antiangio-
genic factors in the third trimester of pregnancy to identify the patient at
risk for stillbirth at or near term and severe late preeclampsia. Am J Obstet
Gynecol. 2013;208:287.e1–287.e15.
46. Whitten AE, Romero R, Korzeniewski SJ, Tarca AL, Schwartz AG,
Yeo L, Dong Z, Hassan SS, Chaiworapongsa T. Evidence of an imbal-
ance of angiogenic/antiangiogenic factors in massive perivillous
 202  Hypertension  February 2014
fibrin deposition (maternal floor infarction): a placental lesion associ-
ated with recurrent miscarriage and fetal death. Am J Obstet Gynecol.
2013;208:310.e1–310.e11.
47. Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler
H, Calda P, Holzgreve W, Galindo A, Engels T, Denk B, Stepan H. The
sFlt-1/PlGF ratio in different types of hypertensive pregnancy disor-
ders and its prognostic potential in preeclamptic patients. Am J Obstet
Gynecol. 2012;206:58.e1–58.e8.
48. Rolfo A, Attini R, Nuzzo AM, Piazzese A, Parisi S, Ferraresi M, Todros T,
Piccoli GB. Chronic kidney disease may be differentially diagnosed from
preeclampsia by serum biomarkers. Kidney Int. 2013;83:177–181.
49. Young B, Levine RJ, Salahuddin S, Qian C, Lim KH, Karumanchi SA,
Rana S. The use of angiogenic biomarkers to differentiate non-HELLP
related thrombocytopenia from HELLP syndrome. J Matern Fetal
Neonatal Med. 2010;23:366–370.
50. Verdonk K, Visser W, Russcher H, Danser AH, Steegers EA, van den
Meiracker AH. Differential diagnosis of preeclampsia: remember the solu-
ble fms-like tyrosine kinase 1/placental growth factor ratio. Hypertension.
2012;60:884–890.
51. Schnettler W, Dukhovny D, Wenger J, Salahuddin S, Ralston S, Rana S.
Cost and resource implications with serum angiogenic factor estimation in
the triage of pre-eclampsia. BJOG. 2013;120:1224–1232.
52. Thangaratinam S, Ismail KM, Sharp S, Coomarasamy A, Khan KS; Tests
in Prediction of Pre-eclampsia Severity review group. Accuracy of serum
Downloaded from http://hyper.ahajournals.org/ by guest on July 30, 2017
uric acid in predicting complications of pre-eclampsia: a systematic
review. BJOG. 2006;113:369–378.
53. Malarewicz A, Gruszka O, Szymkiewicz J, Rogala J. The usefulness of
routine laboratory tests in the evaluation of sudden threat of pregnant
woman and fetus in pre-eclampsia. Ginekol Pol. 2006;77:276–284.
54. Thangaratinam S, Koopmans CM, Iyengar S, Zamora J, Ismail KM, Mol
BW, Khan KS; TIPPS (Tests in Prediction of Preeclampsia’s Severity)
Review Group. Accuracy of liver function tests for predicting adverse
maternal and fetal outcomes in women with preeclampsia: a systematic
review. Acta Obstet Gynecol Scand. 2011;90:574–585.
55. Thangaratinam S, Gallos ID, Meah N, Usman S, Ismail KM, Khan KS;
TIPPS (Tests in Prediction of Pre-eclampsia’s Severity) Review Group.
How accurate are maternal symptoms in predicting impending complica-
tions in women with preeclampsia? A systematic review and meta-analy-
sis. Acta Obstet Gynecol Scand. 2011;90:564–573.
56. von Dadelszen P, Payne B, Li J, et al; PIERS Study Group. Prediction of
adverse maternal outcomes in pre-eclampsia: development and validation
of the fullPIERS model. Lancet. 2011;377:219–227.
57. Ganzevoort W, Rep A, de Vries JI, Bonsel GJ, Wolf H; PETRA-investigators.
Prediction of maternal complications and adverse infant outcome at admis-
sion for temporizing management of early-onset severe hypertensive disor-
ders of pregnancy. Am J Obstet Gynecol. 2006;195:495–503.
