Early Vascular Adjustments During Hypertensive Pregnancy

Phase 4

• Conditions: Hypertension, Pregnancy-Induced; Pre-Eclampsia
• Interventions: Drug: Labetalol; Drug: Nifedipine; Drug: Methyldopa

• Registration Number: NCT02531490
• Lead Sponsor: Maastricht University Medical Center

Brief Summary

Paradoxical fetal and maternal results of studies have led to inconsistent use of antihypertensive drugs or no treatment at all in mild to moderate gestational hypertension in the Netherlands. However, none of the studies have taken the individual maternal circulatory state or the contemplated blood pressure response into account. Hypertension may be accompanied by high (hyperdynamic vasodilated profile), normal (normodynamic profile) of low (hypodynamic vasoconstrictive profile) cardiac output, and preeclampsia is not restricted to one circulatory profile. Therefore antihypertensive drugs should be viewed upon as correctors of the hemodynamic state rather than solely reducers of blood pressure. Without taking the maternal hemodynamic profile and condition into account, generic antihypertensive treatment can be expected to result in disappointing, inadequate and paradoxical results. The investigators hypothesize that in mild to moderate hypertension, personalized hemodynamically guided antihypertensive therapy (with target systolic and diastolic blood pressure \<130/80mmHg), prevents the progression to severe hypertension and/or preeclampsia compared to no treatment, without the alleged side-effects.

Detailed Description

Not available

Study Timeline

• Study Start: 2015-01-01
• Study First Submitted: 2015-08-05
• Study First Submitted QC: 2015-08-21
• Study First Posted: 2015-08-24
• Status Verified: 2021-03
• Last Update Submitted: 2021-03-23
• Last Update Posted: 2021-03-24
• Primary Completion: 2023-02
• Study Completion: 2023-04

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: Female
• Target Recruitment: 368

Inclusion Criteria

• Patients ages 18years or older
• Before 37 weeks of gestational age;
• Diagnosed with mild to moderate gestational hypertension

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Exclusion Criteria

• Women with severe hypertension: systolic blood pressure ≥ 160mmHg and/or diastolic blood pressure ≥ 110mmHg.
• Women with chronic hypertension who are already on antihypertensive drugs. If no antihypertensive drugs are used yet, women with pre-existent hypertension are eligible to participate.
• Women diagnosed with preeclampsia or eclampsia in the current pregnancy.
• Women who are not able to comprehend the study outline.
• Women who have already participated in this study cannot be included a second time.
• Women who have a (relative) contra-indication for one of the possible prescribed medications (for example women who have tested positive for antinuclear antibodies, which is a contraindication for Methyldopa).
• Women who intend to terminate the pregnancy
• Women who have a fetus with a major anomaly or chromosomal abnormality

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
randomized, interventiongroup	Labetalol	Women with a hyperdynamic vasodilated profile, characterized by a mean arterial pressure (MAP)/ Heart rate (Hr) ratio ≤ 1.1 are prescribed a beta-blocker. Women with a hypodynamic vasoconstrictive profile (MAP/Hr ratio ≥ 1.4) are prescribed nifedipine. Women with normodynamic profile (MAP/Hr ratio in between 1.1 and 1.4) are prescribed Methyldopa.
randomized, interventiongroup	Nifedipine	Women with a hyperdynamic vasodilated profile, characterized by a mean arterial pressure (MAP)/ Heart rate (Hr) ratio ≤ 1.1 are prescribed a beta-blocker. Women with a hypodynamic vasoconstrictive profile (MAP/Hr ratio ≥ 1.4) are prescribed nifedipine. Women with normodynamic profile (MAP/Hr ratio in between 1.1 and 1.4) are prescribed Methyldopa.
randomized, interventiongroup	Methyldopa	Women with a hyperdynamic vasodilated profile, characterized by a mean arterial pressure (MAP)/ Heart rate (Hr) ratio ≤ 1.1 are prescribed a beta-blocker. Women with a hypodynamic vasoconstrictive profile (MAP/Hr ratio ≥ 1.4) are prescribed nifedipine. Women with normodynamic profile (MAP/Hr ratio in between 1.1 and 1.4) are prescribed Methyldopa.

