Abstract：
Brain injury and poor neurodevelopment have been consistently reported in infants and adults born before term. These changes occur, at least in part, prenatally and are associated with intra-amniotic inflammation. The pattern of brain changes has been partially documented by magnetic resonance imaging but not by neurosonography along with amniotic fluid brain injury biomarkers.
This study aimed to evaluate the prenatal features of brain remodeling and injury in fetuses from patients with preterm labor with intact membranes or preterm premature rupture of membranes and to investigate the potential influence of intra-amniotic inflammation as a risk mediator.
In this prospective cohort study, fetal brain remodeling and injury were evaluated using neurosonography and amniocentesis in singleton pregnant patients with preterm labor with intact membranes or preterm premature rupture of membranes between 24.0 and 34.0 weeks of gestation, with (n=41) and without (n=54) intra-amniotic inflammation. The controls for neurosonography were outpatient pregnant patients without preterm labor or preterm premature rupture of membranes matched 2:1 by gestational age at ultrasound. Amniotic fluid controls were patients with an amniocentesis performed for indications other than preterm labor or preterm premature rupture of membranes without brain or genetic defects whose amniotic fluid was collected in our biobank for research purposes matched by gestational age at amniocentesis. The group with intra-amniotic inflammation included those with intra-amniotic infection (microbial invasion of the amniotic cavity and intra-amniotic inflammation) and those with sterile inflammation. Microbial invasion of the amniotic cavity was defined as a positive amniotic fluid culture and/or positive 16S ribosomal RNA gene. Inflammation was defined by amniotic fluid interleukin 6 concentrations of >13.4 ng/mL in preterm labor and >1.43 ng/mL in preterm premature rupture of membranes. Neurosonography included the evaluation of brain structure biometric parameters and cortical development. Neuron-specific enolase, protein S100B, and glial fibrillary acidic protein were selected as amniotic fluid brain injury biomarkers. Data were adjusted for cephalic biometrics, fetal growth percentile, fetal sex, noncephalic presentation, and preterm premature rupture of membranes at admission.
Fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes showed signs of brain remodeling and injury. First, they had a smaller cerebellum. Thus, in the intra-amniotic inflammation, non-intra-amniotic inflammation, and control groups, the transcerebellar diameter measurements were 32.7 mm (interquartile range, 29.8-37.6), 35.3 mm (interquartile range, 31.2-39.6), and 35.0 mm (interquartile range, 31.3-38.3), respectively (P=.019), and the vermian height measurements were 16.9 mm (interquartile range, 15.5-19.6), 17.2 mm (interquartile range, 16.0-18.9), and 17.1 mm (interquartile range, 15.7-19.0), respectively (P=.041). Second, they presented a lower corpus callosum area (0.72 mm2 [interquartile range, 0.59-0.81], 0.71 mm2 [interquartile range, 0.63-0.82], and 0.78 mm2 [interquartile range, 0.71-0.91], respectively; P=.006). Third, they showed delayed cortical maturation (the Sylvian fissure depth-to-biparietal diameter ratios were 0.14 [interquartile range, 0.12-0.16], 0.14 [interquartile range, 0.13-0.16], and 0.16 [interquartile range, 0.15-0.17], respectively [P<.001], and the right parieto-occipital sulci depth ratios were 0.09 [interquartile range, 0.07-0.12], 0.11 [interquartile range, 0.09-0.14], and 0.11 [interquartile range, 0.09-0.14], respectively [P=.012]). Finally, regarding amniotic fluid brain injury biomarkers, fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes had higher concentrations of neuron-specific enolase (11,804.6 pg/mL [interquartile range, 6213.4-21,098.8], 8397.7 pg/mL [interquartile range, 3682.1-17,398.3], and 2393.7 pg/mL [interquartile range, 1717.1-3209.3], respectively; P<.001), protein S100B (2030.6 pg/mL [interquartile range, 993.0-4883.5], 1070.3 pg/mL [interquartile range, 365.1-1463.2], and 74.8 pg/mL [interquartile range, 44.7-93.7], respectively; P<.001), and glial fibrillary acidic protein (1.01 ng/mL [interquartile range, 0.54-3.88], 0.965 ng/mL [interquartile range, 0.59-2.07], and 0.24 mg/mL [interquartile range, 0.20-0.28], respectively; P=.002).
