【作者】 周军；

【导师】 王谢桐；

【作者基本信息】 山东大学 ， 妇产科学（专业学位）， 2015， 博士

【摘要】 背景：胎盘植入,定义为由于部分或全部蜕膜基底层缺失,部分乃至整个胎盘绒毛组织异常种植于子宫壁层的病理状态。胎盘绒毛组织可能不仅仅是侵入到子宫肌层,而且可以穿透子宫壁侵入到子宫浆膜层外乃至膀胱组织,使得胎盘无法与子宫剥离。最近50年中,胎盘植入的发病率上升了10倍,这被认为是近年来剖宫产率上升的后果。胎盘植入的发病机理目前尚不明确,但目前普遍认为手术后的疤痕形成过程导致的子宫蜕膜异常血管生成以及继发出现的局部的低氧状态是主要因素。这种低氧状态会导致病理性的蜕膜形成以及诱发滋养细胞的异常侵袭,从而可能导致胎盘植入的发生。胎盘植入的产前诊断对于产科临床医师尤为重要。超声以及核磁共振检查是诊断胎盘植入基本的方法,然而,这两种方法均有各自的局限性。近些年来,研究人员试图寻找母体血液中某些生物以及生化标志物,期望可以用于帮助提高胎盘植入产前诊断的准确性。母体血浆中的游离胎盘mRNA可以稳定存在并定量检测,所以已成为潜在的标记物。已有研究证实,母体血浆中游离人类胎盘泌乳素mRNA水平与胎盘植入相关。游离胎盘β人绒毛膜促性腺激素mRNA亦已用于评估胎盘滞留患者保守治疗疗效。目前尚未有研究表明游离胎盘β人绒毛膜促性腺激素mRNA能否作为产前诊断胎盘植入的分子学标志物。第一章 晚期妊娠前置胎盘合并胎盘植入20例临床分析目的：对胎盘植入患者的临床资料进行分析,结合国内外相关研究,探讨胎盘植入的临床危险因素、早期诊断、手术治疗方法及母婴的预后。方法：选取2011年2月至2013年12月在青岛大学附属医院产科住院分娩晚孕期单胎患者作为研究对象。选择前置胎盘合并胎盘植入患者,作为研究组。另外选择同期诊断前置胎盘但不合并胎盘植入的患者作为对照组。对两组患者的临床特点、临床表现、母婴结局和终止妊娠的治疗方案进行分析。结果：20例前置胎盘合并胎盘植入患者有7例术中行剖宫产术+子宫切除术,而对照组患者均未行子宫切除。对照组中31例患者术中出血量(x±s)为710±392ml,研究组中20例患者术中出血量(x±s)为2540±1633ml,两组间出血量比较有显著性差异(P<0.001,Mann-Whitney U检验)。研究组以及对照组患者新生儿血红蛋白水平(x±s)分别为148.0±17.6g/L以及143.0±23.6g/L,无统计学差异(P=0.645, Mann-Whitney U检验)。研究组患者1分钟Apgar评分(x±s)为9.1±1.4与对照组(8.8±1.7)比较无统计学差异(P=0.776,Mann-Whitney U检验)。在研究组(前置胎盘合并胎盘植入)中,7例粘连性胎盘、8例植入性胎盘、5例穿透性胎盘患者术中出血量(x±s)分别为757±271ml, 3688±1308ml,3437±943ml。三组间出血量有显著差异(P<0.001,Kruskal-Wallis检验)。其中,两两比较植入性胎盘患者以及穿透性胎盘患者的出血量均明显多于粘连性胎盘患者(P=0.002以及P=0.019, Steel-Dwass检验),但植入性胎盘患者以及穿透性胎盘患者之间比较出血量无统计学差异(P=1.000, Steel-Dwass检验)。研究组中5例术中子宫切口避开胎盘患者与15例胎盘打洞娩出胎儿患者术中出血量(x±s)分别为1050±587ml以及3037±1570ml,比较有统计学差异(P=0.023, Mann-Whitney U检验)。研究组中7例患者行子宫切除术,术中出血量(x±s)为2829±1362ml,与13例子宫保留患者出血量(x±s)(2385±1794ml)比较无统计学差异(P=0.360, Mann-Whitney U检验)。结论：(1)有前次剖宫产史,再次妊娠合并前置胎盘并且胎盘组织覆盖子宫瘢痕处的患者是极其危险的。(2)核磁共振检查可作为产前诊断胎盘植入有效的补充检查手段。(3)胎盘植入患者的终止妊娠手术时机及手术方式应根据患者情况和要求做到个体化。(4)前置胎盘是否合并胎盘植入以及胎盘不同植入程度可能与新生儿结局不相关。第二章母体血浆游离胎盘mRNA用于胎盘植入患者的产前诊断目的：判定母体血浆标本中游离β-HCG mRNA以及hPL mRNA水平能否作为分子标志物协助产前诊断胎盘植入。方法：实时定量多聚酶链反应检测胎盘植入患者血浆标本中游离β-HCG mRNA以及hPL mRNA水平。对比同期收治的既往有剖宫产史前置胎盘患者以及既往有剖宫产史的无胎盘植入以及无前置胎盘患者母体血浆中两种标志物水平,判定母体血浆标本中游离β-HCG mRNA以及hPL mRNA水平能否作为分子标志物协助产前诊断胎盘植入。结果：前置胎盘合并胎盘植入组患者血浆游离β-HCG mRNA水平(3.65,2.78-7.19)(MoM值,中位数+范围)显著高于对照组(1.00,0.00-2.69)以及前置胎盘组(0.94,0.00.2.97)(Steel-Dwass检测,P<0.001 and P<0.001).在前置胎盘合并胎盘植入组中,7例术中行剖宫产术+子宫切除术的患者血浆中游离β-HCG mRNA水平(4.41,3.49-7.19)显著高于其余5例保留子宫的患者(3.20,2.78-3.70)(Mann-Whitney U检验,P=0.012)。前置胎盘合并胎盘植入组患者血浆游离HPL mRNA水平(MoM值,中位数+范围)(2.78,1.09-4.56)显著高于对照组(1.00,0.29-2.98)以及前置胎盘组(1.12,0.33.3.25)(Steel-Dwass检验,P<0.001 and P=0.005).血浆游离β-HCG mRNA以及hPL mRNA水平在对照组和前置胎盘组间比较均无无显著差异(Steel-Dwass检验,P=0.863 and P=0.709)。结论：(1)前置胎盘合并胎盘植入患者血浆游离胎盘hPL mRNA以及β-HCG mRNA水平均明显增加。(2)比较未行子宫切除的胎盘植入患者,在剖宫产术中行子宫切除的胎盘植入患者β-HCG mRNA水平更高。(3)比较游离胎盘hPL mRNA,β-HCG mRNA更加适合作为预测胎盘植入的生物学标志物。更多还原

【Abstract】 Background:placenta accreta is defined as the direct attachment of chorionic villi to the uterine wall with a partial or complete absence of decidua basalis. In placenta accreta, the chorionic villi may attach to, invade, or penetrate the myometrium, making the placenta and uterus can not be stripped. The last 50 years, the incidence of placenta accreta is increased by 10 times, which is considered the consequences of rising cesarean section rate in recent years. Pathogenesis of placenta accreta is unclear, but is now generally considered abnormal angiogenesis decidua and local hypoxia secondary to occur due to scar formation after surgery is a major factor. This hypoxia can lead to pathological decidua formation and abnormalities induced invasion of trophoblast cells, which may lead to the occurrence of placenta accreta. Prenatal diagnosis of placenta accreta is particularly important for