Primary Outcome Measures

Name	Time	Method
number of patients with preeclampsia	from date of randomization until the date of this study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)	Preeclampsia is defined as the coexistence of de novo hypertension after 20 weeks of gestation and one or more of the following new-onset conditions: 1. Proteinuria (spot urine protein/creatinine ≥ 30g/mol or ≥ 300mg/day or at least 1 g/L \[2+\] on dipstick testing).; 2. Other maternal organ dysfunction: * Renal insufficiency (creatinine levels ≥ 90μmol/L); * Liver involvement (elevated transaminases: ASAT ≥31 U/L and/or ALAT ≥34U/L); * Neurological complications (hyperreflexia when accompanied by clonus and/or severe headaches, persistent visual scotomata, altered mental status, eclampsia); * Haematological complications (thrombocytopenia, platelet count below 150.000/dL, disseminated intravascular coagulation, haemolysis).
number of patients with severe gestational hypertension	from date of randomization until the date of this study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)	Systolic blood pressure ≥ 160mmHg and/or diastolic blood pressure ≥ 110mmHg, measured at every visit

Secondary Outcome Measures

Name	Time	Method
diameter aortic outflow tract and left ventricular outflow tract measured by transthoracic echocardiography	from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)	cardiac output can be derived from these values + heart rate
left ventricular volume after diastole and systole measured by transthoracic echocardiography	from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)	ejection fraction can be derived from these values
cardiac remodeling during pregnancy: number of patients with concentric left ventricular remodeling or concentric hypertrophy.	from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)	Echocardiographic concentric left ventricular (LV) remodelling and hypertrophy. Concentric remodeling is defined as a relative wall thickness (RWT) \<=0.43 with a Left Ventricular Mass index (LVMi) of \<95 gram/m2. Concentric hypertrophy is defined as a RWT \<0.43 with a LVMi of ≥95 gram/m2.
the pattern of change of the hemodynamic profile, measured by the ratio of mean arterial pressure and heart rate.	at baseline and each study visit/follow up measurement (at 1 week, 2 weeks, etc. up to 23 weeks after inclusion. The expected average is 8 weeks	hemodynamic profiles will be classified as hyperdynamic, hypodynamic vasocontricted or mixed profile.
hemodynamic profile by mean arterial pressure/heart rate ratio	from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)	hemodynamic profiles will be classified as hyperdynamic, hypodynamic vasocontricted or mixed profile.
health status of the newborn by Apgar score	assessed immediately after delivery	scored by gynecologist or paediatrician on a scale of 1 to 10
prevalence of small for gestational age infancy	assessed at delivery date	birth weight and percentile combined with gestational age at delivery
prevalence of premature neonates	assessed at delivery date	gestational age at delivery
number of a composite of adverse neonatal outcomes	from delivery up neonates will be followed for the duration of the hospital stay, an expected average of 6 weeks	Stillbirth, perinatal mortality, morbidity: chronic lung disease, neonatal sepsis, severe intra-ventricular haemorrhage (IVH) \> grade II, periventricular leucomalacia \> grade I, and necrotizing enterocolitis. Days on ventilation support, length of admission in neonatal intensive care, and total days in hospital until 3 months corrected age.
maternal well-being questionnaire,	at baseline and each study visit/follow up measurement (at 1 week, 2 weeks, etc. up to 23 weeks after inclusion. The expected average is 8 weeks	Reported medication side effects, and maternal well-being by signs and symptoms during pregnancy
number of assessed maternal complications	from a study event participants will be followed for the duration of hospital stay, an expected average of 1 week	Composite of maternal complications including: mortality, stroke, eclampsia, blindness, uncontrolled hypertension, respiratory failure, birth related variables, needed level of care
gestational age at the moment of progression to primary outcome.	from baseline/inclusion until a study event is reached (up to 18 weeks after inclusion), with an expected average of 4 weeks.

Trial Locations

Locations (1)

Maastricht UMC; 🇳🇱 Maastricht, Netherlands