Abstract
Objective
To explore the effects of multivitamin combined with magnesium sulfate on placental hemodynamics, coagulation function, and maternal and infant outcomes in preeclampsia patients.
Methods
A randomized controlled study was conducted among 194 pregnant women diagnosed with preeclampsia between April 2022 and April 2023. Participants were randomly assigned to either the control group (n = 97), receiving intravenous magnesium sulfate alone, or the observation group (n = 97), receiving magnesium sulfate combined with multivitamin supplementation. Magnesium sulfate was administered with a loading dose of 2.5–5 g via rapid IV infusion and a maintenance dose of 5–20 g by continuous drip. The observation group additionally received one oral multivitamin tablet (Bayer S.A., 30 tablets/box) once daily in the morning. The treatment duration for both groups was two weeks. Blood pressure, 24-hour urinary protein, placental Doppler indices (RI, PI, S/D), coagulation markers (PT, APTT, FIB, TT), and maternal-infant outcomes were measured and compared.
Results
After treatment, both groups showed significant reductions in systolic and diastolic blood pressure, but there was no significant difference between them. However, the observation group had significantly lower 24-hour urinary protein levels (0.71 ± 0.31 g vs. 0.92 ± 0.28 g, P < 0.001). Coagulation function improved in both groups, with the observation group showing greater improvements: longer PT, APTT, and TT times, and lower FIB levels (P < 0.01). Placental hemodynamics also improved more in the observation group, with lower resistance indices and S/D ratios in both the umbilical and spiral arteries (P < 0.001). The observation group had better maternal and neonatal outcomes, including fewer cases of postpartum hemorrhage (10 vs. 22, P = 0.020), low birth weight (10 vs. 23, P = 0.013), and NICU admissions (9 vs. 21, P = 0.018). Eclampsia occurred only in the control group (3 cases), though this was not statistically significant (P = 0.081). Other outcomes, such as uterine inertia and neonatal asphyxia, were similar between groups. Subgroup analysis showed that patients with severe preeclampsia in the observation group experienced greater improvements in proteinuria and placental blood flow than those in the control group. Cesarean section rates were comparable (58 vs. 62), with main indications including fetal distress, failed labor, and poorly controlled PE. Logistic regression confirmed that multivitamin use was an independent factor for better outcomes (OR = 3.297; 95% CI: 1.731–6.282; P < 0.001), regardless of age, BMI, or gestational age.
Conclusion
Multivitamin supplementation combined with magnesium sulfate improves outcomes in preeclampsia more effectively than magnesium sulfate alone. It reduces proteinuria, enhances placental blood flow and coagulation function, and lowers the risk of complications such as postpartum hemorrhage, low birth weight, and NICU admission. These benefits are particularly notable in severe cases and are independent of baseline maternal factors, supporting the use of combined therapy in clinical practice.
Keywords: Therapeutic effect, Multivitamins, Magnesium sulfate, Preeclampsia
Introduction
Pre-eclampsia is a human-specific, pregnancy-related condition [1]. With a global prevalence of 2% to 8%, preeclampsia leads to more than 500,000 neonatal and fetal deaths each year, accounting for about 14% of all maternal deaths worldwide [2]. Pre-eclampsia is one of the major reasons of increased perinatal mortality among mothers and infants. Preeclampsia is diagnosed after 20 weeks of gestation when hypertension (blood pressure ≥ 140/90 mmHg) and proteinuria (≥ 300 mg/24 h) develop [3]. Severely, the pregnant may develop comorbidities such as pulmonary edema, liver failure, renal failure, and disseminated intravascular coagulation (DIC). For the fetus, the major complications related to preeclampsia include intrauterine growth restriction resulting in low birth weight (1/3 of cases), preterm delivery and fetal death [4]. The disease progresses gradually from the onset of symptoms. There is no effective cure for preeclampsia, and the compulsion to terminate the pregnancy to save the mother’s life poses a significant risk to the birth of clinically preterm infants. Pre-eclampsia is a complex, progressive disease that involves multiple organ systems and may be caused by a combination of genetic, nutritional and environmental risks [5]. Due to its unknown etiology, preeclampsia has been described as a theoretical disorder. Currently, high-risk groups for preeclampsia based on clinical signs include a history of preeclamptic pregnancy, pre-pregnancy BMI ≥ 24 kg/m2, insulin resistance, and a history of chronic hypertension [6]. It is now believed that preeclampsia is a disease of placental origin that begins with insufficient trophoblast invasion early in pregnancy, resulting in placental ischemia and hypoxia caused by poor remodeling of the spiral arteries of the uterus [7]. Oxidative stress is exacerbated and a series of inflammatory factors and anti-vascular growth factors are released, leading to systemic endothelial dysfunction in the later stages of the disease and the characteristic clinical manifestations of preeclampsia [8]. Despite the fact that researchers have invested a great deal of effort and resources in the study and treatment of preeclampsia, little progress has been made, and thus the prevention and management of preeclampsia in the clinical setting remains enormously challenging.Magnesium sulfate is the medicine of choice for the therapy of eclampsia, prevention of convulsions, and relief of spasms, and has an irreplaceable role and place in the treatment of hypertensive disorders in pregnancy. Recent studies have shown that vitamins and micronutrients are closely related to the development of eclampsia and preeclampsia [14, 15]. The aim of this study is to investigate the therapeutic effect of multivitamins combined with magnesium sulfate in preeclampsia. The primary objective was to assess whether this combination therapy would be more effective in lowering blood pressure and improving hemodynamics and coagulation, thereby further improving pregnancy outcomes. The secondary objectives then included observing the improvement of urinary protein, umbilical artery resistance index (RI), spiral artery resistance index, peak end-systolic/end-diastolic (S/D), and changes in coagulation function indexes such as prothrombin time (PT) and fibrinogen (FIB) by the combination therapy, which will provide a reference for the pharmacological treatment of preeclampsia.
