【作者】 秦明春；

【导师】 尤昭玲；

【作者基本信息】 湖南中医药大学 ， 中西医结合临床， 2010， 博士

【摘要】 目的：系统回顾祖国医学和西方医学对先兆流产和习惯性流产的认识和治疗,全面观察导师临床保胎经验总结方-寿胎丸加味方加减治疗肾虚型胎漏、胎动不安、滑胎的临床疗效,以及治疗前后内分泌激素免疫抗体、免疫性NK细胞活性及Th1/Th2细胞因子的变化,以期从内分泌-免疫学角度探讨其保胎的作用机理,为丰富中医药理论、探讨中医药保胎机理和临床研究有效的中药复方制剂做基础性临床研究。同时也是为导师前期动物实验基础上临床研究补充。方法：第一部分临床疗效观察随机选取在湖南中医药大学第二附属医院和湖南省妇幼保健院妇科门诊及住院早期先兆流产、习惯性流产要求保胎中医辨证为肾虚型或肾脾虚弱型的患者和流产不可避免或流产不全要求清宫的患者,妇幼保健科接待的正常孕妇,总共160例,分成4组：寿胎丸加味方治疗组50例,保胎灵治疗对照组50例,流产对照组30例,正常妊娠而未服用保胎药物对照组30例。4组病人同时都口服维生素E：100mg, bid×60天和叶酸：0.4mg, Qd×90天。观察治疗前后的疗效和症候的改变及一般性安全性观察。第二部分寿胎丸加味方临床治疗内分泌—免疫学调节机理研究放射免疫法(RIA)检测寿胎丸加味方治疗组例和保胎灵治疗对照组治疗前后血清HCG、P、β-EP的变化并较正常妊娠组比较。放射免疫法(RIA)检测外周血EMAB(抗子宫内膜抗体)、AsAb(抗精子抗体)、ACA(抗心磷脂抗体)的变化。采用ELSIA方法检测外周血NK细胞活性及血TNF-α、IFN-γ、IL-4、IL-10治疗前后的变化。第三部分保胎治疗后对子代生长发育的初步观察通过电话、网络或上门随访了部分经保胎治疗后新生儿出生时一般情况包括小儿年龄、性别、分娩时孕周、分娩方式、出生时Apgar评分、喂养方式、食量、情绪、有无先天性疾病、有无新生儿窒息史、颅内出血及其他新生儿期疾病等。出生时的身长、体重、头围、胸围等数据,婴幼儿的营养状况、骨骼发育、脑与颅骨发育及胸廓、胸背肌肉、皮下脂肪与肺的发育等情况。第四部分文献研究采用计算机网络技术及其文献检索、流行病学回顾性等研究方法对祖国医学,现代医学以及中西医结合医学关于胎漏、胎动不安及滑胎的病名、病因病机、治疗方法、临床方药研究及当前的临床研究进展进行综述。表明中医药保胎的治疗有良好疗效和优势,值得临床研究和推广。结果：第一部分临床疗效观察50例服用寿胎丸加味方加减治疗后患者经综合疗效判定标准判断,治愈18例,显效17例,有效8例,无效7例,总有效率86%；50例服用保胎灵治疗后患者经综合疗效判定标准判断,治愈12例,显效16例,有效12例,无效10例,总有效率80%；两组有效率均较高,但采用寿胎丸加味方加减治疗后的总有效率(86%)要高于保胎灵对照治疗组(80%),但两组比较,P>0.05,差异无显著意义。而寿胎丸加味方治疗组在改善阴道流血、神疲乏力、夜尿频多方面明显优于保胎灵治疗对照组,且有显著性差异(P<0.05)。两组治疗前后外周血RBC、WBC、HGB, AST、ALT、GGT, CREA、BUN均在正常范围内,前后比较差异统计意义(P>0.05)。第二部分寿胎丸加味方临床治疗内分泌—免疫学调节机理研究检测用药前四组血HCG、P的值,记录用药后两用药组血HCG、P的变化,并同时检测同期正常妊娠组的HCG、P值进行比较,流产对照组相对于其他3组,血HCG、P值明显偏低,与其他3组比较,差异具有显著意义(P<0.01),其他3组比较,发生流产症状治疗两组血HCG、P要低于正常妊娠组,但两用药治疗组比较,差异无显著意义(P>0.05),具有可比性。两用药组用药治疗后血HCG、P上升,前后比较差异具有显著意义(P<0.05)；两组治疗后虽较正常妊娠组低,但差异无显著意义(P>0.05)。两用药组治疗前后上升幅度跟正常妊娠组相当,差异无显著意义(P>0.05)。检测用药前四组外周血的值,记录用药后两用药组血β-EP的变化,并同时检测同期正常妊娠组的β-EP值进行比较,流产对照组相对于其他3组,血β-EP值明显增高,与其他3组比较,差异具有显著意义(P<0.01)；其他3组比较,发生流产治疗两组血β-EP仍要高于正常妊娠组,但低于流产组,用药前两治疗组比较,差异无显著意义(P>0.05),具有可比性。两用药组用药治疗后血β-EP降低,前后比较差异具有显著意义(P<0.01)。两组用药治疗前后血AsAb的阳性率比较差异具有统计意义(P<0.05),血EmAb的阳性率比较差异无统计学意义(P>0.05),而血ACA经寿胎丸加味方治疗后阳性率下降,而保胎灵治疗后无改变。流产对照组的NK细胞活性较正常妊娠对照组明显升高(P<0.01),较寿胎丸加味方治疗组和保胎灵治疗组也显著升高(P<0.01),而寿胎丸加味方治疗组和保胎灵治疗组治疗前较正常妊娠对照组也显著升高(P<0.01),两治疗组治疗前后比较NK细胞活性降低,差异具有统计学意义(P<0.01)。已发生流产的流产对照组TNF-α、IFN-γ含量较正常妊娠组明显升高(P<0.01),较两治疗组治疗前比较也显著升高(P<0.01),两治疗组治疗后较妊娠正常组比较也高,差异具有统计意义(P<0.01)。相反,已发生流产的流产对照组IL-4、IL-10含量较正常妊娠组明显偏低(P<0.01),较两治疗组治疗前比较也显著偏低(P<0.01)。第三部分保胎治疗后对子代生长发育的初步观察随访已生育46例产妇中,新生儿年龄最大1周岁,最小刚出生1周；其中未有早产儿,足月小样儿,畸形儿等,且都未发生新生儿窒息史、颅内出血等其他情况,母儿均正常。出生时的体重、身长、头围、胸围、臀围跟未采取保胎治疗的新生儿比较,差异无统计学意义(P>0.05)。第四部分文献研究通过文献总结和分析,祖国医学对于胎漏、胎动不安及滑胎的认识全面,“肾主生殖”病机主要在肾,滑胎更多责之于肾脾虚弱,寿胎丸临床安胎疗效突出,较西医安胎安全。目前已得到公认。从内分泌免疫方面研究流产和治疗的机理,是目前研究的热点。结论：1.寿胎丸加味方和保胎灵均为临床治疗肾虚型胎漏、胎动不安、滑胎的效果肯定有效方药,尤其是在改善临床症状方面寿胎丸加味方加减疗效要优于保胎灵。2.流产次数越多,再次妊娠流产的可能性更大,保胎治疗的疗效越小,这可能与多次流产损伤子宫内膜有关联,“预培其损”是保胎治疗的关键。3.血HCG、P检测可作为早孕期判断孕囊、胚胎生长发育和判断预后的参考性指标之一,寿胎丸加味方和保胎灵均具有改善黄体黄体功能,促进血HCG, P的增长有助于妊娠的继续4.寿胎丸加味方加减和保胎灵均可以降低因应激而升高的β-内啡肽从神经内分泌和免疫因子的调节方面对妊娠的维持产生一定的作用。而寿胎丸加味方在降低内啡肽方面更突出,初步推断中医采用“宁心安神”降低机体的应激使内啡肽的分泌减少而有助于妊娠的继续。5.寿胎丸加味方和保胎灵均可能降低或消除存在血清自体型抗体或同种异体型抗体而有助于妊娠,而寿胎丸加味方加减更可能有疗效,且中医药治疗较西药安全,无副作用。值得进一步研究。6.发生流产或出现流产症状时外周血NK细胞活性增强,Th1细胞因子的分泌增加,寿胎丸加味方和保胎灵均可能降低外周血NK细胞的活性和降低Th1细胞因子的分泌,促进Th2型细胞因子的分泌,调节Th1/Th2细胞因子的平衡是以Th2为主导的免疫保护,减轻其对胚胎的细胞毒性和免疫损伤作用而有助于妊娠的继续,而寿胎丸加味方随证加减在此方面可能要优于保胎灵。7.补肾益气安胎中药用药安全,对母体无毒副作用,对子代出生和生长发育没有影响。但仍需进一步长时间随访观察和子代智力发育情况,也需要对其进行生殖毒性、遗传毒性等方面的进一步研究。8.通过回顾和总结中医历代文献及现代医学关于流产及治疗的研究进展,祖国医学认为肾脾虚损、气血不足、冲任损伤、胎元不固是主要病机,而肾不固胎,脾失摄养导致胎元不固为发病关键,而现代医学关于复发性习惯性流产多考虑内分泌免疫因素。更多还原

