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.