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.