Associations of HMGB1, sTNFR-1 and NRL with the infectious premature delivery in pregnant women undergoing cervical cerclage

doi:10.21203/rs.3.rs-4316438/v1

ObjectiveTo investigate the associations of changes in the high mobility group box 1 (HMGB1), soluble tumor necrosis factor receptor 1 (sTNFR-1) and peripheral blood neutrophil-to-lymphocyte ratio (NLR) with the infectious premature delivery in pregnant women undergoing cervical cerclage.

MethodsSixty-seven pregnant women with premature delivery after cervical cerclage, who were treated at the Maternal and Child Health Hospital affiliated to Nantong University from January 2022 to October 2023, were enrolled, including 43 with infectious premature delivery (infectious group) and 24 with non-infectious premature delivery (non-infectious group). The pre-delivery serum levels of HMGB1, sTNFR-1 and the peripheral blood level of NRL were compared between the two groups. Further, the clinical value of these three indicators in predicting infectious premature delivery among pregnant women undergoing cervical cerclage was assessed by the receiver operating characteristic (ROC) curve analysis.

Results The infectious group exhibited significantly higher serum levels of HMGB1 (6.85 ± 2.08 mg/L), sTNFR-1 (4.77 ± 1.13 pg/ml) and peripheral blood level of NRL (6.51 ± 2.51) compared to those in the non-infectious group (4.01 ± 1.05 mg/L, 3.75 ± 0.66 pg/ml and 3.60 ± 1.48), showing significant differences (t = 7.44, 4.64 and 5.92, P < 0.05). Logistic regression analysis revealed that the HMGB1 and NRL were independent influencing factors for premature delivery (P < 0.05). According to the ROC curve analysis results, the changes in HMGB1, sTNFR-1 and NRL levels could somewhat reflect the risk of infectious premature delivery among pregnant women undergoing cervical cerclage. The AUC, sensitivity and specificity of combined detection were all markedly higher than those of independent detection.

ConclusionHMGB1, sTNFR-1 and NRL levels are the risk factors for third-trimester premature delivery among pregnant women undergoing cervical cerclage. Timely combined detection of serum HMGB1, sTNFR-1 and peripheral blood NRL at the third trimester can improve the clinical diagnostic rate, which enables early prevention to help lower the risk of premature delivery.

Cervical cerclage

Cervical insufficiency

HMGB1

sTNFR-1

NRL

Infection

Premature delivery

Premature delivery, as a common obstetric disease, refers to the childbirth occurred at 28-36 weeks⁺⁶ of gestation, which easily leads to neonatal organ dysplasia to seriously affect the pregnancy outcome. Cervical insufficiency (CIC), as a crucial risk factor for premature delivery, is defined as the imperfect cervical structure and impaired cervical function caused by congenital developmental factors or acquired injury, whose clinical symptoms include cervical canal shortening and cervical orifice dilation in the second and third trimesters of pregnancy ^[1]. Cervical cerclage is the only confirmed effective operation for treating CIC, which avoids the extension of lower uterine segment by closing the cervical canal surgically and reinforcing the cervix, thereby mitigating the fetus pressure on the internal cervical orifice and effectively prolonging the time to pregnancy of women with CIC^[2]. However, recent research has shown that some pregnant women still experience adverse outcomes like premature delivery after cervical cerclage^[3], so actively searching for the risk factors of premature delivery following cervical cerclage in CIC pregnant women is of great significance to lowering the incidence of adverse pregnancy outcomes. Depending on the presence or absence of infective factors, the premature delivery occurred in cervical cerclage patients can be divided into the infectious and non-infectious types. Early diagnosis of infectious premature delivery can provide a referential value in guiding the early anti-infective therapy or fetal preservation treatment^[4-5]. Research of serological cytokines can offer reference for the clinical diagnosis of infectious diseases. High mobility group box 1 (HMGB1) is a chemotaxis related factor, whose infiltrating effect on uterine smooth muscle cells can induce the contraction of the cells, increasing the risk of premature delivery ^[6-8]. Soluble tumor necrosis factor receptor 1 (sTNFR-1) can induce the activation of downstream TNF-α, strengthen the recruitment of downstream inflammatory factors, and promote the damage of fetal membrane and placenta tissue ^[9]. Other research has demonstrated that placental inflammation is closely associated with the pregnancy conditions like premature delivery, and that the blood neutrophil-to-lymphocyte ratio (NLR) can serve as a hematological parameter reflecting the inflammation, whose correlation with placental inflammation has received growing attention in recent clinical studies ^[10]. The predictive value of serum indicators for the risk of premature delivery after cervical cerclage in CIC pregnant women remains unknown. To this end, this study reveals the correlations of the serum HMGB1, sTNFR-1 and peripheral blood NRL expressions with the infectious premature delivery in cervical cerclage patients, which provides a reference for the early diagnosis and timely intervention of infectious premature delivery among pregnant women undergoing cervical cerclage, with a view to somewhat facilitating the maternal and fetal health protection for the pregnant women with CIC.