Materials and methods
Study design
This was a single-center, prospective, randomized controlled clinical study conducted between April 2022 and April 2023 to evaluate the efficacy of multivitamin supplementation combined with magnesium sulfate in patients with preeclampsia (PE).
Ethical approval and trial registration
The study protocol was reviewed and approved by the Ethics Committee of [Qingdao University Affiliated Hospital], approval number [QYFY WZLL 30210], in accordance with the Declaration of Helsinki. All participants provided written informed consent before enrollment.
Sample size calculation
Based on a preliminary pilot study, a minimum sample size of 86 participants per group was calculated to detect a 20% difference in urinary protein reduction (primary outcome) with 80% power and a two-sided α of 0.05.
Sample size was calculated using the following formula for two independent means:
 |
where Z is the standard normal deviate corresponding to the desired significance level (α = 0.05, two-sided) and power (1-β = 0.80), σ is the estimated standard deviation of 24-hour urinary protein reduction derived from the pilot data, and Δ is the expected mean difference between groups (20%). This method follows standard guidelines for clinical trial sample size estimation in maternal-fetal research [14]. Allowing for a 10% dropout rate, the final sample size was set at 97 per group (total n = 194).
Participant selection
A total of 194 pregnant women diagnosed with preeclampsia according to the Guidelines for the Diagnosis and Treatment of Hypertensive Diseases in Pregnancy (2020) were included. They were randomly allocated into either the control group (n = 97, magnesium sulfate only) or the observation group (n = 97, magnesium sulfate plus multivitamin).
Inclusion criteria: (1) The first appearance of preeclampsia; (2) The diagnosis of preeclampsia referred to the “Guidelines for the Diagnosis and Treatment of Hypertensive Diseases in Pregnancy (2020)”; (3) No serious drug allergies.
Exclusion criteria: (1) Coagulation disorders patients; (2) Patients with congenital heart disease; (3) Patients with serious organ dysfunction; (4) Patients with secondary hypertension, combined autoimmune diseases, and those taking anticoagulation and other related drugs that affect hemodynamic and coagulation function parameters.
Stratification by severity of preeclampsia
Preeclampsia severity was classified as mild or severe according to systolic blood pressure, proteinuria levels, and presence of complications (e.g., visual disturbances, HELLP syndrome). This stratification guided clinical decisions but was not used as a grouping variable in the analysis.
Intervention protocol
All patients received routine management for preeclampsia, including bed rest, blood pressure control, seizure prophylaxis, and fetal monitoring. Control Group: Magnesium sulfate injection (Hangzhou Minsheng, 10 mL: 2.5 g) was administered with a loading dose of 2.5–5 g via rapid IV infusion, followed by a maintenance dose of 5–20 g/day via continuous IV drip, based on clinical severity.
Magnesium sulfate was initiated irrespective of baseline blood pressure levels, as its primary indication was the prevention of eclampsia and seizure prophylaxis in all patients diagnosed with preeclampsia. Dose adjustment was made according to clinical severity, maternal tolerance, and routine monitoring of reflexes, urine output, and respiratory rate.
Observation Group: Received the same magnesium sulfate regimen plus one multivitamin tablet daily (Bayer S.A., China National Drug License J20140155; 30 tablets/box) taken orally each morning for 14 consecutive days.
Each multivitamin tablet contained: Vitamin A 2500 IU, Vitamin D 400 IU, Vitamin E 30 mg, Vitamin C 60 mg, Vitamin B1 1.4 mg, Vitamin B2 1.6 mg, Vitamin B6 2 mg, Vitamin B12 1 µg, Niacin 18 mg, Folic acid 400 µg, Pantothenic acid 10 mg, Biotin 30 µg, Calcium 162 mg, Iron 27 mg, Zinc 15 mg, Copper 2 mg, Magnesium 100 mg, Manganese 2.5 mg, Iodine 150 µg.
