Intrauterine inflammation Exposure may increase the risk of late-onset sepsis in premature infants:a retrospective cohort study

doi:10.21203/rs.3.rs-4967291/v1

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Intrauterine inflammation Exposure may increase the risk of late-onset sepsis in premature infants:a retrospective cohort study

https://doi.org/10.21203/rs.3.rs-4967291/v1

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Background: Preterm birth associated with intrauterine inflammation (IUI) has been linked to alterations in postnatal immunity and severe inflammatory complications during infancy. However, the impact of IUI on late-onset sepsis (LOS), a leading cause of mortality and morbidity in preterm infants, remains unclear. This study aims to elucidate the effect of IUI on the incidence of LOS in preterm infants by analyzing cytokine levels and white blood cell differential counts in cord blood within 24 hours after birth.

Methods: This retrospective cohort study was conducted at a single tertiary neonatal center. Infants born before 37 weeks of gestation between July 2020 and June 2022 were included. Late-onset sepsis (LOS) was defined as sepsis occurring after 72 hours of life during the birth hospitalization. Levels of 12 cytokines, including interleukin-1β (IL-1β), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, tumor necrosis factor-α (TNF-α), interferon-α (IFN-α), and IFN-γ, were measured in cord blood using multiplex bead-based flow immunoassays. Clinical data were extracted from hospital databases. Peripheral white blood cell counts within 24 hours after birth were routinely recorded for preterm infants. Logistic regression analysis was used to assess the impact of cytokines and white blood cell counts on the incidence of LOS.

Results: A total of 628 preterm infants were included in this study. The mean gestational age was 33.17 ± 2.25 weeks, and the mean birth weight was 1929.50 ± 516.77 grams. Of these, 42 infants (6.7%) developed late-onset sepsis (LOS). Compared to the non-LOS group, cord blood levels of IL-6 [127.81 (399.86) vs. 31.02 (127.48), p = 0.004] and IL-8 [130.37 (202.53) vs. 52.91 (101.43), p = 0.001] were significantly higher in the LOS group. No significant differences were observed in the levels of other cytokines between the groups. Peripheral neutrophil and monocyte counts were significantly lower in the LOS group [5.08 ± 3.46 vs. 8.14 ± 4.90, p < 0.001; 0.98 ± 0.56 vs. 1.37 ± 0.72, p = 0.001, respectively]. Multivariable logistic regression analysis revealed that elevated cord blood IL-6 levels and reduced peripheral neutrophil counts were associated with an increased risk of LOS, after adjusting for gestational age, gestational hypertension, and antenatal steroid use (aOR = 3.113, 95% CI: 1.239–7.819, p = 0.016; aOR = 0.340, 95% CI: 0.818–0.994, p = 0.038, respectively).

Conclusions: Elevated cord blood IL-6 levels and low peripheral neutrophil counts on the first day after birth are associated with an increased risk of LOS in preterm infants. These findings suggest that intrauterine inflammation may have a lasting impact on immune system responses, potentially influencing susceptibility to infections later in life.

Late-onset sepsis

Preterm infants

Cytokines

Intrauterine inflammation

Late-onset sepsis (LOS), defined as sepsis occurring after 72 hours of life during the birth hospitalization, is a major cause of morbidity and mortality among preterm infants, with reported incidence rates ranging from 20–30% among the most frequently hospitalized preterm infants¹. Infants who develop LOS are at increased risk of short-term in-hospital complications, mortality, and adverse long-term neurodevelopmental outcomes at 2 years of corrected age among survivors^2,3. Despite numerous prevention strategies implemented over the past decade, outcomes for preterm infants with LOS have remained unchanged.