1.1 Data

1.1.1 General information: A total of 67 CIC patients, who had premature delivery at 28-36 weeks⁺⁶ of gestation after receiving transvaginal cervical cerclage at the Maternal and Child Health Hospital affiliated to Nantong University from January 2022 to October 2023, were enrolled, including 43 with infectious premature delivery (infectious group) and 24 with non-infectious premature delivery (non-infectious group). Patients in the infectious group were aged 23-37 (26.9 ± 2.3) years, whose gestational week of delivery was 32.8 ±2.5 weeks, gravidity was 1.98 ± 0. 64 and parity 0.99 ± 0. 45. Meanwhile, the non-infectious patients were aged 22-36 (27.1 ± 1.9) years, with a gestational week of delivery of 33.1 ± 2.3 weeks, gravidity of 1.89 ± 0.50 and parity of 0.96 ± 0.39. No significant differences in the basic clinical data were noted between the two groups (P > 0.05). Diagnostic and inclusion criteria: 1) Patients with clinically confirmed CIC who underwent elective cervical cerclage at 14-18 weeks of gestation; 2) Gestational age of premature delivery ranging from 28 to 36 weeks⁺⁶; 3) Single pregnancy; 4) Positive pathogenic microorganisms in the cervical secretion culture of pregnant women having infectious premature delivery; 5) Complying with relevant provisions of the Declaration of Helsinki on human clinical trials and receiving approval from the Medical Ethics Committee of our hospital. Exclusion criteria: 1) Diseases of the immune system; 2) Abnormal fetal position; 3) Multiple pregnancy; 4) Accompanied by pregnancy-induced hypertension, gestational diabetes mellitus; 5) Intrahepatic cholestasis of pregnancy; 6) Placental abruption, placenta previa; 7) Hyperthyroidism; 8) Chromosomal abnormality and other congenital defects.

1.2 Methods

1.2.1 Surgical procedure: McDonald's cerclage was implemented. After surgery, the patients were intravenously injected with magnesium sulfate for protection of fetus, inhibition of uterine contractions and prevention of infection. Additionally, the patients were required to rest in bed and abstain from sex. B-ultrasound reexamination was performed 2 weeks after surgery, and stitches were removed before delivery or after 37 weeks of pregnancy, or at any time if signs of uncontrollable contractions or infection were present.

1.2.2 Experimental procedure: Blood samples (each 5 ml) were collected from patients after hospitalization due to premature delivery, and centrifuged at 3500 r/min for 20 min with a centrifugal radius of 10 cm. The sera were separated for detection of HMGB1 and sTNFR-1 levels via peroxidase kit (Evermed Biomedical, Suzhou). Blood routine tests were performed with a LH750 automatic blood cell analyzer (Beckman Coulter, USA), and data including leukocyte, neutrophil, lymphocyte counts and NLR were acquired.

1.3 Statistical processing: SPSS 20.0 software was adopted. Measurement data were compared by t test and expressed as x ± s, while count data were processed by χ2 test and expressed as percentages. Binary logistic regression was employed for multivariate analysis, and the receiver operating characteristic (ROC) curves were drawn. Differences were considered statistically significant when P < 0.05.

