Cell Therapy, Endothelial Injury, Exosome Multiomics, Postpartum, Preeclampsia
Conditions
Keywords
Preeclampsia, Postpartum, Stem Cell, Exosome, Cell Therapy
Brief summary
\--- Why Is This Study Being Done? Women who have preeclampsia during pregnancy face a much higher risk of heart disease later in life. Preeclampsia is a serious pregnancy condition that causes high blood pressure and damages blood vessels. Even after the baby is born, the blood vessels do not fully heal on their own, which can lead to heart problems/cardiovascular years later. This study tests whether a new treatment called exosomes can help repair damaged blood vessels in women who had preeclampsia. Exosomes are tiny particles that come from stem cells and contain healing substances that may help blood vessels work better. \--- What Will Happen in This Study? This study will include 80 women who recently gave birth and had preeclampsia during their pregnancy. Half of the women will receive the exosome treatment through an IV, and half will receive a placebo (a substance with no active treatment). \--- What Will Participants Need to Do? Participants will: * Have blood tests and other health checks * Receive one treatment through an IV * Return for follow-up visits at 1 week after treatment * Have tests to check how well their blood vessels are working Who Can Join This Study? Women who: * Recently gave birth (within 1-2 weeks) * Had preeclampsia during their last pregnancy * Are healthy enough to participate * Can give permission to join the study What Are the Possible Benefits and Risks? The treatment may help repair blood vessel damage and reduce the risk of future heart disease. The exosome treatment appears to be safe based on other studies, but like any medical treatment, there may be side effects. \--- How Long Will the Study Last? The main treatment happens during one visit, with follow-up visits for 1 week to check on participants' health and see if the treatment is working. This research may lead to new ways to protect women's heart health after pregnancy complications.
Detailed description
\--- Background and Rationale Preeclampsia affects 3-5% of pregnancies globally and represents a severe pregnancy-specific syndrome characterized by widespread maternal endothelial dysfunction. The pathophysiology involves abnormal trophoblast invasion leading to placental ischemia. Beyond immediate perinatal risks, preeclampsia carries devastating long-term cardiovascular consequences, with women experiencing a four-fold increased risk of heart failure, a 2.5-fold increased risk of coronary heart disease, and a two-fold increased risk of stroke and cardiovascular death. Moreover, post-cesarean postpartum mothers with a history of preeclampsia face particularly elevated risks, with cesarean delivery increasing postpartum preeclampsia risk by two- to seven-fold compared to vaginal delivery. This increased risk stems from altered hemodynamics, surgical stress responses, and compromised vascular integrity following cesarean procedures. \--- Scientific Innovation This study represents a paradigm shift from symptomatic management to active regenerative therapy using mesenchymal stem cell-derived exosomes (MSC-Exos). MSC-Exos offer several advantages over traditional approaches: natural tropism for vascular tissues, multi-pathway targeting capabilities, reduced immunogenicity compared to cell-based therapies, and superior circulation stability. Recent systematic reviews demonstrate favorable safety profiles with a low incidence of serious adverse events (0.7%). \--- Intervention Details Participants will receive a single intravenous or intramuscular dose of MSC-derived exosomes obtained from fetal adipose stem cells (ASC), produced under Good Manufacturing Practice (GMP) conditions. The exosomes contain bioactive cargo including growth factors, cytokines, proteins, and therapeutic microRNAs (particularly miR-126-3p) that mediate intercellular communication and tissue repair. Control participants will receive sterile saline solution of identical volume via the same route. \--- Biomarker Strategy The study employs miR-126-3p as the primary biomarker based on its exceptional diagnostic performance for endothelial dysfunction. miR-126-3p demonstrates high sensitivity (85.71%) and specificity (81.82%) with an area under the curve (AUC) of 0.792 for detecting endothelial dysfunction. This microRNA serves dual roles as both a pathological mediator and therapeutic target, making it ideal for monitoring treatment response. miR-126-3p is significantly downregulated in preeclampsia and directly regulates key angiogenic pathways including PI3K/AKT and MAPK/ERK signaling. \--- Mechanistic Rationale MSC-derived exosomes promote endothelial repair through multiple complementary mechanisms: * Anti-inflammatory effects by promoting M2 macrophage polarization and reducing pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). * Angiogenic promotion through delivery of pro-angiogenic factors including VEGF, VEGFR-2, and specific microRNAs. * Anti-apoptotic activity protecting endothelial cells via regulation of Bcl-2/Bax/Caspase-3 pathways. * Vascular barrier protection by maintaining intercellular junctions and preventing