The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l

Improving the Prediction of Preeclampsia

Ellen W. Seely, M.D., and Caren G. Solomon, M.D., M.P.H.

Preeclampsia is a leading cause of maternal and
neonatal death in the United States and world-
wide,1 yet effective strategies are lacking for
prevention and treatment. Since delivery remains
the only “cure,” preeclampsia is a major cause of
iatrogenic prematurity.
Although the pathogenesis of preeclampsia is
not completely understood, altered levels of an-
giogenic factors appear to play a role.2 Elevated
levels of soluble fms-like tyrosine kinase 1 (sFlt-1;
an inhibitor of vascular endothelial growth fac-
tor), reduced levels of placental growth factor
(PlGF), and an increased sFlt-1:PlGF ratio have
been reported both in women with established
preeclampsia and in women before the develop-
ment of preeclampsia.3 However, the values in
women in whom preeclampsia develops overlap
with the values in women in whom preeclampsia
does not develop, and it has been unclear whether
these values can be used to discriminate be-
tween these women in practice. Prospective
studies assessing whether the levels of these
angiogenic factors early in pregnancy (before 20
weeks of gestation) could predict preeclampsia
have yielded disappointing results.4,5 However,
prospective single-center studies of women later
in pregnancy have suggested that the sFlt-1:PlGF
ratio may be useful as a diagnostic aid for triag-
ing women with singleton pregnancies and sus-
pected preeclampsia.6,7
Caring for women who present with elevated
blood pressure in the second half of pregnancy,
without other signs of preeclampsia, can be ex-
tremely challenging. The presentation may reflect
gestational hypertension, previously undiagnosed
chronic hypertension (which may go unnoticed
earlier in pregnancy, when blood pressure typi-
cally falls), or an early stage of preeclampsia.
With monitoring and treatment as indicated,
women with gestational hypertension and chron-
ic hypertension generally have good pregnancy
outcomes. However, preeclampsia requires care-
ful inpatient monitoring of both the mother and
the fetus and possibly early delivery. Given the
uncertainty and the serious maternal and fetal
risks associated with preeclampsia, women pre-
senting with hypertension after 20 weeks of ges-
tation are often hospitalized for evaluation and
monitoring, with substantial attendant costs.
Therefore, a test that could help clinicians decide
which women can be followed safely on an out-
patient basis and which women need to be admit-
ted to the hospital would be of great benefit.
In this issue of the Journal, Zeisler et al.8 report
the results of a multicenter, prospective study of
the ratio of sFlt-1 to PlGF in two cohorts of
women between 24 weeks and 37 weeks of ges-
tation with singleton pregnancies who presented
with a clinical suspicion of preeclampsia or the
HELLP syndrome (characterized by hemolysis,
elevated liver-enzyme levels, and low platelet
counts). In the development cohort (500 women),
an sFlt-1:PlGF ratio of 38 was the optimal cutoff
in distinguishing between women in whom pre-
eclampsia would develop and those in whom it
would not develop in the next week. In a subse-
quent validation cohort (550 women), a ratio of
38 or lower had a negative predictive value of
99.3% (95% confidence interval [CI], 97.9 to
99.9); that is, a woman with results in this range
was extremely unlikely to have progression to
preeclampsia or HELLP within the next week. A
low ratio also predicted the absence of fetal ad-
verse outcomes in the same time frame. How-

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 Editorial
ever, a ratio above 38 had a positive predictive
value for preeclampsia in the next 4 weeks of
only 36.7% (95% CI, 28.4 to 45.7%).
Strengths of this study include its multisite
prospective design, the large sample size, and
the inclusion of a validation cohort. However,
several features of the study require consider-
ation in translating its findings into clinical
practice. The test was applied only to women
between 24 weeks and 37 weeks of gestation
who had “suspected” preeclampsia (on the basis
of new-onset or worsening hypertension or pro-
teinuria) or other suggestive clinical findings
(e.g., headache, visual disturbances, and abnor-
malities in laboratory test results). It cannot be
expected to perform as well if it is applied non-
selectively in populations in which the likeli-
hood of preeclampsia is low or if it is used in
women at weeks of gestation outside the range
of weeks studied. The study participants were
mostly white, and more than one quarter were
obese before pregnancy; levels of sFlt-1 and PlGF
may be affected by obesity,9 and limited data
have suggested possible differences in levels ac-
cording to race or ethnic background.10 Also, the
present report was limited to women with single-
ton gestations, although women with multiple
gestations were also recruited. Women with
multiple gestations are at higher risk for pre-
eclampsia, and thus data on such women would
be valuable to guide practice.
This study used Elecsys immunoassays (Roche
Diagnostics), run in a single laboratory, for both
components of the ratio; as the authors note, the
ratio for discrimination may well vary with the
assay used. The study focused on the negative
predictive value of the ratio during the following
week, suggesting the need for weekly retesting of
women with low ratios; determining the best in-
terval before retesting will require further study.
As the authors acknowledge, a randomized
trial is needed to determine the effects of the
use of the ratio, as compared with usual care, in
84 n engl j med 374;1 nejm.org  January 7, 2016
The New England Journal of Medicine
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triage decisions. Of particular interest would be
its effects on the rates of hospitalization, pre-
term delivery, and other adverse pregnancy out-
comes, as well as on the costs of care. Mean-
while, because a low sFlt-1:PlGF ratio has a very
high negative predictive value for the develop-
ment of preeclampsia and HELLP, the use of the
ratio has a role in identifying women with sin-
gleton pregnancies and suspected preeclampsia
who have a very low risk of the development of
preeclampsia in the ensuing week.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the Endocrinology, Diabetes, and Hypertension Division,
Brigham and Women’s Hospital, Boston (E.W.S.).
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DOI: 10.1056/NEJMe1515223
Copyright © 2016 Massachusetts Medical Society.