• I Wayan Artana Putra 
  • Evert Solomon Pangkahila 
  • I Nyoman Bayu Mahendra 
  • Kadek Fajar Marta 
  • I Made Darmayasa 
  • Putu Ngurah Aeland Prilaksana Kalimantara 

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Introduction: Preeclampsia (PE) is a major cause of maternal morbidity and mortality, particularly in low-resource settings. Although Magnesium Sulfate (MgSO4) is the standard treatment for preventing eclampsia, its precise effects on vascular function, especially regarding Endothelin-1 (ET-1) levels, remain unclear. ET-1, a potent vasoconstrictor, is elevated in hypertensive disorders of pregnancy, contributing to endothelial dysfunction in PE. This study aims to investigate the impact of MgSO4 therapy on plasma ET-1 levels in pregnant women diagnosed with severe PE.

Method: This observational follow-up study was conducted at RSUP Prof. Dr. I. G. N. G. Ngoerah, Denpasar, starting in October 2022. Participants included pregnant women with severe PE, aged 20–40 weeks of gestation, receiving MgSO4 therapy. Patients with chronic conditions such as diabetes or pre-existing hypertension were excluded. Blood samples were collected before and after MgSO4 administration, and plasma ET-1 levels were measured using enzyme-linked immunosorbent assay (ELISA). Statistical analysis was conducted using the Wilcoxon test, with a significance level set at p < 0.05.

Results: A total of 31 participants, with a mean age of 32.09 ± 6.48 years, were included. Most patients were nulliparous (32.3%) and had a single marriage history (71.0%). Baseline characteristics showed high systolic and diastolic blood pressures (mean 165 and 110 mmHg, respectively), elevated MAP (131 mmHg), and significant proteinuria (+3 in 38.7% of cases). Laboratory results indicated abnormal levels of AST, ALT, LDH, and creatinine, with an average platelet count of 241.35 ± 69.77 x 103/L. Following MgSO4 therapy, ET-1 levels significantly decreased from a median of 12.45 ng/mL to 5.55 ng/mL (p = 0.004), suggesting an improvement in endothelial function.

Conclusion: The study findings suggest that MgSO4 not only prevents seizures but also plays a role in reducing vasoconstriction in PE patients through the modulation of ET-1 levels. This supports the potential use of ET-1 as a marker to evaluate the therapeutic efficacy of MgSO4 in PE management, highlighting MgSO4’s broader vascular benefits in treating PE.

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Introduction

Preeclampsia (PE) is a complex hypertensive disorder of pregnancy defined by new-onset hypertension and proteinuria after 20 weeks of gestation, often accompanied by signs of systemic organ involvement, such as hepatic or renal dysfunction, thrombocytopenia, and fetal growth restriction. This condition remains a leading cause of maternal and perinatal morbidity and mortality worldwide, particularly in developing countries, where access to adequate healthcare resources may be limited. The World Health Organization (WHO) reports that preeclampsia and related hypertensive disorders contribute to approximately 10%–15% of direct maternal deaths globally, emphasizing the critical need for effective management strategies in affected populations [1].

The pathophysiology of PE is not fully understood, but current evidence suggests it involves abnormal placentation, endothelial dysfunction, and an imbalance between vasoconstrictive and vasodilative factors. Central to this imbalance is Endothelin-1 (ET-1), a potent vasoconstrictor peptide produced by endothelial cells. Elevated levels of ET-1 have been implicated in the pathogenesis of hypertensive disorders and are notably higher in patients with PE, where they contribute to increased vascular resistance, endothelial injury, and systemic hypertension [2]. Studies have shown that high ET-1 levels correlate with PE severity and adverse pregnancy outcomes, positioning ET-1 as a potential biomarker for disease progression and therapeutic targeting [3], [4].

The standard treatment to prevent eclampsia (the progression of PE to convulsions) is Magnesium Sulfate (MgSO4), which is widely accepted due to its neuroprotective properties and its effectiveness in reducing the incidence of seizures among preeclamptic patients [5]. MgSO4’s primary function is believed to be neuromuscular blockade, acting centrally and peripherally to prevent convulsions. However, emerging evidence suggests that MgSO4 may have additional vascular effects that contribute to its therapeutic profile, possibly by inducing vasodilation and modulating endothelial function [6]. Animal and clinical studies have indicated that MgSO4 may reduce systemic vascular resistance and improve blood flow, effects that could be beneficial in mitigating the hypertension associated with PE [7]. Despite these potential benefits, the precise impact of MgSO4 on ET-1 levels in humans remains uncertain, and few studies have specifically addressed its effects on vasoconstrictive biomarkers such as ET-1 in PE patients [8], [9].

