ETV6::RUNX1 positive pediatric acute lymphoblastic leukemia frequently has a prenatal origin and follows a two-hit model: a first somatic alteration leads to the formation of the oncogenic fusion gene ETV6::RUNX1 and the generation of a preleukemic clone in utero. Secondary hits after birth are necessary to convert the preleukemic clone into clinically overt leukemia. However, prenatal factors triggering the first hit are still not determined. Here, we explore the influence of maternal factors during pregnancy on the prevalence of the ETV6::RUNX1 fusion. To this end, we employed a nested interventional cohort study ( IMPACT-BCN trial), including 1221 pregnancies (randomized into usual care, Mediterranean diet, or mindfulness-based stress reduction) and determined the prevalence of the fusion gene in DNA of cord blood samples at delivery (n=741) using the state-of-the-art GIPFEL ( genomic inverse PCR for exploration of ligated breakpoints) technique. 6.5% (n=48 of 741) of healthy newborns tested positive for ETV6::RUNX1. Our multiple regression analyses showed a trend towards lower ETV6::RUNX1 prevalence in offspring of the high-adherence intervention groups. Strikingly, corticosteroid use for lung maturation during pregnancy was significantly associated with ETV6::RUNX1 (adjusted OR 3.9, 95%CI 1.6-9.8) in 39 neonates, in particular if applied before 26 weeks of gestation (OR 7.7, 95%CI 1.08-50) or if betamethasone (OR 4.0, 95%CI 1.4-11.3) was used. Prenatal exposure to corticosteroids within a critical time window may therefore increase the risk to develop ETV6::RUNX1+ preleukemic clones and potentially leukemia after birth. Taken together, this study indicates that ETV6::RUNX1 preleukemia prevalence may be modulated and potentially prevented.

ABSTRACT Objective: To assess the predictive value for adverse neonatal outcome of Doppler ultrasound, angiogenic factors and multi-parametric risk-score models in women with early-onset severe preeclampsia. Design: Prospective cohort study. Setting: Maternity units in two Spanish hospitals. Population: Women with diagnosis of early-onset severe pre-eclampsia. Methods: A multi-parametric risk score model, Doppler ultrasound, and levels of angiogenic factors were measured at admission. The predictive value for adverse neonatal outcome was calculated. Main outcome measures: Composite of adverse neonatal outcome. Results: Of 63 women with early-onset severe preeclampsia, 18 (28.6%) presented an adverse neonatal outcome. PlGF showed the best discrimination between neonatal outcomes among angiogenic factors. Good predictive values for the prediction of neonatal complications were found with the combination of PREP-L score with advanced Doppler (AUC ROC 0.9 95% CI 0.82-0.98]) and with PlGF levels (AUC ROC 0.91 [95% CI 0.84-0.98]). Conclusions:  The combination of maternal risk scoring (PREP-L score) with angiogenic factors or fetal Doppler ultrasound at the time of diagnosis of early-onset preeclampsia with severe features performs well in predicting adverse neonatal outcome. Keywords: Angiogenic factors; Early-onset severe preeclampsia; Hypertension in pregnancy; Neonatal adverse outcome; Doppler ultrasound; Placental growth factor; Soluble fms-like tyrosine kinase 1.

Background: Maternal levels of angiogenic factors are promising prognostic parameters in patients with suspected preeclampsia, but in women with confirmed preeclampsia this performance has been less explored. Objective: To assess in women with early-onset severe preeclampsia whether longitudinal changes in angiogenic factors improve the prediction of adverse outcome. Study design: A cohort was created of consecutive women admitted for early-onset severe preeclampsia with no indication for immediate delivery. Levels of placental growth factor [PlGF], soluble fms-like tyrosine kinase [sFlt-1] and sFlt-1/PlGF ratio were measured at admission and before delivery; and average daily change was calculated. The association of longitudinal changes of angiogenic factors with maternal complications and with the time interval to delivery was evaluated by logistic and Cox regression. Results: Sixty-three women were analyzed, of which 23 (36.5%) had a complication. Longitudinal changes of sFlt-1 were more pronounce in complicated pregnancies (median: 1079.5 vs. 343.7 pg/mL/day; p=0.04). On the multivariate analysis, the baseline model (clinical risk score and sFlt-1 at admission) explained a 6.6% of the uncertainty for complication (R2-Naegelkerke). The addition of sFlt-1 longitudinal changes improved this performance to 23.2% (p=0.004). The median time from admission to delivery was 3 days (95% confidence interval: 1.9-4.05) in those in the highest quartile of sFlt-1 longitudinal changes vs. 10 days (95% confidence interval: 8.1-11.9) in the remaining women (Log-rank test p<0.001). Conclusions: Longitudinal changes in sFlt-1 maternal levels from admission for confirmed early-onset severe preeclampsia add to baseline characteristics in the prediction of maternal complications.