Plant-based antioxidant strategies with potential for preeclampsia prevention: clinical and mechanistic insights

Study design

This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement [21] (Figure 9). A prospectively designed protocol was used to ensure methodological rigor and reproducibility.

Figure 9:

Systematic literature search and study selection based on PRISMA 2020 guidelines. This PRISMA 2020 flow diagram illustrates the systematic process of study selection for the present review. A total of 852 records were initially identified through database searching across PubMed, scopus, web of science, and the cochrane library. After the removal of duplicates, titles and abstracts were screened by two independent reviewers, resulting in 126 articles retained for full-text eligibility assessment. Following detailed evaluation based on predefined inclusion and exclusion criteria – specifically focusing on human clinical trials or mechanistic studies involving endothelial or placental models relevant to preeclampsia prevention – 32 studies met the eligibility criteria and were included in the final qualitative synthesis. The stepwise filtering and decision-making process ensured methodological transparency, minimized bias, and adhered to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.

Search strategy

A comprehensive search was performed in PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library, covering publications from January 1, 2000, to April 25, 2025. In addition, grey literature sources such as the WHO Global Index Medicus and Google Scholar were screened to capture potentially overlooked traditional medicine studies. Search terms combined Medical Subject Headings (MeSH) and free-text keywords related to preeclampsia, oxidative stress, antioxidants, and specific medicinal plants (C. longa, M. oleifera, O. aristatus, C. asiatica) using Boolean operators (AND/OR). Reference lists of eligible studies and relevant reviews were also checked manually to ensure completeness.

Eligibility criteria

Studies were included if they reported human clinical data evaluating one of the four target plants for outcomes related to oxidative stress, endothelial function, or maternal–fetal health. Eligible designs included randomized controlled trials, non-randomized intervention studies, or observational clinical studies with well-described interventions. Studies exclusively based on in vitro or animal models, narrative reviews, editorials, commentaries, conference abstracts without full texts, or polyherbal interventions where individual plant effects could not be isolated were excluded.

Study selection

Two reviewers independently screened titles and abstracts using the Rayyan QCRI platform. Full-text assessment was performed for studies meeting or potentially meeting inclusion criteria. Discrepancies were resolved by consensus or by consulting a third reviewer. The selection process is summarized in the PRISMA 2020 flow diagram (Figure 9).

Data extraction

Two reviewers independently extracted study characteristics, including authors, publication year, design, region, participant profile, intervention details (plant part, preparation, dosage, duration), comparators, outcome measures (oxidative stress biomarkers, endothelial markers, clinical maternal or fetal outcomes), and adverse events. Extracted data were summarized in structured tables (Tables 1–4). Disagreements were reconciled by discussion.

Quality assessment

Randomized trials were evaluated using the Cochrane Risk of Bias 2.0 tool (RoB 2) [22], and non-randomized studies using the ROBINS-I tool [23]. The overall certainty of evidence was assessed using the GRADE methodology [24].

Data synthesis and analysis

Given the heterogeneity of study populations, interventions, and outcomes, findings were synthesized narratively rather than pooled quantitatively. Studies were grouped by plant species and then by outcome domain (pregnancy-specific clinical outcomes, general clinical outcomes, and mechanistic or biomarker effects). Quantitative results (mean differences, effect sizes, p-values) are reported descriptively where available.

Presentation of results

Results are presented through structured evidence tables (Tables 1–4) and mechanistic pathway figures (Figures 1–5) describing the antioxidant, anti-inflammatory, and endothelial-protective effects of each plant. Cultivation profiles illustrating agricultural feasibility and scalability are included (Figure 6), and an integrated mechanistic model and future research roadmap are depicted (Figures 7 and 8).

Study selection following PRISMA guidelines

A comprehensive systematic search was performed using PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library for articles published between January 1, 2000, and April 25, 2025. Search terms combined Medical Subject Headings (MeSH) and keywords related to preeclampsia, oxidative stress, antioxidants, traditional medicinal plants, and the specific botanical species (C. longa, M. oleifera, O. aristatus, C. asiatica). The search strategy employed Boolean operators as follows: (“preeclampsia” OR “hypertensive disorders of pregnancy”) AND (“oxidative stress” OR “antioxidants” OR “inflammation”) AND (“C. longa” OR “turmeric” OR “M. oleifera” OR “O. aristatus” OR “C. asiatica”) AND (“clinical trial” OR “randomized controlled trial” OR “human study”).

Following duplicate removal, titles and abstracts of 852 articles were screened independently by two reviewers. After screening, 126 articles were selected for full-text review. Based on eligibility criteria – focusing on human clinical trials involving pregnant women or relevant mechanistic models in human endothelial or placental cells – 32 studies were included in the final synthesis. The selection process is presented in the PRISMA flow diagram (Figure 9). Table 3 outlines the main characteristics of the clinical and preclinical studies evaluated, detailing sample sizes, intervention types, and key outcome measures across the included studies. Due to heterogeneity in study design, populations, and outcomes, a meta-analysis was not feasible; findings were synthesized narratively.

