【作者】 朱鹏；

【导师】 陶芳标；

【作者基本信息】 安徽医科大学 ， 儿少卫生与妇幼保健学， 2010， 博士

【摘要】 背景现有的流行病学研究已经证明,孕期心理应激与儿童期神经行为发育之间存在显著关联。这种关联的作用机制目前尚不清楚,有关孕期应激可对胎儿HPA轴发育产生宫内编程效应的假说尚没有直接的研究证据。除了HPA轴宫内编程这一途径外,是否还存在其它的影响途径目前也未见研究报道。一些有关孕期心理应激与新生儿出生结局关联的研究将孕期心理应激的关键暴露时间指向了孕早期,而有关孕早期与儿童神经行为发育关联的研究还较少。目的①评价孕早期应激性生活事件暴露对新生儿在急性应激刺激下垂体-肾上腺轴反应性的影响;②验证孕早期应激性生活事件是否会改变早期母乳喂养行为;③探讨孕早期应激性生活事件暴露与16～18个月幼儿的精神发育、运动发育及气质特征是否存在独立的关联。通过上述3个研究验证以下假说:孕早期心理应激可通过影响胎儿HPA轴宫内编程和改变产后早期母乳喂养行为两个途径对儿童早期神经行为发育产生影响。方法对2 522名于2008年1月至10月在合肥市妇幼保健院产科住院分娩并自愿参加本研究的孕产妇在住院待产时进行问卷调查,收集人口统计学信息、孕期健康状况、孕期BMI、社会支持情况,评价孕早、中、晚期生活事件发生情况、。在分娩后即刻,收集新生儿脐血并采用放射免疫法检测血浆中的CORT、ACTH和DHEAS水平。在产后2小时进行分娩时应激自评并记录分娩方式及新生儿出生结局。在产后72小时进行泌乳启动评价。在产后2个月和4个月分别进行电话随访以获得母乳喂养信息。在幼儿16～18个月时进行预约,评价智力发育指数、精神运动发育指数、气质特征并记录母乳喂养持续时间。将生活事件自评得分≥2分界定为应激性生活事件暴露,有86名孕妇仅在孕早期存在应激性生活事件暴露,其中有64名符合研究条件的孕产妇作为研究一中的暴露组(31名自然分娩孕产妇作为暴露组A,33名剖宫产孕产妇作为暴露组B),另选择无孕期生活事件的64名孕产妇作为对照组(31名自然分娩孕产妇作为对照组A,33名剖宫产孕产妇作为对照组B)。在产后15～16个月时,有38名暴露母子和114名对照母子(按分娩时母亲年龄相差3岁、分娩方式相同、幼儿性别相同、自评家庭经济状况相同、户口分类相同、母亲受教育程度相同作为匹配条件)接受了神经行为发育评价。结果暴露组A的CORT水平为408.80±100.56 ng/ml,略低于对照组A,但差异无统计学意义(Z=1.86, P=0.063);ACTH水平为8.98±2.86 pg/ml,显著高于对照组A(Z=2.38, P=0.018);而DHEAS水平、CORT/ACTH值和DHEAS/ACTH值均显著低于对照组A(Z=3.23, P=0.001;Z=3.29, P=0.001;Z=3.92, P<0.001)。暴露组B的CORT水平、ACTH水平、CORT/ACTH值、DHEAS/ACTH值与对照组B相比,差异均无统计学意义,但DHEAS水平显著低于对照组B(Z=2.96, P=0.003)。对照组A的CORT水平显著高于对照组B,差异有统计学意义(Z=5.40, P<0.001)。对自然分娩的新生儿按性别进行分层分析后发现,暴露组女婴的皮质醇水平为382.79±81.74 ng/ml,显著低于对照组女婴的461.04±87.43 ng/m(lZ=2.23, P=0.026),而暴露组男婴的皮质醇水平与对照组则无统计学差异。男女婴的CORT/ACTH值和DHEAS/ACTH值均分别低于对照组的男女婴,差异均有统计学意义(男婴:Z=2.44, P=0.015;Z=3.20, P=0.001。女婴:Z=2.29, P=0.022;Z=2.42, P=0.016)。产后泌乳启动延迟发生率为9.8%。产后2个月时的母乳喂养终止率为12.0%。控制协变量(母亲年龄、户口、母亲受教育程度、自评家庭经济状况、孕期社会支持等级)后的多因素Logistic回归分析显示,孕早期应激性生活事件暴露(RR=2.59, 95%CI: 1.52-4.40)、孕期BMI增幅≥7.61(RR=1.90, 95%CI: 1.27-2.86)、分娩方式为剖宫产(RR=2.11, 95%CI: 1.46-3.05)、产后第一天母乳喂养次数<3次(RR=2.14, 95%CI: 1.57-2.91)会显著增加产后泌乳延迟发生的风险。孕晚期应激性生活事件暴露(RR=3.44, 95%CI: 1.67-7.37)、孕前BMI<18.45(RR=1.88, 95%CI: 1.19-2.97)、孕期BMI增幅≥7.61(RR=1.56, 95%CI: 1.02-2.39)、分娩方式为剖宫产(RR=2.06, 95%CI: 1.42-2.97)、产后第一天母乳喂养次数<3次(RR=1.62, 95%CI: 1.18-2.22)及产后泌乳启动延迟(RR=2.24, 95%CI: 1.46-3.44)显著增加产后2个月母乳喂养终止的风险。通径模型分析显示,孕早期应激性生活事件暴露、孕期BMI增幅≥7.61、分娩时自评紧张感得分≥7、剖宫产、产后第一天母乳喂养次数<3可通过显著增加产后泌乳延迟的风险进而显著增加产后2个月母乳喂养终止的风险。孕早期应激性生活事件暴露可通过4种途径影响产后2个月时的母乳喂养行为。暴露组幼儿的出生体重显著低于对照组。在控制协变量后,暴露组幼儿的智力发育指数为102.43(95%CI: 99.29-105.57),显著低于对照组的110.31(95%CI: 108.55-112.08),差异有统计学意义。但两组的运动发育指数差异无统计学意义。在控制协变量后,暴露组幼儿的气质维度中的节律性、情绪本质和持久性得分均显著低于对照组,差异有统计学意义。结论①孕早期应激性生活事件可导致新生儿的肾上腺皮质对ACTH的敏感性下降,显著下调垂体-肾上腺轴的反应性。这种影响对女婴可能更为显著。②孕早期应激性生活事件暴露可通多种途径影响产后早期的母乳喂养行为。③孕早期应激性生活事件可独立的影响人类子代的神经行为发育,且神经行为损伤存在特异性。本研究的结果支持“孕早期心理应激可通过影响胎儿HPA轴宫内编程和改变产后早期母乳喂养行为两个途径对儿童早期的神经行为发育产生影响”这一假说。更多还原

【Abstract】 BackgroundPreliminary studies have demonstrated a link between prenatal psychological stress and cognitive, behavioral, and emotional problems in the child. Little is known about the possible underlying mechanisms and there are no direct evidences about the hypothesis that prenatal psychological stress could lead to deleterious programming effects on the fetal HPA axis. It is not clear by now whether there exist other pathways besides fetal programming, through which prenatal stress affect the neurobehavioral development of offspring. Some researches about the effect of prenatal psychological stress on birth outcomes had found that the first trimester is an important window period for exposure while little research involved in the impact of prenatal psychological stress during first trimester on the neurobehavioral development of child.Objectives1. To evaluate the effects of maternal exposure to stressful life events during first trimester on pituitary-adrenocortical axis response to acute stress (delivery).2. To identify whether