Cord Blood Cytokines As Predictors Of Intrauterine Inflammatory Response And Preterm Morbidity

ObjectiveWe sought to determine whether the changes in cord blood cytokines, such as IL-1β, IL-6, IL-8, IL-10 and TNF-a level, are associated with the pathological findings placental umbilical cord of intra-uterine inflammatory response and the preterm morbidity in the neonatal period. Expect to find predictors of maternal inflammatory response (MIR) and fetal inflammation response (FIR) in uterine and early treatment for those preterm infants after birth.MethodsThe parturient women with gestational age at less than 37 weeks were enrolled in this open and prospective study between January and Decmember,2010.Umbilical cord blood and a small placenta umbilical tissue were obtained at the time of delivery. The cord blood IL1β,IL6,IL8,IL10,TNF-αlevels were measured with ELISA methods. Placentas were examined pathologically for maternal inflammatory response (MIR), defined as subchorionitis, chorioamnionitis, deciduitis, or free membranitis, and fetal inflammatory response (FIR), defined as inflammation extending to the umbilical cord or chorionic plate.Maternal and infant clinical information and placental histopathological features are recorded prospectively for all enrolled births. Those pregnant women with intrapartum fever, premature rupture of membrance (PROM) and fetal distress were all regarded as probable infection group and with placental abruption, hypertension of pregnancy as non-infection group. Infectious pneumonia in utero and neonatal early sepsis were regarded as early infectious diseases. Preterm complications during hospitalized were assessed for intraventricular hemorrhage (IVH) grade 3 or 4, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC) and patent ductus arteriosus (PDA) of prematurity.Data analyses were performed with SPSS 17.0 version software. Chi-square test, One-way ANOVA and Binary Logistic regression analyses were performed. A P-value≤0.05 was chosen to define statistical significance. ResultsComplete clinical and placental data were available for 265 mother-infant pairs enrolled in at the first part of this study. Infant clinical information and placental histopathological features were recorded to study whether maternal inflammatory response and fetal inflammatory response were associated with the poor neonatal outcomes among premature infants in the neonatal period. At the second part of this study, besides Infant clinical information and placental histopathological features were recorded,78 umbilical cord blood IL1β. IL6,IL8,IL10,TNF-αconcentration levels were measured to evaluate whether the cord cytokines could be as a predictors for intra-uterine inflammation response and preterm morbidity.Associations between placental histopathological features and postnatal morbidity22 of total 171 (12.9%) pregnant women with intra-uterine inflammation response showed the symptom of infection during pregnancy before the birth. the association was significant stronger with either MIR or FIR than no inflammation response, X2 was 6.827 and 41.427, P value was 0.009 and 0.000, respectively. The incidence of symptom increased to 66.7% (8/12 cases) in pregnant women with FIR. But there were not significant difference between the pregnant women in the non-infection symptom group and with MIR or FIR, X2 was 0.256 and 0.093, P value was 0.613 and 0.761, respectively.The incidence of intrauterine infectious pneumonia after birth was statistically significant higher in both of MIR or FIR, X2 was 5.476 and 13.745, P value was 0.019 and 0.000, respectively. The incidence of early neonatal sepsis was similarly significant higher in these premature infants born of pregnant women with FIR before birth, X2=7.773, P=0.005; but it was not statistically different in these preterm whose mother with MIR before birth, X2=0.525, P=0.469.The incidence of early infectious diseases of preterm postnatal was statistically significant increase in these pregnant women with intrauterine inflammation response, X2=7.305,P=0.007. Most pregnant women with FIR had complicated with MIR when the intrauterine inflammation response happened (except one case). Only 51 in 171 (29.8%) preterm infants their mothers