Preeclampsia (PE), new-onset hypertension with proteinuria after mid-pregnancy, is divided into early-onset (<34 weeks) and late-onset (≥34 weeks) forms. A landmark 24-week cross-sectional study (Valensise et al., Hypertension 2008) found that the two subtypes occupy opposite latent hemodynamic states: early PE with high total vascular resistance (TVR) and low cardiac output (CO) plus frequent bilateral uterine artery notching, and late PE with low TVR, high CO, and higher prepregnancy body mass index (BMI). The study left open three linked questions that remain unsettled in 2026 — the first flagged explicitly in its Perspectives as needing 'further longitudinal data from early pregnancy to be clarified', the other two left by its hedged hypotheses that the cross-sectional design could not establish: the temporal sequence of hemodynamic change from early pregnancy to clinical onset (does early PE pass through an earlier low-TVR/high-CO phase?), whether maternal adiposity causally produces the late-PE hemodynamic phenotype or is merely a correlated marker, and whether divergent postpartum hemodynamics cause differential long-term cardiovascular disease. Prospective longitudinal cohorts published through 2026 give conflicting trajectories, and the 2025 consensus statement of the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) explicitly flags the classification as unresolved.

Background

Preeclampsia (PE) is a hypertensive disorder of pregnancy defined by new-onset hypertension (blood pressure >140/90 mmHg) with proteinuria after 20 weeks' gestation; it affects roughly 2–8% of pregnancies and is a leading cause of maternal and perinatal morbidity. PE is conventionally split by gestational age at delivery into early-onset (<34 weeks) and late-onset (≥34 weeks) forms, which are widely held to differ in origin: early PE is considered predominantly placental (defective trophoblast invasion of the spiral arteries, reflected in abnormal uterine artery Doppler waveforms such as bilateral diastolic notching), whereas late PE is considered more maternal, linked to constitutional cardiometabolic factors such as high prepregnancy body mass index (BMI, weight in kg divided by height in m squared).

Maternal hemodynamics are described by two coupled quantities: cardiac output (CO, the volume of blood the left ventricle ejects per minute) and total vascular resistance (TVR, also called systemic vascular resistance, the resistance the circulation presents to flow; by Ohm's law, mean arterial pressure ≈ CO × TVR, so hypertension can arise from high CO, high TVR, or both). CO and TVR are measured non-invasively in pregnancy by echocardiography or by bioreactance/bioimpedance devices. In normal pregnancy, plasma volume expansion drives CO up and TVR down by mid-pregnancy.

Before 2008, longitudinal work (Bosio et al., Obstet Gynecol 1999) had proposed a hyperdynamic disease model: women destined for PE had elevated CO with normal TVR during the latent (preclinical) phase, then crossed over to low CO and high TVR at clinical onset, while women with gestational hypertension remained hyperdynamic throughout. Against this background, Valensise, Vasapollo, Gagliardi and Novelli (Hypertension 2008;52:873-880, published full title 'Early and late preeclampsia: two different maternal hemodynamic states in the latent phase of the disease') measured TVR by echocardiography and uterine artery Doppler at 24 weeks in 1345 nulliparous asymptomatic women. Of the 107 who later developed PE, the 75 with early PE had already, at 24 weeks, high TVR (1605±248 vs 739±244 dyn·s·cm⁻⁵) and low CO (4.49±1.09 vs 8.96±1.83 L/min), with bilateral uterine notching in 60%, whereas the 32 with late PE were in a low-resistance/high-output state with higher prepregnancy BMI (28±6 vs 24±2 kg/m²). The authors interpreted early PE as placental-mediated and late PE as linked to constitutional factors such as BMI. Because the study was cross-sectional at a single time point, it could not establish what happened earlier than 24 weeks, whether the BMI association was causal, or what the postpartum and long-term consequences of the two hemodynamic states are; individual patients also fell outside the dominant patterns (some early-PE women had low TVR, some late-PE women high TVR).

