Risk factors and postnatal biomarkers for acute placental inflammatory lesions and intrauterine infections in preterm infants

Methods

1. Patient selection

Maternal and neonatal charts were reviewed retrospectively for clinical features, laboratory data and placental pathological examinations for infants born at less than 37 weeks of gestation from January 1, 2018 to December 31, 2020 at China-Japan Friendship Hospital. Inclusion criteria were: (1) infants were born with a gestational age of fewer than 37 weeks, (2) their placentas were taken pathological examinations, (3) the medical records of maternal application of glucocorticoids and antibiotics were accurate. The following exclusion criteria included: (1) neonates with congenital abnormalities, chromosome anomalies, or genetic and metabolic disorders, (2) family members decided to quit treatment within 24 hours after infants’ birth causing incomplete clinical records during hospitalization, (3) family members refused the placental pathological examination.

2. Placental pathology and group criteria

The placental pathological examination was performed in the mothers who gave preterm labor in our hospital. After delivery, the placenta disc, fetal membranes and umbilical cord tissues were sent for pathology within 24 hours. Specimens were collected by pathologists, and gross and microscopic observations were conducted.

Diagnosis criteria of acute inflammatory lesions of the placenta complied with the Amsterdam Placental Workshop Group Consensus Statement [9]. Generally, the inflammatory lesions of the placenta were divided into acute inflammatory lesions, chronic inflammatory lesions, mixed inflammatory lesions depending on the type of inflammatory cells. Also, there were non-inflammatory lesions of the placenta, such as small calcification, vascular malperfusion. In this study, we focused on acute inflammatory lesions and non-inflammatory lesions.

Considering the shortage of feasibility and effectiveness of the existing category system of acute placental inflammatory lesions, we defined neutrophils infiltration according to the placental histological structure from maternal to fetal side and divided the subjects into four subgroups: acute subchorionitis (including deciduitis and villitis), chorionitis, HCA and funisitis. In addition, due to the inadequate number of infiltrating neutrophils to be given a concrete diagnosis, we nominated this situation as ‘suspected inflammation’ which was the fifth subgroup in the study. The clinical data of mothers and premature infants in 5 subgroups were analyzed.

3. Clinical data collection

Clinical data and pathological data were collected from obstetrical and neonatal medical records, including: (1) general information: (a) maternal chart: maternal age, parity, amniotic fluid situation, pregnancy complications, delivery methods, prenatal antibiotics and dexamethasone usage, (b) infant chart: gestational age, gender, birth weight, Apgar score at 1 min, fetal distress, and premature rupture of membranes (PROM). (2) neonatal hematological indices were assessed in medical laboratory of China-Japan-Friendship Hospital as routine blood tests within 1 hour after birth. The parameters included the total number and classification of white blood cells (WBCs), platelet (PLT) count, C-reactive protein (CRP), phospholipids, serum sialic acids (SIA), superoxide dismutase (SOD), monoamine oxidase (MAO) and α-L-fucosidase (AFU). (3) clinical complications and outcomes of infants: usage of mechanical ventilation, intrauterine infectious complications (intrauterine pneumonia, neonatal EOS, purulent meningitis, urinary tract infection, etc.), neonatal respiratory distress syndrome (NRDS), patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD) and hypoxic-ischemic encephalopathy (HIE). The diagnostic criteria for maternal diseases referred to Williams Obstetrics (25th Edition) [11], while that of neonates’ referred to the fourth edition of Practical Neonatology [12].

4. Statistical analysis

Statistical analysis was performed using SPSS 23.0 software. Quantitative data were compared with t test and one-way ANOVA followed by Dunnet’s tests (parametric) or with Kruskal-Wallis rank test followed by Dunn’s multiple comparison tests (nonparametric). Normally distributed data were described by means±standard deviation (means±SD), while non-normally distributed data were described by median (interquartile). The qualitative data were expressed as proportion (%), and comparisons between groups were done with Chi-squared (χ² ) test or Fisher's exact test. Logistic regression analysis was used to analyze the correlation between the risk factors/biomarkers and acute inflammatory lesions of the placenta. A p-value of <0.05 was considered statistically significant.