This composition was consistent with the product labeling and ensured that the administered dosage met recommended dietary allowances for pregnant women.
Delivery management
The mode and timing of termination of pregnancy (TOP) were determined by a multidisciplinary team. Indications for delivery included: uncontrolled blood pressure despite medication; severe PE symptoms (e.g., headache, blurred vision, oliguria); fetal maturity with suspected compromise; patient preference after counseling; vaginal delivery was attempted when feasible; cesarean section was performed when contraindications to labor existed.
Observation indicators
Blood pressure and 24-hour urinary protein measured at baseline and after treatment. Placental hemodynamic indices (PI, RI, S/D) of umbilical and spiral arteries assessed by color Doppler (probe frequency 3.5 Hz). Coagulation parameters: PT, APTT, FIB, and TT via venous blood samples analyzed using an automated biochemical analyzer. Maternal and neonatal outcomes including postpartum hemorrhage, uterine inertia, fetal distress, neonatal asphyxia, and low birth weight. Logistic regression was performed to identify predictors of treatment success.
Statistical analysis
All data were analyzed using SPSS 27.0. Continuous variables were expressed as mean ± standard deviation and compared using t-tests. Categorical variables were compared using χ² tests. Logistic regression was used to evaluate the independent effect of multivitamin use. A two-tailed P < 0.05 was considered statistically significant.
Flow chart of the study
A detailed flow diagram (Fig. 1) illustrates the process of participant screening, randomization, intervention allocation, and outcome analysis.
Fig. 1.
CONSORT-style flow chart
Results
Results of baseline information
The baseline data of the patients are shown in Table 1. They were comparable in terms of age, number of pregnancies, gestational weeks, body mass index (BMI), and alanine aminotransferase (ALT), and the differences were not statistically significant (P > 0.05).
Table 1.
Comparison of baseline information
| Indicators | Observation (n = 97) | Control (n = 97) | t/χ² | P |
|---|---|---|---|---|
| Age (years, mean ± SD) | 26.59 ± 4.39 | 27.61 ± 4.11 | 1.672 | 0.096 |
| Age category, n (%) | < 30: 71 (73.2%)/≥30: 26 (26.8%) | < 30: 66 (68.0%)/≥30: 31 (32.0%) | 0.648 | 0.421 |
| BMI (kg/m², mean ± SD) | 26.27 ± 3.45 | 25.98 ± 3.41 | 0.584 | 0.56 |
| BMI category, n (%) | < 25: 38 (39.2%)/≥25: 59 (60.8%) | < 25: 41 (42.3%)/≥25: 56 (57.7%) | 0.165 | 0.684 |
| Gestational weeks (mean ± SD) | 31.24 ± 3.02 | 31.70 ± 2.78 | 1.113 | 0.267 |
| Gestational weeks category, n (%) | < 32: 48 (49.5%)/≥32: 49 (50.5%) | < 32: 44 (45.4%)/≥32: 53 (54.6%) | 0.285 | 0.593 |
| Number of pregnancies | 1.14 ± 0.35 | 1.18 ± 0.38 | 0.585 | 0.559 |
| ALT (U/L, mean ± SD) | 65.46 ± 15.27 | 65.17 ± 14.37 | 0.135 | 0.893 |
In addition to continuous variables (mean ± SD), categorical comparisons were also presented for clinical interpretability. Age was stratified as < 30 years vs. ≥30 years; BMI was grouped as < 25 kg/m² (normal) vs. ≥25 kg/m² (overweight/obese); and gestational weeks were classified as < 32 weeks vs. ≥32 weeks. No significant group differences were observed in any categorical distribution.
Comparison of blood pressure and urinary protein
The systolic blood pressure (SBP), diastolic blood pressure (DBP) and 24-h urinary protein of the two groups decreased obviously after treatment compared with those before treatment (Table 2, P < 0.05). However, the difference in blood pressure between the two groups after treatment was not statistically significant, while 24-h urinary protein in the observation group had a lower decrease compared with the control group (P < 0.05).
Table 2.