Intrauterine infection/inflammation (IUI) is a significant etiological factor for preterm birth and is associated with conditions such as chorioamnionitis, maternal infection, and premature rupture of membranes (PROM). The concept of chorioamnionitis, also known as intrauterine inflammation or infection (commonly referred to as ‘Triple I’), encompasses both clinical and histological criteria⁴. Clinical chorioamnionitis is often accompanied by histological chorioamnionitis (HCA)⁵; however, many cases of HCA present without clinical symptoms in the mother or fetus^6,7. Despite the absence of clinical symptoms, asymptomatic intrauterine inflammation may still adversely affect the fetus, even in the absence of overt infection.

Evidence suggests a complex relationship between intrauterine inflammation and preterm delivery, as well as the development of LOS^8,9,10. Studies have shown conflicting results: Kriti Puri et al. reported that intrauterine inflammation increased the incidence of LOS in preterm infants less than 28 weeks' gestation⁸, while a systematic review indicated that chorioamnionitis was associated with culture-proven LOS (OR 1.31, CI 1.12–1.53, I² = 64%)⁹. Conversely, other studies have found no association or even a reverse relationship between LOS and intrauterine inflammation^11,12.

These discrepancies may be attributed to variations in the timing and duration of intrauterine inflammation. Infection without a corresponding fetal or maternal inflammatory response may not lead to preterm delivery. As the inflammatory process progresses, both pro-inflammatory cytokines (e.g., IL-1β, IL-4, IL-6, IL-8) and anti-inflammatory cytokines (e.g., IL-10) are produced. Given that pro-inflammatory cytokines rarely cross the placenta¹³, cord blood cytokine levels can accurately reflect intrauterine inflammation, while peripheral white blood cell counts provide insight into the newborn's immune status.

Assessing the relationship between intrauterine inflammation and LOS is crucial for enhancing our understanding of the innate immune response in preterm infants. This knowledge could inform the development of novel strategies for preventing and managing LOS. Therefore, this study aims to elucidate the association between intrauterine inflammation exposure and LOS by analyzing venous cord blood levels of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, TNF-α, IFN-α, IFN-γ, and counts of neutrophils, lymphocytes, and monocytes in a cohort of preterm neonates.

Study design, setting, and participants

This retrospective cohort study was conducted in the Department of Neonatology at Shanghai Children’s Medical Center, Shanghai, China. We included preterm infants admitted to our center from July 2020 to June 2022. The exclusion criteria were: absence of cord blood samples, death within 72 hours of birth, early-onset sepsis, and major congenital anomalies. Data were collected by trained data abstractors at Shanghai Children’s Medical Center. Late-onset sepsis (LOS) was defined as a positive blood or cerebrospinal fluid culture occurring after 72 hours of life, excluding cases of specimen contamination. Gestational hypertension was defined as a blood pressure reading greater than 140 mm Hg systolic or greater than 90 mm Hg diastolic, measured on at least two separate occasions. Gestational diabetes was defined as any degree of glucose intolerance with onset or first recognition during pregnancy. Small for gestational age (SGA) was defined as infants with a weight below the 10th percentile of the Fenton growth curve for their gestational age. Preterm premature rupture of membranes (PPROM) was defined as the rupture of membranes occurring before 37 weeks of gestation. Antenatal steroids were routinely administered to mothers at risk of preterm delivery between 24 and 34 weeks gestational age.

Exposure

We measured the serum concentrations of various cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, TNF-α, IFN-α, IFN-γ) from 2 mL cord blood samples collected from all participants. The cytokine concentrations were assessed using MBFFI test kits (MAGPIX®, USA). Additionally, white blood cell counts, including neutrophils, lymphocytes, and monocytes, were routinely performed in preterm infants within 24 hours after birth.

Statistical analysis

Continuous variables were expressed as mean and standard deviation (SD) or median and interquartile range (IQR; [Q1, Q3]) as appropriate, while categorical variables were presented as number and percentage. Differences between patients and controls were analyzed using Student’s t-test for normally distributed values, and the Mann–Whitney U-test for non-normally distributed data. Categorical variables were compared using the Chi-square test or Fisher’s exact test. Spearman correlation analysis was employed to evaluate the relationships between cytokines and clinical parameters. Multivariable logistic regression was utilized to assess the association of intrauterine inflammation with late-onset sepsis, adjusting for gestational age, gestational hypertension, and antenatal steroid use. All statistical analyses were conducted using IBM SPSS Statistics version 26.0 (IBM, Armonk, NY, USA), with a significance level set at P < 0.05 (two-sided).