Results

1. Correlation between acute inflammatory lesions of the placenta and the perinatal clinical characteristics of mothers and offspring

A total of 427 premature infants were admitted and treated in the neonatal intensive care unit during the study period. According to the inclusion and exclusion criteria, 194 preterm infants conformed to the criteria. Based on the placental pathology, 94 cases were diagnosed as acute placental inflammatory lesions, while 87 cases belonged to the non-inflammatory lesion group. Finally, a total of 181 cases were included in this study (Fig. 1).

Compared between the acute inflammatory lesion group and the non-inflammatory lesion group, there was no significant difference in premature infant’s gender, gestational age, birth weight, the incidence of fetal distress, and amniotic fluid contamination (all p>0.05). The occurrence and duration of PROM in the acute inflammatory lesion group were dramatically increased compared with those in the non-inflammatory lesion group (both p<0.001). The maternal childbearing age and parity were not related to the presence of acute inflammatory lesions in the placenta (both p>0.05). In the non-inflammatory lesion group, the incidence of gestational hypertension and that of intrahepatic cholestasis of pregnancy (ICP) were obviously higher than these of the acute inflammatory lesion group, and the differences were statistically significant (both p<0.05). But there was no significant difference in the incidence of gestational diabetes mellitus (GDM), placenta praevia, placental abruption, hypothyroidism, prenatal fever, and HELLP syndrome between the two groups (all p>0.05). In the respect of delivery mode, the mothers in the acute inflammatory lesion group mostly used vaginal labor (p<0.001). It showed a higher proportion of complete dexamethasone treatment before delivery to accelerate fetal lung maturity in the acute inflammatory lesion group (p<0.05), and the number of cases receiving preventive antibiotics treatment in this group was nearly 4 times of that in the non-inflammatory lesion group (p<0.05) (Table 1).

2. Association between acute inflammatory lesions of the placenta and early laboratory examinations and complications in preterm infants

The preterm infants with the acute placental inflammatory lesions had a 14.5% higher concentration of serum SIA within 1-hour afterbirth than that of the non-inflammation group (p<0.001). But the WBCs count and the counts of WBC category, PLT count, CRP, SOD, MAO, AFU and phospholipids in serum showed no statistical difference between the two groups (all p>0.05). The results exhibited no significant difference in Apgar score at 1 min, the application of mechanical ventilation, and as well as the prevalence of intrauterine infectious complications, NRDS, PDA, BPD, NEC, and HIE of the premature babies between the two groups (all p>0.05) (Table 2).

3. Exploration of risk factors and potential serum biomarkers of acute inflammatory lesions of the placenta

We examined the possible high-risk factors of acute placental inflammatory lesions in preterm infants by logistic regression analysis and it showed that the duration of PROM, the administration of antibiotics before delivery, and the serum SIA of infants were all the risk factors of acute placental inflammatory lesions. The choices of delivery methods and antibiotic treatments were both medical interventions that obstetricians considered it necessary to adopt, so the statistical results of the two factors could not indicate the predictive risk efficiency for acute placental inflammatory lesions. Therefore, the duration of PROM might be one of the independent risk factors for acute placental inflammatory lesions, and meanwhile, the higher the concentration of serum SIA in infants was, the greater the possibility of acute inflammatory lesions occurring in the placenta was (Table 3).

4. Comparison of early clinical indicators and infectious complications in preterm infants among anatomical subgroups of acute placental inflammatory lesions

According to the different histological structures and degrees of neutrophil infiltration, the acute inflammation group was divided into 5 subgroups: acute subchorionitis group, acute chorionitis group, acute HCA group, acute funisitis group, and the suspected inflammation group (the degree of neutrophils infiltration was not sufficient to give a diagnosis of acute inflammation). The classification rule of the previous 4 subgroups conformed to the anatomical continuity from maternal to fetal side of the placenta. Next, we observed that there were still significant differences in the risk factors (gestational age, the duration of PROM, antibiotic administration rate and serum SIA of premature infants) among the 5 subgroups and the non-inflammatory lesion group (all p<0.05). Furthermore, all of the infants whose placentas were diagnosed pathologically with HCA (12 cases) and funisitis (7 cases) suffered from intrauterine infectious diseases though there was no significance statistically in the occurrence of infectious complications among the 6 groups (Table 4).