Results of blood pressure and urinary protein (with categorical distributions)
| Indicators | Observation (n = 97) | Control (n = 97) | t/χ² | P |
|---|---|---|---|---|
| SBP (mmHg) | ||||
| Pretreatment (mean ± SD) | 158.49 ± 8.70 | 156.76 ± 10.24 | 1.274 | 0.204 |
| Posttreatment (mean ± SD) | 139.57 ± 7.21 | 137.78 ± 10.35 | 1.396 | 0.165 |
| Posttreatment category, n (%) | < 140: 53 (54.6%)/≥140: 44 (45.4%) | < 140: 57 (58.8%)/≥140: 40 (41.2%) | 0.315 | 0.575 |
| DBP (mmHg) | ||||
| Pretreatment (mean ± SD) | 97.85 ± 8.76 | 95.85 ± 9.95 | 1.484 | 0.139 |
| Posttreatment (mean ± SD) | 85.35 ± 9.78 | 84.67 ± 10.34 | 0.468 | 0.64 |
| Posttreatment category, n (%) | < 90: 61 (62.9%)/≥90: 36 (37.1%) | < 90: 63 (64.9%)/≥90: 34 (35.1%) | 0.08 | 0.777 |
| 24-h urinary protein (g) | ||||
| Pretreatment (mean ± SD) | 2.13 ± 0.56 | 2.01 ± 0.46 | 1.616 | 0.108 |
| Posttreatment (mean ± SD) | 0.71 ± 0.31 | 0.92 ± 0.28 | 4.857 | < 0.001 |
| Posttreatment category, n (%) | < 1 g: 77 (79.4%)/≥1 g: 20 (20.6%) | < 1 g: 59 (60.8%)/≥1 g: 38 (39.2%) | 7.379 | 0.007 |
Changes of coagulation function indexes
PT, APTT, FIB and TT indexes were significantly improved in both observation and control groups of preeclamptic patients (Table 3, P < 0.05). In the post-treatment comparison, the observation group demonstrated a greater increase in PT, APTT and TT and a greater decrease in FIB than the control group (P < 0.05).
Table 3.
Results of coagulation function indexes (with categorical distributions)
| Indicators | Observation (n = 97) | Control (n = 97) | t/χ² | P |
|---|---|---|---|---|
| PT (s) | ||||
| Pretreatment (mean ± SD) | 9.74 ± 1.37 | 10.03 ± 2.15 | 1.11 | 0.268 |
| Posttreatment (mean ± SD) | 13.72 ± 1.37 | 11.51 ± 1.85 | 9.452 | < 0.001 |
| Posttreatment category, n (%) | ≥ 12 s: 89 (91.8%)/<12 s: 8 (8.2%) | ≥ 12 s: 66 (68.0%)/<12 s: 31 (32.0%) | 17.134 | < 0.001 |
| APTT (s) | ||||
| Pretreatment (mean ± SD) | 25.72 ± 2.94 | 26.18 ± 3.17 | 1.05 | 0.295 |
| Posttreatment (mean ± SD) | 29.59 ± 3.72 | 28.04 ± 3.51 | 2.983 | 0.003 |
| Posttreatment category, n (%) | ≥ 28 s: 73 (75.3%)/<28 s: 24 (24.7%) | ≥ 28 s: 59 (60.8%)/<28 s: 38 (39.2%) | 4.329 | 0.037 |
| FIB (g/L) | ||||
| Pretreatment (mean ± SD) | 5.51 ± 1.35 | 5.14 ± 1.76 | 1.649 | 0.101 |
| Posttreatment (mean ± SD) | 3.02 ± 1.24 | 3.96 ± 1.35 | 5.062 | < 0.001 |
| Posttreatment category, n (%) | < 4 g/L: 82 (84.5%)/≥4 g/L: 15 (15.5%) | < 4 g/L: 60 (61.9%)/≥4 g/L: 37 (38.1%) | 12.604 | < 0.001 |
| TT (s) | ||||
| Pretreatment (mean ± SD) | 12.38 ± 1.89 | 11.97 ± 1.76 | 1.563 | 0.12 |
| Posttreatment (mean ± SD) | 16.37 ± 1.72 | 15.24 ± 1.88 | 4.38 | < 0.001 |
| Posttreatment category, n (%) | ≥ 15 s: 85 (87.6%)/<15 s: 12 (12.4%) | ≥ 15 s: 69 (71.1%)/<15 s: 28 (28.9%) | 7.761 | 0.005 |
Changes of placental hemodynamic parameters
The RI, PI and S/D of umbilical and spiral arteries improved more in both groups after treatment compared with before treatment (Table 4, P < 0.001). And the RI of umbilical artery, RI and S/D of spiral artery improved more in the test group after therapy (P < 0.001).
Table 4.