Fetuses with preterm labor with intact membranes or preterm premature rupture of membranes had prenatal signs of brain remodeling and injury at the time of clinical presentation. These changes were more pronounced in fetuses with intra-amniotic inflammation.
This study aimed to evaluate the prenatal features of brain remodeling and injury in fetuses from patients with preterm labor with intact membranes or preterm premature rupture of membranes and to investigate the potential influence of intra-amniotic inflammation as a risk mediator.
In this prospective cohort study, fetal brain remodeling and injury were evaluated using neurosonography and amniocentesis in singleton pregnant patients with preterm labor with intact membranes or preterm premature rupture of membranes between 24.0 and 34.0 weeks of gestation, with (n=41) and without (n=54) intra-amniotic inflammation. The controls for neurosonography were outpatient pregnant patients without preterm labor or preterm premature rupture of membranes matched 2:1 by gestational age at ultrasound. Amniotic fluid controls were patients with an amniocentesis performed for indications other than preterm labor or preterm premature rupture of membranes without brain or genetic defects whose amniotic fluid was collected in our biobank for research purposes matched by gestational age at amniocentesis. The group with intra-amniotic inflammation included those with intra-amniotic infection (microbial invasion of the amniotic cavity and intra-amniotic inflammation) and those with sterile inflammation. Microbial invasion of the amniotic cavity was defined as a positive amniotic fluid culture and/or positive 16S ribosomal RNA gene. Inflammation was defined by amniotic fluid interleukin 6 concentrations of >13.4 ng/mL in preterm labor and >1.43 ng/mL in preterm premature rupture of membranes. Neurosonography included the evaluation of brain structure biometric parameters and cortical development. Neuron-specific enolase, protein S100B, and glial fibrillary acidic protein were selected as amniotic fluid brain injury biomarkers. Data were adjusted for cephalic biometrics, fetal growth percentile, fetal sex, noncephalic presentation, and preterm premature rupture of membranes at admission.
Fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes showed signs of brain remodeling and injury. First, they had a smaller cerebellum. Thus, in the intra-amniotic inflammation, non-intra-amniotic inflammation, and control groups, the transcerebellar diameter measurements were 32.7 mm (interquartile range, 29.8-37.6), 35.3 mm (interquartile range, 31.2-39.6), and 35.0 mm (interquartile range, 31.3-38.3), respectively (P=.019), and the vermian height measurements were 16.9 mm (interquartile range, 15.5-19.6), 17.2 mm (interquartile range, 16.0-18.9), and 17.1 mm (interquartile range, 15.7-19.0), respectively (P=.041). Second, they presented a lower corpus callosum area (0.72 mm2 [interquartile range, 0.59-0.81], 0.71 mm2 [interquartile range, 0.63-0.82], and 0.78 mm2 [interquartile range, 0.71-0.91], respectively; P=.006). Third, they showed delayed cortical maturation (the Sylvian fissure depth-to-biparietal diameter ratios were 0.14 [interquartile range, 0.12-0.16], 0.14 [interquartile range, 0.13-0.16], and 0.16 [interquartile range, 0.15-0.17], respectively [P<.001], and the right parieto-occipital sulci depth ratios were 0.09 [interquartile range, 0.07-0.12], 0.11 [interquartile range, 0.09-0.14], and 0.11 [interquartile range, 0.09-0.14], respectively [P=.012]). Finally, regarding amniotic fluid brain injury biomarkers, fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes had higher concentrations of neuron-specific enolase (11,804.6 pg/mL [interquartile range, 6213.4-21,098.8], 8397.7 pg/mL [interquartile range, 3682.1-17,398.3], and 2393.7 pg/mL [interquartile range, 1717.1-3209.3], respectively; P<.001), protein S100B (2030.6 pg/mL [interquartile range, 993.0-4883.5], 1070.3 pg/mL [interquartile range, 365.1-1463.2], and 74.8 pg/mL [interquartile range, 44.7-93.7], respectively; P<.001), and glial fibrillary acidic protein (1.01 ng/mL [interquartile range, 0.54-3.88], 0.965 ng/mL [interquartile range, 0.59-2.07], and 0.24 mg/mL [interquartile range, 0.20-0.28], respectively; P=.002).
