早期介入與多巴胺及血清素相關基因對於早產兒發展預後之影響

Effects of Early Intervention and Dopamine- and Serotonin-Related Genes on Developmental Outcomes in Preterm Children

姚乃嘉(Nai-Jia Yao)

指導教授 ： 鄭素芳

國立臺灣大學/醫學院/物理治療學研究所/博士(2020年)

https://doi.org/10.6342/NTU202001836

摘要

背景：過去研究顯示有些早產兒的早期介入計畫對短期兒童發展和親職壓力有益，但大多數研究採用單點分析而未能呈現長期趨勢變化。此外，曾有研究發現多巴胺相關基因與兒童神經發展障礙相關，但其在早產兒發展所扮演的角色以及和環境可能的交互作用則尚待釐清。
目的：探討以家庭為中心之早期介入在極低出生體重（出生體重小於1,500公克）早產兒從6至48個月之兒童發展和父母親職壓力的療效，以及基因和基因─環境交互作用對其發展預後之影響。
方法：本研究包含兩個長期觀察性研究和兩個多中心隨機臨床試驗（介入組和常規照護組）共513名極低出生體重早產兒和111名足月兒。兒童發展和行為使用貝萊氏嬰幼兒發展量表第二版與第三版以及兒童行為檢核表/1½-5歲進行評估，其父母親則分別填寫長版親職壓力量表。介入組的照顧者並填寫居家活動操作紀錄。另外，也對兒童採集生物檢體以進行單核苷酸多型性（SNPs）和變異重覆序列（VNTRs）於多巴胺和血清素相關基因（DRD2，DRD3，DRD5，DAT1，COMT，MAOA和SLC6A4）之基因採樣與分析。統計分析則分別比較介入組與常規組於早產兒兒童發展與父母親職壓力之長期影響，並比較早產兒與足月兒發展之基因關聯性，以及基因─環境交互作用於早產兒發展之影響。
結果：療效結果顯示，早期介入明顯提升早產兒12至24個月之間的認知與粗大動作發展（所有p <0.05；24個月時最大效果量分別為0.11和0.31），於其他年齡段的變化則與常規組相似。而兩組在語言、精細動作和行為發展方面均無顯著差異。同時，早產兒介入組父親從足月到四歲在兒童（-13.1比-5.1，p=0.014）和總壓力分數（-18.6比-6.0，p=0.033）較早產兒常規組父親呈現顯著較大降幅。母親在所有壓力分數則均顯著高於父親壓力（p <0.05）。父母親職壓力與兒童動作與行為發展呈現明顯相關（p=0.0001~0.060），但與居家活動執行者則無關。至於基因結果的部分，MAOA基因（以rs2239448作為代表）與早產兒認知發展相關，包括顯著之主效應及其與年齡趨勢相關之交互作用（p <0.0001；24個月時最大效果量為0.65），而且該結果亦在獨立樣本獲得驗證（p=0.026）。然而，所選定的基因則皆與早產兒的動作發展無關，與足月兒的認知或動作發展也無關。最後，多巴胺或血清素相關基因與早期介入在早產兒兒童發展上之交互作用並不顯著。
結論：以家庭為中心之早期介入有利於極低出生體重早產兒的認知和粗大動作之中長期發展，亦能有效降低其父親從足月至四歲的親職壓力，且MAOA基因與早產兒兒童期之認知發展明顯相關。本研究結果能夠做為臺灣極低出生體重早產兒早期介入設計與成效評估之參考。

關鍵字

早產 ； 早期介入 ； 兒童發展 ； 親職壓力 ； 多巴胺與血清素相關基因 ； 長期分析

並列摘要

Background Although benefits on child development and parenting stress have been found for certain intervention programs in preterm children, the use of single-time data analyses in most of previous studies failed to capture the longitudinal trend. In addition, dopamine-related genes have been found to associate with neurodevelopmental disorders in children, however, their roles in neurodevelopment and gene-environmental interactions in preterm children remain unclear.
Aims To examine the effects of family-centered intervention on child development and parenting stress, genetic effects and gene-environmental interactions in preterm children with very low birth weight (VLBW; birth weight <1,500 g) from 6 to 48 months of age.
Methods This study combined two longitudinal observational studies and two multi-centered randomized controlled trials (intervention and usual care group) that consisted of 513 preterm children with VLBW and 111 term children. Children were assessed for their developmental and behavioral outcomes using the Bayley Scales of Infant Development – 2nd Edition, the Bayley Scales of Infant and Toddler Development – 3rd Edition and the Child Behavior Checklist for Ages 1½-5. Their mothers and fathers respectively reported their parenting stress using the Parenting Stress Index - Long Form. The caregivers of the intervention group further documented the child home activities. Children were also genotyped for single-nucleotide polymorphisms (SNPs) and variable number of tandem repeats (VNTRs) in dopamine- and serotonin- related genes (DRD2, DRD3, DRD5, DAT1, COMT, MAOA and SLC6A4). The intervention and usual care groups were compared with their child development and parenting stress across ages. The relations of dopamine- and serotonin-related genes with child developmental outcomes in preterm and term children were examined. Finally, the gene-environment interaction on child developmental outcomes in preterm children was tested.
Results The intervention group exhibited a significantly greater increase in mental and gross motor raw scores from 12 to 24 months (all p < 0.05; largest effect size of 0.11 and 0.31 at 24 months), but similar changes at other ages, than the usual care group. However, the groups showed comparable changes in language, fine motor and behavioral scores across ages. The intervention group fathers showed a significantly greater reduction of parenting stress from term to 48 months of age than the usual care group in the child domain (-13.1 vs. -5.1, p = 0.014) and total stress (-18.6 vs. -6.0, p = 0.033). Mothers of preterm children perceived higher parenting stress than fathers throughout term to 4 years of age (all p < 0.05). A higher maternal stress was associated with poorer child behavior (all p <0.0001); whereas, a greater reduction of paternal stress had borderline relations with better child motor development (p = 0.051 for gross motor and 0.060 for fine motor). The MAOA (rs2239448 as a tag) variants were significantly associated with the mental scores of preterm children for the main effect and its interaction with the age trend (p < 0.0001; largest effect size of 0.65 at 24 months) for which findings were replicated in an independent sample (p = 0.026). However, none of the SNPs were associated with the motor scores of preterm children, and neither were related to the mental or motor scores of term children. Finally, the dopamine- and serotonin-related genes showed no interaction with the early intervention on developmental outcomes in preterm children.
Conclusions and Implications Family-centered intervention yielded late-occurring and medium-term effects on mental and gross motor development in preterm children. Furthermore, the intervention was effective in reducing paternal parenting stress in preterm children with VLBW, especially toward 4 years of age. Finally, the genetic variants of the MAOA gene exerted influence on mental development throughout early childhood for preterm children. The results provide insightful information for design and outcome assessment of early intervention for preterm children with VLBW in Taiwan.

並列關鍵字

Premature ； Early intervention ； Child development ； Parenting stress ； Dopamine- and serotonin- related genes ； Longitudinal analysis

參考文獻

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