2. 1 Comparison revealed that the prepartal serum HMGB1, sTNFR-1, neutrophil, leukocyte and NRL levels were all significantly higher in the infectious group than in the non-infectious group, showing statistical significance (P all < 0.05). Meanwhile, the infectious group exhibited lower lymphocyte level than the non-infectious group, without showing significant difference (P > 0.05) (See Table 1).

2. 2 For regression analysis on the associations of HMGB1, sTNFR-1 and NRL with the premature delivery in pregnant women undergoing cervical cerclage, a binary regression model was created using HMGB1, sTNFR-1 and NRL as the independent variables and the occurrence of premature delivery as the dependent variable (1 = infectious premature delivery, 0 = non-infectious premature delivery). According to the binary Logistic regression results, the expressions of HMGB1, sTNFR-1 and NRL were upregulated, and HMGB1 and NRL were independent risk factors for the premature delivery in cervical cerclage patients (OR > 1, P < 0.05) (See Table 2).

2.3 As revealed by the ROC analysis evaluating the clinical value of HMGB1, sTNFR-1 and NRL levels in predicting the incidence of infectious premature delivery among cervical cerclage patients, the area under the curve (AUC), sensitivity and specificity of prediction by serum HMGB1 were 0.740, 53.49% and 87.50%, respectively. The serum sTNFR-1 exhibited an AUC of 0.626, a sensitivity of 51.16% and a specificity of 79.17% for predicting infectious premature delivery. The corresponding AUC, sensitivity and specificity for NRL were 0.825, 69.77% and 91.67%, respectively. The joint prediction with HMGB1, sTNFR-1 and NRL yielded an AUC of 0.883, a sensitivity of 79.07%, and a specificity of 100%. (See Table 3 and Figure 1).

3.1 Research background

Although cervical cerclage has improved gradually with the rapid development of medical technology, there remains a certain probability of adverse pregnancy outcomes ^[11]. The occurrence of infectious premature delivery can lead to adverse clinical outcomes like neonatal asphyxia and neonatal respiratory distress syndrome, increasing the risk of maternal and infant disability during the perinatal period. Currently, there lacks early diagnostic indicators for infectious premature delivery. Despite the certain referential value of common serum hypersensitive C-reactive protein or procalcitonin in the diagnosis of early infectious premature delivery, their sensitivity for evaluating the risk of infectious premature delivery is below 40%, making their reliability for the early diagnosis of infectious premature delivery low ^[12]. The search for reliable and valid novel infection diagnostic markers is of great practical significance to the diagnosis and treatment of infectious premature delivery. Through the analysis of serum HMGB1, sTNFR-1 and NRL in pregnant women with infectious premature delivery, this study reasonably explains the progression mechanism of infectious premature delivery and provides an innovative reference for its clinical diagnosis and treatment.

3.1 Research results and analysis

As a member of the chemokine family, HMGB1 induces the softening and relaxation of internal cervical orifice by recruiting the downstream complement or chemokine C3a; low HMGB1 level can recruit the immune cells and promote the proliferation and differentiation of endometrial stromal cells required for normal pregnancy, while high HMGB1 level is associated with pregnancy failure ^[13–14]. sTNFR-1 is a member of the TNFR family, whose regulatory effects on different TNF-α receptors can enhance the pathological role of inflammatory factors, intensifying their damage to amniotic sac wall cells to increase the risk of premature delivery ^[15–16]. NLR is a sensitive inflammatory index discovered in current research, which not only indicates the role of neutrophils in infection, but also correlates with the lymphocyte count in the body. Neutrophils primarily exert their role in non-specific inflammatory responses, while lymphocytes play a role in immune system regulatory pathways. Upon the bodily infection by bacteria, the lymphocytes in the body diminish, accompanied by a quantitative increase in neutrophils. The latter can secrete a variety of inflammatory mediators, including chemokines and cytokines, to stimulate the chemotaxis, as well as the production and release of substantial neutrophils in the bone marrow, resulting in gradual local and systemic increases in the number of neutrophils. Thus, NLR is the ratio of two different but complementary immune pathways, which is considered a crucial indicator reflecting the inflammatory and immune states of the body. So far, global scholars have found in their studies on the early diagnosis of bacterial infectious diseases and blood infections ^[17–19] that NLR is closely associated with the early diagnosis and severity of bacterial infectious diseases. When the bodily infection by bacteria is at an early stage, NLR is the most rapid, simple and inexpensive early indicator available, which can more accurately reflect the infection status than conventional inflammatory indicators (e.g. leukocyte count, central granulocyte ratio). However, the correlation of NLR with premature delivery has rarely been reported worldwide, and studies on its association with infectious premature delivery caused by cervical cerclage are even rarer.

