# Preeclampsia 2.0: limitations and challenges of the two-stage hypothesis, and beyond

## TL;DR

This paper reviews the limitations of the two-stage hypothesis for preeclampsia and highlights the need for new theories to better understand and manage this pregnancy-related condition.

## Contribution

The paper critically evaluates the outdated two-stage hypothesis and advocates for new conceptual frameworks to explain preeclampsia's diversity.

## Key findings

- The two-stage hypothesis fails to explain the full spectrum of preeclampsia cases.
- No single early biomarker or preventive treatment exists for all preeclampsia types.
- New hypotheses are needed to improve predictive and personalized treatment options.

## Abstract

The pregnancy-specific syndrome preeclampsia remains the syndrome of hypotheses. Still, there is not a single hypothesis explaining the etiology of the full spectrum of preeclampsia. This has direct consequences for the clinical management of the syndrome. So far, no single early biomarker has been identified to predict all women who will develop preeclampsia later in pregnancy. Similarly, no preventive treatment for all types of preeclampsia has been integrated into clinical routine. Interestingly, the last decade has not seen much progress in the quest of identifying the pathophysiological processes resulting in the clinical syndrome preeclampsia. This could be due to the following: (i) the preeclampsia definition has been immensely altered and widened to include a large variety of clinical subgroups; and/or (ii) scientists and clinicians still adhere to the already challenged two-stage hypothesis and give only little room for new hypotheses. These two reasons could have thwarted the deciphering of the etiology of preeclampsia. This review will describe the limitations and challenges of the two-stage hypothesis. It will also highlight some of the new ideas and theories that have been put forward. In conclusion, there is an urgent need for new concepts that allow a better explanation of the diversity of preeclampsia regarding symptoms and time of occurrence. This in turn will result in more options to develop specific predictive biomarkers and personalized treatment options.

Challenges of the ‘two-stage hypothesis’ of preeclampsia: each of the challenges (yellow boxes) of the two-stage hypothesis may result in its falsification. FGR, fetal growth restriction; PE, preeclampsia; PlGF, placental growth factor; pO2, oxygen partial pressure; sFlt-1, soluble Fms-like tyrosine kinase-1.

Challenges of the ‘two-stage hypothesis’ of preeclampsia: each of the challenges (yellow boxes) of the two-stage hypothesis may result in its falsification. FGR, fetal growth restriction; PE, preeclampsia; PlGF, placental growth factor; pO2, oxygen partial pressure; sFlt-1, soluble Fms-like tyrosine kinase-1.