To clarify evidence hierarchy for readers and reviewers, results are organized as:

1. Tier A: Pregnancy-specific clinical studies

2. Tier B: General human clinical studies related to oxidative stress and vascular function

3. Tier C: Mechanistic and preclinical studies providing biological plausibility

Risk of bias assessment

The quality of evidence across the included studies was heterogeneous. Randomized controlled trials (RCTs) were assessed using the Cochrane Risk of Bias 2.0 (RoB 2) tool, while non-randomized clinical studies were evaluated using the ROBINS-I instrument. Most RCTs demonstrated low to moderate risk of bias in the randomization process and outcome measurement domains but often lacked details on allocation concealment and blinding. Non-randomized studies showed higher risk of bias, particularly in confounding and selection domains, reflecting inherent limitations of observational designs. For mechanistic and preclinical studies (in vitro endothelial/placental models and animal studies), formal risk of bias assessment tools were not applied because these were included only to provide biological plausibility (Tier C evidence). Overall, the certainty of evidence supporting pregnancy-specific clinical effects was rated as low to very low, highlighting the need for adequately powered pregnancy-focused RCTs with standardized interventions and robust reporting.

Integrative synthesis: multitarget potential against preeclampsia (Figures 6–8)

The convergence of antioxidant, anti-inflammatory, endothelial-protective, and renal-protective mechanisms observed across C. longa, M. oleifera, O. aristatus, and C. asiatica underscores a multidimensional therapeutic potential in preeclampsia prevention. Each plant independently modulates distinct but overlapping molecular pathways that contribute to the pathogenesis of the disorder, creating a robust synergistic model for maternal vascular and renal protection. Beyond simple antioxidant capacity, these botanicals orchestrate coordinated suppression of inflammatory cascades, enhancement of endothelial function, and preservation of renal glomerular integrity. Such multi-mechanistic actions are particularly valuable given the complex, multifactorial etiology of preeclampsia, which has historically challenged monotherapy approaches. These mechanisms are synthesized in Table 2 and visualized in Figure 7.

However, as outlined in Table 4 and illustrated in Figure 8, significant research gaps remain – including pharmacokinetics, standardized dosing, and pregnancy-specific safety evaluations – that must be addressed before clinical translation can be safely pursued. These outcomes highlight translational potential but require pregnancy-specific pharmacokinetic, dosing, and safety studies before clinical integration.

Overview of key findings

This systematic review synthesized emerging evidence on the preventive potential of four indigenous Indonesian medicinal plants – C. longa, M. oleifera, O. aristatus, and C. asiatica – in mitigating preeclampsia risk (Table 2; Figures 2–5). Findings demonstrate that these botanicals target multiple pathological pathways implicated in preeclampsia, including oxidative stress, inflammatory signaling, endothelial dysfunction, and renal impairment.

1. C. longa, via its principal polyphenol curcumin, modulates oxidative and inflammatory pathways, offering endothelial and renal protection [14], 15], 31].

2. M. oleifera, rich in flavonoids and vitamin C, enhances antioxidant defenses and attenuates vascular inflammation [16], 17].

3. O. aristatus combines antioxidant, anti-inflammatory, diuretic, and nephroprotective effects [18], 32].

4. C. asiatica improves microvascular function, mitigates oxidative injury, and preserves renal integrity [19], 20], 25].

Collectively, these plants present a promising multi-targeted phytotherapeutic framework aligned with the complex etiology of preeclampsia (Figure 7). While integration of clinical and mechanistic data provides an encouraging foundation, critical knowledge gaps remain regarding optimal dosing, pharmacokinetics, and pregnancy-specific safety, necessitating additional investigation before clinical implementation.

Integration with existing knowledge

The findings support and expand prior research emphasizing oxidative stress, inflammatory dysregulation, and endothelial dysfunction as central to preeclampsia pathogenesis [4], [5], [6], [7, 26], 27]. Historically, antioxidant strategies using vitamins C and E failed to prevent preeclampsia [28], underscoring the need for agents with broader bioactivity.

1. C. longa and M. oleifera demonstrated dual antioxidant and anti-inflammatory actions, suppressing NF-κB-mediated cytokine production while enhancing enzymatic antioxidant defenses [14], [15], [16], [17].

2. O. aristatus exhibited renal-protective and vascular-relaxant effects, partly mediated by nitric oxide (NO) signaling enhancement [18], 32].

3. C. asiatica improved endothelial barrier integrity and inhibited pro-inflammatory cytokine expression [19], 20], 25].

These effects directly target early pathophysiological events in preeclampsia, including impaired trophoblast invasion, placental ischemia, and systemic endothelial activation (Figure 1; Table 1). Moreover, emerging preclinical studies suggest multi-target phytotherapeutics may outperform single-pathway interventions in complex pregnancy disorders [30]. By integrating indigenous botanical pharmacology with modern pathophysiological models, this review highlights potential complementary strategies to reduce maternal vascular risk.

