The Combined Effect of Magnesium, Palmitoylethanolamide, High-Molecular-weight Hyaluronic Acid, Vitamin B6, and Vitamin D in Preventing Preterm Birth:

The Combined Effect of Magnesium, Palmitoylethanolamide, High-Molecular-weight Hyaluronic Acid, Vitamin B6, and Vitamin D in Preventing Preterm Birth: A Randomized Controlled Trial

The aim of the study is to assess the effect of a combination of Magnesium, Palmitoylethanolamide, high-molecular-weight Hyaluronic Acid, Vitamin B6, and Vitamin D in women at risk of preterm birth (PTB).

Study Overview

• Status: Recruiting
• Conditions: Preterm Labor
• Intervention / Treatment: Drug: Magnesium-PEA-HMW Hyaluronic Acid-Vitamin B6-Vitamin D + Vaginal Progesterone; Other: Standard Treatment (Guideline-Based)

Detailed Description

Preterm birth (PTB) remains one of the leading causes of neonatal morbidity and mortality worldwide. The transition of the myometrium from a quiescent state to active contractility is driven by a complex interplay of genetic predisposition, inflammatory mediators, endocrine factors, and uterine environmental conditions. Increased expression of pro-inflammatory cytokines (including IL-6, IL-1β, TNF-α), activation of NF-κB pathways, prostaglandin synthesis, cervical remodeling, and alterations in progesterone signaling contribute to the premature onset of labor.

Several natural molecules have demonstrated potential roles in modulating uterine quiescence, inflammatory pathways, and cervical integrity. Magnesium participates in more than 600 enzymatic reactions and reduces inflammatory cytokine production, while low serum magnesium levels have been associated with a higher risk of PTB. Vitamin B6 contributes to fetal neurodevelopment and has been linked to reduced rates of preeclampsia and preterm birth. High-molecular-weight hyaluronic acid (HMWHA) plays a crucial role in immune tolerance at the maternal-fetal interface, promotes anti-inflammatory cytokine secretion, and supports progesterone-mediated uterine quiescence through upregulation of the progesterone receptor membrane component-1 (PGRMC1). Palmitoylethanolamide (PEA), an endogenous bioactive lipid, exerts anti-inflammatory and mast-cell-stabilizing properties and has been found at significantly higher levels in women with PTB as part of a compensatory physiological response. Vitamin D, a steroid-like hormone, modulates immune pathways and downregulates CRH, prostaglandin production, and oxytocin signaling, all of which are implicated in the initiation of labor.

This randomized, prospective, open-label pilot study aims to evaluate whether the combination of Magnesium, Palmitoylethanolamide, high-molecular-weight Hyaluronic Acid, Vitamin B6, and Vitamin D, administered in addition to standard vaginal progesterone, can reduce the incidence of preterm birth in women at increased risk due to a sonographic cervical length of 15-30 mm between 20 and 34 weeks' gestation.

A total of 150 women with singleton pregnancies will be randomized 1:1 to receive either standard care with vaginal progesterone alone (control group) or vaginal progesterone plus the oral combination supplement (treatment group). Cervical length will be assessed at baseline, 1 week, and 2 weeks after enrollment. Participants will be followed until 37 weeks of gestation or delivery.

The primary outcome is the proportion of women delivering at or beyond 36 weeks of gestation. Secondary outcomes include the incidence of preterm uterine contractions, emergency department visits for uterine contractions, time interval from treatment initiation to delivery, and longitudinal changes in cervical length.

As the first study to investigate this specific molecular association for PTB prevention, it is designed as a pilot trial to generate preliminary efficacy data and inform future larger randomized controlled studies.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Giuseppe RIZZO, Professor; Phone Number: +393386973001; Email: giuseppe.rizzo@uniroma1.it

Study Locations

• Italy
  • RM
    • Rome, RM, Italy, 00161
      • Recruiting
      • Policlinico Umberto I

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed informed consent

Singleton pregnancy

Maternal age ≥ 18 years

Gestational age between 20+0 and 34+0 weeks at enrollment

Cervical length between 15 mm and 30 mm measured by transvaginal ultrasound

Exclusion Criteria:

• Fetal structural anomalies

Maternal chronic diseases or pregnancy-related conditions, including diabetes, hypertension, preeclampsia, cardiovascular disease, infections, or autoimmune disorders

Multiple gestation

Fetal growth abnormalities (estimated fetal weight <10th or >90th percentile)

Prelabor rupture of membranes (PROM)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment: Magnesium-PEA-HMW Hyaluronic Acid-Vitamin B6-Vitamin D + Vaginal Progesterone	Drug: Magnesium-PEA-HMW Hyaluronic Acid-Vitamin B6-Vitamin D + Vaginal Progesterone; Participants randomized to the treatment arm will receive a combination oral supplement containing Magnesium (450 mg), Palmitoylethanolamide (200 mg), high-molecular-weight Hyaluronic Acid (200 mg), Vitamin B6 (2.6 mg), and Vitamin D (50 µg / 2000 IU), administered as two tablets per day. The supplement will be given in addition to standard vaginal progesterone (200 mg once daily). Treatment begins at enrollment (20-34 weeks' gestation) and continues until 37 weeks of gestati
Active Comparator: Control: Vaginal Progesterone Only	Other: Standard Treatment (Guideline-Based); Participants randomized to the control arm will receive standard therapy consisting of vaginal progesterone (200 mg once daily) from enrollment (20-34 weeks' gestation) until 37 weeks of gestation. No additional supplements or investigational products will be administered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preterm Birth before 37 weeks	Proportion of participants who deliver before 37+0 weeks of gestation in each study arm.	Up to 37 weeks of gestation or delivery, whichever occurs first.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Preterm Uterine Contractions	Number of episodes of uterine contractions requiring clinical evaluation, as reported by participants or documented during hospital visits.	From enrollment until 37 weeks of gestation or delivery.
Emergency Department Visits for Preterm Contraction	Number of emergency department or obstetric triage visits due to symptoms of preterm uterine activity.	From enrollment until 37 weeks of gestation or delivery.
Interval From Treatment Initiation to Delivery	Number of days between study enrollment (start of therapy) and delivery.	From baseline (T0) to delivery.
Change in Cervical Length at 1 Week	Difference in transvaginal cervical length (mm) between baseline and 1 week after randomization.	Baseline (T0) and 1 week (T1).
Change in Cervical Length at 2 Weeks	Difference in transvaginal cervical length (mm) between baseline and 2 weeks after randomization.	Baseline (T0) and 2 weeks (T2).

Collaborators and Investigators

• Sponsor: University of Roma La Sapienza

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2026
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: December 12, 2025
• First Submitted That Met QC Criteria: December 12, 2025
• First Posted (Actual): December 26, 2025

Study Record Updates

• Last Update Posted (Actual): April 29, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Vitamin D; preterm birth; preterm labor; prematurity; magnesium; hyaluronic acid; vitamin B6
• Additional Relevant MeSH Terms: Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Obstetric Labor Complications; Pregnancy Complications; Premature Birth; Obstetric Labor, Premature
• Other Study ID Numbers: PEATB_2025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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