vascular permeability. Clinical Assessment Protocol The study incorporates comprehensive clinical monitoring including Hematology examination (Hemoglobin, MCV & MCHC, Hematocrit, Leukocyte, Platelets), Vital Signs Assessment (Blood Pressure, Respiratory Rate, Heart Rate), Edema assessment (Upper Extremity Edema, Lower Extremity Edema, Facial Edema), proteinuria evaluation, and Imaging Outcome (Pulsatility Index (PI), and Resistance Index (RI) Uterine Artery, Uterine Involusion) \--- Therapeutic Window and Follow-Up The intervention targets the critical postpartum period (first-second week) when endothelial regeneration naturally occurs but may be compromised in preeclampsia patients. The 24-month follow-up period aligns with evidence suggesting therapeutic interventions during early postpartum may help reset long-term cardiovascular risk trajectories. This extended monitoring allows assessment of sustained therapeutic effects and long-term cardiovascular protection. \--- Statistical Considerations Sample size calculation (n=40 per group) is based on power analysis with α=0.05 and 80% power, accounting for a 10% dropout rate. The study design incorporates interim analysis at 50% recruitment with predetermined safety stopping rules monitored by an independent Data Safety Monitoring Board. \--- Expected Clinical Impact This study could establish a new therapeutic paradigm for postpartum care, shifting from reactive symptomatic management to proactive regenerative intervention. Success would provide the foundation for developing standardized exosome therapy protocols, potentially reducing long-term cardiovascular disease burden in high-risk postpartum populations, and contributing to improved maternal health outcomes with significant economic implications for healthcare systems. \--- Regulatory and Safety Framework The study operates under comprehensive ethical oversight with approval from the institutional Health Research Ethics Committee. Safety monitoring includes comprehensive adverse event reporting protocols and predefined safety stopping criteria to ensure participant protection throughout the study duration.
Interventions
BIOLOGICALMesenchymal Stem Cell-Derived Exosomes
Mesenchymal stem cell-derived exosomes isolated from adipose-derived stem cells (ASC). The exosomes contain bioactive molecules including microRNAs (particularly miR-126-3p), proteins, and lipids that promote endothelial repair and regeneration. The product is manufactured under GMP conditions and administered as a single Intravenous or Intramuscular infusion.
OTHERPlacebo (Sterile Saline Solution)
Sterile saline solution (0.9% sodium chloride) administered Intravenous or Intramuscular as placebo control. The volume and administration method are identical to the active treatment to maintain blinding.
Sponsors
Dr. Hasan Sadikin General Hospital, Bandung, Indonesia
Dr Cipto Mangunkusumo General Hospital
Dr. Sardjito Hospital, Yogyakarta
Universitas Padjadjaran
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomized, placebo-controlled clinical trial with parallel group design. Participants will be randomized 1:1 to receive either MSC-derived exosomes or placebo (sterile saline solution). Both groups will be followed for the same duration with identical assessment schedules.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Postpartum * Confirmed diagnosis of preeclampsia in the last pregnancy * Postpartum period of first week and second week * Able to provide informed consent
Exclusion criteria
* History of chronic hypertension prior to pregnancy * Major cardiovascular disease history * Active systemic infection * Endothelial Injury history * Active smoking status including vape, alcohol, drug addiction.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Endothelial Function Biomarker (miR-126-3p) | Baseline and 1 week post-intervention | Measure: Change in miR-126-3p expression levels from baseline to 1 week post-intervention. Method: RT-PCR analysis of blood samples. Unit: Fold change (relative expression). Scale Description: Continuous variable measured as fold change relative to baseline. Higher values indicate improved endothelial function. Normal range: 0.8-1.2 fold change. Values \<0.8 indicate dysfunction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Systolic Blood Pressure | Baseline, first week, and 1 week post-intervention | Measure: Change in systolic blood pressure from baseline. Unit: mmHg. Normal Range: 90-140 mmHg (postpartum). Values ≥140 mmHg indicate hypertension. |
| Diastolic Blood Pressure | Baseline, first week, and 1 week post-intervention | Measure: Change in diastolic blood pressure from baseline. Unit: mmHg. Normal Range: 60-90 mmHg (postpartum). Values ≥90 mmHg indicate hypertension. |
| Hemoglobin Level | Baseline and 1 week post-intervention | Measure: Change in hemoglobin concentration from baseline. Unit: g/dL. Normal Range: 11.0-15.0 g/dL (postpartum). Values \<11.0 g/dL indicate anemia. |
| Hematocrit Level | Baseline and 1 week post-intervention | Measure: Change in hematocrit percentage from baseline. Unit: Percentage (%). Normal Range: 33-45% (postpartum). Values \<33% indicate anemia. |