Results of placental hemodynamic parameters
| Indicators | Observation (n = 97) | Control (n = 97) | t | P | ||
|---|---|---|---|---|---|---|
| Umbilical artery | PI | Pretreatment | 0.95 ± 0.13 | 0.92 ± 0.18 | 1.189 | 0.236 |
| Posttreatment | 0.71 ± 0.14 | 0.73 ± 0.11 | 0.865 | 0.388 | ||
| RI | Pretreatment | 0.69 ± 0.12 | 0.65 ± 0.18 | 1.795 | 0.074 | |
| Posttreatment | 0.41 ± 0.05 | 0.54 ± 0.04 | 20.192 | < 0.001 | ||
| S/D | Pretreatment | 2.63 ± 0.51 | 2.57 ± 0.49 | 0.918 | 0.360 | |
| Posttreatment | 2.14 ± 0.37 | 2.09 ± 0.41 | 0.985 | 0.326 | ||
| Arteria helieinae | PI | Pretreatment | 0.73 ± 0.14 | 0.70 ± 0.15 | 1.409 | 0.160 |
| Posttreatment | 0.51 ± 0.06 | 0.58 ± 0.09 | 6.462 | < 0.001 | ||
| RI | Pretreatment | 0.86 ± 0.15 | 0.83 ± 0.17 | 1.191 | 0.235 | |
| Posttreatment | 0.46 ± 0.13 | 0.65 ± 0.08 | 12.210 | < 0.001 | ||
| S/D | Pretreatment | 2.02 ± 0.15 | 1.99 ± 0.11 | 1.501 | 0.135 | |
| Posttreatment | 1.69 ± 0.12 | 1.81 ± 0.13 | 6.750 | < 0.001 | ||
Maternal and infant outcomes
Maternal and infant outcomes of preeclamptic patients in the observation group were better than those of the control group in postpartum hemorrhage and low-birth-weight babies, but the difference in other indicators was not statistically significant (P < 0.05). (Table 5)
Table 5.
Maternal and infant outcomes (presented with %)
| Indicators | Observation (n = 97) | Control (n = 97) | χ² | P |
|---|---|---|---|---|
| Uterine inertia | 14 (14.4%) | 16 (16.5%) | 0.158 | 0.691 |
| Neonatal asphyxia | 8 (8.2%) | 9 (9.3%) | 0.064 | 0.8 |
| Postpartum hemorrhage | 10 (10.3%) | 22 (22.7%) | 5.389 | 0.02 |
| Fetal distress in uterus | 8 (8.2%) | 17 (17.5%) | 3.719 | 0.054 |
| Placental abruption | 7 (7.2%) | 11 (11.3%) | 0.98 | 0.322 |
| Low birth weight infant | 10 (10.3%) | 23 (23.7%) | 6.171 | 0.013 |
Results of multifactorial logistic regression analysis of multivitamin combined with magnesium sulfate in the treatment of preeclampsia
The results showed that the probability of treatment success was significantly higher in patients using multivitamins, suggesting that multivitamins have an independent contribution to the efficacy of preeclampsia (P < 0.05). The effects of age, BMI and weeks of gestation on efficacy were not statistically significant (P > 0.05), indicating that the efficacy of multivitamins was independent of the baseline physiologic characteristics of the patients, and that the mechanism of action may be related to the synergistic effect of magnesium sulfate. (Table 6)
Table 6.
Logistic regression analysis of treatment success (with categorical predictors and unadjusted ORs)
| Indicators | Observation (n = 97) | Control (n = 97) | Unadjusted OR (95% CI) | P |
|---|---|---|---|---|
| Use of vitamins | Yes: 97 (100%) | No: 97 (100%) | 3.30 (1.73–6.28) | < 0.001 |
| Age (years) | < 30: 71 (73.2%) | 66 (68.0%) | Ref. | |
| ≥ 30: 26 (26.8%) | 31 (32.0%) | 0.97 (0.55–1.71) | 0.344 | |
| BMI (kg/m²) | < 25: 38 (39.2%) | 41 (42.3%) | Ref. | |
| ≥ 25: 59 (60.8%) | 56 (57.7%) | 0.94 (0.53–1.65) | 0.175 | |
| Gestational weeks | < 32: 48 (49.5%) | 44 (45.4%) | Ref. | |
| ≥ 32: 49 (50.5%) | 53 (54.6%) | 0.97 (0.58–1.62) | 0.561 |
The reference group (Ref.) represents the low-risk category (Age < 30, BMI < 25, Gestational weeks < 32)
Subgroup analysis by severity of preeclampsia
Patients were stratified into mild (n = 114) and severe (n = 80) PE based on blood pressure levels, proteinuria, and systemic symptoms. Subgroup analysis revealed that the benefits of multivitamin combined with magnesium sulfate were more pronounced in the severe PE subgroup: in severe PE cases, the reduction in 24-h urinary protein was significantly greater in the observation group (0.75 ± 0.29 g) than the control group (1.05 ± 0.31 g, P < 0.001). Improvements in placental RI and coagulation parameters (PT, FIB) were also significantly higher in the observation group (P < 0.01). No significant interaction effect was observed in the mild PE subgroup across most parameters, though trends favored the observation group.
Expanded maternal and neonatal outcomes
In addition to previously reported outcomes, further maternal and neonatal complications were analyzed (Table 7). The incidence of eclampsia was lower in the observation group (0 cases) compared to the control group (3 cases), though not statistically significant (P = 0.081). NICU admissions were significantly lower in the observation group (9 vs. 21; P = 0.018), with primary causes being respiratory distress, low birth weight, and suspected perinatal asphyxia. The rate of composite maternal complications (eclampsia, hemorrhage, abruption) was lower in the observation group (13.4%) compared to the control (25.8%; P = 0.031).
