Interpretation in light of other evidence
To improve the prediction of adverse outcomes related to PE different
tools such as the combination of signs and symptoms of PE, the
evaluation of fetal and maternal Doppler ultrasound and biochemical
markers alone and in combination with clinical factors have been
investigated. In 2017, Thangaratinam et al demonstrated that the
PREP-model predicts maternal outcomes in patients with clinical
early-onset PE, but the prediction of perinatal outcomes was not
evaluated (9). In our study, the PREP-L score had a limited predictive
value of the adverse neonatal outcomes in early-onset PE with severe
features (AUC ROC 0.69 [95% CI 0.51-0.86]).
There is controversy regarding the role of fetal Doppler in PE in
predicting adverse neonatal outcome. Rani et al reported that Doppler
indices of MCA and UA have good specificity but low sensitivity for
detecting adverse perinatal outcomes in PE with or without severe
features (13). Two prospective studies, including respectively 100 and
60 patients with severe PE, support CPR as a tool for the prediction of
adverse perinatal outcomes but the majority of cases were late-onset PE
(mean gestational age at admission 37 weeks of gestation) (10,11).
Similarly, Orabona et al in a cohort study on 168 women with PE
diagnosed at a mean gestational age of 32+6 weeks
found that CPR was more accurate than each of their components alone in
predicting adverse neonatal outcomes, albeit only marginally (34). The
heterogenicity of the women included in these studies (mixing early and
late; and non-severe and severe PE) may account for the inconsistent
results. In our population of early-onset PE with severe features,
Doppler indices of MCA, DV and CPR were not significantly different
between the groups with and without adverse neonatal outcomes, and only
the composite proportion of fetuses with advanced Doppler findings
(absent/reversed diastolic flow in the UA or pulsatile DV) showed
differences between groups. This could be explained by the greater
placental involvement in the early-onset cases and the higher
association with FGR; and the stronger impact of prematurity in these
cases.
In the last years, several studies have shown that angiogenic factors
can increase the prediction of PE and its adverse outcomes in patients
with impending signs and symptoms of the disease (18,19,35). However,
the role of angiogenic factors is not similarly promising in women with
established severe PE. In 2014, Pinheiro et al reported a correlation
between angiogenic imbalance and poor neonatal outcome in early-onset PE
(36). Simon et al demonstrated an association between sFlt-1/PlGF ratio
>655 and risk of delivery in less than 48 hours,
nevertheless none of the angiogenic factors evaluated were good
predictors of adverse maternal or perinatal outcomes (37). In addition,
because both the degree of angiogenic imbalance and the neonatal
outcomes are highly correlated with the gestational age at onset of the
disease (5,21), we propose that the predictive role of these markers
should be evaluated as the added value over a baseline risk capturing
the gestational age at onset, such as the PREP score.
In 2021, Droge et al found that integrating all available clinical and
biochemical markers into a regression model yields the best predictive
performance of PE-related adverse outcomes, including both maternal and
perinatal (the AUC of blood pressure and proteinuria was 69%, the AUC
of the sFlt-1/PlGF on its own was 85.7% and including all clinical
information was 88.7%). The cohort were women with suspected disease
(n=1117) and only 351 women (31.4%) had the final diagnosis of PE, most
with late-onset disease (38). Gomez-Arriaga et al, in 2014, using a
cohort of 51 singleton pregnancies with early-onset PE suggested that
the sFlt-1/PlGF ratio in combination with gestational age is useful for
the prognostic assessment of neonatal complications (AUC was 89%
corresponding to sensitivity, specificity PPV and NPV of 64%, 83%,
57% and 97% respectively), but this combination has limited value for
the prediction of maternal complications (12). In the present study, we
found that the combination of maternal characteristics at admission
(PREP-L score) and advanced Doppler or PlGF has a good predictive value
(AUC ~ 90%) for the prediction of neonatal
complications.
Delivery is the definitive treatment of PE but the optimal time of
delivery in severe cases remains controversial because the net benefit
between reducing maternal risks by planned delivery and the secondary
neonatal risk associated with prematurity is unclear. Therefore, it is
important to develop prognostic tools to counsel the trade-off between
neonatal benefits versus maternal risks of expectant management. While
patients and health professionals give a similar importance to maternal
complications as core outcomes of PE, neonatal complications are seen as
more relevant by patients than by professionals or researchers (39).
Therefore, to advance towards a patient-centered care and shared
decision-making, prediction models for adverse neonatal outcomes are
needed in the management of PE. The combination of a maternal risk score
(which includes gestational age at onset of PE) and fetal Doppler and/or
PlGF predicts with good accuracy those cases at risk of adverse neonatal
outcomes.