In this study, based on the changes in the serum levels of HMGB1, sTNFR-1 and NRL detected among pregnant women with premature delivery following cervical cerclage, those positive to pathogenic microorganisms in cervical secretion culture were assigned into the infectious group, while those negative to pathogenic microorganisms were assigned into the non-infectious group. It was found that the levels of HMGB1, sTNFR-1 and NRL in the infectious group were all significantly higher than those in the non-infectious group, suggesting that the high expression of serum HMGB1, sTNFR-1 and NRL could all affect the occurrence of infectious premature delivery in cervical cerclage patients. Findings of relevant cause analysis were as follows: 1) Increased expression of HMGB1 could increase the degree of oxytocin receptor upregulation on the uterine smooth muscle cell membrane by inducing the activation of downstream NF-KB signaling pathway, thereby triggering contraction of uterine smooth muscle cells to promote the occurrence of premature delivery. According to a study by Wallenstein et al. ^[20], the serum concentration of HMGB1 in preterm or infected pregnant women could increase by above 40% on average, and such increase was more significant among those with younger gestational age or complicated by adverse neonatal clinical outcomes. 2) Increased expression of sTNFR-1 could aggravate the damage of fetal membrane and the occurrence of premature membrane rupture by increasing the spread of inflammatory cascade response, thereby heightening the risk of premature delivery ^[21]. 3) The reason for the increase of NLR level is considered to be the intrauterine infection. The stimulation of chorionic and decidual inflammatory regions provoke the release of cytokines, which leads to changes in the number of leukocyte subsets in the body to promote the increase of neutrophil count and the decrease of lymphocyte count, thereby inducing premature delivery.

Through the multivariate Logistic regression analysis of serological indicators in pregnant women having premature delivery after cervical cerclage, this study found that the serum HMGB1 level and NRL were independent risk factors for premature delivery, which had certain value in the independent diagnosis of infectious premature delivery among pregnant women undergoing cervical cerclage. ROC analysis revealed that the peripheral blood NLR had high sensitivity and specificity for predicting infectious premature delivery in cervical cerclage patients, with an AUC of 0.825. Consistent with previous findings, close monitoring of NLR level facilitated early prediction of the infectious premature delivery ^[22]. Additionally, joint prediction by serum HMGB1, sTNFR-1 and NRL exhibited the maximum AUC, which was nearly 0.9. In clinical practice, microbes are usually cultured to determine whether infection is present. However, given the long cycle of microbial culture and the fast progression of premature delivery, the optimal intervention time may be missed. Serological indicators are characterized by fast detection. Through the detection of serum HMGB1, sTNFR-1 and NRL levels in pregnant women with signs of premature delivery, early screening of and anti-infective therapy for infectious premature delivery are possible, which can control the patient condition as soon as possible, prolong the gestational age, and improve the maternal and fetal pregnancy outcomes. Due to the small specimen size of this study and the failure to compare preoperative serological indicators, there are still limitations in conclusions. In the future research, more clinical data should be included to reduce experimental errors, the factors associated with infectious premature delivery in pregnant women undergoing cervical cerclage should be further analyzed, relevant measures should be formulated, and the pregnancy outcome of cervical cerclage patients after receiving active intervention should be included to further corroborate the findings.

