L-Citrulline in Pregnancy: Boosts Key Biomarkers for Hypertension

randomized-controlled-trial PMID: 37789125

L-Citrulline in Pregnancy: Boosts Key Biomarkers for Hypertension

Quick Summary: A small trial tested L-citrulline supplements in pregnant women with chronic high blood pressure to see if it could help blood vessels and lower blood pressure. Women liked taking it and saw rises in helpful blood markers linked to better blood flow, but it didn't clearly lower blood pressure. This early study shows promise but needs more research for real-world use.

What the Research Found

This study, called CHERRY, looked at how L-citrulline—a natural amino acid that helps make nitric oxide for healthy blood vessels—affects pregnant women with ongoing high blood pressure. Here's what stood out in simple terms:

High Acceptance: Most women found the supplement easy to take, with few complaints about taste or side effects.
Improved Blood Markers: It raised levels of citrulline and arginine in the blood, plus a key ratio (arginine to ADMA) that supports better blood vessel relaxation. This was strongest in women who took it consistently. (ADMA is a substance that blocks good blood flow; improving this ratio means less blockage.)
No Big Blood Pressure Drop: Diastolic blood pressure (the bottom number) didn't change much—about a tiny 1.8 mmHg drop with L-citrulline versus 5 mmHg with placebo. But the study wasn't big enough to prove a real difference.
No Changes in Other Areas: It didn't improve uterine artery blood flow (measured by Doppler ultrasound) or markers for blood vessel growth (like sFlt-1 and PlGF), which are important in pregnancy.

Overall, L-citrulline seemed safe but didn't deliver clear wins on blood pressure or pregnancy-specific vascular health.

Study Details

Who Was Studied: 36 pregnant women with chronic hypertension (high blood pressure before pregnancy). They were between 12 and 16 weeks pregnant when the study started—early in the second trimester.
How Long: The treatment lasted 8 weeks, a short time to test if it's doable and has early effects.
What They Took: Women got either 3 grams of L-citrulline powder twice a day (total 6 grams daily) or a fake placebo. It was mixed into drinks or food for easy use. The study tracked how well they stuck to it.

This was a randomized trial, meaning participants were split randomly into groups to fairly compare results. It was registered under EudraCT 2015-005792-25 and ISRCTN12695929.

What This Means for You

If you're pregnant with chronic high blood pressure, this research suggests L-citrulline might be worth discussing with your doctor—it's well-tolerated and could gently support blood vessel health by boosting nitric oxide pathways. For example:

Potential Benefits: It may help with vascular markers, which could indirectly ease hypertension symptoms or pre-eclampsia risks, based on animal studies and non-pregnant human trials.
Not a Quick Fix: Don't expect it to replace meds or drop your blood pressure right away; the trial showed no strong effect there.
Real-Life Tips: Start with medical advice, as pregnancy changes how your body handles supplements (like faster clearance, so effects might be milder). Aim for good compliance—taking it regularly seemed key. If you're searching for natural ways to manage pregnancy hypertension, this is an early green light for feasibility, but wait for bigger studies before relying on it.

Always check with a healthcare provider before trying supplements, especially in pregnancy, to avoid interactions.

Study Limitations

This was an early "feasibility" trial, not a full proof-of-concept study, so keep these points in mind:

Small Group Size: Only 36 women total, so it couldn't spot small blood pressure changes under 9 mmHg—results might look neutral but could mean something in a larger group.
Pregnancy Changes Everything: Your body processes L-citrulline differently when pregnant (e.g., kidneys clear it faster), leading to smaller boosts in blood markers than in non-pregnant people.
Short Timeframe: 8 weeks might not be long enough to see lasting effects on blood pressure or baby-related outcomes.
Varying Stickiness: Not everyone took it perfectly, and effects were weaker for those who didn't—real life might vary.
Not Definitive: It focused on if it's doable, not if it fully works, so more research (like dose tweaks or longer trials) is needed for solid advice.

For more on L-citrulline benefits in pregnancy hypertension, search terms like "natural supplements for high blood pressure in pregnancy" to find related studies.

Key Findings

Pregnant women with chronic hypertension reported high acceptability of oral L-citrulline supplementation (3g twice daily). L-citrulline significantly increased maternal plasma citrulline, arginine, and the arginine:asymmetric dimethylarginine (ADMA) ratio, particularly in participants with good compliance. However, no statistically significant effects were observed on diastolic blood pressure (BP), uterine artery Doppler indices, or angiogenic biomarkers. The study was underpowered to detect BP changes <9 mmHg, and pregnancy-related pharmacokinetic differences may have influenced efficacy outcomes.

Study Design

This was an early-phase, randomized, placebo-controlled feasibility trial conducted in pregnancy. Participants (n=36 total: 24 L-citrulline, 12 placebo) were enrolled between 12–16 weeks gestation and treated for 8 weeks. The primary objectives were to assess acceptability and vascular biomarker changes. Trial registration: EudraCT 2015-005792-25 and ISRCTN12695929.

Dosage & Administration

L-citrulline was administered orally at 3g twice daily. Supplementation occurred over 8 weeks, starting at 12–16 weeks of pregnancy. Compliance was monitored retrospectively, with varying adherence across participants.

Results & Efficacy

Biomarker Changes:
Maternal plasma citrulline and arginine levels increased significantly in the L-citrulline group.
Arginine:ADMA ratio improved in L-citrulline recipients, especially among those with high compliance (effect size not quantified).
Blood Pressure:
Diastolic BP changes: L-citrulline (-1.82 mmHg, 95% CI -5.86 to 2.22) vs. placebo (-5.00 mmHg, 95% CI -12.76 to 2.76). No significant between-group differences (p-values not reported).
Vascular Outcomes:
No improvements in uterine artery Doppler or angiogenic biomarkers (e.g., sFlt-1, PlGF).

Limitations

Small Sample Size: The study was underpowered (n=36) to detect clinically meaningful BP changes (<9 mmHg), limiting conclusions on efficacy.
Pharmacokinetic Variability: Pregnancy-induced physiological changes (e.g., increased renal clearance) likely reduced the arginine:ADMA ratio increase compared to non-pregnant populations.
Short Duration: An 8-week intervention may be insufficient to observe long-term vascular or pregnancy outcomes.
Compliance Heterogeneity: Effects on biomarkers were more pronounced in compliant participants, suggesting dose-response variability.
Exploratory Nature: Designed as a feasibility trial, not powered for definitive efficacy endpoints.

Clinical Relevance

For pregnant women with chronic hypertension, L-citrulline supplementation appears safe and well-accepted, with potential to improve nitric oxide-related vascular biomarkers. However, the lack of BP reduction and neutral Doppler/angiogenic results suggest larger trials are needed to clarify its role in managing hypertensive disorders of pregnancy. Clinicians should note the underpowered BP analysis and altered pharmacokinetics in pregnancy, which may necessitate higher doses or adjusted administration timing. Supplement users should prioritize medical supervision, as efficacy for blood pressure control remains unproven in this population. Future research should focus on pharmacokinetic optimization and longer-term outcomes.

Analysis based on PubMed ID: 37789125 (2024 study)