Premature infants with funisitis had a dominant longer duration of PROM and a higher rate of antibiotics usage before birth than these of other babies (all p<0.05). The infants in the funisitis group were 1.53 to 3.71 weeks younger than these preterm neonates with other placental lesions, and they had the highest content of serum SIA above other groups. Likewise, these parameters in the acute HCA group displayed a similar trend with the funisitis group, although the magnitude of the change was smaller than that of the funisitis group. Moreover, the closer the placental lesions were to the fetus, the lower the gestational age of preterm infants was, and the higher the serum SIA level was (Fig. 2).

Discussion

Placental inflammatory lesion is the immune response of mother and fetus to intrauterine infection[13]. The general definition of HCA refers to the infiltration of neutrophils in the placenta, fetal membranes and umbilical cord which would lead to adverse pregnancy outcomes, such as premature delivery, PROM and neonatal EOS [13, 14]. The premature birth rate with HCA was about twice that without HCA [15]. The mechanism might be that when HCA occurs, bacterial endotoxins or exotoxins are recognized by Toll-like receptors and stimulate the placental tissue to produce inflammatory cytokines which could induce prostaglandin release and directly initiate uterine contractions [16] or trigger T cells proliferation in response to maternal antigens through pro-inflammatory reactions via interferon-γ and tumor necrosis factor-α pathways [17]. Previous studies indicated that HCA or amniotic cavity infection and neonatal EOS were closely connected [6, 7]. Moreover, Apgar score, endotracheal intubation rate, mechanical ventilation rate, pulmonary surfactant application, severe PDA rate and the incidence of BPD in very low birth weight infants were related to HCA [18]. Maternal amnionitis led to the low gestational age and low birth weight of preterm infants, and it was an independent risk factor for intraventricular hemorrhage [19]. Therefore, it is extraordinarily urgent to discover possible risk factors and predictive biomarkers of intrauterine infection in the early stage to reduce the complications of preterm infants by intervening timely.

PROM and intrauterine infection are reciprocal causation [13]: PROM could motivate pathogen to retrograde causing intrauterine infection, while inflammatory factors released during intrauterine infection could trigger PROM. Preterm PROM was responsible for about one-third of the preterm delivery rate [20], and with the prolongation of premature rupture of membranes, especially those with premature rupture longer than 24 hours, the probability of EOS would increase by 2–10 times [21]. In this study, it was found that PROM was one of the independent risk factors for acute inflammatory lesions of the placenta. The vaginal delivery rate and PROM rate were higher in the group of acute placental inflammatory lesions, and the duration of PROM in this group was obviously longer than that in the non-inflammation group. Analysis of anatomical subgrouping revealed that the longer the duration of PROM last, the closer the neutrophils infiltration was to the fetal side. However, in the present research, there was no statistically significant association between the acute placental inflammatory lesions and the infectious complications of premature infants. This result might be explained by the fact that the antepartal intervention of antibiotics could influence the prevalence of infectious diseases of preterm babies. The duration of PROM is often used to predict the possibility of intrauterine infection, so as to apply timely intervention and to minimize the occurrence of infection-related complications in preterm infants. Nevertheless, because the time course of PROM is not 100% correlated to intrauterine infection, there must be a misapplication of antepartal antibiotics and misjudgment of postnatal infectious complications. Since there is a lack of tools to accurately predict intrauterine infection before delivery, the combination of the time of PROM, the contamination of amniotic fluid and the clinical manifestations of pregnant women to anticipate intrauterine infection is still one of the most effective methods as the guidance of applying antibiotics in advance to diminish the intrauterine infectious complications of preterm infants. However, there was only 5.3% maternal fever occurring in the acute inflammation group and 1.1% of pregnant women in the non-inflammation group getting prenatal fever which might be considered as “isolated maternal fever” [13], suggesting that maternal fever could not give us a reliable hint of intrauterine infection. Additionally, due to the uncertainty of the timing of terminating the pregnancy, the course of anti-infection treatment before delivery is often insufficient. Moreover, the results of the placental pathology could not be obtained in time. Therefore, pediatricians need objective indicators to evaluate whether the newborns suffer intrauterine infections and whether the intrauterine infection has been effectively controlled.