with intrauterine inflammation response happened early infectious disease postnatal. Still had another 70.2%(120 in 171 cases) premature birth with intrauterine inflammation response not showed any clinical symptom of infection after birth. It was no significant difference between intrauterine inflammation response and early non-infectious diseases, such as aspiration pneumonia,X2=0.620, P=0.431; Hyaline member disease of premature infant, X2=1.287, P=0.257. But the incidence of asphyxia of newborn was statistically significant increase in these with intrauterine inflammation response, X2=7.812, P=0.005.The morbidity of complications (≥IVH grade 3, ROP, BPD, NEC, PDA) during premature infants hospitalized were significant increased when the MIR or FIR happened, X2=3.984, P=0.046.Associations between cord blood cytokines and intrauterine inflammation response, postnatal morbidityThe concentration level of umbilicus cord blood IL-1β,IL-6,IL-8 were significantly increase in these with any stage MIR, F was 11.961,8.495,9.017, P was 0.001,0.002,0.002, respectively. But the level of IL-10 or TNF-a was not statistically significant deference, F was 1.548,0.408, P was 0.221,0.748, respectively. And the concentration of cord blood IL-1β,IL-6,IL-8,IL-10, TNF-a were not statistically significant difference in these with any type FIR, F was 1.215,1.639,1.589,0.401, 0.366, P was 0.387,0.302,0.345,0.671,0.695, respectively.According to the instruction of Cytokine Measurement Kit, the cutoff value of IL-1β, IL-6, IL-8, IL-10 and TNF-a were defined as 3.9 pg/ml,12.5 pg/ml,31.2 pg/ml, 7.8 pg/ml and 45 pg/ml.Associations between cord blood IL-8>31.2pg/ml and MIR was significant deference, X2=4.212, P=0.040. The incidence of MIR was significantly increase when the level of cord IL-8>31.2 pg/ml. The susceptibility was 47.2%, the specificity 80.0%, positive predictive value (PPV) 83.3% and negative predictive value (NPV) 41.7%. But there were not significantly deference for MIR when IL-1β>3.9 pg/ml, IL-6>12.5 pg/ml, IL-10>7.8 pg/ml, TNF-a>45 pg/ml, X2 was 1.472,1.442,0.146, 0.107, P was 0.225,0.230,0.703,0.743, respectively.Further using Binary Logistic Regression analysis showed:IL-8>31.2 pg/ml was the most significant cord blood cytokine for predicating whether the pregnant woman happened with MIR in utero. The prediction accuracy could be 67.9%.It was significantly valuable cytokine for predicating MIR of≥stage 2 when the cord blood IL-6>12.5 pg/ml or IL-8>31.2 pg/ml. but it was more valuable for predicating MIR≥stage 2 when IL-6>12.5 pg/ml than IL-8>31.2 pg/ml, the prediction accuracy was 70.5%.All of them could be as a predictive cytokines for predicating MIR stage 3 when IL-1β>3.9 pg/ml, IL-6>12.5 pg/ml, TNF-a>45 pg/ml excepting IL-10>7.8 pg/ml. Among them, IL-6> 12.5 pg/ml or TNF-α> 45 pg/ml was the most significant cord blood cytokines for predicating MIR grade 3.In other side, the cord blood IL-6>12.5 pg/ml or IL-8>31.2 pg/ml was significantly associated with FIR. When the concentration of IL-6>12.5 pg/ml, it was statistically significant difference for FIR,X2=5.078, P=0.024; The susceptibility was 100.0%, the specificity 70.8%, positive predictive value (PPV) 19.2% and negative predictive value (NPV) 98.1%. When IL-8>31.2 pg/ml, it was also statistically significant difference for FIR,X2=7.774, P=0.005; The susceptibility was 100.0%, the specificity 66.7%, positive predictive value (PPV) 20.0% and negative predictive value (NPV) 100.0%. The cord blood IL-1β>12.5 pg/ml,IL-10>7.8 pg/ml or TNF-a >45 pg/ml was not statistically significant difference for FIR, X2 was 1.625,2.385, 3.644, P value was 0.202,0.122,0.056, respectively.Further analysis with Binary Logistic Regression for association of umbilicus cord blood with FIR,92.3% pregnant women occurred fetal inflammation response (FIR) when cord blood IL-1(3>3.9 pg/ml, IL-6>12.5 pg/ml, and IL-8>31.2 pg/ml. Among them, the concentration of IL-8>31.2 pg/ml or IL-6>12.5 pg/ml was the most valuable for predicating FIR, especially the NPV was 100.0% for cord blood IL-8 level.To evaluate whether cord blood cytokines was associated with the complications of premature infants postnatal. The incidence of early infectious diseases after birth was significantly increase