58. Menzies J, Magee LA, Macnab YC, et al. Current CHS and NHBPEP
criteria for severe preeclampsia do not uniformly predict adverse maternal
or perinatal outcomes. Hypertens Pregnancy. 2007;26:447–462.
59. Thadhani R, Kisner T, Hagmann H, et al. Pilot study of extracorporeal
removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation.
2011;124:940–950.
60. Fox KA, Longo M, Tamayo E, Kechichian T, Bytautiene E, Hankins
GD, Saade GR, Costantine MM. Effects of pravastatin on mediators of
vascular function in a mouse model of soluble Fms-like tyrosine kinase-
1-induced preeclampsia. Am J Obstet Gynecol. 2011;205:366.e1–366.e5.
61. Kumasawa K, Ikawa M, Kidoya H, Hasuwa H, Saito-Fujita T, Morioka
Y, Takakura N, Kimura T, Okabe M. Pravastatin induces placental growth
factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl
Acad Sci U S A. 2011;108:1451–1455.
62. Costantine MM, Cleary K; Eunice Kennedy Shriver National Institute of
Child Health and Human Development Obstetric–Fetal Pharmacology
Research Units Network. Pravastatin for the prevention of preeclamp-
sia in high-risk pregnant women. Obstet Gynecol. 2013;121(2 pt
1):349–353.
63. Conrad KP. Emerging role of relaxin in the maternal adaptations to normal
pregnancy: implications for preeclampsia. Semin Nephrol. 2011;31:15–32.
64. Jiang X, Bar HY, Yan J, Jones S, Brannon PM, West AA, Perry CA, Ganti
A, Pressman E, Devapatla S, Vermeylen F, Wells MT, Caudill MA. A
higher maternal choline intake among third-trimester pregnant women
lowers placental and circulating concentrations of the antiangiogenic fac-
tor fms-like tyrosine kinase-1 (sFLT1). FASEB J. 2013;27:1245–1253.
65. Myatt L, Clifton RG, Roberts JM, et al; Eunice Kennedy Shriver National
Institute of Child Health and Human Development (NICHD) Maternal-
Fetal Medicine Units (MFMU) Network. First-trimester prediction
of preeclampsia in nulliparous women at low risk. Obstet Gynecol.
2012;119:1234–1242.
66. Staff AC, Benton SJ, von Dadelszen P, Roberts JM, Taylor RN, Powers
RW, Charnock-Jones DS, Redman CW. Redefining preeclampsia using
placenta-derived biomarkers. Hypertension. 2013;61:932–942.
67. Powers RW, Roberts JM, Plymire DA, Pucci D, Datwyler SA, Laird
DM, Sogin DC, Jeyabalan A, Hubel CA, Gandley RE. Low placental
growth factor across pregnancy identifies a subset of women with pre-
term preeclampsia: type 1 versus type 2 preeclampsia? Hypertension.
2012;60:239–246.
68. Sheehan HL, Lynch JB. Pathology of Toxaemia of Pregnancy. Baltimore,
MD: Williams and Wilkins Co.; 1973.
69. Li Z, Zhang Y, Ying Ma J, Kapoun AM, Shao Q, Kerr I, Lam A, O’Young
G, Sannajust F, Stathis P, Schreiner G, Karumanchi SA, Protter AA,
Pollitt NS. Recombinant vascular endothelial growth factor 121 attenuates
hypertension and improves kidney damage in a rat model of preeclampsia.
Hypertension. 2007;50:686–692.
 Angiogenic Factors in Diagnosis, Management, and Research in Preeclampsia
Sarosh Rana, S. Ananth Karumanchi and Marshall D. Lindheimer

Hypertension. 2014;63:198-202; originally published online October 28, 2013;

doi: 10.1161/HYPERTENSIONAHA.113.02293
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