Fetuses with preterm labor with intact membranes or preterm premature rupture of membranes had prenatal signs of brain remodeling and injury at the time of clinical presentation. These changes were more pronounced in fetuses with intra-amniotic inflammation.
摘要：
背景：在早产的婴儿和成人中一直有脑损伤和神经发育不良的报道。这些变化至少部分发生在产前，并与羊膜腔内炎症有关。磁共振成像已部分记录了大脑变化的模式，但未将神经超声与羊水脑损伤生物标志物结合使用。
目的：评估胎膜完整早产或胎膜早破早产患者胎儿脑重塑和损伤的产前特征，并探讨羊膜腔内炎症作为风险介质的潜在影响。
方法：在这项前瞻性队列研究中，通过神经超声和羊膜穿刺术对24.0-34.0周早产胎膜完整或早产胎膜破裂的单胎妊娠患者进行胎儿脑重塑和损伤评估，有（n=41）和没有（n=54）羊膜腔内炎症。神经超声检查的对照是没有早产或胎膜早产破裂的门诊妊娠患者，在超声检查时胎龄为2：1。羊水对照组是指除早产或早产胎膜破裂而没有脑或遗传缺陷以外的羊水穿刺术患者，其羊水收集在我们的生物库中，用于研究目的，与羊水穿刺术的胎龄相匹配。羊膜腔内炎症组包括羊膜腔内感染（微生物侵入羊膜腔和羊膜腔内炎症）和无菌炎症。羊膜腔的微生物侵袭定义为羊水培养阳性和/或16S核糖体RNA基因阳性。炎症定义为羊水白细胞介素-6>13.4ng/ml早产和>1.43ng/ml早产胎膜破裂。神经超声检查包括评估大脑结构生物特征参数和皮质发育。作为羊水脑损伤的生物标志物，我们选择了神经元特异性烯醇化酶，蛋白S100B和胶质纤维酸性蛋白。数据根据头部生物特征进行了调整，胎儿生长百分位数,胎儿性别,入院时非头颅表现和早产胎膜破裂。
结果：母亲早产胎膜完整或早产胎膜破裂的胎儿有脑重塑和损伤的迹象。首先,他们的小脑较小。因此，在羊膜内炎症中，非羊膜腔内炎症和对照组，小脑直径（中位数（第25百分位数；第75百分位数））为32.7mm（29.8;37.6），35.3mm(31.2;39.6)和35.0mm(31.3;38.3),分别为（p=0.019）；Vermian高度为16.9mm（15.5；19.6），17.2毫米(16.0;18.9)和17.1毫米(15.7;19.0)，分别(p=0.041)。第二,他们呈现出较低的call体面积（0.72mm2（0.59；0。81),0.71mm2(0.63；0.82)和0.78mm2(0.71；0。91),分别(p=0.006)。第三，他们显示了一个延迟的皮质成熟(Sylvian裂隙深度/双顶直径比为0.14(0.12;0.16),0.14(0.13;0.16)和0.16(0.15;0.17)，分别(p<0.001)，右侧顶枕骨沟深度比为0.09（0.07；0.12），0.11(0.09;0.14)和0.11(0.09;0.14)，分别(p=0.012))。最后,关于羊水脑损伤生物标志物，胎膜完整的早产或早产胎膜破裂的母亲的胎儿，有较高浓度的神经元特异性烯醇化酶（11804.6pg/ml（6213.4;21098.8），8397.7pg/ml（3682.1;17398.3）和2393.7pg/ml（1717.1;3209.3），分别（p<0.001））；蛋白质S100B（2030.6pg/ml（993；4883.5），1070.3pg/ml（365.1-1463.2）和74.8pg/ml（44.7;93.7），分别为（p<0.001）），和胶质纤维酸性蛋白（1.01ng/ml（0.54;3.88），0.965ng/ml（0.59;2.07）和0.24mg/ml（0.20;0.28），分别（p=0.002））。