Ethics statement

The study protocol was reviewed and approved by the Ethics Board of Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University (SCMCIRB-K2021016-1). Written informed consent was obtained from all participants’ legal guardians, and approval to access clinical data was granted by the hospital's medical director’s office. All patient information was kept confidential.

A total of 1,094 preterm neonates were admitted to our center from July 1, 2020, to June 30, 2022. Due to the unavailability of cord blood samples—either because of transfers from other hospitals or emergency deliveries—433 infants were excluded from the study. Additionally, 33 infants were excluded due to death within 72 hours, major congenital abnormalities, early-onset sepsis, and fetal genetic abnormalities. Consequently, 628 infants were included in the analysis (Fig. 1). The mean gestational age (GA) of the cohort was 33.17 ± 2.25 weeks, and the mean birth weight (BW) was 1929.50 ± 516.77 g (Table 1). During the study period, 42 preterm infants developed late-onset sepsis (LOS), with a mean onset age of 15.69 days. The majority of infected infants were born before 32 weeks of gestation, representing 57% of cases. Notably, there was a positive correlation between gestational age and the incidence of LOS, indicating that a lower gestational age was associated with a higher occurrence of LOS (Fig. 2). The gestational age and birth weight of the LOS group were significantly lower compared to the non-sepsis group [31.26 ± 2.41 vs. 33.30 ± 2.18, p = 0.000; 1507.02 ± 498.27 vs. 1959.78 ± 505.07, p = 0.000, respectively]. Except for maternal hypertension and antenatal steroid use, there were no significant differences between the two groups regarding small for gestational age (SGA), sex, delivery mode, preterm premature rupture of membranes (PPROM), 1- and 5-minute Apgar scores, and gestational diabetes (Table 1).

Table 1

Demographic and clinical characteristics of the study population
	LOS group (n = 42)	Non-sepsis group (n = 586)	Total	p
Gestational age(wks)	31.26 ± 2.41	33.30 ± 2.18	33.17 ± 2.25	0.000**
Birth weight(g)	1507.02 ± 498.27	1959.78 ± 505.07	1929.50 ± 516.77	0.000**
Age of onset (days)	15.69 ± 8.23	/	/	/
SGA	7 (16.7%)	61 (10.5%)	68 (10.8%)	0.316
Gender, male	23(54.8%)	316(53.9%)	339(54.0%)	1.000
Cesarean	32(76.2%)	487(83.1%)	519(82.6%)	0.351
1 min Apgar ≤ 7	74 (14.6%)	7 (16.7%)	81 (12.9%)	0.609
5 min Apgar ≤ 7	18 (3.1%)	3 (7.1%)	21 (3.3%)	0.316
PPROM	8(19.0%)	76(13.0%)	84(13.4%)	0.377
Gestational hypertension, n (%)	13 (31.0%)	92 (15.7%)	105 (16.7%)	0.019*
Gestational diabetes, n (%)	12 (28.6%)	114 (19.5%)	126 (20.1%)	0.220
Antenatal steroid, n (%)	37 (88.1%)	398 (67.9%)	435 (69.3%)	0.010*
P < 0.05, *P < 0.01

Table 2 reports the comparison of 12 cord blood cytokines between the LOS and non-sepsis groups. Levels of IL-6 [127.81(399.86) vs. 31.02(127.48), p = 0.004] and IL-8 [130.37(202.53) vs. 52.91(101.43), p = 0.001] were significantly higher in the LOS group. No differences in other cytokine concentrations were observed between the groups. Analysis of quartile data for IL-6 and IL-8 revealed that patients in the highest quartile for IL-6 had an increased risk of LOS (OR = 3.554, 95% CI: 1.464–8.625, p = 0.005), which remained significant after adjusting for gestational age, gestational hypertension, and antenatal steroids (aOR = 3.113, 95% CI: 1.239–7.819, p = 0.016). Similarly, patients in the highest quartile for IL-8 also had an increased risk of LOS (OR = 4.282, 95% CI: 1.548–11.844, p = 0.005); however, this significance disappeared after adjustment (aOR = 2.431, 95% CI: 0.839–7.042, p = 0.102) (Table 3).

