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Introduction

As a common pregnancy-related complication, pregnancy-induced hypertension is one of the main causes of perinatal morbidity and mortality (1). Reports show that the prevalence of pregnancy-induced hypertension is 4.6-13.1% worldwide, and the neonatal mortality is 9.2% (2). Studies have shown that pregnancy-induced hypertension not only causes serious complications during the perinatal period, but also increases the incidence of cardiovascular and cerebrovascular diseases, seriously affecting the health and safety of pregnant women (3,4). Moreover, due to the particularity of drug action mechanism when pregnant women and fetuses take drugs (5), it is particularly important to choose a safe and effective drug treatment.

Magnesium sulfate could relieve spasmolysis, diuresis and pain (6). It could also relax the vascular smooth muscle, dilate the spasmolysis peripheral blood vessels, reduce blood pressure, which is suitable for the treatment of patients with moderate and severe pregnancy-induced hypertension when receiving intravenous injection (7,8). Nifedipine is a type of dihydropyridine calcium antagonist, it is applicable to various types of hypertension (9-11) and has a good effect on intractable and severe hypertension. Wen and Li (12) found that the combined use of the above two drugs had a good effect in treating pregnancy-induced hypertension. A previous study confirmed that inflammation response may be involved in the occurrence and development of hypertension (13). Suppressors of cytokine signaling-3 (SOCS-3) is a cytokine signal inhibitor. It inhibits various inflammatory factors by mediating JAK/STAT cytokine signal transduction pathway, playing a role in inhibiting inflammatory reactions (14). By staining, Wang et al (15) found expression of SOCS-3 in the vascular endothelium of pregnant women with preeclampsia, and the expression of SOCS-3 was lower than that of healthy pregnant women. Interleukins play important roles in many processes, including information transmission, activation and regulation of immune cells, activation of mediating cells T and B, proliferation and differentiation, and inflammatory response (16). Interleukin-10 (IL-10) is a key biomarker for the diagnosis and treatment of adverse preeclampsia, a common complication of pregnancy-induced hypertension (17). Krishnan et al (18) proved that hypertension was closely related to the abnormal expression of interleukin-18 (IL-18).

At present, the therapeutic effect of magnesium sulfate combined with nifedipine on pregnancy-induced hypertension has been confirmed in the clinic, but there are few studies on the related changes of patients' inflammatory factors. We speculated that the changes in inflammatory factors in patients can better assess the clinical efficacy and adverse reactions. In order to confirm our conjecture, this investigation explored the changes of serum inflammatory factors during the treatment of pregnancy-induced hypertension syndrome with magnesium sulfate combined with nifedipine. It is expected that the progress of pregnancy-induced hypertension syndrome will be predicted by the level of inflammatory factors.

Patients and methods

General data

This study is a prospective non-randomized controlled study. A total of 188 cases were collected as research objects. These patients had pregnancy-induced hypertension, and were admitted to the hospital from June 2016 to February 2018. Among them, 94 cases were treated with magnesium sulfate and were the control group, and further 94 cases of patients were treated with magnesium sulfate with nifedipine and were the study group. The study was approved by the Ethics Committee of The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology). Signed informed consents were obtained from the patients and/or guardians.

Inclusion and exclusion criteria

Inclusion criteria: patients who met the diagnostic criteria and were diagnosed with pregnancy-induced hypertension; patients received treatment in the hospital; patients aged 18-40 years; patients who cooperated with research; patients or their immediate family member signed the informed consent; patients with complete medical records.

Exclusion criteria: patients with heart, liver, spleen, lung, kidney and other important organs injury; patients combined with mental illness and speech dysfunction; patients with diabetes; patients with lymph node, organ and tissue metastasis or drug allergy.

Therapies

Both groups received routine antihypertensive therapy, and continuous ambulatory blood pressure and vital signs of mothers and infants were monitored. Pregnant women were required to take a left lying position to improve uterine placental blood supply. Control group: patients in the control group received 25% magnesium sulfate injection (60 ml) (Tianjin KingYork Pharmaceutical Co., Ltd., SFDA approval no. H12020994), and 5% glucose solution (500 ml) was added for intravenous infusion. Study group: after being given the same intravenous infusion of magnesium sulfate as the control group, patients received nifedipine controlled-release tablet (Shanghai Xiandai Pharmaceutical Co., Ltd., SFDA approval no. H12020994), 3 mg/t.i.d. orally. The treatment in both groups continued for more than half a month. Both groups were treated for seven continuous days.