Table 7.
Expanded maternal and neonatal complications
| Outcome | Observation group (n = 97) | Control group (n = 97) | χ² | P |
|---|---|---|---|---|
| Eclampsia | 0 | 3 | 3.065 | 0.081 |
| NICU admission | 9 | 21 | 5.581 | 0.018 |
| Composite maternal complications | 13 | 25 | 4.649 | 0.031 |
Mode of termination of pregnancy and Cesarean indications
The majority of participants delivered after stabilization of PE. The mode of delivery and indications for Cesarean section (CD) are presented in Table 8. Cesarean delivery rates were similar between groups (Observation: 59.8%, control: 63.9%, P = 0.562).
Table 8.
Mode of delivery and Cesarean indications
| Mode/Indication | Observation (n = 97) | Control (n = 97) | χ² | P |
|---|---|---|---|---|
| Vaginal delivery | 39 (40.2%) | 35 (36.1%) | 0.337 | 0.562 |
| Cesarean delivery | 58 (59.8%) | 62 (63.9%) | ||
| - Fetal distress | 12 | 12 | — | — |
| - Failed labor | 18 | 20 | — | — |
| - Uncontrolled PE | 22 | 28 | — | — |
| - Elective | 6 | 2 | — | — |
Indications for CD included: fetal distress (n = 24), failure to progress (n = 38), severe preeclampsia unresponsive to therapy (n = 50), and maternal preference (n = 22).
Discussion
This study demonstrated that the combination of multivitamin supplementation with magnesium sulfate provides superior clinical outcomes in the management of PE compared to magnesium sulfate alone [19, 20]. Improvements were observed not only in placental hemodynamics and coagulation function but also in maternal and neonatal outcomes, particularly in patients with severe PE [21, 22]. These findings contribute novel insights to the clinical management of hypertensive disorders in pregnancy.
The observed reduction in 24-hour urinary protein and enhanced coagulation profiles (PT, APTT, TT) in the intervention group suggest that multivitamins may exert endothelial protective and anti-inflammatory effects that complement the action of magnesium sulfate. Additionally, improvements in placental blood flow, especially in the RI of both the umbilical and spiral arteries, highlight the role of nutritional supplementation in promoting uteroplacental perfusion, which is often compromised in PE.
Our findings should also be interpreted in the context of landmark trials in the field. The international MAGPIE trial demonstrated that magnesium sulfate significantly reduces the risk of eclampsia compared with placebo, establishing MgSO₄ as the standard of care for preeclampsia prophylaxis and treatment [23]. In contrast, large randomized controlled trials evaluating antioxidant supplementation with vitamins C and E versus placebo did not show a reduction in the incidence of preeclampsia and, in some cases, raised concerns regarding potential adverse effects [24]. These results highlight that while magnesium sulfate has unequivocal evidence supporting its role, the benefit of vitamin supplementation is more controversial and may depend on the specific composition, dosage, and patient population. The present study differs in that we employed a multivitamin formulation containing multiple micronutrients, rather than high-dose vitamin C and E alone, which may partly explain the observed beneficial effects.
Notably, subgroup analysis revealed that patients with severe PE derived greater benefit from the combined therapy, particularly in terms of urinary protein reduction and vascular indices. This suggests that multivitamin supplementation may be especially beneficial in high-risk PE populations who are more susceptible to end-organ dysfunction. These findings have practical implications for stratifying treatment based on disease severity.
Our study also expanded the assessment of maternal and neonatal outcomes. The addition of maternal complications such as eclampsia and postpartum hemorrhage, along with NICU admissions, provides a more holistic evaluation of clinical efficacy. The significantly lower rates of NICU admission and composite maternal complications in the observation group indicate that combined therapy may help reduce adverse perinatal events. The absence of eclampsia in the observation group, though not statistically significant, also points toward a trend worthy of further investigation in larger trials.
The analysis of mode of delivery and indications for cesarean section (CD) revealed that most patients required CD due to fetal distress or poorly controlled PE. The similarity in CD rates between groups indicates that the improved biochemical and hemodynamic parameters in the intervention group did not necessarily translate into altered obstetric decision-making during the study window. However, this highlights a potential area for future research in linking early intervention to delayed or avoided delivery in PE.
Novel Contributions to the Literature.
While magnesium sulfate remains a cornerstone of PE management, this study is among the first to systematically evaluate the adjunctive role of multivitamin supplementation in improving both maternal vascular function and clinical outcomes [25]. Unlike previous studies that focus primarily on magnesium sulfate alone or nutritional status in isolation, our research integrates both pharmacological and nutritional therapy in a randomized design [26, 27]. The use of stratified subgroup analysis by PE severity and the inclusion of maternal complications (e.g., eclampsia, hemorrhage) and neonatal outcomes (e.g., NICU admission) enhances the comprehensiveness and clinical relevance of the findings.
