Study protocol for the randomized controlled EVA (early vascular adjustments) trial: tailored treatment of mild hypertension in pregnancy to prevent severe hypertension and preeclampsia

Eva Mulder, Chahinda Ghossein-Doha, Evine Appelman, Sander van Kuijk, Luc Smits, Rogier van der Zanden, Joris van Drongelen, Marc Spaanderman, Eva Mulder, Chahinda Ghossein-Doha, Evine Appelman, Sander van Kuijk, Luc Smits, Rogier van der Zanden, Joris van Drongelen, Marc Spaanderman

Abstract

Background: In contrast to severe gestational hypertension, it is questioned whether antihypertensive medication for mild to moderate gestational hypertension prevents adverse maternal and offspring outcomes. Hypertensive drugs halve the risk of severe hypertension, but do not seem to prevent progression to preeclampsia or reduce the risk of complications in offspring. In fact, beta-blockers, a first line therapy option, are suspected to impair foetal growth. Disappointing effects of antihypertensive medication can be anticipated when the pharmacological mode of action does not match the underlying haemodynamic imbalance. Hypertension may result from 1) high cardiac output, low vascular resistance state, in which beta blockade is expected to be most effective, or 2) low cardiac output, high vascular resistance state where dihydropyridine calcium channel blockers or central-acting alpha agonists might be the best corrective medication. In the latter, beta-blockade might be maternally ineffective and even contribute to impaired foetal growth by keeping cardiac output low. We propose a randomized controlled trial to determine whether correcting the haemodynamic imbalance in women with mild to moderate hypertension reduces the development of severe hypertension and/or preeclampsia more than non-pharmacological treatment does, without alleged negative effects on foetal growth.

Methods: Women diagnosed with mild to moderate hypertension without proteinuria or signs of other organ damage before 37 weeks of pregnancy are invited to participate in this randomized controlled trial. Women randomized to the intervention group will be prescribed tailored antihypertensive medication, using a simple diagnostic and treatment algorithm based on the mean arterial pressure/heart rate ratio, which serves as an easy-to-determine proxy for maternal circulatory state. Women randomized to the control group will receive non-pharmacological standard care according to national and international guidelines. In total, 208 women will be randomized in a 1:1 ratio. The primary outcome is progression to severe hypertension and preeclampsia and the secondary outcomes are adverse maternal and neonatal outcomes.

Discussion: This trial will provide evidence of whether tailoring treatment of mild to moderate gestational hypertension to the individual haemodynamic profile prevents maternal disease progression.

Trial registration: NCT02531490 , registered on 24 August 2015.

Keywords: Antihypertensive drugs; Gestational hypertension; Haemodynamic profile; Preeclampsia; Pregnancy; Tailored treatment.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Haemodynamic profiles in mild hypertension, associated complications and appropriate antihypertensive treatment
Fig. 2
Fig. 2
Schedule of enrolment, intervention, and assessments
Fig. 3
Fig. 3
SPIRIT timetable of the study
Fig. 4
Fig. 4
Assessment of underlying haemodynamic profile by MAP/HR ratio and the likelihood of vasoconstricted, low output or vasodilated high-output hypertension
Fig. 5
Fig. 5
Tailored antihypertensive treatment strategy in the intervention group

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