3.3 Conclusion

When the pregnant women undergoing cervical cerclage have infectious premature delivery, their serum levels of HMGB1, sTNFR-1 and NRL are significantly upregulated. Joint prediction by serum HMGB1, sTNFR-1 and NRL has a crucial referential value in diagnosing infectious premature delivery among the cervical cerclage patients. Early diagnosis of infectious premature delivery and early anti-infective therapy are necessary, in order to avoid irreversible premature delivery in cervical cerclage patients to gain time for early treatment, control the disease as early as possible, prolong the gestational age, and improve both the maternal and fetal pregnancy outcomes.

Statement：I promise that all experimental protocols were approved by Affiliated Matern&Child Care Hospital of Nantong University.

Consent for publication：Not applicable.

Availability of data and material：All data generated or analysed during this study are included in this published article.

Competing interests：The authors declare that they have no competing interests.

Funding :This study was funded by Nantong Science and Technology Bureau Social Livelihood Science and Technology Plan Project (Grant No:MSZ2022035)and Nantong Youth Talent Project(Grant No:YQY202310)and Nantong Innovation Team Project(Grant No:NTXK202302).

Ethical approval :This article does not contain any studies with animals performed by any of the authors. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

This nvestigate was reviewed by the Ethics Committee of Nantong Maternal and Child Health Hospital on December 20, 2017.trial registration number is Y2017031.

Informed consent :Informed consent was obtained from all individual participants included in the study.

Acknowledgements：

We appreciated Jie Zhang for Language polish for the manuscript.

Author's contribution

Dr.Shengnan Cai:Experimental design, case collection and article writing

Dr.Yanting Wu:Case collection and data analysis

Yiqian Ding:Cervical cerclage operator

Dr.Li Zeng:Experimental design, review of experimental process

All authors reviewed the manuscript.

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Table 1 Comparison of prepartal serum HMGB1, sTNFR-1, neutrophil, leukocyte and NRL levels between two groups (x̄± s)

Indicator Group	Number of cases (n)	HMGB1 (mg/L)	sTNFR-1 (pg/ml)	Neutrophil (10⁹/L)	Lymphocyte (×10⁹/L)	Leukocyte (×10⁹/L)	NRL
Infectious premature delivery	43	5.40±1.96	4.06±0.85	10.06±2.46	1.72±0.53	10.82±3.02	6.51±2.51
Non-infectious premature delivery	24	3.85±0.89	3.69±0.61	6.63±1.80	1.94±0.32	9.03±2.34	3.60±1.48
t		7.44	4.64	5.98	-1.91	2.54	5.97
P		<0.01	0.045	<0.01	0.06	<0.01	<0.01

Table 2 Multivariate Logistic regression results concerning the occurrence of infectious premature delivery in pregnant women undergoing cervical cerclage

Result Indicator	β value	S.E	Wald	OR	95% CI	P value
Serum HMGB1 level	1.317	0.532	6.126	3.730	1.315-10.581	0.013
Serum sTNFR-1 level	-1.713	0.879	3.794	0.180	0.032-1.011	0.051
NRL	0.555	0.178	9.663	1.741	1.227-2.470	0.002

Table 3 Clinical values of HMGB1, sTNFR-1 and NRL levels in predicting the infectious premature delivery in cervical cerclage patients

Indicator	Youden	Sensitivity (%)	Specificity (%)	FNR (%)	FPR (%)	AUC	95% CI
Serum HMGB1 level	0.410	53.49	87.50	46.51	12.50	0.740	0.619-0.840
Serum sTNFR-1 level	0.303	51.16	79.17	48.84	20.83	0.626	0.500-0.742
NRL	0.614	69.77	91.67	30.23	8.33	0.825	0.712-0.907
Joint prediction	0.791	79.07	100.00	20.93	0	0.883	0.781-0.948

No competing interests reported.

Associations of HMGB1, sTNFR-1 and NRL with the infectious premature delivery in pregnant women undergoing cervical cerclage

Status:

Version 1

Abstract

Figures

Introduction

1 Data and Methods

2 Results

3 Discussion

3.1 Research background

3.1 Research results and analysis

3.3 Conclusion

Declarations

References

Tables

Additional Declarations

Status:

Version 1