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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 6, November/December 2018
AFRICA
389
prediction models is that a significant level of expertise is required
to perform Doppler, with substantial training needed to reach
high intra- and inter-observer variability coefficients. Therefore
the availability of these screening tests may not be widespread and
may be confined to specialised foetal units. Furthermore, costs
of routinely doing complex placental hormone determinations,
such as PLGF and pregnancy-associated plasma protein A
(PAPPA), would also be a limiting factor.
However, from a clinical perspective, late-onset PE is probably
not as important as the early-onset type, as it tends to be less
aggressive, and due to the more advanced gestational age and
therefore lower risk of prematurity, the threshold for delivery
is low. On the other hand, screening for mainly early-onset PE,
which has a good detection rate with an acceptable false-positive
rate, and is the type of PE that appears to be more aggressive,
will result in earlier, closer foeto-maternal monitoring and earlier
management protocols being instituted, which would contribute
to reducing materno-foetal compromise. Screening in the first
trimester also has the critical advantage that prophylaxis can be
instituted in the form of low-dose aspirin, which has been shown
to prevent PE if commenced in the first trimester (see below).
Screening is divided into the three trimesters.
First-trimester screening for PE
PE screening forms part of the 11- to 14-week risk assessment,
which also incorporates chromosomal screening for trisomies 21,
18 and 13, as well as an early anatomical scan. The conventional
view is that physiological transformation of the spiral artery
occurs in the first and early second trimester of pregnancy.
Therefore observations that a higher proportion of spiral arteries
show failure of physiological transformation in placental bed
biopsies from patients with PE than in those with normal
pregnancies suggest that reduced utero-placental flow precedes
the clinical manifestations of PE.
23
The identification of UtADV as a surrogate marker of utero-
placental ischaemia, which reflects the maladaptive placental
process, allowed the next important development – that of risk-
prediction models in combination with maternal blood tests,
blood pressure and other non-invasive vascular indices.
26,27,34
These now exclusively use either the mean or lowest pulsatility
index (PI) of the two uterine arteries, the latter having marginally
better screening performance for some early-onset complications.
In this model, maternal history plus the lowest uterine artery PI
gave 80% sensitivity for diagnosis of early-onset PE at a 10%
false-positive rate.
26
In a further step in the development of a first-trimester
screening model, it soon became clear that first-trimester
biomarkers of placentation prior to 13 weeks – most notably
PAPPA, plasma protein 13 and PLGF – are associated
individually with a risk of PE. Poon
et al
.
26,34
found that a
combination of maternal factors, serum markers and lowest
uterine artery PI at 11 to 13 weeks gave a detection rate of just
under 90% for a 5% false-positive rate for early-onset PE (
<
34
weeks). Foidart
et al
. obtained a particularly high sensitivity
for PE requiring delivery before 34 weeks, of 97% for a screen
positive of 10%, by using s-Eng in combination with PLGF,
lowest uterine artery PI and maternal factors at 11 to 13 weeks.
Khalil
et al
.
35
reported a novel approach to screening:
contingency screening at 11 to 13-plus-six weeks, combining
a non-invasive vascular measurement (augmentation index)
with plasma protein 13 and mean uterine artery PI, with
sensitivities of 93% for a screen-positive 10% rate. The first-
trimester screen, that is, between 11 and 14 weeks’ gestation, has
become a premier screening assessment that incorporates not
only aneuploidy screening for risks for trisomies 21, 18 and 13
[using a combination of chromosomal markers, such as nuchal
translucency, nasal bone assessment, ductus venosus Doppler
and tricuspid regurgitation, and placental hormones PAPPA
and beta-human chorionic gonadotropin (BHCG)] with a
sensitivity of 90% for a 5% false-positive rate, but also risks for
pre-eclampsia and growth restriction, using a combination of
maternal history, biophysical maternal parameters, mean arterial
blood pressure, uterine artery PI and PAPPA, with a sensitivity
of 80% for a 10% false-positive rate.
26,34
First-trimester screening can confer risks with a sensitivity of
80% for a 10% false-positive rate for pre-eclampsia and growth
restriction, using a combination of maternal history, biophysical
maternal parameters, mean arterial blood pressure, uterine
artery PI and PAPPA.
Second-trimester screening for PE
As noted above, there is very good evidence indicating that
abnormal UtADV in the second trimester of pregnancy is a
risk factor for the development of PE in the index pregnancy.
23-25
Collectively, evidence indicates that abnormal UtADV during
pregnancy is a surrogate marker of chronic utero-placental
ischaemia and an important risk factor for the development of
PE.
Chronic utero-placental ischaemia appears to be more
relevant in the pathogenesis of early-onset PE than in term or
post-term PE.
13,14
This view is supported by the observation
that high impedance to blood flow in both uterine arteries in
the second trimester is associated with a higher risk for PE at
<
34 weeks than at
>
34 weeks of gestation.
23-25
This is important
because early-onset PE is more severe,
36
associated with a
higher proportion of growth-restricted fetuses,
36
a higher risk of
maternal death,
37
and a higher frequency of placental pathology
38
than late-onset PE. An abnormal UtADV is an independent
factor for identifying patients at risk for PE with an OR of 25.7
(95% CI: 9.01–73.31)
39
in the second trimester.
To improve sensitivities of PE, one could even introduce a
sequential model of screening using the first-trimester PE risk
assessment as an
a priori
risk and adjusting with the second-
trimester uterine artery Doppler assessment, and possibly even
adding a second-trimester maternal serum alpha foetoprotein
assessment, which is a known marker of placental disease,
reflecting breaks in the placental intervillous barriers.
40
As a
significant level of expertise is required to perform this test
correctly, as mentioned above, large colleges would be reluctant
to introduce it as universal screening as it would be become
standard of care and the expertise may not be generally available.
Until there is dissemination of the technique through awareness
and training of Doppler, it will unfortunately not find its way as
universal screening at this stage.
The high diagnostic and predictive value of the sFlt-1/PLGF
ratio in patients at risk of pre-eclampsia has been shown in
the recent literature, and estimation of the sFlt-1/PLGF ratio
has therefore become an additional tool in the management of