Investigating the relationship between MgSO4 and ET-1 could yield valuable insights into the broader therapeutic mechanisms of MgSO4 in PE. By potentially reducing ET-1 levels, MgSO4 could help alleviate the vascular constriction and endothelial dysfunction central to PE pathology. Therefore, understanding how MgSO4 influences ET-1 could enhance its role in PE management beyond seizure prevention, positioning it as a multifaceted therapeutic agent in hypertensive disorders of pregnancy [10]. This study aims to evaluate the effects of MgSO4 on plasma ET-1 levels in pregnant women with severe PE. By analyzing ET-1 concentrations before and after MgSO4 administration, this research seeks to clarify the vascular benefits of MgSO4, offering new perspectives on its efficacy and expanding its potential as a cornerstone in PE treatment protocols.

Materials and Methods

Study Design and Setting

This observational follow-up study was conducted at RSUP Prof. Dr. I. G. N. G. Ngoerah in Denpasar, Indonesia, starting in October 2022. Its purpose was to evaluate the impact of Magnesium Sulfate (MgSO) therapy on plasma Endothelin-1 (ET-1) levels in pregnant women diagnosed with severe preeclampsia (PE). The study received ethical approval from the institutional review board of RSUP Prof. Dr. I. G. N. G. Ngoerah, and all participants signed written informed consent forms.

Participants

The study included pregnant women between 20 and 40 weeks of gestation who had been diagnosed with severe preeclampsia, defined by a systolic blood pressure of ≥160 mmHg or a diastolic blood pressure of ≥110 mmHg on two separate occasions at least four hours apart, accompanied by significant proteinuria or evidence of end-organ damage. Exclusion criteria included pre-existing conditions such as chronic hypertension, diabetes, kidney disease, or other systemic illnesses that could affect ET-1 levels or alter the response to MgSO4 therapy.

Intervention

All patients received standard MgSO4 therapy according to hospital protocol, beginning with a loading dose of 4 grams intravenously over 15–20 minutes, followed by a maintenance dose of 1 gram per hour for 24 hours. This dosing regimen was selected based on its efficacy in preventing eclampsia and its potential vascular effects.

Data Collection and Sample Processing

Venous blood samples were collected from each participant at two time points: immediately before initiating MgSO4 therapy (baseline) and 24 hours after the initiation of therapy (post-treatment). Blood samples were drawn into EDTA tubes, immediately placed on ice, and centrifuged at 3000 rpm for 10 minutes within one hour of collection. Plasma was then aliquoted and stored at −80 °C until analysis to prevent ET-1 degradation.

Laboratory Analysis

Plasma levels of ET-1 were quantified using a commercially available enzyme-linked immunosorbent assay (ELISA) kit specifically validated for ET-1 (Abcam, Cambridge, UK), following the manufacturer’s protocol. The ELISA method was chosen for its high sensitivity and specificity in detecting low levels of ET-1. Each sample was analyzed in duplicate to ensure accuracy, and the mean of the two measurements was used for statistical analysis. The intra-assay and inter-assay coefficients of variation were below 10%.

Outcome Measures

The primary outcome measure was the change in plasma ET-1 levels from baseline to 24 hours after MgSO4 administration. Secondary outcomes included the correlations between ET-1 levels and clinical parameters, such as blood pressure and proteinuria severity, to evaluate the potential clinical implications of ET-1 modulation.

Statistical Analysis

Data analysis was performed using IBM SPSS Statistics version 25. Baseline characteristics were summarized using descriptive statistics. Continuous variables were presented as means with standard deviations or medians with interquartile ranges based on the data distribution. Due to the non-parametric nature of the data, the Wilcoxon signed-rank test was used to compare ET-1 levels before and after treatment. A p-value below 0.05 was considered indicative of statistical significance.