obstetric clinicians. Ultrasonography and magnetic resonance imaging (MRI) are the primary methods for diagnosis of placenta accreta. However, neither method is sufficient to predict placenta accreta reliably in clinical practice. For several years, investigators have attempted to identify biochemical and/or biological markers that could be used to improve the accuracy of antenatal diagnosis of placenta accreta. Circulating cell-free placenta mRNAs have emerged as potential markers because they can be stably isolated and quantified from maternal plasma. Studies have demonstrated that the maternal plasma levels of cell-free human placental lactogen mRNA associated with placenta accreta. Cell-free mRNA encoding the β subunit of human chorionic gonadotropin (β-HCG) primarily is produced by proliferating cytotrophoblasts and has been used to evaluate the efficacy of conservative treatment for retained adherent placenta. Until now, there is no any reports about the association between cell-free β-HCG mRNA and antenatal diagnosis of placenta accreta.The first chapterClinical Analysis of 20 placenta previa with accreta in late pregnancy. Objective:To investigate the clinical characteristics, outcomes of maternal and neonatal treatments of patients with placenta previa and placenta accreta in late pregnancy.Methods:this study recruited singleton pregnant women with a history of one or more CDs between February 2011 and December 2013. Of 51 women included in this study,31 women had placenta previa alone (placenta previa group), and 20 women had both placenta previa and placenta accreta (placenta previa/accreta group). Thereafter, clinical characteristics, outcomes of maternal and neonatal treatments of patients in the two groups were investigated retrospectively.Results:seven cases in the 20 patients with both placenta previa and placenta accreta ultimately underwent cesarean hysterectomies because of uncontrolled bleeding, while there was no hysterectomy in the control group. The blood loss of 31 patients in the control group was 710± 392ml (x±s), the blood loss of 20 patients in the study group was 2540 ±1633ml(x±s), there was a significant difference between the two groups (P<0.001, Mann-Whitney U test) amount. The neonatal hemoglobin levels (x±s) in study group and the control group respectively were 148.0±17.6g/L and 143.0±23.6g/L, there is no significant statistically difference (P-0.645, Mann-Whitney U test). There was no significant statistically difference (P= 0.776, Mann-Whitney U test) between the study group(9.1±1.4) and control group (8.8±1.7) with one minute Apgar score (x±s). In the study group (placenta previa/accreta group), the blood loss (x±s) of seven cases with adhesive placenta, eight cases with accreta placenta, five cases with penetrating were 757±271ml,3688±1308ml,3437±943ml respectively. There was significant statistically difference among the three groups (P <0.001, Kruskal-Wallis test). Among them, the pairwise comparison of blood loss in accreta placenta patient and penetrating placenta patient were significantly more than that of adhesive placenta patients (P= 0.002 and P-0.019, Steel-Dwass test), but the pairwise comparison of blood loss between accreta placenta patient and penetrating placenta patient showed no significant statistically difference (P= 1.000, Steel-Dwass test). In study group,5 cases’by avoiding placenta and 15 cases’fetus were delivered throughout placenta, the blood loss (x±s) of this two group were 1050±587ml and 3037+1570ml respectively, there were significant