the stressful life events during first trimester could reduce early breastfeeding.3. To investigate whether the prenatal stress during first trimester was associated independently with neurobehavioral development of offsprings after controlling the family environment and breastfeeding behavior.The final purpose of this paper was to identify the hypothesis that prenatal psychological stress may influence the neurobehavioral development of offsprings through two different paths including deleterious programming effects on the fetal HPA axis and reducing early breastfeeding.MethodsA total 2 522 pregnant women who delivery in the Department of Obstetrics of Hefei Maternal and Child Healthcare Hospital from January to October 2008 participated in the project willingly and were required to complete a questionnaire including Life Events Checklist and Social Support Scale before delivery. Demographic characteristics, pregnancy history and BMI during pregnancy were assessed through the interview/medical charts and delivery outcomes including gestational age at birth, birth weight were obtained from medical charts after delivery. Cord blood were collected immediately after delivery and cortisol (CORT), adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) level were detected by radioimmunity. Two hours after delivery, pregnant women were required to report the perceived impact rating of pain and tension during delivery. Lactation guidance was provided and the onset of lactation data was collected in the hospital during 0-3 days after parturition, and the onset of lactation was defined based on maternal perception of changes in breast fullness. Information about the breastfeeding postpartum was obtained during the telephone interview at 2 month and 4 month postpartum. when infants reach 16-18 months old, the mental development, psychomotor development, and temperament were assessed using Bayley Scales of Infant Development of China Revision (BSID-CR) and Toddler Temperament Scale (TTS).Taken total score of perceived impact to life events during first trimester≥2 as exposure to stressful life events, there were 64 out of 86 pregnant women who were collected cord blood and exposed to stressful life events during first trimester fit the reach requirements and taken as exposed group in section 1 of this study. Among the 64 pregnant women, 31 ones who delivery by spontaneous labour were defined as Exposed group A (EA), and 33 ones who delivery by caesarean section were defined as Exposed group B (EB). Another 64 pregnant women who were collected cord blood and without exposure to stressful life events including 31 ones delivered by spontaneous labour and 33 ones deliverd by caesarean section were defined as Controlled group A (CA) and Controlled group B (CB), respectively. Thirty eight exposed mother-infant pairs and 114 control pairs (matched 1:3 with exposed mother-infant pairs for mother age, education status, delivery mode, infant sex, family economic status, residence ) received follow-up visit when infants was 16-18 months old.ResultsDemographic characteristic and perceived impact rating of pain and tension during delivery had no significant difference between exposed group and control. CORT concentration of EA was 408.80±100.56 ng/ml, which was lower than CA but had no significant difference (Z=1.86, P=0.063). ACTH level in cord blood of EA was significantly higher than CA(8.98±2.86 vs 7.60±2.22; Z=2.38, P=0.018), while DHEAS, ratio of CORT/ACTH and DHEAS/ACTH were significantly lower than CA, (Z=3.23, P=0.001 ; Z=3.29, P=0.001 ; Z=3.92, P<0.001; respectively). Compared with Controlled group B (CB), the level of CORT and ACTH, ratio of CORT/ACTH and