【Abstract】 Objective:The system reviews the Chinese tradition medicine and the Western medicine the understanding and the treatment which miscarries to the threatened miscarriage and routine, observes teacher the clinical fetus protection experience to summarize the side-long-lived embryo pill comprehensively to add the taste side addition and subtraction treatment spleen kidney two empty embryos to leak, painful fetal movement, the abortion clinical curative effect, as well as around the treatment the endocrine hormone, the immunity immune body, immunity NK cell activeness and Thl/Th2 cell factor change, discusses its fetus protection by the time from the endocrine-immunology angle the action mechanism, for the rich Chinese medicine theory, the discussion Chinese medicine fetus protection mechanism and the clinical research effective Chinese native medicine compound prescription preparation does the foundational clinical research.Simultaneously also is for teacher in the preliminary animal experimentation foundation the clinical research supplement.Methods:The first part Clinical curative effect observationStochastic selection in the Hunan Chinese medicine university second affiliated hospital and the Hunan Province women’s and children’s dispensary gynecology department outpatient service and in hospital early time threatened miscarriage, the routine miscarriage requests the fetus protection Chinese medicine dialectical empty either the spleen kidney two empty patients and miscarries the patient for the kidney who inevitable or the miscarriage not all requests the clear palace, the normal pregnant woman who the mother and child care branch reception embryo works, the altogether 160 examples, divide into 4 groups:The long-lived embryo pill adds the taste side treatment group 50 examples, guarantees the treatment control group 50 examples, miscarries the control group 30 examples, the eukyesia has not taken the fetus protection medicine control group 30 examples.4 group of patients simultaneously all take orally the Vitamin E:100mg, bid×60 day and the folic acid:0.4mg, Qd×90 day.Around observation treatment curative effect and symptom change and general secure observation.The second part Clinical endocrine internal secretion-immunology researchEmission immunity law (RIA) examines the long-lived embryo pill to add the taste side treatment group example and the fetus protection spirit treatment control group treats blood serum HCG, P,β-EP the change and the eukyesia group comparison.Emission immunity law (RIA) examination circumference blood EMAB (anti-endometrium immune body), AsAb (anti-sperm immune body), ACA (anti-cuorin immune body) change.Uses ELSIA method examination circumference blood NK cell activeness and the blood TNF-α, IFN-γ, IL-4, around the IL-10 treatment change.Around third part Fetus protection treatment the antithetical couplet generation of growth growth preliminary observationThrough the telephone, the network or visits made a follow-up visit the part after the fetus protection treatment when the newborn birth the ordinary circumstances including when the young child age, the sex, the childbirth is pregnant when the week, the childbirth way, the birth the Apgar grading, feeds the way, the appetite, the mood, whether there is the congenital disease, whether there is the newborn suffocates the history, the skull internal hemorrhage and other newborn time disease and so on.Time the birth height, the body weight, encircle, data and so on chest measurement, babies and infants’ nutrition condition, the skeleton growth, the brain and the skull growth and the chest gallery, chest back muscle, hypodermic fat and lung situations and so on growth..The fourth part Literature researchUses research techniques and so on computer network technology and literature retrieval, epidemiology review to the motherland