Curative effect assessment

Evaluation standards were formulated based on reference (19). Marked effect: edema, proteinuria and other clinical symptoms disappeared, blood pressure was <140/90 mmHg. Effective: edema, proteinuria and other major clinical symptoms were significantly reduced, with blood pressure of 140-150/90-100 mmHg. Ineffective: clinical symptoms and blood pressure such as edema and proteinuria were not significantly improved compared with before treatment, or even aggravated. Total effectiveness = marked effect + effective. For patients with large thrombus and patients who failed to respond to conservative treatment, lower extremity venous thrombectomy and lower extremity venous ligation were taken into consideration.

Determination of inflammatory factors in serum

Blood samples were collected before treatment (on the day of admission) and after treatment (on the day of delivery). The samples were sent to the clinical laboratory of the hospital for determination in the morning of the same day. Inflammatory indexes included SOCS-3 (USCNK, SEB684Hu-1), IL-10 (FineTest, ESH0009), and IL-18 (FineTest, ECH0039). Blood samples were added with 0.2 ml of 2% coagulant, centrifuged at 1,505 x g, 4˚C for 30 min, and stored at -20˚C. Enzyme-linked immunosorbent assay (ELISA) was used for detection, and the procedure was strictly in accordance with the kit instructions.

Observational indexes

Clinical efficacy were observed and compared between the two groups. Delivery and incidence of adverse reactions were compared between the two groups. The levels of serum SOCS-3, IL-10 and IL-18, and the predictive value of SOCS-3, IL-10, and IL-18 for therapeutic effects in the two groups were compared before and after treatment.

Statistical analysis

SPSS 24.0 statistical software (Shanghai Yuchuang Network Technology Co., Ltd.) was used for statistical calculation of all experimental results. Graphpad 8 (Softhead Inc.) was used for drawing all images and for checking the results twice. Enumeration data were all expressed in the form of (rate), and χ2 test was used for comparison between groups. Measurement data were all expressed in the form of (mean ± SD), and t-test was used for comparison between groups. The predictive value was analyzed by ROC curve. P<0.050 was considered statistically significant.

Results

Comparison of general data

There were no significant differences in age, BMI, gestational age, fertility circumstance, mean arterial pressure, place of residence, ethnicity, smoking history, the degree of edema, proteinuria, drinking history and exercise habits in the study group and the control group (P>0.050), indicating that the two groups of patients were comparable (Table I).

Table I Comparison of clinical data [mean ± SD, n (%)].

Table I

Comparison of clinical data [mean ± SD, n (%)].

Characteristics	Research group (n=94)	Control group (n=94)	χ2 or t	P-value
Age (years)			1.751	0.0815
	29.38±1.64	28.91±2.02
BMI (kg/m2)			0.594	0.553
	25.42±2.39	25.61±1.97
Gestational age (weeks)			0.432	0.665
	31.13±3.16	31.32±2.85
Mean arterial pressure (mmHg)			1.319	0.189
	154.62±8.62	152.85±9.74
Fertility circumstance			0.447	0.503
Unipara	72 (76.60)	68 (72.34)
Multipara	22 (23.40)	26 (27.66)
Place of residence			0.223	0.636
City	83 (88.30)	85 (90.43)
Countryside	11 (11.70)	9 (9.57)
Ethnicity			0.495	0.483
Han	75 (79.78)	71 (75.53)
Minority	19 (20.21)	23 (24.47)
Smoking history			0.046	0.829
Yes	13 (13.83)	12 (12.77)
No	81 (86.17)	81 (87.23)
Drinking history			0.367	0.544
With	16 (17.02)	13 (13.83)
Without	78 (82.98)	81 (86.17)
Exercise habit			0.101	0.74
With	27 (28.72)	29 (30.85)
Without	67 (71.28)	65 (69.15)
Proteinuria (g/24 h)			1.190	0.236
	1.84±0.54	1.94±0.61
Degree of edema			0.426	0.808
+ (extended to the thigh)	24 (25.53)	28 (29.79)
++ (extends to the vulva and abdomen)	54 (57.45)	51 (54.26)
+++ (systemic edema or ascites)	16 (17.02)	15 (15.96)

Efficacy evaluation and adverse occurrence comparison

The total effective rate of clinical efficacy was 95.74% in the study group, which was significantly higher than that in the control group (82.97%), P<0.05 (Table II).

Table II Comparison of clinical efficacy between the two groups [n (%)].

Table II

Comparison of clinical efficacy between the two groups [n (%)].