Table 2

Umbilical cord cytokine levels (pg/ml) in preterm infants with and without LOS.
	LOS group [median (IQR)] #	Non-sepsis group [median (IQR)]	Total	p
IL-1β	2.44(3.14)	3(2.2)	3(2.2)	0.583
IL-2	2.44(1.56)	2.44(1.56)	2.44(1.56)	0.668
IL-4	2.44(0.22)	2.44(0.56)	2.44(0.56)	0.335
IL-5	3(2.64)	3(1.17)	3(1.17)	0.254
IL-6	127.81(399.86)	31.02(127.48)	33.58(140.72)	0.004**
IL-8	130.37(202.53)	52.91(101.43)	56.5(114.50)	0.001**
IL-10	7.00(22.45)	5.6(11.30)	5.88(11.71)	0.190
IL-12p70	2.44(0.12)	2.44(1.56)	2.44(0.56)	0.196
IL-17	2.44(1.17)	2.44(2.56)	2.55(2.56)	0.487
IFN-α	2.44(1.49)	2.44(2.56)	2.55(2.56)	0.239
IFN-γ	3.3(9.59)	2.605(4.24)	2.61(4.26)	0.251
TNF-α	2.44(0.64)	2.44(1.56)	2.44(1.56)	0.367
P < 0.05, *P < 0.01 #2.44 is the minimum detection value

Table 3

Relationship between IL-6, IL-8 and LOS before and after adjustment.
Unadjusted				Adjusted#
	OR	95CI%	P	OR	95CI%	P
IL-6	Q1 Ref	-	-	-	-	-
Q2	1.020	0.349–2.958	0.971	1.218	0.401–3.703	0.728
Q3	1.020	0.349–2.958	0.971	1.605	0.524–4.911	0.407
Q4	3.554	1.464–8.625	0.005**	3.113	1.239–7.819	0.016*
IL-8	Q1 Ref	-	-	-	-	-
Q2	1.409	0.438–4.534	0.565	1.317	0.397–4.368	0.653
Q3	2.672	0.919–7.774	0.071	1.511	0.499–4.571	0.465
Q4	4.282	1.548–11.844	0.005**	2.431	0.839–7.042	0.102
#: Gestational age, Gestational hypertension and Antenatal steroid were included as covariates in this model
P < 0.05, *P < 0.01

Peripheral white blood cell counts, including neutrophils, lymphocytes, and monocytes, are detailed in Table 4. Neutrophil and monocyte counts were significantly lower in the LOS group [5.08 ± 3.46 vs. 8.14 ± 4.90, p = 0.000; 0.98 ± 0.56 vs. 1.37 ± 0.72, p = 0.001, respectively]. Binary logistic regression analysis of variables with p-values < 0.05 showed that lower gestational age (OR = 0.748; 95% CI: 0.649–0.863; p = 0.000), lack of antenatal steroid administration (OR = 0.902; 95% CI: 0.127–0.912; p = 0.032), and low peripheral neutrophil count within 24 hours (OR = 0.340; 95% CI: 0.818–0.994; p = 0.038) were significantly associated with the development of LOS (Table 5).