Clinical implications

Given the limited therapeutic options for preeclampsia prevention, safe, orally administered, plant-based agents could provide an important complementary approach (Table 3).

1. Curcumin is generally well tolerated but exhibits poor bioavailability, necessitating novel delivery methods (e.g., nanoparticle or phospholipid carriers) [31].

2. M. oleifera is widely consumed in Indonesian diets, with observational data supporting improved maternal nutrition and reduced oxidative stress [16], 17].

3. O. aristatus and C. asiatica are common in Indonesian traditional medicine and demonstrate vascular and renal benefits, although pregnancy-specific clinical data are limited [18], [19], [20, 32].

However, dose-ranging and pharmacokinetic (PK/PD) data remain absent. No studies define minimum effective doses (MED), maximum tolerated doses (MTD), or long-term maternal-fetal safety (NOAEL/LOAEL thresholds). Without these data, clinical translation remains speculative. Future work must prioritize structured dose-finding studies, pregnancy-specific PK/PD investigations, and standardized extract development to ensure efficacy and safety.

Regulatory and safety considerations

The regulatory status and safety of botanical interventions in pregnancy require careful consideration. None of the included studies conducted formal dose-ranging, pharmacokinetic, or maternal-fetal safety evaluations specific to pregnancy. For all four plants, current evidence is largely based on general population data or preclinical studies, which cannot be directly extrapolated to pregnant women.

From a regulatory perspective.

1. C. longa (turmeric) and M. oleifera are widely consumed as food or supplements, but concentrated extracts have not been assigned specific pregnancy safety categories by regulatory bodies such as the U.S. FDA or European Medicines Agency (EMA).

2. O. aristatus and C. asiatica are traditionally used for diuresis and microcirculatory health but lack standardized pregnancy safety profiles and dosage guidelines.

3. The WHO Traditional Medicine Strategy 2023–2032 emphasizes the need for pharmacovigilance, quality control of herbal products, and ethical bioprospecting before recommending any plant-based intervention for vulnerable groups such as pregnant women.

Potential risks include.

1. Drug–herb interactions, particularly in women taking antihypertensive medications, anticoagulants, or low-dose aspirin.

2. Variability in active phytochemical content due to differences in plant species, cultivation, and extraction methods.

3. Teratogenic and reproductive toxicity data are largely unavailable, especially for concentrated formulations used beyond traditional culinary amounts.

Given these uncertainties, any clinical translation must be preceded by standardized extract development, reproductive toxicity testing (e.g., OECD TG 414 and 421), and structured pregnancy-specific pharmacovigilance systems.

Cultural relevance and indonesian context

Indonesia is recognized as one of the world’s biodiversity hotspots and possesses a rich tradition of maternal herbal medicine [13]. Many communities already use C. longa (kunyit), M. oleifera (kelor), O. aristatus (kumis kucing), and C. asiatica (pegagan) to promote maternal well-being.

Integrating such culturally familiar and accessible plants into maternal health strategies aligns with the WHO Traditional Medicine Strategy 2023–2032 [34] and offers opportunities for community-based implementation in resource-limited settings. Utilizing existing local knowledge and agricultural supply chains could enhance program feasibility, affordability, and acceptance, especially where pharmaceutical access is limited.

Strengths, limitations, and future directions

A key strength of this review is the integration of clinical trial data (Table 3) with molecular mechanism evidence (Figures 2–5), offering a multidimensional perspective rarely achieved in pregnancy-related phytotherapy. The PRISMA-guided methodology (Figure 9) enhances reproducibility and transparency.

However, several limitations persist:

1. Limited pregnancy-specific RCTs – most data are extrapolated from non-pregnant or mixed populations.

2. Heterogeneity – extract formulations, dosage, and treatment timing vary significantly across studies.

3. Safety gaps – pregnancy-specific PK/PD and reproductive toxicity data are lacking.

Future research priorities include.

1. Well-powered, pregnancy-specific RCTs.

2. Comprehensive PK/PD profiling, including placental transfer assessments.

3. Reproductive toxicity evaluations aligned with OECD guidelines (TG 414, 421).

4. Synergistic phytochemical combination studies and advanced delivery systems (e.g., nanoformulations).

5. Ethical bioprospecting and equitable benefit-sharing with indigenous communities (WHO Strategy [34]).

Table 4 and Figure 8 outline a strategic roadmap to address these gaps.

Concluding perspectives

The synthesis of current evidence highlights a potential paradigm shift in preeclampsia prevention: moving beyond isolated antioxidant therapy toward multi-target, culturally rooted phytomedicine. C. longa, M. oleifera, O. aristatus, and C. asiatica provide a biologically plausible and locally relevant framework to restore redox balance, suppress inflammation, preserve endothelial function, and protect renal integrity.

Responsible clinical translation demands rigorous validation, including standardized dosing frameworks, PK/PD characterization, and maternal-fetal safety evaluations. Collaboration among clinical researchers, ethnobotanists, pharmacologists, regulatory agencies, and local communities will be essential to ethically integrate these botanicals into modern maternal care.