medicine, the modern medicine as well as the cooperation of Chinese and Western medicine medicine leaks, about the embryo painful fetal movement and the abortion sickness name, the cause of disease pathogenesis, the method of treatment, clinical Fang Yao studies and the current clinical research progress carries on the summary.Indicated the Chinese medicine fetus protection treats has the good effect and the superiority, is worth the clinical research and the promotion.Results:The first part Clinical curative effect observes50 examples to take the long-lived embryo pill to add the taste side addition and subtraction treatment future trouble after the synthesis curative effect determination standard judgment, cures 18 examples, shows results 17 examples, effective 8 examples, invalid 7 examples, total effectiveness 86%; 50 examples take the fetus protection spirit treatment future trouble after the synthesis curative effect determination standard judgment, cures 12 examples, shows results 16 examples, effective 12 examples, invalid 10 examples, total effectiveness 80%; Two groups of effectiveness are high, after but uses the long-lived embryo pill to add the taste side addition and subtraction treatment total effectiveness (86%) to have to be higher than the fetus protection spirit comparison treatment group (80%), but two groups of differences after Radit analysis, P>0.05, difference not remarkable significance.But the long-lived embryo pill adds the taste side treatment group to improve the vagina to bleed, the god tired strength, a night of frequent micturition many, surpasses the fetus protection spirit treatment control group obviously, also has the significance difference (P>0.05).Around two groups treat circumference blood RBC, WBC, HGB, AST, ALT, GGT, CREA, BUN in the normal range, around the comparison difference statistics significance (P>0.05).The second part Clinical endocrine internal secretion-immunologyResearch examination medication four group of blood HCG, the P value, the recording applies drugs latter two medication group blood HCG, the P change, and simultaneously examines the same time eukyesia group HCG, the P value carries on the comparison, miscarries the control group to be opposite obviously in other 3 groups, blood HCG, the P value somewhat low, compares with other 3 groups, the difference has the remarkable significance (P<0.01), other 3 groups compare, have the miscarriage symptom to treat two group of blood HCG, P must be lower than the eukyesia group, but two medication treatment group compares, the difference not remarkable significance (P>0.05), has the commeasurability.After two medication group medication treatment blood HCG, the P rise, around the comparison difference has the remarkable significance (P<0.01); Although after two groups treat the eukyesia group to be low, but difference not remarkable significance (P>0.05). Around two medication groups treat the rise scope with the eukyesia group quite, difference not remarkable significance (P>0.05).Before the examination medication four group of circumference blood value, the recording applies drugs the latter two medication group bloodβ-EP change, and simultaneously examines the same time eukyesia groupβ-EP the value to carry on the comparison, miscarries the control group to be opposite in other 3 groups, the bloodβ-EP value obvious markup, compares with other 3 groups, the difference has the remarkable significance (P<0.01); Other 3 groups of comparisons, had the miscarriage to treat two groups of blood P-EP still to have to be higher than the eukyesia group, but was