A series of recent publications have shown that early preeclampsia can be successfully
predicted in the first trimester using a combination of maternal, biophysical and
biochemical factors [1]
[2]
[3]
[4], and administration of low-dose aspirin to women identified as high-risk can reduce
the development of preterm preeclampsia by about 60 % [5]. Given that abnormal placentation and placental insufficiency are commons pathway
to many cases of preeclampsia and fetal growth restriction (FGR), we intuitively use
the same strategies to predict and prevent FGR. However, are we as successful in FGR
as we are in preeclampsia?
A variety of definitions
In contrast to preeclampsia, which is a clearly defined condition, multiple terms
describe suboptimal fetal growth, and two of them, i. e. small for gestational age
(SGA) and FGR, are often used interchangeably. This happens despite the two being
two different conditions. SGA merely signifies a fetus (or a neonate) that is smaller
than a given centile (usually the 10th), whereas FGR involves the failure of the fetus to reach its developmental potential,
and it normally refers to a small fetus with some evidence of hypoxia. Therefore,
one might say that FGR is a subset of SGA, and this is the case most of the times,
but not always. A growth-restricted fetus can be non-SGA (i. e. > 10th centile for estimated weight or abdominal circumference) and still be FGR, if its
growth potential was meant to be higher. This reality has been acknowledged by the
recent consensus definition for FGR, which introduces the option of a fetus crossing
centiles, even if its eventual centile is > 10th [6]. Despite this development, different definitions have traditionally been used in
the existing studies, even within the terms SGA and FGR (different cutoffs, Doppler
parameters, pre- or postnatal weight etc), adding to the heterogeneity of the literature.
Targeting small fetuses
Prediction of FGR (or SGA) has been pursued along that of preeclampsia, and it was
early acknowledged that the yield of screening models is higher when FGR coexists
with preeclampsia rather than when it is an isolated condition. Four years ago, the
Fetal Medicine Foundation (FMF) developed a dedicated screening algorithm targeting
SGA, and they reported that, by combining maternal, biochemical and biophysical factors,
about 50 % of SGA can be predicted for a 10 % false positive rate [7]. However, is this the case?
Prediction of small fetuses through preeclampsia-oriented screening
Prediction of small fetuses through preeclampsia-oriented screening
What happens in practice is that we screen for preeclampsia, we treat screen-positive
cases aiming to prevent preeclampsia, and along the way we predict some of the FGR
cases and prevent a subgroup of them. This is beautifully illustrated in a recent
publication by the FMF, where data from the SPREE study (which is a screening study)
were combined with data of the ASPRE trial (which is an interventional study) to show,
among else, what happens with SGA when we screen and treat for preeclampsia. What
this study found is that, by screening for preeclampsia, and using a cut-off of 1:100
for preeclampsia, we can predict 31 % of neonates with birth weight < 10th centile requiring delivery before 37 weeks, and 35 % of such babies requiring delivery
before 32 weeks [1]. Of course, the prediction rates significantly increased for small neonates with
coexisting preeclampsia, but this is a different group whatsoever. Focusing on even
smaller neonates (birthweight < 3rd centile) in the absence of preeclampsia, this screening strategy can predict about
40 % of those requiring delivery before 37 or 32 weeks [1]. So, in practice, screening for preeclampsia with a 10 % screen-positive rate (which
is where 1:100 corresponds to) can predict about 35 – 40 % of the small and very small
fetuses requiring early delivery.
Prevention of small fetuses through preeclampsia-oriented screening
Prevention of small fetuses through preeclampsia-oriented screening
Administration of prophylactic aspirin to these screen-positive (for preeclampsia)
cases, will significantly reduce the risk for small neonates with preeclampsia, but
will only reduce the risk for the subgroup of such neonates without preeclampsia that
require delivery before 32 weeks, by about 60 %. Of course this is quite an important
group in terms of morbidity, but it only comprises about 0.25 % of the population
[1].
A synopsis…
It appears thus that combined first-trimester screening for preeclampsia can predict
about 40 % of the subgroup of small fetuses who will need a preterm delivery. Prophylactic
aspirin in screen-positive cases will reduce the risk for the small but clinically
important group of very preterm (< 32 weeks) small fetuses by about 60 %.
…and some more unanswered questions
…and some more unanswered questions
There are yet more unanswered questions, including the possible role of maternal hemodynamics
as part of a combined screening, or the ability of the fetal fraction of cell-free
DNA in the maternal blood to act as an independent predictor. And, of course, there
is the issue with twins. There is an ongoing debate whether twin-specific growth charts
should be used, or charts of singleton are applicable as well, so problems like this
need to be solved before aiming at screening.
Dr Alexandros Sotiriadis
Dr Konstantinos Dinas
Second Department of Obstetrics and Gynecology
Faculty of Medicine, Aristotle University of Thessaloniki, Greece
