Early Vascular Adjustments to Prevent Preeclampsia

Early Vascular Adjustments to Prevent Preeclampsia and Related Complications

Women destined to develop gestational hypertensive complications often exhibit deviant hemodynamic adaptation patterns before overt clinical disease. Gestational hypertension and late onset preeclampsia are associated with an exaggerated rise in cardiac output on top of a higher prepregnant value, whereas a shallow rise in cardiac output and the lack of a peripheral resistance drop predisposes to the much less common early onset-preeclampsia along with impaired fetal growth. Early treatment of altered cardiac output and peripheral resistance adjustments might prevent development of gestational hypertensive complications. The investigators aim to evaluate early cardiovascular adjustments during pregnancy in a high-risk population, and to pharmaceutically adjust deviant cardiovascular adaptations with beta-blockade, centrally acting sympatholytic agents or vasodilating agents when appropriate to prevent adverse effects on neonatal birth weight.

Study Overview

• Status: Completed
• Conditions: Preeclampsia; HELLP Syndrome; Small for Gestational Age at Delivery
• Intervention / Treatment: Drug: tailored pharmaceutical treatment

Detailed Description

Healthy pregnancy is accompanied by major hemodynamic changes that benefit the uteroplacental circulation. A first-trimester drop in vascular resistance triggers several compensatory mechanisms, amongst an increase in blood volume and cardiac output, to maintain blood pressure. These adaptations continue and stand until delivery.

Women destined to develop gestational hypertensive complications often exhibit deviant hemodynamic adaptation patterns before overt clinical disease. On the one hand, gestational hypertension and late onset preeclampsia are associated with an exaggerated rise in cardiac output on top of a higher prepregnant value, whereas a shallow rise in cardiac output and the lack of a peripheral resistance drop predisposes to the much less common early onset-preeclampsia along with impaired fetal growth.

Antihypertensive therapy based on correction of the hemodynamic imbalance between cardiac output and peripheral resistance seems an effective strategy to improve blood pressure control in hypertensive pregnant women. Even more sophisticated, early treatment of altered cardiac output and peripheral resistance adjustments might prevent development of gestational hypertensive complications. One randomized controlled trial treated pregnant women with an augmented cardiac output with a selective beta-blocker, which resulted in a decreased prevalence of preeclampsia from 18% in the placebo group to 4% in the atenolol group (p = 0.04), at a cost of 440gram birth weight.

In line of this reasoning, the investigators aimed to evaluate early cardiovascular adjustments during pregnancy in a high-risk population (i.e. women with preeclampsia in their first pregnancy). In this health care traject, women with deviant adaptation to pregnancy were advised tailored medication, i.e. beta-blockade in women with an pronounced high cardiac output profile effectuated by a high heart rate, and a vasodilating agent in women with a high-resistance hemodynamic profile. Women with a mixed hemodynamic profile were advised a centrally acting sympatholytic agent. The investigators aimed to retrospectively compare outcome of women attending this health care project with women who received care as usual in their second pregnancy.

• Study Type: Observational
• Enrollment (Actual): 314

Contacts and Locations

Study Locations

• Netherlands
  • Maastricht, Netherlands
    • Maastricht UMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Pregnant women who had preeclampsia in their first pregnancy

Description

Inclusion Criteria:

• first pregnancy complicated by preeclampsia
• admitted to an extensive non-pregnant cardiovascular and metabolic risk factor assessment

Exclusion Criteria:

• women without an ongoing pregnancy after 24 weeks' gestational age

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Retrospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Tailored treatment advise in suboptimal adaptation; High-risk women admitted to a non-pregnant cardiovascular and cardiometabolic risk factor assessment are invited to participate in a follow-up program at four time-points during a subsequent pregnancy (i.e. at 12, 16, 20 and 30 weeks of gestational age). This program is additive to regular pregnancy check-ups, and all women are otherwise managed by their referring physicians. The aim of this program is to evaluate adaptation of maternal hemodynamic parameters in response to pregnancy, and to adjust deviant adaptation with tailored antihypertensive medication. Participation in this program is on voluntary basis, and not restricted to severity of complications in the first pregnancy.	Drug: tailored pharmaceutical treatment; Tailored medication is advised in women with inadequate hemodynamic adaptation to pregnancy. Type of medication depends on total peripheral vascular resistance and heart rate. In short, women with a low peripheral vascular resistance in parallel with a high heart rate are advised a betablocker (labetalol), while a vasodilating agent (calcium channel blocker, nifedipine) was advised in women with a high total peripheral vascular resistance in combination with a low heart rate. Women with suboptimal adaptation to pregnancy without an extreme pronounced vascular profile are advised a centrally acting sympatholytic agent (methyldopa).; Other Names: Betablocker; Centrally acting sympatholytic agent; Calcium channel blocker
Care as usual during pregnancy; High-risk women admitted to a non-pregnant cardiovascular and cardiometabolic risk factor assessment who do not participate in the additional follow-up program.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of women that develop preeclampsia	Preeclampsia is defined as new-onset hypertension along with de novo proteinuria or other maternal organ dysfunction (i.e. renal insufficiency, liver involvement, neurological complications or hematological complications) after 20 weeks of gestation in previously normotensive women, or superimposed on chronic hypertension.	during pregnancy, or up to 6 weeks after delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of women that develop HELLP syndrome	HELLP-syndrome is defined as hemolysis (LDH > 600 U/L), elevated liver enzymes (AST -aspartate aminotransferase- and ALT -alanine aminotransferase- > 70 U/L) and low platelets (platelet count < 100.109/L)	during pregnancy, or up to 6 weeks after delivery
Number of women that develop eclampsia	Seizures in women with preeclampsia	during pregnancy, or up to 6 weeks after delivery
Number of women that have placental abruption during pregnancy		During pregnancy or at delivery
Stillbirth	Number of stillbirths in included women	during pregnancy until delivery
Neonatal mortality	Number of neonatal demise related to prematurity or as a consequence of maternal disease related to preeclampsia	after delivery up to hospital discharge, which is assessed 6 weeks after due date of the mother
Neonatal birth weight	birth weight of neonates	measured at delivery
Neonatal birth weight centile	Neonatal birth weight centile (adjusted for sex of neonate, gestational age at delivery and maternal parity)	birth weight and other parameters measured at delivery
Pregnancy outcome of women included	Gestational age at delivery	at delivery

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center

Publications and helpful links

General Publications

• Mulder EG, Ghossein-Doha C, Cauffman E, Lopes van Balen VA, Schiffer VMMM, Alers RJ, Oben J, Smits L, van Kuijk SMJ, Spaanderman MEA. Preventing Recurrent Preeclampsia by Tailored Treatment of Nonphysiologic Hemodynamic Adjustments to Pregnancy. Hypertension. 2021 Jun;77(6):2045-2053. doi: 10.1161/HYPERTENSIONAHA.120.16502. Epub 2021 Apr 5.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2014
• Primary Completion (Actual): January 1, 2020
• Study Completion (Actual): March 1, 2020

Study Registration Dates

• First Submitted: December 19, 2019
• First Submitted That Met QC Criteria: December 30, 2019
• First Posted (Actual): January 3, 2020

Study Record Updates

• Last Update Posted (Actual): March 11, 2020
• Last Update Submitted That Met QC Criteria: March 10, 2020
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: cardiac output; tailored treatment; total peripheral vascular resistance; hemodynamic parameters; adaptation to pregnancy
• Additional Relevant MeSH Terms: Pregnancy Complications; Hypertension, Pregnancy-Induced; Pre-Eclampsia; HELLP Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Sympatholytics
• Other Study ID Numbers: 14-4-118

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No