We discovered that serum SIA in preterm infants might be one of the postnatal biomarkers of intrauterine infection. Interleukin (IL)-6 in amniotic fluid is specific as an antenatal biomarker for intrauterine infection, but it is still controversial to use it in clinical practice not just because the way to acquire the sample is invasive [13]. Though the levels of CRP, procalcitonin, IL-6 and IL-8 in umbilical cord blood or neonatal blood could be used as postnatal biomarkers for potential EOS, getting a sufficient amount of blood samples is most difficult in clinical practice, and those biomarkers are influenced by the postnatal physiological changes [22]. Therefore, they are not practical postnatal biomarkers for intrauterine infections. In our study, we observed that the serum SIA level of preterm infants with acute placental inflammatory lesions was significantly higher than that of the non-inflammation group. But at the same time, the CRP displayed no variation between the two groups, suggesting that serum SIA might be one of the indicators with higher sensitivity to predict intrauterine inflammation in the early postnatal period.

SIA, also known as sialome, is a generic term for a family of nine carbon monosaccharides, which are derivatives of neuraminic acid. The main forms in vertebrates are N-acetylneuraminic acid (Neu5Ac), N-glycolylneuraminic acid (Neu5Gc) and deaminoneuraminic acid (Kdn) [23]. SIA isoforms establish SIA cycle in the body, including the participation in the sialylation modification of glycoproteins and glycolipids in cells’ surfaces for providing the recognition sites for the formation of glycocalyxes which can manipulate the cellular interaction of immune cells, nerve cells and other cells [21, 23]. Previous studies showed that SIA played a predominant role in the biological process of breast cancer metastasis, atherosclerosis, pancreatic cancer, immune response of nervous system, atopic diseases, and muscle aging [24–29]. The normal content of serum SIA in full-term infants is: (27.3 ± 1.7) mg/dL for male newborns and (27.3 ± 1.7) mg/dL for females [30]. A single-center study discovered that the serum SIA level of preterm infants was lower than that of full-term infants (26.6 ± 7.5 vs 29.8 ± 9.3) mg/dL, suggesting that serum SIA concentration might be positively correlated with gestational age [31]. SIA was also engaged in the fetal lung maturation, for the elevated SIA expression in fetal lung witnessed the better differentiation of bronchoalveolars [32].

After the further analysis of histopathological subgroups, it was interesting to discover that although the gestational age of preterm infants with funisitis was significantly lower than that of other groups, the content of serum SIA, which should gradually drop down accompanied by the decrease of gestational age, was about 58.0% higher than that of non-inflammatory lesion group. Similarly, HCA group showed an up-regulating serum SIA level (about 26.0% higher than that of non-inflammatory lesion group) though the difference did not reach statistical significance. The infectious complications ratios of newborns in the funisitis group and the HCA group were both 100%, implying that when neutrophils infiltrated into the amniotic membrane, the serum SIA level of preterm infants increased substantially, representing a greater possibility of fetal inflammatory response and high prevalence of infectious complications in premature babies. This result further confirmed that the serum SIA content might be one of the potential early-stage biomarkers to reflect the intrauterine fetal inflammatory response, whose sensitivity within 1-hour afterbirth was prior to that of CRP, and it might play a guiding role in the early postnatal anti-infection treatments. In addition, an animal experiment revealed the SIA biological function on the nervous system. After the newborn rats were exposed to lipopolysaccharide, the neuraminidase (Neu) 1 and Neu4 were up-regulated in the brain tissue through the interaction of sialyltransferase and Neu, resulting in the continuous down-regulation of neuronal glycoprotein sialylation, which might be one of the mechanisms of perinatal inflammatory stimulation leading to neonatal neuropathological sequelae [33]. Thereby, our research found that the increased level of serum SIA in premature infants with acute placental inflammatory lesions probably reflected a decreased sialylation modification of cells in vivo, especially attributing to the change of glycosylation degree on the cell membrane of the immune system and nervous system, which could influence a long-term prognosis of nervous system development of preterm infants. However, we still need further follow-up studies to evaluate the association of free SIA and nervous complications of preterm newborns.

