This study demonstrates that the use of sFlt-1/PlGF ratio in risk assessment for prenatal counseling in late-onset FGR and SGA pregnancies may help to predict adverse pregnancy outcomes at the time of diagnosis.
Two multivariable models were constructed (one including sFlt-1/PlGF and one without sFlt-1/PlGF) and their predictive ability was compared to that of the model with sFlt-1/PlGF alone. No significant differences were found between the multivariable model with sFlt-1/PlGF and the model with sFlt-1/PlGF alone in terms of predicting elective delivery before 37 WG and APOs. However, when comparing both multivariable models, the one without sFlt-1/PlGF had a significantly poorer performance than the one with sFlt-1/PlGF for predicting elective delivery before 37 WG and APOs. In the univariable analysis, the sFlt-1/PlGF ratio was the best marker for predicting delivery before 35 WG, with a predictive ability higher than that of UtAPI, although not significantly.
Recently, two algorithms with sFlt-1/PlGF have been published, showing a good performance for predicting adverse outcomes in early-onset FGR [35,36]. Nevertheless, few studies have investigated the added value of a predictive model for individual risk assessment in late-onset FGR and SGA.
A recent publication made among 175 gestations with SGA explored the potential value of a combined predictive model including maternal risk factors, EFW centile, fetal Doppler assessment and the combination of estriol and PlGF. This group showed a detection rate of 62% for the prediction of APO with the combined model . In that study, sFlt-1/PlGF was not measured and the prediction of elective delivery was not assessed; therefore, the results cannot be compared to our study.
A previous study conducted in 198 SGA pregnancies between 30 and 40 WG concluded that PlGF and sFlt-1 values at diagnosis can predict adverse outcomes with a similar performance to that of Doppler parameters . Additionally, the combination of angiogenic factors and Doppler parameters did not improve the predictive ability of sFlt-1/PlGF or Doppler. In that study, for APO prediction, the ROC curves for CPR, PlGF multiples of the median (MoM) and the combination of both were 0.652, 0.656 and 0.684, respectively. However, the definition of APO in that study was different to the definition given in this study, and therefore, comparisons between AUC and DR were not possible.
Another study conducted in 62 SGA pregnancies at more than 34 WG showed that sFlt-1/PlGF>38 at diagnosis was associated with a lower birth weight (2045 g vs 2405 g, P<0.001). In that study a positive correlation between sFlt-1/PlGF and UtAPI was also found .
These studies provide evidence that the sFlt-1/PlGF ratio is a good marker for identifying SGA fetuses at a greater risk of adverse outcomes, but do not provide a model to determine a patient’s specific risk for elective preterm delivery or the occurrence of APOs. With the exception of these studies, research published to date on predicting pregnancy outcomes is mainly focused on feto-placental Doppler findings and the progression of these findings; however, in late-onset FGR and SGA, the progression of Doppler findings is not as predictable as in early-onset FGR and SGA . Therefore, the uncertainty regarding pregnancy prognosis added to the fact that a larger number of ultrasonographic examinations are usually performed in FGR and SGA pregnancies, render both late-onset FGR and SGA deeply stressful pregnancy conditions for parents, as well as a healthcare burden .
The multivariable model with sFlt-1/PlGF and the model with sFlt-1/PlGF alone showed a similar ability to predict delivery before 37 WG; therefore, both models may potentially be used to evaluate a patient-specific risk. However, when different approaches with comparable results are available, the simplest approach should be used according to the statistical principle of parsimony , and thus, the use of sFlt-1/PlGF alone is preferred for individual risk assessment. The multivariable model without the sFlt-1/PlGF ratio showed a good overall performance for predicting APOs and may; therefore, be useful when the sFlt-1/PlGF ratio is not available. In addition, for predicting delivery before 35 WG, the univariable model with UtAPI may be used when the sFlt-1/PlGF ratio is not available.
The main strengths of this study are its prospective design with a relatively large cohort of late-onset FGR and SGA pregnancies, and the incorporation of the sFlt-1/PlGF ratio for assessing potential adverse pregnancy outcomes at the time of diagnosis. Additionally, since sFlt-1/PlGF might not be available at diagnosis in all clinical settings, we also provide a model based on maternal characteristics and ultrasonographic markers, which allows a risk calculation without including the sFlt-1/PlGF ratio.
We acknowledge some limitations of this study. Firstly, our results could be of great value for individualized prenatal counseling; however, they could be overfitted since they were developed in a single population. Therefore, these preliminary findings should undergo external validation in a larger cohort before being used in clinical practice. Secondly, sFlt-1/PlGF results were not blinded to the investigators, which may have influenced the decision-making process for planning follow-up or steroid administration for fetal maturation in some cases, even though management was intended to be undertaken without taking into consideration sFlt-1/PlGF results. Nevertheless, the indication for elective delivery was based strictly on EFW, Doppler assessment and CTG findings in all cases. Finally, as this was an observational study, our findings cannot be used for planning delivery or tailoring follow-up. These decisions should be based exclusively on current evidence-based protocols guided by EFW, CTG and Doppler findings.