Table 4

Neutrophil, lymphocyte, and monocyte counts (10⁹/L) in peripheral blood of preterm infants with and without LOSs.
	LOS group	Non-sepsis group	t	p
Neutrophil count	5.08 ± 3.46	8.14 ± 4.90	3.974	0.000**
Lymphocyte count	3.38 ± 1.80	3.23 ± 2.19	-0.242	0.809
Monocyte count	0.98 ± 0.56	1.37 ± 0.72	3.411	0.001**
**P < 0.01

Table 5

Multivariate logistic regression analysis showing the relationship between independent variables and the risk of LOS in preterm infants.
	OR	95CI%	P
Neutrophil count	0.340	0.818–0.994	0.038*
Gestational age	0.748	0.649–0.863	0.000**
Gestational hypertension	0.666	0.313–1.416	0.291
Antenatal steroid	0.902	0.127–0.912	0.032*
P < 0.05, *P < 0.01

In this retrospective cohort study, the incidence of late-onset sepsis (LOS) and its trend across different gestational ages align with previous reports^14,15. We found that cord blood levels of IL-6 and IL-8 were significantly higher in the LOS group compared to preterm infants without sepsis, while neutrophil and monocyte counts in peripheral blood were lower in the LOS group. Multivariable logistic regression analysis indicated that the association between IL-6 and neutrophil counts with LOS remained significant after adjusting for other confounding factors, which has not been previously reported.

During the early stages of chorioamnionitis, the maternal immune response predominates and infiltrates the membranes. As the infection or inflammation progresses, fetal leukocytes begin to infiltrate, resulting in elevated concentrations of pro-inflammatory cytokines such as IL-1β, IL-4, IL-6, and IL-8¹⁶. Research has shown that neonates with severe intra-amniotic inflammation exhibit significantly elevated cord blood cytokine levels, which can persist beyond the immediate neonatal period^17,18. Increasing evidence suggests that intrauterine inflammation exposure during pregnancy impacts subsequent immune responses^19,20. However, most clinical studies linking chorioamnionitis to offspring LOS have focused solely on placental pathology without direct evidence of fetal inflammatory responses. The stage and duration of intrauterine inflammation exposure remain unclear, leading to varying conclusions. Our study utilized cord blood cytokine levels to provide precise evidence that intrauterine inflammation exposure in preterm infants alters immune status and increases the risk of LOS, with IL-6 playing a crucial role.

IL-6, a pro-inflammatory cytokine, is a hallmark of fetal inflammatory response syndrome (FIRS)²¹. Maternal infection can induce inflammation in offspring through IL-6 independently of the microbiota²². Additionally, IL-6 is an independent predictor of adverse neonatal outcomes, including bronchopulmonary dysplasia (BPD) and white matter injury (WMI) in preterm infants^23,24,25. Our findings suggest that IL-6 may also serve as an independent predictor of LOS.

The neonatal innate immune system typically adopts a more regulatory, anti-inflammatory phenotype to accommodate rapid colonization with commensal organisms after birth and to prevent excessive inflammation and tissue injury. In vitro studies have shown that neonatal innate immune cells exhibit reduced pro-inflammatory cytokine expression compared to adult cells²⁶. When intrauterine inflammation leads to the secretion of pro-inflammatory cytokines, this is followed by an anti-inflammatory response. We hypothesize that this immune milieu in preterm neonates exacerbates the initial anti-inflammatory response, increasing susceptibility to microbial infections.

Supporting this hypothesis, studies in both humans and animal models have observed similar patterns. Infants born to HIV-positive mothers with chorioamnionitis had higher HIV positivity rates²⁷, and LPS-induced chorioamnionitis in preterm sheep resulted in immune paralysis of monocytes²⁸. Additionally, chronic fetal exposure to Ureaplasma parvum suppresses innate immune responses in sheep²⁹.