Limitations:

The present study had some limitations. First, it is a single-center retrospective study with a small case number, so each subgroup by the anatomical categories of placental lesions shared less case number, which could affect a real clinical significance. Second, also due to the small sample number, it is impossible to calculate the cut-off value of serum SIA between the funisitis group and the non-inflammatory group. Third, as described above, the investigation of SIA’s potential biological function on the nervous system needs, at least, a follow-up evaluation of infants’ neurodevelopment.

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Tables

Table 1. Comparison of clinical characteristics of premature infants and their mothers in acute placental inflammatory lesion group and non-inflammatory lesion group

	Acute inflammatory lesion group (N=94)	Non-inflammatory lesion group (N=87)	Statistical value	p value
General information of preterm infants
Male	63（67.0%）	45（51.7%）	4.393	0.036
Gestational age (weeks)	34.25±2.17	34.69±1.92	-1.235	0.217
Birth weight (g)	2239.20±569.08	2302.64±552.73	-0.795	0.427
Delivery information
Vaginal delivery	46（48.9%）	15（17.2%）	20.314	＜0.001
Fetal stress	19（20.2%）	14（16.1%）	0.515	0.473
PROM	52（55.3%）	24（27.6%）	14.266	＜0.001
Duration of PROM (hours)	8.5（0, 54）	0 (0, 2)	-4.372	＜0.001
Amniotic fluid contamination	4（4.3%）	6（6.9%）	0.604	0.437
Clinical data of mothers
Age (years)	32.27±3.58	32.97±4.36	-1.735	0.083
Parity 1	62（66.0%）	59（67.8%）	0.1	0.95
Administration of antibiotics within 12 hours before labor	46（48.9%）	11（12.6%）	27.584	＜0.001
Complete Dex therapy	58（61.7%）	41（47.1%）	3.874	0.049
Pregnancy complications
GDM	31（33%）	23（26.4%）	0.924	0.336
Gestational hypertension	9（9.6%）	20（23.0%）	6.042	0.014
Placenta praevia	9（9.6%）	15（17.2%）	2.309	0.129
Placental abruption	3（3.2%）	6（6.9%）	1.313	0.252
Hypothyroidism	11（11.7%）	15（17.2%）	1.127	0.288
HELLP syndrome	2（2.1%）	1（1.1%）	0.265	0.607
ICP	0（0%）	5（5.7%）	5.556	0.018
Prenatal fever	5（5.3%）	1（1.1%）	2.451	0.117

Note: Quantitative data: normally distributed data are represented by mean±SD; non-normally distributed data are described by median (interquartile); and the statistical value is t. Qualitative data: expressed as N (%), the statistical value is χ². Dex: Dexamethasone; PROM: premature rupture of membranes; GDM: gestational diabetes mellitus; ICP: intrahepatic cholestasis of pregnancy.

Table 2. Early laboratory examinations, clinical outcomes and complications of preterm infants compared between acute placental inflammatory lesion group and non-inflammatory lesion group

	Acute placental inflammation (n=94)	No-inflammation (n=87)	Statistical value	p value
Apgar score at 1 min ≤7	7	8	0.182	0.670
Hematological tests within 1 hour after birth
WBC count (×10⁹/L)	12.83 ± 5.3	12.49 ± 5.43	-0.701	0.483
Neutrophils count (×10⁹/L)	7.24 ± 3.45	7.0 ± 3.85	-0.864	0.388
Lymphocytes count (×10⁹/L)	3.56 ± 1.25	3.83 ± 1.61	-0.611	0.541
PLT count (×10⁹/L)	250 ± 67	246 ± 64	-0.647	0.517
Abnormality of CRP	11 (11.7%)	5 (5.7%)	1.988	0.159
SOD (U/ml)	210.3 ± 56.8	197.5 ± 43.6	-1.556	0.12
MAO (U/L)	6.92 ± 3.63	6.49 ± 3.75	-1.261	0.207
Phospholipids (mmol/L)	1.51 ± 0.24	1.48 ± 0.32	-1.354	0.176
AFU (U/L）	27.20 ± 9.65	25.86 ± 7.96	-1.106	0.269
SIA (mg/dL)	24.63 ± 5.71	21.52 ± 3.81	-3.558	＜0.001
Invasive mechanical ventilation	15 (16.0%)	12 (13.8%)	0.167	0.693
Days of ventilation	0 (0, 0)	0 (0, 0)	-0.521	0.602
Noninvasive mechanical ventilation	41 (43.6%)	31 (35.6%)	1.203	0.273
Days of ventilation	0 (0, 5.37)	0 (0, 3)	-1.299	0.194
Intrauterine infectious complications	84 (89.4%)	69 (79.3%)	3.491	0.062
Intrauterine pneumonia	81 (86.2%)	68 (78.2%)	1.991	0.158
Early-onset sepsis	10 (10.6%)	7 (8.0%)	0.357	0.550
Purulent meningitis	2 (2.1%)	0 (0%)	1.872	0.171
Urinary tract infection	1 (1.0%)	0 (0%)	0.931	0.335
Cutaneous infection	2 (2.1%)	0 (0%)	1.872	0.171
NRDS	23 (24.5%)	19 (21.8%)	0.175	0.675
PDA	8 (8.5%)	4 (4.6%)	1.118	0.29
BPD	2 (2.1%)	1 (1.1%)	0.265	0.607
NEC	5 (5.3%)	1 (1.1%)	2.451	0.117
HIE	5 (5.3%)	3 (3.4%)	0.156	0.583

