DISCUSSION
Our findings demonstrate that the longitudinal changes in sFlt-1 levels
from admission for early-onset severe PE improve the prediction of
maternal complications and the interval to delivery over baseline
clinical and analytical parameters.
Several previous studies have showed the ability of angiogenic factors
when cross-sectionally measured at admission for suspected PE in
stratifying the risk of adverse outcome, and demonstrated that abnormal
values were associated with a shorter duration to delivery (14,15,33).
The angiogenic factors changes during pregnancy are also well known
(34–36). In light of this evidence, it is reasonable to assume that the
change of the angiogenic factors levels over time may add further
predicting capacity for adverse outcome. Indeed, Zeisler et al (37)
found that in patients with suspected PE there was a greater
longitudinal increase in the sFlt-1/PlGF ratio in women who developed PE
and adverse maternal outcome than in those who did not develop it.
Additionally, Schoofs et al (16) suggested that repeated measurements of
the sFlt-1/PlGF ratio seem to be superior in predicting PE and its
complications to a single measurement.
All this evidence, however, come from studies in women with suspected PE
and whether these findings apply to women with diagnosed PE was unclear,
especially in early-onset severe PE. A retrospective study including 34
patients with diagnosed PE demonstrated that early-onset cases had a
higher daily increase in sFlt-1 (11% vs. 3%) and sFlt-1/PlGF ratio
(23% vs. 8%) compared to late-onset PE (17). More recently, Baltajian
et al (18) reported in a prospective cohort of 99 women with suspected
PE (53 of them confirmed) admitted before 37 weeks that daily changes of
sFlt-1 and sFlt-1/PlGF ratio were significantly higher in women ending
up having a maternal or fetal adverse outcome. This study could be
criticized because many of the described complications like FGR and
transaminitis were likely already present at admission. Thus, rather
than assessing the role of the angiogenic factors longitudinal changes
in predicting complications, this study may have addressed the
association of these changes with features of severe PE. Our results
strengthen the findings from previous studies and demonstrate the
clinical value of the angiogenic factors longitudinal changes even in
confirmed early-onset severe PE.
Interestingly, we found sFlt-1 more strongly associated with maternal
complications than PlGF. Consistently with our findings, the series by
Baltajian et al (18), that included women admitted for PE suspicion,
found that the median daily increase of sFlt-1 was 6 times higher in
women with adverse outcome, while no significant difference were found
in daily decrease of PlGF between women with and without adverse
outcome. In PE, maternal sFlt-1 levels drop after delivery to
< 1% of its pre-delivery value while PlGF drops to 30% (36),
suggesting that sFlt-1 is almost uniquely produced by the placenta while
PlGF have other sources. Indeed, PlGF is expressed in a variety of
organs , tissues and cells (38). As the stressed endothelium produces
PlGF (39), this may be a compensatory mechanism to keep minimum levels
of circulating PlGF. Thus, one may speculate that being more closely
correlated with placental disease, sFlt-1 is a better marker of PE
severity than PlGF. The increased sFlt-1 values may trigger the
endothelial dysfunction that leads to PE complications (40).
Most guidelines recommend expectant management in selected cases of PE
until 34 weeks (41), based on the evidence that the risk of serious
complications is low when appropriate care is provided and on the
derived neonatal benefits (9,10,42). However, the selection of cases at
especially high-risk for maternal complications is clinically
challenging. All guidelines recommend a similar set of severity criteria
(41), that were established from experts opinion without a good evidence
on their individual performance in predicting complications. In
addition, except for the Canadian guideline (43), gestational age at
diagnosis was not included as a severity criteria, while there is good
evidence on its independent contribution in predicting maternal
morbidity (44). A step forward was made by the PRE-EMPT consortium
developing and validating a scoring tool for risk-stratification of
women admitted with PE (the PIERS score), with good capacity and
predictive performance (11). However, this model included women with any
onset PE, and not specifically those with early-onset. More recently,
the PREP-L model was specifically derived for early-onset PE. Compared
to the PIERS model, which had an AUC between 0.7-0.8 at one week after
admission, the PREP-L model showed discrimination of 0.82 for a longer
period until postnatal discharge from hospital (12). Our study shows
that the addition of sFlt-1 delta values may increase the prediction of
maternal complications achieved by PREP-L and sFlt-1 at admission. If
confirmed, our results would enable the use of longitudinal changes in
angiogenic factors as a stratifying tool to stablish time of delivery.
Our series has some unique features. It is a prospective cohort of women
admitted for confirmed early-onset severe PE. The angiogenic factors
were longitudinally measured and evaluated for the prediction of
incident complications. In addition, managing clinicians were blinded to
these measurements. We also acknowledge some limitations. First, the
relatively small sample size which does not allow the evaluation of
individual complications. However, this sample size has to be regarded
in the context of the very low incidence of early-onset PE
(~0.5%), which is even lower if we consider severe
cases without complications at admission (7). Thus, 63 cases correspond
to a base population of more than 15,000 deliveries. Second, we only
measured the angiogenic factors at two time points, and, therefore,
other non-linear trends could not be explored. In particular, whether
the rise in sFlt-1 precedes the onset of the complication could not be
assessed in our study. Finally, our findings do not necessarily mean
that modifying the clinical management according to longitudinal changes
in sFlt-1 would improve the maternal outcomes.