DHEAS/ACTH in Exposed group B (EB) had no significant difference but DHEAS level was significantly lower(Z=2.96, P=0.003). CORT level of CA was significantly higher than CB(Z=5.40, P<0.001). Analysis according to neonatal sex showed that CORT level of female neonate in EA was significantly lower than female neonate in CA(382.79±81.74 ng/ml vs 461.04±87.43 ng/ml; Z=2.23, P=0.026) while there was no significant difference between male neonates from EA and CA. Ratios of CORT/ACTH and DHEAS/ACTH in female and male neonate of EA were significantly lower than female and male of CA, respectively(male: Z=2.44, P=0.015;Z=3.20, P=0.001. female: Z=2.29, P=0.022;Z=2.42, P=0.016).The prevalence of delayed onset of lactation (OL) and termination of full breastfeeding were 9.8% and 12.0%, respectively. Multiple logistic regression model after controlling mother age, residence, education status, perceived family economy and social support during pregnancy showed that exposure to stressful life events during first trimester (RR=2.59, 95%CI: 1.52-4.40), gestational BMI gain≥7.61(RR=1.90, 95%CI: 1.27-2.86), cesarean section (RR=2.11, 95%CI: 1.46-3.05), frequency of breastfeeding on day 1 after deliver(RR=2.14, 95%CI: 1.57-2.91) may increase significantly risk of delayed OL. Exposure to stressful life events during third trimester(RR=3.44, 95%CI: 1.67-7.37), pregnant BMI < 18.45(RR=1.88, 95%CI: 1.19-2.97), gestational BMI gain≥7.61(RR=1.56, 95%CI: 1.02-2.39), cesarean section (RR=2.06, 95%CI: 1.42-2.97), frequency of breastfeeding on day 1 after deliver<3 (RR=1.62, 95%CI: 1.18-2.22) and delayed OL(RR=2.24, 95%CI: 1.46-3.44) may increase the risk of early termination of any breastfeeding significantly. Path analysis model showed that delayed OL was an important intermediary role on association among exposure to stressful life events during first trimester, gestational BMI gain, rating of perceived tension to delivery, cesarean section, frequency of breastfeeding on day 1 after deliver and early termination of any breastfeeding. Furthermore, it was identified that maternal stressful life events during first trimester may increase the risk of early termination of any breastfeeding through four pathways.There was no statistic difference of demographic characteristics between control group and exposed group while the infant birth weight of exposed group was significantly lower than control group. Mental Development Index (MDI) of infant in exposed group was significantly lower than that of the control group after controlling gestational age, infant birth weight, duration of full breastfeeding and any breastfeeding(102.43, 95%CI: 99.29-105.57 vs 110.31, 95%CI: 108.55-112.08; F=18.18, P<0.001) while Psychomotor Development Index (PDI) had no significant difference between the two groups. The scores of rhythmicity, emotion and persistency in temperament of exposed infants were significantly higher than control group after controlling covariates, respectively.Conclusions1. Maternal stressful life events during first trimester may change the sensitivity of fetal adrenal cortex to ACTH and down-regulate the response of pituitary-adrenocortical axis to acute stress.2. Exposure to stressful life events during first trimester may reduce early breastfeeding through multiple pathways.3. Prenatal stress during first trimester was associated independently with special impairment of neurobehavioral development in toddler.Evidences from this study support previous hypothesis that prenatal psychological stress may influence neurobehavioral development of offspring through two different pathways including deleterious programming effects on the fetal HPA axis and reducing early breastfeeding.更多还原