结论：早产胎膜完整或早产胎膜破裂的胎儿在临床表现时具有脑重塑和损伤的产前体征。这些变化在羊膜腔内炎症患者中更为明显。
目的：评估胎膜完整早产或胎膜早破早产患者胎儿脑重塑和损伤的产前特征，并探讨羊膜腔内炎症作为风险介质的潜在影响。
方法：在这项前瞻性队列研究中，通过神经超声和羊膜穿刺术对24.0-34.0周早产胎膜完整或早产胎膜破裂的单胎妊娠患者进行胎儿脑重塑和损伤评估，有（n=41）和没有（n=54）羊膜腔内炎症。神经超声检查的对照是没有早产或胎膜早产破裂的门诊妊娠患者，在超声检查时胎龄为2：1。羊水对照组是指除早产或早产胎膜破裂而没有脑或遗传缺陷以外的羊水穿刺术患者，其羊水收集在我们的生物库中，用于研究目的，与羊水穿刺术的胎龄相匹配。羊膜腔内炎症组包括羊膜腔内感染（微生物侵入羊膜腔和羊膜腔内炎症）和无菌炎症。羊膜腔的微生物侵袭定义为羊水培养阳性和/或16S核糖体RNA基因阳性。炎症定义为羊水白细胞介素-6>13.4ng/ml早产和>1.43ng/ml早产胎膜破裂。神经超声检查包括评估大脑结构生物特征参数和皮质发育。作为羊水脑损伤的生物标志物，我们选择了神经元特异性烯醇化酶，蛋白S100B和胶质纤维酸性蛋白。数据根据头部生物特征进行了调整，胎儿生长百分位数,胎儿性别,入院时非头颅表现和早产胎膜破裂。
结果：母亲早产胎膜完整或早产胎膜破裂的胎儿有脑重塑和损伤的迹象。首先,他们的小脑较小。因此，在羊膜内炎症中，非羊膜腔内炎症和对照组，小脑直径（中位数（第25百分位数；第75百分位数））为32.7mm（29.8;37.6），35.3mm(31.2;39.6)和35.0mm(31.3;38.3),分别为（p=0.019）；Vermian高度为16.9mm（15.5；19.6），17.2毫米(16.0;18.9)和17.1毫米(15.7;19.0)，分别(p=0.041)。第二,他们呈现出较低的call体面积（0.72mm2（0.59；0。81),0.71mm2(0.63；0.82)和0.78mm2(0.71；0。91),分别(p=0.006)。第三，他们显示了一个延迟的皮质成熟(Sylvian裂隙深度/双顶直径比为0.14(0.12;0.16),0.14(0.13;0.16)和0.16(0.15;0.17)，分别(p<0.001)，右侧顶枕骨沟深度比为0.09（0.07；0.12），0.11(0.09;0.14)和0.11(0.09;0.14)，分别(p=0.012))。最后,关于羊水脑损伤生物标志物，胎膜完整的早产或早产胎膜破裂的母亲的胎儿，有较高浓度的神经元特异性烯醇化酶（11804.6pg/ml（6213.4;21098.8），8397.7pg/ml（3682.1;17398.3）和2393.7pg/ml（1717.1;3209.3），分别（p<0.001））；蛋白质S100B（2030.6pg/ml（993；4883.5），1070.3pg/ml（365.1-1463.2）和74.8pg/ml（44.7;93.7），分别为（p<0.001）），和胶质纤维酸性蛋白（1.01ng/ml（0.54;3.88），0.965ng/ml（0.59;2.07）和0.24mg/ml（0.20;0.28），分别（p=0.002））。
结论：早产胎膜完整或早产胎膜破裂的胎儿在临床表现时具有脑重塑和损伤的产前体征。这些变化在羊膜腔内炎症患者中更为明显。
