Leg Heating in Pregnant Women With Obesity

Official title

Vascular and Neural Mechanisms of Chronic Leg Heating in Pregnant Women With Obesity

Overview

Obesity is a major risk factor for hypertensive disorders of pregnancy (HDP). The underlying mechanisms are largely unclear, but maternal vascular endothelial dysfunction is likely involved. Endothelial dysfunction in HDP could be attributed to 1) alterations in the L-arginine/nitric oxide (NO) pathway, and 2) an increase in endothelin-1 (ET-1). Additionally, augmented sympathetic vasoconstriction may also contribute to HDP. Chronic (repeated) whole-body heat exposure has been shown to increase NO bioavailability, decrease ET-1, and cause functional and structural adaptations in the vasculature. All these can improve vascular function, attenuate sympathetic (re)activity, lower blood pressure (BP), and reduce cardiovascular risk in non-pregnant individuals. Whether this is also true after regional (leg) heating in high-risk pregnant women is unknown. The investigators' central hypothesis is that chronic leg heating will be effective in improving vascular endothelial function and attenuating sympathetic vasoconstriction, leading to a reduction of the risk for HDP in pregnant women with obesity. The overarching goal of this proposal is to determine the vascular and neural effects of chronic leg heating in obese pregnancy. The study team plans to enroll pregnant women with obesity between 12-14 weeks of gestation and randomly assign them to either an intervention group or a control group (1:1 ratio). Participants in the intervention group will perform 16 weeks of home-based leg heating using a portable sauna blanket up to the hip (temperature of the blanket will be set at 65°C, 4 times/week, 45 min/session), whereas women in the control group will set the temperature of the blanket at 35°C at the same frequency and duration. Participants will be evaluated at baseline and then at 28-30 weeks of gestation. Aim 1 will determine the effects of chronic leg heating on maternal vascular function and surrogate markers of HDP. Aim 2 will determine the effects of chronic leg heating on sympathetic vasoconstriction and BP. Findings from this project will provide insight on the extent and potential mechanisms of how chronic leg heating works for improving vascular endothelial function and sympathetic vasoconstriction in pregnant women with obesity. Results obtained will set a foundation for future large multicenter clinical trials to determine the efficacy and generalizability of home-based leg heat therapy as a safe, ease-of-use, cost-effective, and non-drug approach for reducing the risk of HDP.

Detailed description

Obesity is a major risk factor for hypertensive disorders of pregnancy (HDP). The underlying mechanisms are unclear, but maternal vascular endothelial dysfunction is likely involved. Endothelial dysfunction in HDP could be attributed in part to: 1) alterations in the L-arginine/nitric oxide (NO) pathway, and 2) an increase in endothelin-1 (ET-1). Conversely, augmented sympathetic vasoconstriction may also contribute to the development of HDP in women with obesity. Exercise training increases NO production, decreases ET-1, improves vascular function, attenuates sympathetic (re)activity, and reduces the risk for HDP. However, pregnant women, especially those with obesity, have poor adherence to exercise. Thus, there is an urgent need to develop novel, safe, convenient, low-cost, and well-tolerated strategies that have similar beneficial effects as exercise training. One such novel approach may be "heating".

During passive whole-body heating, body core temperature increases and cutaneous and muscle vascular resistance decreases, leading to increases in blood flow and shear stress throughout the entire arterial tree. Chronic (i.e., repeated) exposure to these temperature-dependent responses induces an increase in NO bioavailability, a decrease in ET-1, and functional and structural adaptations in the vasculature - all these can improve vascular function, attenuate sympathetic (re)activity, lower blood pressure (BP), and reduce the risk for cardiovascular morbidity and mortality. Evidence suggests that maternal body core temperature below 38.9°C is safe for the fetus.

The study team proposes to use regional (e.g., leg) rather than whole-body (e.g., hot tub or sauna) heating, since leg heating does not substantially elevate body core temperature (i.e., 37.32°C at peak in pregnant women with obesity in our pilot study), is more tolerable than whole-body heating, and can be performed in-home. Importantly, the study team's preliminary work showed that chronic home-based leg heating is safe, and can improve endothelial function, attenuate sympathetic vasoconstriction, and reduce ambulatory awake BP in pregnant women with obesity.

The investigators' central hypothesis is that chronic leg heating will be effective in improving vascular endothelial function and attenuating sympathetic vasoconstriction, leading to a reduction of the risk for HDP in pregnant women with obesity.

Aim 1: Determine the effects of chronic leg heating on maternal vascular function and surrogate markers of HDP.

Hypothesis 1: Chronic leg heating will improve vascular endothelial function due to an increase in NO bioavailability and a decrease in ET-1, which may be associated with a reduction of the risk for HDP in pregnant women with obesity.

Aim 2: Determine the effects of chronic leg heating on sympathetic vasoconstriction and BP.

Hypothesis 2: Chronic leg heating will attenuate sympathetic-dependent vasoconstriction due to a decrease in sympathetic (re)activity, which may be associated with a reduction of BP in pregnant women with obesity.

Impact: Findings from this project will provide insight on the extent and potential mechanisms of how chronic leg heating works for improving vascular endothelial function and sympathetic vasoconstriction in pregnant women with obesity. Results obtained will set a foundation for future large multicenter clinical trials to determine the efficacy and generalizability of home-based leg heat therapy as a safe, ease-of-use, cost-effective, and non-drug approach for reducing the risk of HDP, and its most severe form, preeclampsia.

Interventions

• Other Leg heating
  Participants will perform home-based leg heating using a portable sauna blanket set at different temperature.