Later work complicated rather than settled the picture. A prospective study (Tay et al., Am J Obstet Gynecol 2018) found that both early and late PE had high CO and that low CO was driven by coexisting fetal growth restriction (FGR, delivery of an abnormally small fetus), not by onset timing. A large longitudinal unselected cohort (Ling et al., Am J Obstet Gynecol MFM 2023) found that PE overall was hyperdynamic (higher stroke volume and CO) in the first trimester and crossed to low CO/high resistance only after 20 weeks. In contrast, a 2026 longitudinal study within a first-trimester screen-and-prevent program (Lin et al., Ultrasound Obstet Gynecol 2026) found preterm PE to be hypodynamic (low CO, high SVR) already from 12–16 weeks with no preceding high-output phase, and term PE indistinguishable from high-risk controls in CO/SVR. The 2025 consensus statement of ISUOG (International Society of Ultrasound in Obstetrics and Gynecology) on maternal hemodynamic assessment states that classifying PE into resistance-dominant and volume-dominant phenotypes challenges the reported longitudinal hemodynamic evolution, that the phenotypes are linked though not invariably to onset timing, and that FGR is the most important discriminator — i.e., the field itself regards the temporal and mechanistic structure as unresolved. On the BMI thread, population studies (Robillard et al. 2019; Bicocca et al. 2020) confirmed that maternal obesity is specifically and linearly associated with late-onset PE, obesity shifts pregnancy hemodynamics toward a high-output state (Charakida et al. 2025), and Mendelian randomization (an instrumental-variable method that uses inherited genetic variants as natural experiments to test whether an exposure causally affects an outcome) applied to genome-wide summary statistics suggests a causal, blood-pressure-mediated BMI→PE effect (Yang et al. 2025), but the pathway from cardiometabolic syndrome to the late-PE hemodynamic phenotype remains unknown. On the postpartum thread, persistent differential cardiac impairment after preterm versus term PE (Melchiorre et al. 2011; Giorgione et al. 2023) and higher long-term cardiovascular event rates after early- versus late-onset PE (Dall'Asta et al. 2021 meta-analysis) are established epidemiologically, yet whether the divergent postpartum hemodynamics are on the causal path — as opposed to a shared predisposition — and whether hemodynamically targeted or subtype-specific postpartum management improves outcomes remain open, with 2026 systematic reviews concluding that adequately powered interventional trials are still needed (Loheit et al. 2026).

Problem Statement

Establish the causal hemodynamic pathogenesis that distinguishes early-onset (<34 weeks' delivery) from late-onset (≥34 weeks) preeclampsia, in the three linked respects left open by Valensise et al. (2008), whose Perspectives explicitly calls for longitudinal data from early pregnancy and whose hedged BMI and postpartum hypotheses its 24-week cross-sectional design could not establish:

  1. Temporal sequence. Determine, in initially asymptomatic women before 24 weeks' gestation, the subtype-specific trajectories leading to clinical onset: does early PE pass through an earlier low-TVR/high-CO phase before crossing into the high-TVR/low-CO latent state seen at 24 weeks, is it hypodynamic from early pregnancy, or does the trajectory depend on coexisting fetal growth restriction and on between-patient heterogeneity rather than on onset subtype alone; and is late PE in a high-CO/low-TVR (volume-dominant) state throughout, as the 24-week cross-section suggested?

  2. Causal role of maternal body mass index. Determine whether maternal adiposity causally produces the late-PE low-TVR/high-CO phenotype or is a correlated constitutional marker.

  3. Postpartum consequences. Determine whether the divergent hemodynamic states of early and late PE persist differentially postpartum as a cause — rather than a correlate of shared predisposition — of the established differential long-term cardiovascular event risk.

These three questions jointly serve one scientific objective — deciding whether early and late preeclampsia arise from distinct, temporally traceable and causally attributable maternal hemodynamic pathways that justify differentiated prediction and follow-up. The source also acknowledged within-subtype heterogeneity as context for this objective: some early-PE patients fall in the low-TVR area and some late-PE patients in the high-TVR area (Valensise et al., Discussion and Figure 4), 'testifying to the complex pathophysiology of PE in which factors favoring the early or late appearance of the disease might interact differently', and early-PE hemodynamics interact with coexisting fetal growth restriction.

All three questions are posed jointly.

References

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