Leg Heating in Pregnant Women With Obesity

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.

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.

Eligibility Criteria:
Inclusion Criteria:

* Women with obesity (self-reported pre-pregnancy body mass index ≥30 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)42 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).
* Severe sleep apnea (an apnea-hypopnea index ≥30 events/h43 based on the results from in-home sleep testing) or previously diagnosed and treated sleep apnea.
* Evidence of cardiovascular, pulmonary, or neurological diseases.
* Diabetes mellitus or a history of gestational diabetes (to avoid its effects on vascular endothelial function and sympathetic vasoconstriction).
* Kidney disease (serum creatinine \>0.9 mg/dL).44, 45
* Psychiatric diseases or medically treated psychological disorders.
* 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).