Note: Quantitative data: normally distributed data are represented by mean±SD, non-normally distributed data are described by median (interquartile), and the statistical value is t. Qualitative data: expressed as N (%), the statistical value is χ². WBC: white blood cell; PLT: platelet; CRP: C-reactive protein; SOD: superoxide dismutase; MAO: monoamine oxidase; AFU: α-L-fucosidase; SIA: sialic acids; NRDS: neonatal respiratory distress syndrome; PDA: patent ductus arteriosus; BPD: bronchopulmonary dysplasia; NEC: necrotizing enterocolitis; HIE: hypoxic-ischemic encephalopathy.

Table 3. Analysis of risk factors for acute inflammatory lesions of the placenta

	Odds ratio	95%CI	p value
PROM	3.250	1.746～6.051	＜0.001
Cesarean section vs vaginal delivery	0.217	0.109～0.432	＜0.001
Administration of antibiotics within 12 hours before labor	6.621	3.126～14.025	＜0.001
Serum SIA	1.158	1.074～1.249	＜0.001

Note: CI: confidence interval; PROM: premature rupture of membranes; SIA: sialic acids.

Table 4. Potential risk factors and biomarkers for various histological inflammatory lesions of the placenta

	N(%)	Gestational age^a(weeks)	Duration of PROM^b (hours)	Serum SIA^a(mg/dL)	Administration of antibiotics before labor	Intrauterine infectious complication
Non-inflammation	87（48.1）	34.69 ± 1.92	0 (0,2）	21.52 ± 3.81	11 (12.6%)	69 (79.3%)
Suspected inflammation	12（6.6）	34.95 ± 1.72	10 (0,25.25)	22.33 ± 2.81	4 (33.3%)	10 (83.3%)
Subchorionitis	4（2.2）	35.36 ± 1.39	12 (1,41）	23.25 ± 1.71	1 (25.0%)	3 (75%)
Chorionitis	59（32.5）	34.56 ± 2.08	0 (0,48)	23.58 ± 4.65	30 (50.8%)	52 (88.1%)
HCA	12（6.6）	33.18 ± 2.47	14.5 (0,59.5)	27.1 ± 7.72	4 (33.3%)	12 (100%)
Funisitis	7（3.9）	31.65 ± 0.68	96 (60,168)	34 ± 5.86	7 (100%)	7 (100%)
Statistical value	-	18.397	27.583	27.34	39.915	6.167
p value	-	0.002	<0.001	<0.001	<0.001	0.29

Note: a. Described as mean±SD; b. Described as median (interquartile). Data were analyzed by Kruskal-Wallis test. PROM: premature rupture of membranes; SIA: sialic acids; HCA: histological chorioamnionitis.

Risk factors and postnatal biomarkers for acute placental inflammatory lesions and intrauterine infections in preterm infants

Abstract

What Is Known

Introduction

Methods

Results

Discussion

Conclusion

Abbreviations

Declarations

References

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