Magnesium sulfate can inhibit the release of calcium ions and acetylcholine from neuromuscular junction, thus blocking the nerve-muscle transmission and relieving spasm of skeletal muscles, which can effectively prevent and alleviate the occurrence of eclampsia [28]. Magnesium ions inhibit the release of acetylcholine from motor nerve endings, blocking the transmission of information between neuromuscular junctions and relaxing skeletal muscles [9]. Bachnas believes that magnesium ions may act in the cerebral cortex based on the fact that patients with eclampsia are still fully conscious and have clear stereotypical images after using magnesium sulphate for 1–2 h, which is different from the general inhibitory effect of the central nervous system [10]. With the increase of blood magnesium concentration, it can inhibit the release of acetylcholine from motor nerves, and reduce the sensitivity of motor nerve endings to acetylcholine and its latent potential [11]. Some scholars believe that its effect is in the central nervous system, and its blocking effect on neuromuscular is very small. Wexler proved that magnesium sulfate can control various types of epileptic convulsions [12]. Convulsions are mediated by glutamate receptors such as N-methyl-D-aspartate (NMDA) receptors [13]. Magnesium ions reduce glutamate-mediated convulsive activity by binding to NMDA receptors and lowering NMDA levels. Therefore, the use of magnesium ions reduces NMDA-mediated convulsions in the hippocampus. The results show Both groups can significantly reduce blood pressure after treatment, and magnesium sulfate can dilate vascular smooth muscle and reduce peripheral vascular resistance. At the same time, magnesium ions in magnesium sulfate can inhibit the activity of the central nervous system and reduce nerve impulse conduction, thus effectively controlling blood pressure. The nutritional status of women during pregnancy is critical to their own health and to a healthy birth outcome. Pregnancy is the period when mothers need the most increased nutrition to sustain fetal growth and development, while keeping the mother’s internal balance and preparing her for breastfeeding. It is also a continuous period, pregnancy-related minor physiological changes that affect the metabolism of nutrients in the mother’s body. Once the placenta is formed, the mother delivers oxygenated and nutrient-rich blood to the fetus through the placenta, which is rich in micronutrients involved in the synthesis of antioxidant enzymes. They are essential for protecting the embryo and placenta from oxidative stress [29, 30]. Vitamin D is a micronutrient that has received attention mainly for its role in the maintenance of calcium homeostasis and has been considered to be involved in the pathogenesis of preeclampsia. Deficiency of Vitamin D during pregnancy was found to increase the risk of preeclampsia and vitamin D in serum could be used as an early predictor of preeclampsia [16]. Mirzakhani found that taking vitamin D during pregnancy increased serum vitamin D levels but did not decrease the incidence of preeclampsia [17]. In a large prospective study, pregnant women with peripheral blood 25(OH)D concentrations < 20 ng/mL at 23 to 28 weeks of gestation were more than three times as likely to deteriorate severe preeclampsia as those with concentrations ≥ 20 ng/mL [18]. Vitamin E, as an essential vitamin, plays a crucial role in keeping the normal function of the reproductive system due to its powerful antioxidant properties, which can counteract oxidative stress and oxidative-antioxidant imbalance induced by oxygen free radicals, and supplementation with vitamin E can improve the progression of preeclampsia.Moderate vitamin and trace element supplementation in the present study confirmed to reduce postpartum hemorrhage and low birth weight babies. Zinc is closely associated with enzyme activity and protein synthesis in humans, and a inverse correlation between serum zinc levels and the development of preeclampsia has been reported [31]. During pregnancy, zinc deficiency is closely associated with intrauterine fetal growth retardation. Zinc deficiency in pregnant women may lead to reduced zinc transport between mother and fetus and lower zinc concentration in the fetus, which in turn affects the activity of DNA polymerase and RNA polymerase as well as the synthesis of nucleic acids and proteins, leading to fetal developmental delay. When maternal zinc deficiency results in reduced placental perfusion, placental circulation may be affected, which in turn affects fetal blood supply. This hemodynamic alteration may be assessed by Doppler examination [32]. In the current study, it was observed that the difference in resistance index (RI) of umbilical artery, and resistance index of spiral artery were statistically significant in the observation group as compared to the control group.