| Leukocyte Count | Baseline and 1 week post-intervention | Measure: Change in white blood cell count from baseline. Unit: cells/μL. Normal Range: 9,000-25,000 cells/μL (postpartum, elevated due to normal physiologic stress). Values \>25,000 may indicate infection. |
| Platelet Count | Baseline and 1 week post-intervention | Measure: Change in platelet count from baseline. Unit: cells/μL. Normal Range: 150,000-400,000 cells/μL. Values \<150,000 indicate thrombocytopenia. |
| Mean Corpuscular Volume (MCV) | Baseline and 1 week post-intervention | Measure: Change in mean corpuscular volume from baseline. Unit: femtoliters (fL). Normal Range: 80-100 fL. Values \<80 fL indicate microcytic anemia; \>100 fL indicate macrocytic anemia. |
| Mean Corpuscular Hemoglobin Concentration (MCHC) | Baseline and 1 week post-intervention | Measure: Change in mean corpuscular hemoglobin concentration from baseline. Unit: g/dL. Normal Range: 32-36 g/dL. Values \<32 g/dL indicate hypochromic anemia. |
| Uterine Artery Pulsatility Index (PI) | Baseline and 1 week post-intervention | Measure: Change in Pulsatility Index of uterine artery measured by Doppler ultrasound. Unit: Ratio (dimensionless). Scale Description: Calculated as (peak systolic velocity - end diastolic velocity)/mean velocity. Normal postpartum range: 0.5-1.2. Higher values indicate increased vascular resistance. |
| Uterine Artery Resistance Index (RI) | Baseline and 1 week post-intervention | Measure: Change in Resistance Index of uterine artery measured by Doppler ultrasound. Unit: Ratio (dimensionless). Scale Description: Calculated as (peak systolic velocity - end diastolic velocity)/peak systolic velocity. Normal postpartum range: 0.4-0.8. Higher values indicate increased vascular resistance. |
| Heart Rate | Baseline, first week, and 1 week post-intervention | Measure: Change in heart rate from baseline. Unit: beats per minute (bpm). Normal Range: 60-100 bpm (postpartum may be slightly elevated 70-110 bpm). Values \>110 bpm may indicate tachycardia. |
| Respiratory Rate | Baseline, first week, and 1 week post-intervention | Measure: Change in respiratory rate from baseline Unit: breaths per minute Normal Range: 12-20 breaths per minute. Values \>20 may indicate tachypnea. |
| Upper Extremity Edema Grade | Baseline and 1 week post-intervention | Measure: Change in upper extremity edema grading from baseline. Unit: Grade on standardized scale. Scale Description: Postpartum Edema Grading Scale (0-4): Grade 0: No edema Grade 1: Mild pitting edema, barely perceptible Grade 2: Moderate pitting edema, clearly visible Grade 3: Severe pitting edema with obvious swelling Grade 4: Very severe pitting edema with marked deformity. Interpretation: Higher grades indicate worse edema. Grade 0-1 considered normal postpartum; Grades 2-4 indicate pathological edema. |
| Lower Extremity Edema Grade | Baseline and 1 week post-intervention | Measure: Change in lower extremity edema grading from baseline. Unit: Grade on standardized scale. Scale Description: Postpartum Edema Grading Scale (0-4) - same as above. Interpretation: Higher grades indicate worse edema. Grade 0-1 considered normal postpartum; Grades 2-4 indicate pathological edema. |
| Facial Edema Grade | Baseline and 1 week post-intervention | Measure: Change in facial edema grading from baseline. Unit: Grade on standardized scale. Scale Description: Postpartum Edema Grading Scale (0-4) - same as above. Interpretation: Higher grades indicate worse edema. Grade 0 considered normal postpartum; Grades 1-4 indicate pathological edema. |
| Uterine Involution Status | Baseline and 1 week post-intervention | Measure: Assessment of uterine involution progress measured by uterine height. Unit: centimeters (cm) above symphysis pubis. Normal Range: Day 1 postpartum: At umbilicus (\ 12 cm) Day 7 postpartum: 7-9 cm above symphysis pubis Day 14 postpartum: 4-6 cm above symphysis pubis. Interpretation: Expected decrease of \ 1 cm per day. Slower decrease may indicate subinvolution. |
| Proteinuria Level | Baseline and 1 week post-intervention | Measure: Change in urine protein level from baseline using dipstick urinalysis. Unit: Dipstick protein scale (qualitative). Scale Description: Urine Dipstick Protein Scale: Negative/Trace: Normal (no significant proteinuria) 1. (30 mg/dL): Mild proteinuria 2. (100 mg/dL): Moderate proteinuria 3. (300 mg/dL): Severe proteinuria 4. (\>2000 mg/dL): Very severe proteinuria Normal Range: Negative to Trace in postpartum period. Interpretation: Higher grades indicate worse proteinuria. Grades 2+ and above indicate clinically significant proteinuria requiring monitoring. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with clinically significant abnormal laboratory test results | Baseline to 7 days after last dose of exosomes. | Number and percentage of participants with ≥1 clinically significant abnormal laboratory result after baseline. Clinically significant = laboratory value outside normal reference range and meeting pre-specified criteria in protocol (investigator-assessed clinically important change). Each participant counted once regardless of number of abnormal tests. |
Countries
Indonesia
Contacts
Primary ContactPrima N Fauziah, S.Si., M.Si.
Backup ContactNurul Azizah, S.Tr.Keb.
Outcome results
None listed