Preeclampsia with Doppler signs of increased Pulse Wave reflection in uterine and ophthalmic Artery: association with extreme levels of angiogenic Markers of placental Dysfunction

Introduction:

Severe preeclampsia (PE) is characterized by maternal cardiovascular dysfunction with increased pulse wave (PW) reflection (Hausvater 2011, Melchiorre 2014). Two Doppler waveform changes may be observed: appearance of a systolic shoulder (S) in the uterine artery (UtA): UtA-S, and simultaneously an augmentation of the 2nd systolic peak, P2 in the ophthalmic artery (OA), relative to the initial peak, P1. We assume that both changes may result from increased PW reflection, probably induced by bioactive factors linking placental ischemia to vasoconstriction (Shah 2015).

Methods:

In hemodynamics PW propagation and reflection is well established, with back and forth movements along the systemic arterial tree, with time of return, Tr during mid-systole: Tr = 2·τ (Fig). Superposition of reflected waves (RW) exert an accelerative impulse to flow when both propagate in the same direction: in cerebral arteries after body reflection and cranial transmission, and in UtA after re-reflection at cardiac level and 2nd downstream propagation (Mynard 2017). In both cases transient flow acceleration may be observed, if reflection is strong enough.

According to this model, OA-P2 will increase and timing Δt of UtA-S should correspond to Tr, due to the additional back and forth movement along the arterial system (Fig.). To test this model we performed UtA- and OA-Doppler in severe PE and measured sFlt-1/PlGF-ratio. When UtA-S appeared, we assessed the time intervall Δt to UtA-S onset (given by the systolic downslope inflection point) and the OA peak ratio OA-PR = P2/P1. Then we compared the observed Δt result with published Tr data in severe PE, and the obtained OA-PR and sFlt-1/PlGF results with reference data.

Results:

We identified 10 patients with severe PE, where finally a UtA-S appeared, and delivery ≤34wks was required at mean GA = 29 ± 3wks (± SD). Doppler assessment revealed: Δt = 133 [126 – 140]ms and OA-PR = 0.9 [0.80 – 1.0] (mean[95% CI]), and sFlt-1/PlGF ratio was 772 [405 – 1139].

Thus observed UtA-S timing Δt shows good agreement with Tr data in severe PE: Tr = 136 ms (Kaihura 2009) and 133 ms (Avni 2010), and observed OA-PR agrees fairly with OA-PR published in severe PE: 0.81 ± 0.12 (Takata 2002), exceeding significantly normal values: 0.52 ± 0.12 (Matias 2014). Finally sFlt-1/PlGF ratio by far exceeds normal ranges: P95 < 34 (Verlohren 2014) and even levels found in early onset PE: 279 ± 137 (Schoofs 2013).

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Discussion:

This proof of principle study based on hemodynamic modelling shows evidence that UtA-S appearance and OA-P2 augmentation may result from increased PW reflection in severe PE, indicating maternal cardiovascular dysfunction, and this, in turn, is paralleled by extreme levels of serum markers of placental dysfunction.

UtA-S might have the potential to detect, and OA-PR the potential to monitor maternal cardiovascular deterioration in severe PE, as well as to monitor medication targeted to modulate PW reflection (McLaughlin 2018).