Results and Discussion

Main Characteristics of the Sample

This study was ethically approved by the Ethics Committee of RSUP Prof. Dr. I. G. N. G. Ngoerah, Denpasar, on June 19, 2023. A total of 31 pregnant women with severe preeclampsia receiving MgSO4 were included, with blood plasma samples collected both before and 24 hours after MgSO4 administration. The mean age of the participants was 32.09 ± 6.48 years. The median gestational age was 37 weeks, with a range of 29 to 40 weeks. Regarding marital history, 22 (71%) participants were married once, 6 (19.4%) were married twice, and 3 (9.7%) were unmarried. The study population was predominantly multiparous, with 21 multiparous women (67.7%) and 10 primigravidas (32.3%).

The median body mass index (BMI) was 23.5 kg/m2, ranging from 18.75 to 39.66 kg/m2. The median systolic blood pressure was 165 mmHg (range: 157–205 mmHg), and the median diastolic blood pressure was 110 mmHg (range: 100–120 mmHg). The mean arterial pressure (MAP) had a median value of 131 mmHg, with values ranging from 120 to 161 mmHg. Proteinuria was observed with a dipstick test, showing 12 participants (38.7%) with +3, 11 participants (35.5%) with +2, 5 participants (16.1%) with +4, and 3 participants (9.7%) with +1.

Laboratory results indicated a median SGOT level of 21 µg/L (range: 12–236 µg/L) and a median SGPT level of 11 µg/L (range: 4–235 µg/L). The median LDH level was 179 IU/L, with a range of 135 to 1440 IU/L, while creatinine had a median of 0.65 mg/dL (range: 0.40–2.22 mg/dL). The platelet count showed a mean of 241.35 ± 69.77 x 103/µL. The initial ET-1 levels before MgSO4 administration had a median of 12.45 pg/mL (range: 2.31–84.85 pg/mL), which decreased to a median of 5.55 pg/mL (range: 1.66–58.57 pg/mL) post-administration. Detailed characteristics are presented in Table I.

Variable Value/Frequency Normality test (Kolmogorov-Smirnov)
Age (years), Mean ± SD 32.09 ± 6.48 0.200
Gestational age (weeks), median (min-max) 37 (29–40) 0.003
Marital history, n (%)
- Unmarried 3 (9.7)
- Married once 22 (71.0)
- Married twice 6 (19.4)
Parity, n (%)
- Primigravida 10 (32.3)
- Multiparous 21 (67.7)
Body mass index, median (min-max) 23.5 (18.75–39.66) 0.004
Systolic blood pressure (mmHg), median (min-max) 165 (157–205) <0.001
Diastolic blood pressure (mmHg), median (min-max) 110 (100–120) 0.003
Mean arterial pressure (MAP) (mmHg), median (min-max) 131 (120–161) 0.004
Proteinuria, n (%)
- +1 3 (9.7)
- +2 11 (35.5)
- +3 12 (38.7)
- +4 5 (16.1)
SGOT level (µ/L), median (min-max) 21 (12–236) <0.001
SGPT level (µ/L), median (min-max) 11 (4–235) <0.001
LDH level (IU/L), median (min-max) 179 (135–1440) <0.001
Creatinine (mg/dL), median (min-max) 0.65 (0.40–2.22) <0.001
Platelet (103/µL), Mean ± SD 241.35 ± 69.77 0.200
Endothelin-1 level before MgSO4 (pg/mL), median (min-max) 12.45 (2.31–84.85) <0.001
Endothelin-1 level after MgSO4 (pg/mL), median (min-max) 5.55 (1.66–58.57) <0.001
Table I. Characteristics of the Study Subjects

Analysis of ET-1 Levels Before and After MgSO4 Administration

Differences in ET-1 levels before and after MgSO4 treatment were analyzed using the Wilcoxon test. A significant decrease in ET-1 levels was observed 24 hours after MgSO4 administration, with a p-value of 0.004 and a 95% confidence interval (CI) of 1.75–8.34 pg/mL. The Wilcoxon test results are shown in Table II, and a graphical representation is provided in Fig. 1.

Variable MgSO4 administration median (min-max) p-value 95% CI
Before After
Endothelin-1 level (pg/mL) 12.45 (2.31–84.85) 5.55 (1.66–58.57) 0.004** 1.75–8.34
Table II. Wilcoxon Analysis of Endothelin-1 Levels Before and After MgSO4 Administration

Fig. 1. Wilcoxon test for differences in endothelin-1 levels before and after administration of MgSO4. **p < 0.01.