as the concentration of IL-8>31.2 pg/ml or IL-6>12.5 pg/ml. When IL-6>12.5 pg/ml, X2=10.556, P=0.001, the prediction accuracy could be 73.1%. When IL-8>31.2 pg/ml, X2= 13.195, P=0.000, and the prediction accuracy could be 73.1%. There was not statistically significant difference between the incidence of the early infectious diseases and the concentration of cord blood IL-1β>3.9 pg/ml, IL-10>7.8 pg/ml, TNF-a>45 pg/ml; X2 was 0.065,0.088,2.338, P value was 0.799,0.767,0.126, respectively. We further analyzed the incidence of the early infectious diseases according to the concentration of cord blood cytokines using Binary Logistic Regression. It showed that the IL-6 and IL-8 level were significant associated with the incidence of the early infectious diseases (P value was 0.001, 0.000, respectively). Further entering with Forward LR methods, the IL-6>12.5 pg/ml was not statistically significant difference after the variable of IL-8 was not in the equation. Therefore, the IL-8 level was the most valuable cytokine for predicting the early infectious diseases of premature infants postnatal.Increasing of the cord blood IL-1β, IL-6, IL-8, IL-10 or TNF-a concentration was not significantly associated the morbidity of complications (≥IVH grade 3, ROP, BPD, NEC, PDA) during premature infants hospitalized, X2 was 0.269,0.134,1.513, 0.000,1.236, P value was 0.604,0.714,0.219,0.989,0.266, respectively.ConclusionsAmong all of the premature infants and pregnant women in this group we reviewed, there were 64.5%(171/265 cases) pregnant women occurred with intrauterine inflammation response before birth. Only did 65 among 265 (24.6%) preterm infants occurred with early infectious diseases postnatal. And there were 51 (29.8%) premature infants born of among 171 pregnant women with intrauterine inflammation response having early infectious diseases.Pregnant women with intrauterine inflammation response prenatal had 12.9% (22/171 cases) showed the symptoms of infection during pregnancy before the birth. When the pregnant women happened with FIR, the incidence rate of infectious symptoms during pregnancy rose to 66.7%(8/12 cases).Most pregnant women with FIR had complicated with MIR when the intrauterine inflammation response happened (except one case). Only 51 among 171 (29.8%) preterm infants born of their mothers with intrauterine inflammation response happened early infectious diseases postnatal. Still had another 70.2%(120 in 171 cases) premature newborn not showed the early infectious symptoms. These premature infants may need early antibiotic treatment to avoid infection worsen and illness delayed.The incidence of asphyxia of newborn during delivery was remarkable increased in these with intrauterine inflammation response before birth. And the morbidity of complications (>IVH grade 3, ROP, BPD, NEC, PDA) during premature infants hospitalized were also significant increased when the MIR or FIR happened.The concentration of cord blood IL-1β, IL-6, IL-8 was significantly associated with the intrauterine inflammation response prenatal. The overall change trend of cord blood cytokines concentration was rose as the MIR aggravated. But this rising trend was not significantly difference when the FIR occurred, the concentration of cord cytokines was increased with the different type FIR.IL-8>31.2 pg/ml was the most significant cord blood cytokine for predicating whether the pregnant woman happened with MIR prenatal. Although both of the cord blood IL-6>12.5 pg/ml and IL-8>31.2 pg/ml were significantly valuable cytokines for predicating MIR of≥stage 2, but IL-6>12.5 pg/ml was more valuable than IL-8 >31.2 pg/ml. The concentration of IL-6>12.5 pg/ml or TNF-α> 45 pg/ml was the most significant cord blood cytokines for predicating MIR stage 3.The concentration of IL-8>31.2 pg/ml or IL-6>12.5 pg/ml was the most valuable for predicating FIR; especially the NPV was 100.0% for cord blood IL-8 level. It showed that the FIR could be eliminated as the IL-8≤31.2 pg/ml.The IL-6>12.5 pg/ml and IL-8>31.2 pg/ml were significant associated with the incidence of the early infectious diseases. They were the valuable predicators for the early infectious diseases especially as the concentration of IL-8 was higher than the 31.2 pg/ml.