lower than the miscarriage group, before the medication two treatment group comparison, the difference not remarkable significance (P>0.05), had the commeasurability. After two medication group medication treatment the blood P-EP reduces, around the comparison difference has the remarkable significance (P<0.01); Two groups’treated the eukyesia group to be still high, but difference not remarkable significance (P>0.05).Around but two group of medication treatments blood AsAb, masculine gender rate comparison difference has the statistical significance (P<0.05) blood ACA to add the taste side treatment after the long-lived embryo pill the masculine gender rate drop, after but the fetus protection spirit treatment does not have changes.The miscarriage control group’s NK cell activeness eukyesia control group elevates obviously (P<0,01), the long-lived embryo pill adds the taste side treatment group and the fetus protection spirit treatment group also obviously elevates (P<0.01) around, but the long-lived embryo pill adds the taste side treatment group and the fetus protection spirit treatment group treats the eukyesia control group also obviously to elevate (P<0.01), two treatment groups treats compares the NK cell activeness to reduce, the difference has statistics significance (P<0.01). After two treatment groups treated the eukyesia group to compare still are also high, the difference also had statistics significance (P<0.Ol).Has had the miscarriage miscarriage control group TNF-α, IFN-γthe content eukyesia group elevates obviously (P<0.01) before, two treatment groups treat compare also obviously elevate (P<0.01), after two treatment groups treat compare the eukyesia group to compare also high, the difference has the statistical significance (P<0.01).On the contrary, has had miscarriage miscarriage control group IL-4, the IL-10 content eukyesia group obvious somewhat low (P<0.01) before, two treatment groups treat obviously compare also somewhat low (P<0.01).The third part Fetus protection treatment the antithetical couplet generation of growth growth preliminary observationRevisit has given birth in 46 example parturient women, the newborn age is biggest 1 full year old, smallest just was born 1 week; In which has not had the premature infant, the full-term galley proof, abnormal and so on, also all has not had the newborn to suffocate the history, the skull internal hemorrhage and so on other situations, the mother is normal.Time the birth body weight, the height, encircle, the chest measurement, the hips with have not adopted the fetus protection treatment the newborn comparison, the difference non-statistics significance (P>0.05).The fourth part Literature researchThrough the literature summary and the analysis, the motherland medicine leaks, regarding the embryo painful fetal movement and the abortion knows comprehensively, "the kidney host reproduction" the pathogenesis in the kidney, abortion Yu of Pishen more responsibility two empty, the long-lived embryo pill clinical peaceful embryo curative effect is mainly prominent, compares the doctor practicing western medicine peaceful embryo security.At present obtained the recognition. Studies the mechanism from the endocrine-immunity aspect which miscarries and treats, is hot spot which at present studies.Conclusion:1. Long-lived embryo pills add the taste side and the fetus protection work leak, for the clinical treatment spleen kidney two empty embryos painful fetal movement, the abortion effect affirmation effective side medicine, in particular adds the taste side addition and subtraction curative effect in the improvement clinical symptom aspect long-lived embryo pill to have to surpass the fetus protection spirit. 