Multivariate Analysis

Multivariate linear regression analysis identified significant predictors of pre-treatment ET-1 levels, with age and parity showing statistical significance. Pre-treatment analysis results are presented in Table III. Post-treatment analysis showed age as the only significant variable affecting ET-1 levels (Table IV).

Variable B Exp (B) Standard error p-value 95% CI
Age 2.052 0.605 0.866 0.032* 0.206–3.898
Gestational age 2.104 0.350 1.616 0.213 (−1.341)–5.549
Marital history −0.920 −0.025 9.998 0.928 (−22.231)–(20.391)
Parity −3.826 −0.664 1.750 0.045* (−7.556)–(−0.096)
Body mass index −1.563 −0.428 0.974 0.129 (−3.638)–0.512
Systolic blood pressure 0.366 0.244 0.450 0.429 (−0.594)–1.326
Diastolic blood pressure 2.016 0.579 1.081 0.082 (−0.288)–4.320
MAP −0.650 −0.257 0.993 0.523 (−2.767)–1.467
SGOT level −1.318 −2.672 1.042 0.225 (−3.540)–0.904
SGPT level 1.854 3.864 1.122 0.119 (−0.538)–4.246
LDH level −0.125 −1.494 0.061 0.059 (−0.256)–0.05
Creatinine level −0.276 −0.005 11.847 0.982 (−25.528)–24.976
Proteinuria 6.858 0.292 5.217 0.208 −4.262–17.978
Platelet count 0.083 0.281 0.066 0.231 −0.058–0.224
Table III. Multivariate Analysis of the Effect of Independent Variables on Endothelin-1 Levels Before MgSO4 Administration
Variable B Exp (B) Standard error p-value 95% CI
Age 1.564 0.634 0.645 0.028* 0.189–2.940
Gestational age 1.401 0.320 1.204 0.263 (−1.166)–3.968
Marital history −0.793 −0.030 7.450 0.917 (−16.672)–15.087
Parity −2.468 −0.588 1.304 0.078 (−5.247)–0.311
Body mass index −0.915 −0.344 0.725 0.227 (−2.461)–0.632
Systolic blood pressure 0.219 0.200 0.336 0.524 (−0.496)–0.934
Diastolic blood pressure 1.232 0.486 0.805 0.147 (−0.484)–2.949
MAP −0.611 −0.332 0.740 0.422 (−2.189)–0.966
SGOT level −0.450 −1.254 0.777 0.571 (−2.106)–1.205
SGPT level 0.869 2.488 0.836 0.315 (−0.913)–2.652
LDH level −0.095 −1.559 0.046 0.055 (−0.192)–0.002
Creatinine level −2.457 −0.061 8.828 0.785 (−21.273)–16.359
Proteinuria 5.875 0.343 3.887 0.151 (−2.411)–14.161
Platelet count 0.049 0.227 0.049 0.340 (−0.057)–0.154
Table IV. Multivariate Analysis of the Effect of Independent Variables on Endothelin-1 Levels After MgSO4 Administration

Endothelin-1 Levels in Preeclampsia Before and After MgSO4 Administration

As far as the authors are aware, this is the first study to examine ET-1 levels before and after MgSO4 administration in the same individuals. A study by Ariza et al. [11] observed ET-1 expression in PE patients given MgSO4 using the northern blotting method; however, ET-1 levels before MgSO4 administration were not reported, and MgSO4 therapy was only administered to selected groups by the researchers [12]. In that study, a significant decrease in ET-1 expression was observed in patients receiving MgSO4 compared to those given 0.9% NaCl (p < 0.05) [13], [14].

Recently, Verdonk et al. [15] examined the relationship between disrupted angiogenic balance, arterial pressure, and ET-1 levels in pregnant women with either a high (≥85; n = 38) or low (<85) ratio of soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF). Their findings revealed elevated plasma ET-1 levels among those with a high ratio3, suggesting that ET-1 may contribute to the pathogenesis of preeclampsia (PE) as a mediator influenced by anti-angiogenic factors like sFlt-1 and soluble endoglin (sEng) released by the placenta. This is supported by the observed positive correlation between plasma ET-1 and sFlt-1 levels [16]. In a related study, Aggarwal et al. investigated the associations between ET-1 and levels of sFlt-1, PlGF, and sEng in both normotensive pregnancies and PE, demonstrating a link between increased levels of sFlt-1, sEng, and ET-1 in maternal blood in PE cases [17].