Recent interest has also focused on trained immunity, where innate immune cells are "trained" by initial stimuli or infections to respond more robustly to subsequent challenges³⁰. Research has demonstrated altered DNA methylation signatures in placentas associated with chorioamnionitis, consistent with the activation of innate immune responses³¹. In our study, in addition to changes in cord blood IL-6, we also found significant differences in the neutrophil and monocyte counts in preterm infants on the first day of life. And in neutrophils this difference still exists after adjusting confounders. Similar observations of neutrophil-driven inflammation have been observed in animal models. LPS-induced maternal inflammation promotes fetal leukocyte recruitment and prenatal organ infiltration in mice³². During the inflammatory process, IL-6 trans-signaling is involved in many processes including mononuclear cell recruitment and apoptosis of neutrophils³³. This may lead to a decreased level of neutrophils and monocyte in peripheral blood. Emma de Jong et al. showed that chorioamnionitis-exposure is associated with reduced monocyte expression of key immune genes and Global analysis of monocyte transcriptome reveals hypo-responsiveness to S. epidermidis in infants exposed to chorioamnionitis³⁴. An animal study conducted by Ai Ing Lim, further showed that increasing maternal IL-6 levels during pregnancy can alter the innate immune response of offspring by changing the epigenome²². Our study supports the hypothesis that elevated cord blood IL-6 increases the incidence of LOS through “trained immunity”.Our study supports the idea that elevated IL-6 levels in cord blood increase the incidence of LOS through mechanisms akin to trained immunity.

IL-8, a pro-inflammatory cytokine from the chemokine family, is crucial in inflammation, immune response, and tissue repair. Although the highest quartile of IL-8 was associated with increased LOS risk, this significance disappeared after adjusting for gestational age. Elevated antenatal vaginal IL-8 levels have been reported in high-risk women who delivered preterm compared to term deliveries, with IL-8 being an independent predictor of preterm birth³⁵. Thus, the association between IL-8 and LOS may be primarily mediated by gestational age.

To our knowledge, this study is among the few cohort studies investigating the relationship between cord blood cytokine levels, peripheral white blood cell counts, and LOS in preterm infants. It is also relatively comprehensive in its cytokine detection. Nevertheless, the study has several limitations. Firstly, the inclusion of all preterm infants means that the sample size of very preterm infants, who are particularly prone to LOS, is relatively small. Secondly, we did not conduct further cell differentiation or transcriptional response analyses in cord blood, limiting our ability to fully explain the observed phenomena. Lastly, due to the detection method's limitations, the precision of measurements at the lower detection limits may be less reliable than those in the midrange.

High levels of IL-6 in cord blood and low peripheral neutrophil counts on the first day of life are associated with an increased risk of late-onset sepsis in preterm infants. Prenatal exposure to inflammation may elevate the risk of late-onset sepsis in preterm infants, partially by altering immune system responses later in life.

Ethics approval and consent to participate

This study protocol was reviewed and approved by the Ethics Board of Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University (SCMCIRB-K2021016-1). All methods were performed in accordance with the ethical standards as laid down in the Declaration of Helsinki and its later amendments or comparable ethical standards. Written informed consent was obtained from all participants' legal guardian.

Consent for publication

Not applicable

Availability of data and materials

The original contributions presented in the study are included in the article/supplementary material, futher inquiries can be directed to the corresponding authors.

Competing interests:

The authors have no conflicts of interest relevant to this article to disclose.

Funding

This study was supported by the Scientific and Technology Commission of Shanghai Municipality (Grant No. 20Z11900600), and Clinical research project of Shanghai Children's Medical Center (LY-SCMC2020-01).

Author Contributions

XC and XZ conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript.

RX, LM, YL and JB, GZ designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscript.

FB conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content.

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Acknowledgments

The authors would like to thank Dr. Yanchen Wang for the help in the preliminary statistical analysis.

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Reviewers invited by journal
01 Sep, 2024
Editor assigned by journal
24 Aug, 2024
First submitted to journal
23 Aug, 2024

You are reading this latest preprint version

Intrauterine inflammation Exposure may increase the risk of late-onset sepsis in premature infants:a retrospective cohort study

Status:

Version 1

Abstract

Figures

Background

Study design, setting, and participants

Exposure

Statistical analysis

Ethics statement

Results

Discussion

Discussion

Declarations

References

Status:

Version 1