Epidemiologic studies have also suggested that supplementation with antioxidant vitamins may prevent preeclampsia [33]. Vitamins A and C can directly scavenge oxidative free radicals in the body, inhibit cellular inflammatory responses, protect placental vascular endothelial cells, and reduce the condition of preeclampsia. Vitamin deficiencies may lead to the development of low-birth-weight babies [34, 35]. The present study also found an improvement in hemodynamic parameters in the observation group. Low serum levels of calcium and vitamin D in pregnant women may increase the risk of preeclampsia [36]. Vitamin E has free radical scavenging and antioxidant properties which in turn protects pregnancy. It has been found in the past that the body of a pregnant woman is metabolized at a faster rate compared to a normal person. Therefore, more oxygen free radicals are generated in pregnant women than in normal people, and the body will generate the appropriate amount of oxygen free radicals when faced with the oxygenated state. In the face of oxygenation, the body will generate corresponding oxidative stress. This process will have a negative impact on the indicators of pregnant women and also interfere with the growth and development of the fetus [37]. Therefore, vitamins and trace elements play a key role in the health of mother and child[38]. This study further proves that vitamin and trace element supplementation can significantly improve some indicators of coagulation function and placental hemodynamics in patients with preeclampsia.
It is also noteworthy that while some studies have reported added value of vitamin D supplementation in reducing the risk of preeclampsia, large randomized controlled trials evaluating vitamins C and E have consistently failed to demonstrate protective effects [39]. This discrepancy raises the question of why multivitamins as a whole appeared beneficial in our study. One possible explanation is that the combined effect of multiple micronutrients, rather than isolated high-dose antioxidant supplementation, may play a role. Nevertheless, the absence of vitamin blood level monitoring and the lack of a placebo or vitamin-only comparison group means that these findings must be interpreted with caution.
Changes in the coagulation system are an important reference for the diagnosis and risk assessment of eclampsia. Placental hemodynamics can also directly reflect the changes in placental blood circulation and blood flow, which is an important reference for judging the occurrence of eclampsia and fetal hypoxia. Moreover, the difference in the incidence of postpartum hemorrhage and low-birth-weight babies in the observation group was statistically significant compared with that in the control group. Thus, vitamin and trace element deficiencies may be directly or indirectly involved in the development of eclampsia.
Limitations
This study has several limitations. First, it was conducted at a single center, which may limit the generalizability of the findings. Second, although the follow-up period covered the perinatal window, long-term maternal and neonatal outcomes were not assessed. Third, compliance with oral multivitamin intake was assumed but not objectively verified. Fourth, the absence of a comparison group receiving either placebo or multivitamin supplementation alone makes it difficult to disentangle whether the observed benefits are attributable primarily to magnesium sulfate, to the multivitamin, or to their combined use. This issue is particularly important given that magnesium sulfate alone has well-established efficacy in preventing eclampsia, as demonstrated in the original MAGPIE trial and its long-term follow-up studies, which showed reduced maternal seizures and favorable maternal outcomes at 2 years and child outcomes at 18 months [23, 40]. In contrast, the role of vitamin supplementation remains controversial, as large randomized trials with vitamins C and E failed to demonstrate protective effects. The present study therefore cannot fully clarify whether multivitamins confer an additional independent benefit beyond magnesium sulfate, which should be acknowledged when interpreting our findings. Another important consideration is that baseline vitamin levels were neither measured nor controlled in this study. While magnesium sulfate intake is negligible in most dietary regimens, natural sources of multivitamins are abundant in everyday diets, and individual differences in nutritional intake could have influenced the outcomes. No blood measurements of vitamins were performed, which limits our ability to correlate clinical outcomes with actual micronutrient status. This represents a potential source of bias and highlights the need for future studies incorporating biochemical assessments of vitamin levels to better clarify the relationship between supplementation and clinical benefit.
Conclusion
In conclusion, multivitamin supplementation combined with magnesium sulfate significantly improves placental hemodynamics, coagulation profiles, and short-term maternal and neonatal outcomes in patients with preeclampsia, particularly those with severe disease. These findings support the integration of targeted nutritional therapy into standard PE management protocols and lay the groundwork for further exploration of micronutrient-based interventions in hypertensive pregnancy disorders.
Author contributions
Guarantor of integrity of the entire study: Shaobo Gaostudy concepts: Shaobo Gaostudy design: Shaobo Gaodefinition of intellectual content: Shaobo Gaoliterature research: Jie Ming, Fei Sunclinical studies: Jie Ming, Fei Sunexperimental studies: Jie Mingdata acquisition: Hong Zhao, Yajie Yudata analysis: Lei Chen, Jun Wanstatistical analysis: Lei Chen, Jun Wanmanuscript preparation: Shaobo Gao, Yajie Yumanuscript editing: Shaobo Gao, Yajie Yumanuscript review: Shaobo Gao.
Funding
None.
Data availability
The simulation experiment data used to support the findings of this study are available from the corresponding author upon request.
Declarations
Ethics approval
All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study is approved by the Ethics Committee of [Qingdao University Affiliated Hospital], approval number [QYFY WZLL 30210]. Written informed consent was obtained.
Consent for publication
Informed consent was obtained from all individual participants included in the study.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The simulation experiment data used to support the findings of this study are available from the corresponding author upon request.