Curative effect	Research group (n=94)	Control group (n=94)	χ2	P-value
Significant effect	74 (78.72)	55 (58.51)
Effective	16 (17.02)	23 (24.47)
No effect	4 (4.26)	16 (17.02)
Overall response	90 (95.74)	78 (82.97)	8.057	0.004

The eutocia rate of the study group was higher than that of the control group, and the cesarean section rate was lower than that of the control group, P<0.05 (Table III).

Table III Comparison of labor outcomes between the two groups [n (%)].

Table III

Comparison of labor outcomes between the two groups [n (%)].

Groups	Eutocia	Cesarean section	Premature birth
Research group (n=94)	75 (79.78)	13 (13.82)	6 (6.38)
Control group (n=94)	61 (64.89)	24 (25.53)	11 (11.70)
χ2	5.21	4.072	1.617
P-value	0.02	0.043	0.203

There were a total of 9 adverse reactions in the study group, including 3 cases of postpartum hemorrhage, 1 case of eclampsia, 1 case of pulmonary edema, and 4 cases of cardiovascular disease. In the control group, there were 4 cases of eclampsia, 5 cases of postpartum hemorrhage, 2 cases of placental abruption, 3 cases of pulmonary edema, and 5 cases of cardiovascular diseases, a total of 19 cases of adverse reactions occurred in the control group. The incidence of adverse reactions was significantly lower in the study group than that in the control group, P<0.05 (Table IV).

Table IV Comparison of adverse reactions of patients in the two groups [n (%)].

Table IV

Comparison of adverse reactions of patients in the two groups [n (%)].

	Research group (n=94)	Control group (n=94)	χ2	P-value
Eclampsia	1 (1.06)	4 (4.25)
Postpartum hemorrhage	3 (3.19)	5 (5.32)
Placental abruption	0 (0.00)	2 (2.12)
Pulmonary edema	1 (1.06)	3 (3.19)
Cardiovascular disease	4 (4.25)	5 (5.32)
Total adverse reactions	9 (9.57)	19 (20.21)	4.196	0.040

Comparison of SOCS-3, IL-10 and IL-18 levels between the two groups before and after treatment

Before treatment, no differences were found in SOCS-3, IL-10 and IL-18 between the two groups (P>0.050). After treatment, the levels of SOCS-3 and IL-10 were significantly increased in the two groups, and they were higher in the study group than those in the control group (P<0.050). The IL-18 levels of the two groups were significantly decreased, and they were significantly lower in the study group than those in the control group (P<0.050 (Fig. 1).

Figure 1 Curative effect of magnesium sulfate combined with nifedipine on pregnancy-induced hypertension and the effect of serum inflammatory factors. (A) Comparison of SOCS-3 levels before and after treatment between the two groups. Before treatment, there were no differences in SOCS-3 between the two groups (P>0.050). After treatment, SOCS-3 was significantly increased in both groups, and this in the study group was higher than that in the control group (P<0.050). (B) Comparison of IL-10 levels before and after treatment in both groups. Before treatment, there were no differences in IL-10 between the two groups (P>0.050). After treatment, IL-10 increased significantly in both groups, and this in the study group was higher than that in the control group (P<0.050). (C) Comparison of IL-18 levels before and after treatment in both groups. Before treatment, there were no differences in IL-18 between the two groups (P>0.050). After treatment, IL-18 decreased significantly in both groups, and this in the study group was lower than that in the control group (P<0.050). #P<0.05, compared with the control group; aP<0.05, compared with before treatment. SOCS-3, cytokine signaling-3; IL-10, interleukin-10; IL-18, interleukin-18.

Predictive value of SOCS-3, IL-10 and IL-18 in patients with poor efficacy

All the patients were divided into good efficacy group (n=168) and poor efficacy group (n=20) in accordance with efficacy. According to the expression of SOCS-3, IL-10 and IL-18 in the two groups, ROC curve was drawn to analyze its predictive value for efficacy. The area under the curve (AUC) of SOCS-3 was 0.717 (95% CI, 0.577-0.857). When the cut-off value was <0.553 ng/l, the optimal specificity was 76.19%, the sensitivity was 70.00%, and the Youden index was 46.19. The AUC of IL-10 was 0.727 (95% CI, 0.6356-0.817). When the cut-off value was <48.06 ng/ml, the optimal specificity was 52.98%, the sensitivity was 94.74%, and the Youden index was 47.71. The AUC of IL-18 curve was 0.725 (95% CI, 0.630-0.821). When the cut-off value was <269.4 ng/ml, the optimal specificity was 61.90%, the sensitivity was 85.00%, and the Youden index was 46.90 (Fig. 2).