Primary outcome measures

• Change in vascular endothelial function [Time frame: Baseline, 16 weeks after leg heating]
• Change in sympathetic neural control [Time frame: Baseline, 16 weeks after leg heating]
• Change in sympathetic vascular transduction [Time frame: Baseline, 16 weeks after leg heating]

Secondary outcome measures (10)

• Change in blood concentration of nitrate [Time frame: Baseline, 16 weeks after leg heating]
• Change in blood concentration of nitrite [Time frame: Baseline, 16 weeks after leg heating]
• Change in L-arginine level [Time frame: Baseline, 16 weeks after leg heating]
• Change in asymmetric dimethylarginine level [Time frame: Baseline, 16 weeks after leg heating]
• Change in 3-nitrotyrosine level [Time frame: Baseline, 16 weeks after leg heating]
• Change in concentration of endothelin-1 [Time frame: Baseline, 16 weeks after leg heating]
• Change in 24-hour ambulatory blood pressure [Time frame: Baseline, 16 weeks after leg heating]
• Change in placental growth factor level [Time frame: Baseline, 16 weeks after leg heating]
• Change in solube fms-like tyrosine kinase-1 level [Time frame: Baseline, 16 weeks after leg heating]
• Change in soluble endoglin level [Time frame: Baseline, 16 weeks after leg heating]

Eligibility criteria

Inclusion criteria

• Women with overweight or obesity (self-reported pre-pregnancy body mass index ≥25 kg/m2) between 10-14 weeks of gestation and aged 18-45 years old will be enrolled.
• Both normotensive and hypertensive (office sitting systolic BP 140-150 mmHg and/or diastolic BP 90-100 mmHg) pregnant women will be enrolled if they are not on any antihypertensive drug treatment.
• We will enroll both nulliparous and multiparous women.
• There is no restriction regarding race/ethnicity and socioeconomic status.
• Women with a history of HDP will be allowed to participate.
• Women taking low-dose aspirin will be allowed to participate and aspirin use will be documented.

Exclusion criteria

• Current multiple pregnancies (e.g., twins, triplets, etc.).
• Known major fetal chromosomal or anatomical abnormalities diagnosed during the study.
• Recurrent miscarriage (three or more, to avoid antiphospholipid antibody syndrome).
• Office sitting BP <100/55 mmHg or >150/100 mmHg (for safety reasons).
• Evidence of cardiovascular, pulmonary, or neurological diseases.
• Diabetes mellitus (to avoid its effects on vascular endothelial function and sympathetic vasoconstriction).
• Kidney disease (serum creatinine >0.9 mg/dL).
• Clinical known deep vein thrombosis, clinical symptoms and history of deep vein thrombosis, or dermatological lesions.
• History of drug or alcohol abuse within the last 2 years.
• Current tobacco use.
• Pregnant women who do not have air conditioning at home during summer (for safety reasons).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Other

Study locations

United States · 1 center

• UT Southwestern Medical Center; Institute for Exercise and Environmental Medicine — Dallas

Publications

• Lisonkova S, Joseph KS. Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease. Am J Obstet Gynecol. 2013 Dec;209(6):544.e1-544.e12. doi: 10.1016/j.ajog.2013.08.019. Epub 2013 Aug 22. PMID 23973398
• Ford ND, Cox S, Ko JY, Ouyang L, Romero L, Colarusso T, Ferre CD, Kroelinger CD, Hayes DK, Barfield WD. Hypertensive Disorders in Pregnancy and Mortality at Delivery Hospitalization - United States, 2017-2019. MMWR Morb Mortal Wkly Rep. 2022 Apr 29;71(17):585-591. doi: 10.15585/mmwr.mm7117a1. PMID 35482575
• Bicocca MJ, Mendez-Figueroa H, Chauhan SP, Sibai BM. Maternal Obesity and the Risk of Early-Onset and Late-Onset Hypertensive Disorders of Pregnancy. Obstet Gynecol. 2020 Jul;136(1):118-127. doi: 10.1097/AOG.0000000000003901. PMID 32541276
• Wang MC, Freaney PM, Perak AM, Greenland P, Lloyd-Jones DM, Grobman WA, Khan SS. Trends in Prepregnancy Obesity and Association With Adverse Pregnancy Outcomes in the United States, 2013 to 2018. J Am Heart Assoc. 2021 Sep 7;10(17):e020717. doi: 10.1161/JAHA.120.020717. Epub 2021 Aug 25. PMID 34431359
• Aksin S, Andan C, Tunc S, Goklu MR. Comparison of brachial artery flow-mediated dilatation, uterine artery Doppler, and umbilical artery Doppler measurements in obese and normal pregnant women. J Obstet Gynaecol Res. 2022 Feb;48(2):340-350. doi: 10.1111/jog.15092. Epub 2021 Nov 2. PMID 34729866
• Stewart FM, Freeman DJ, Ramsay JE, Greer IA, Caslake M, Ferrell WR. Longitudinal assessment of maternal endothelial function and markers of inflammation and placental function throughout pregnancy in lean and obese mothers. J Clin Endocrinol Metab. 2007 Mar;92(3):969-75. doi: 10.1210/jc.2006-2083. Epub 2006 Dec 27. PMID 17192290
• Petrella E, Pignatti L, Neri I, Facchinetti F. The l-arginine/nitric oxide pathway is impaired in overweight/obese pregnant women. Pregnancy Hypertens. 2014 Apr;4(2):150-5. doi: 10.1016/j.preghy.2014.01.001. Epub 2014 Feb 3. PMID 26104420
• Chin-Dusting JP, Willems L, Kaye DM. L-arginine transporters in cardiovascular disease: a novel therapeutic target. Pharmacol Ther. 2007 Dec;116(3):428-36. doi: 10.1016/j.pharmthera.2007.08.001. Epub 2007 Aug 28. PMID 17915331

Identifiers

NCT: NCT06932250 · STU20250500

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