2. Miscarriage number of times are more, the pregnancy miscarries once more the possibility is bigger, the fetus protection treatment curative effect is smaller, this possible and miscarries many times damages the endometrium to have the connection, "cultivates it to damage is the fetus protection treatment key in advance".3. Blood HCG, the P examination may take the early gestation period judgment is pregnant the pouch, the embryo growth grows and judges one of prognosis referential targets, the long-lived embryo pill adds the taste side and the fetus protection works has improves Huang Tihuang the body function, promotion blood HCG, the P growth is helpful in the pregnancy continuation4. Long-lived embryo pill adds the taste side addition and subtraction and the fetus protection works may reduce theβ-endorphin which elevates because of the stress from the god internal secretion and the immunity factor adjustment aspect to the pregnancy maintenance has certain function.But the long-lived embryo pill adds the taste side the peptide aspect to be more prominent in depression in, infers the Chinese medicine use "rather the heart to calm the nerves" initially to reduce organism the stress to causeβ-endorphin secretion to reduce is helpful to the pregnancy continuation.5. Long-lived embryo pills add the taste side and the fetus protection work possibly reduce or the elimination existence blood serum are helpful from the build immune body or the homogeneous foreign body immune body to the pregnancy, but the long-lived embryo pill adds the taste side to add and subtract possibly has the curative effect, also the Chinese medicine treatment compares the western medicine security, does not have the side effect.Is worth further studying.6. Has the miscarriage or has when the miscarriage symptom the circumference blood NK cell activeness to strengthen the Th1 cell factor the secretion increase, the long-lived embryo pill adds the taste side and the fetus protection works possibly reduces the circumference blood NK cell activeness and reduces the Thl cell factor the secretion, promotes the Th2 cell factor secretion, adjusts the Th1/Th2 cell factor the balance to the Th2 direction displacement, reduces it is helpful to the embryo cell toxicity and the immunity damage function to the pregnancy continuation, but the long-lived embryo pill adds taste Fang Suizheng to add and subtract in this aspect possibly must surpass the fetus protection spirit.7. Invigorates the kidney the profit to be mad the peaceful embryo Chinese native medicine medication security, to the parent substance non-toxic side effect, an antithetical couplet generation of birth and the growth growth has not affected.But still had further the long time revisit observation and the filial generation intelligence growth situation observation, also needed to carry on aspect and so on reproduction toxicity, heredity toxicity to it further research. 8. Progresses through the review and the summary Chinese medicine all previous dynasties literature and the modern medical research, the motherland medicine thought the kidney empty damages, the vitality insufficient, flushes no matter what damages, the embryo Yuan does not solidify is the main pathogenesis, but the kidney not solid embryo, the spleen loses conserves health causes the embryo Yuan not to solidify is the morbidity key, but the modern medicine miscarries the multi-consideration internal secretion immunity factor about recurrence routine.更多还原