Figure 2 Predictive value of serum SOCS-3, IL-10 and IL-18 levels in patients with poor efficacy. SOCS-3, cytokine signaling-3; IL-10, interleukin-10; IL-18, interleukin-18.

Discussion

Pregnancy-induced hypertension is an idiopathic disease and prone to occur in the third trimester of pregnancy (20,21). Severe complications such as eclampsia appear in intensive cases (22,23), which seriously affects the health and safety of pregnant women and infants. Early intervention can effectively prevent the occurrence of severe symptoms. The level of inflammatory factors in serum were studied to carry out early screening for pregnancy-induced hypertension and early drug intervention. In previous research, indexes such as IL-1, IL-2, IL-6, and PCT have been studied thoroughly, and were found with abnormal manifestations in many diseases (24-28), with low specificity.

Our study found that the total effective rate of clinical efficacy in the study group was 95.74%, which was significantly higher than that in the control group (82.97%), and the eutocia rate in the study group was higher than that in the control group, with better pregnancy results. It suggested that magnesium sulfate combined with nifedipine could effectively improve the clinical efficacy of in pregnancy-induced hypertension. Then the incidence of adverse reactions between the two groups were compared, and it was found that the incidence of adverse reactions in the study group was significantly lower than that in the control group, and there was only one case of adverse reactions (eclampsia) in the study group. This suggested that combination therapy reduces the incidence of adverse reactions, and some studies have shown that magnesium sulfate and nifedipine in the treatment of eclampsia does not increase the risk of serious magnesium-related effects, confirming the safety of combination therapy (29). In this study, we first analyzed the changes of SOCS-3, IL-10 and IL-18 levels in observation group and control group before and after treatment. It was found that SOCS-3, IL-10 levels in both groups increased significantly after treatment, and the level of IL-18 in both groups decreased significantly. The levels in the study group were significantly lower than those in the control group. This is consistent with the study of Chen et al (30) that IL-6 level in pregnant women with preeclampsia treated with magnesium sulfate combined with nifedipine decreased. SOCS-3 is an important molecule that regulates the function of trophoblasts during placental development (31). Clinical studies have shown that SOCS-3 is the target of miR-203(32), and the decreased expression of SOCS-3 has been confirmed in the maternal vascular endothelium of preeclampsia. Wang et al (33) found that the expression of miR-203 was increased in the maternal vascular endothelium of women with preeclampsia, and the overexpression of miR-203 could down-regulate the expression of SOCS-3 in the endothelial cells, accompanied by inhibition of TNF-α-induced increase in adhesion of neutrophils to endothelial cells. This suggests that the down-regulation of SOCS-3 and increased inflammatory response in the maternal vascular system may be the result of increased expression of miR-203 in preeclampsia. Subsequently, ROC curve analysis of the curative effect was performed and found that the AUC of the predictive value of SOCS-3, IL-10 and IL-18 in pregnancy-induced hypertension was 0.717, 0.727 and 0.725, respectively. The best specificity was 76.19, 52.98 and 61.90%, respectively, when the cut-off value was <0.553 ng/l, 48.06 ng/ml and 269.46 ng/ml, and the sensitivity was 70.00, 94.74 and 85.00%, respectively. This suggests that SOCO-3, IL-10 and IL-18 have certain value in predicting the efficacy of pregnancy-induced hypertension, and may be used as biomarkers to predict the clinical efficacy. We speculate that the combined detection of the above indicators in the future clinical practice can effectively determine the clinical efficacy of patients.

Although this study observed changes in inflammatory factors before and after treatment in the two groups of patients, we did not specifically analyze the treatment time and efficacy, leaving certain limitations. Thus, further studies are required on the relationship between SOCS-3, IL-10 and IL-18 and pregnancy-induced hypertension, to further corroborate the results of this study.

In conclusion, magnesium sulfate combined with nifedipine can significantly improve the prevalence of pregnancy-induced hypertension. The levels of SOCS-3, IL-10 and IL-18 in patients are related to the curative effect of pregnancy-induced hypertension, suggesting that they have important value in the treatment and monitoring of gestational hypertension.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

Authors' contributions

FZ, FA and XD conceived and designed the study, and drafted the manuscript. FZ, FA, JW and XD collected, analyzed and interpreted the experimental data. FZ revised the manuscript for important intellectual content. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology). Signed informed consents were obtained from the patients and/or guardians.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References