Experimental models of PE have shown heightened tissue levels of the ET-1 precursor, prepro-ET-1 mRNA. Significant elevations of prepro-ET-1 were found in the renal cortex and medulla of placental ischemic rats when compared to controls [17]. Additionally, prolonged elevation of sFlt-1 in pregnant rats was shown to directly increase prepro-ET-1 gene expression within the renal cortex. In vivo experiments indicate that introducing the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) leads to hypertension in pregnant rats, which is associated with a notable rise in prepro-ET-1 expression in maternal blood vessels, as well as in the placenta and kidneys [18].

One potential pathway for increased ET-1 in PE may involve matrix metalloproteinase (MMP) activity. MMPs, particularly MMP-2 and MMP-1, can cleave the ET-1 precursor, big-ET-1, to form active ET-1, and increased expression of these enzymes has been noted in women who later develop PE. Abdalvand et al. recently suggested that elevated MMP-2 expression could enhance the conversion of big-ET-1, contributing to heightened vasoconstriction. This study noted an increase in vascular reactivity to big-ET-1 in a reduced uterine perfusion pressure (RUPP) model of PE, potentially through initial enzymatic pathways [19]. Furthermore, explored the role of MMP-1 as a possible activator of protease-activated receptor 1 (PAR1), which can induce ET-1 release in endothelial cells, reporting higher levels of serum and vascular MMP-1 in PE and proposing that MMP-1 activation of PAR-1 could have vasoconstrictive effects [17]–[19].

One of the main mechanisms MgSO4 employs to prevent seizures in preeclampsia is its ability to suppress neural inflammation. Studies have shown that MgSO4 therapy reduces seizure susceptibility and lowers neural inflammation in severe preeclampsia animal models [17]. This neural inflammation reduction may contribute to eclampsia prevention during severe preeclampsia [20]. MgSO4 has been found to have protective effects against the development of eclampsia, particularly in women with severe preeclampsia or warning signs like blurred vision, severe epigastric pain, or headache [19]. Additionally, MgSO4 has been shown to reduce seizure susceptibility in animal models of conditions like eclampsia, evidenced by longer latency to seizures, shorter seizure duration, and decreased seizure frequency [20]. MgSO4’s anticonvulsant effects are crucial in preventing and controlling seizures in women with severe preeclampsia and eclampsia [21].

MgSO4’s anticonvulsant mechanism is not fully understood, but its ability to reduce peripheral resistance is known to be one of its mechanisms. This property counters vasospasm induced by vasoconstrictor agents and affects most types of calcium channels in vascular smooth muscle, likely reducing intracellular calcium. Low intracellular calcium results in the inactivation of myosin light chain kinase, reducing contraction, relaxing arteries, lowering resistance in cerebral and peripheral vessels, alleviating vasospasm, and lowering arterial blood pressure This correlates with seizure mechanisms due to autoregulatory disturbances caused by vasospasm and vasoconstriction due to increased Endothelin-1 in preeclamptic pregnant women. Significant differences in Endothelin-1 levels before and after MgSO4 administration in preeclamptic pregnant women in this study support the theory of seizures caused by cerebral vasospasm and vasoconstriction [22].

Furthermore, MgSO4 has been shown to prevent increases in brain water content and cerebrospinal fluid cytokines induced by placental ischemia. In vivo studies highlight MgSO4’s neuroprotective effects in eclampsia, potentially reducing overall seizure risk in preeclampsia.

Limitations of the Study

This study has limitations that should be considered when drawing conclusions and could be addressed in future research. These limitations include sample collection at only one time point—24 hours after MgSO4 administration. Additionally, the sample collection timing varied between morning, afternoon, and evening, which is another limitation. This could influence the study analysis results, as Endothelin-1 production is physiologically influenced by time.

Conclusion

The study concluded that there is a significant difference in Endothelin-1 levels in pregnant women with preeclampsia before and after the administration of MgSO4, with a notable reduction in serum Endothelin-1 levels observed 24 hours after MgSO4 administration. This finding highlights the potential of Endothelin-1 as a marker for predicting the effectiveness of MgSO4 therapy in managing severe preeclampsia. Future studies are recommended to include better control of confounding variables to enhance the accuracy of the findings.

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