statistically differences between the two groups (P= 0.023 Mann-Whitney U test). The blood loss (x±s) was not significant difference between the 7 women who underwent hysterectomies (2829+ 1362ml) and women whose deliveries did not result in hysterectomy (2385 ±1794ml) in the placenta previa/accreta group(P-0.360 Mann-Whitney U test.Conclusions:(1) Women at greatest risk of placenta accreta are those who have myometrial damage caused by an earlier cesarean delivery with either an anterior or posterior placenta previa overlying the uterine scar. (2) MRI can be used as an effective supplementary examination means for prenatal diagnosis of placenta accreta. (3) Surgical management of patients with placenta accreta should be individualized according to the patient’s condition and requirements. (4) Different placenta implanted degrees and whether placenta previa accompany with placenta accreta may not be associated with neonatal outcomes.The second chapterMaternal plasma levels of cell-free placenta mRNA as a prenatal diagnostic indicator of placenta accretaObjective:several biomarkers, including maternal serum creatinine kinase and a-fetoprotein have been described as potential tools for the diagnosis of placental abnormalities. This study aimed to determine whether maternal plasma mRNA levels of the P subunit of human chorionic gonadotropin (β-HCG) and hPL mRNA could predict placenta accreta prenatally.Methods:sixty-eight singleton pregnant women with prior cesarean deliveries (CDs) were classified into three groups:normal placentation (35 women, control group); placenta previa alone (21 women, placenta previa group); and both placenta previa and placenta accreta (12 women, placenta previa/accreta group). Maternal plasma concentrations of cell-free β-HCG mRNA and hPL mRNA were measured by real-time reverse-transcription polymerase chain reaction and were expressed as multiples of the median (MoM).Results:cell-free β-HCG mRNA concentrations (MoM, range) were significantly higher in women with placenta accreta (3.65,2.78-7.19) than in women with placenta previa (0.94,0.00-2.97) or normal placentation (1.00,0.00-2.69) (Steel-Dwass test, P< 0.01 and P< 0.01, respectively). In the placenta previa/accreta group, the concentration of cell-free β-HCG mRNA was significantly higher among women who underwent CDs with hysterectomy (4.41,3.49-7.19) than among women whose CDs did not result in hysterectomy (3.20,2.78-3.70) (Mann-Whitney U test, P= 0.012). The MoM value of cell-free hPL mRNA concentrations (median and range) were significantly higher in the placenta accreta group (2.78, 1.09-4.56) than in the control group (1.00,0.29-2.98) or the placenta previa group (1.12,0.33-3.25) (Steel-Dwass test, P< 0.001 and P= 0.005, respectively). The MoM value of cell-free hPL mRNA concentrations (median and range) from maternal plasma samples was not significant difference between the women who underwent hysterectomies (2.96,1.38-4.56) and women whose deliveries did not result in hysterectomy (2.36,1.09-3.25) in the placenta accreta group (Mann-Whitney U test, P= 0.372).Conclusions:(1) The cell-free hPL mRNA and β-HCG mRNA levels were significantly increased in women with placenta accreta. (2) Women who underwent cesarean hysterectomy had markedly higher β HCG mRNA levels compared with patients did not undergo hysterectomy in patients with placenta previa and placenta accreta. (3) Compared with cell-free placenta hPL mRNA,β-HCG mRNA is more suitable as a predictive biomarker for prenatal dianosis of placenta accreta.更多还原