目的
產科併發症是指在懷孕中、生產時或生產後的併發症，是造成孕婦及胎兒死亡的主要因素。有文獻指出嚴重的產科併發症會影響胎兒大腦發育，進而導致孩童發展遲緩。更有文獻指出有神經發展疾病的婦女在懷孕過程中有較高的機率罹患產科併發症，因此我們認為神經發展指標可能是某些產科併發症的潛在標記，可用來早期預測產科併發症。另一方面，先前研究結果提到孕婦的肥胖會面臨胎兒有較高的死亡率，脂肪細胞激素是一群由脂肪細胞製造並在體內調節代謝相關機制，例如瘦素、脂聯素、白細胞介素-1 beta及腫瘤壞死因子-alpha。過去已有研究發現脂肪細胞激素表現異常與產科併發症的相關性，因此脂肪細胞激素可能是潛在的生物標記，可用來預測特定的產科併發症。因目前尚未有良好的準則來判斷可能罹患產科併發症的高風險族群，因此本篇研究希望探討與產科併發症及新生兒健康狀態相關的危險因子，以利早期預測及治療。
方法
本研究收案20-50歲及懷孕20周以上的孕婦，共有健康組人數150人，產科併發症婦女90人，測量孕婦的細微體質特徵及神經軟性功能，並評估孕婦的精神狀態。另外會收集第二孕期、生產前及臍帶血的血液樣本。血液樣本用來測量血清中與代謝相關之因子，如瘦素、脂聯素、白細胞介素-1 beta及腫瘤壞死因子-alpha。並於產婦生產後收集孕婦生產相關資訊、慢性病史及新生兒健康狀態。鑑別分析利用線性鑑別分析與接收者操作特徵曲線(ROC)並計算曲線下面積(AUC)來進行分析。
結果
在細微體質特徵的質性項目中，早產及早期破水的組別與健康組相比有較高的勝算比。而在細微體質特徵的量性項目中，產科併發症及妊娠糖尿病的組別與健康組相比有較高的勝算比。分析不同時間點的代謝訊號濃度的結果顯示，白細胞介素-1 beta在早產及早期破水的表現量明顯與健康組不同；子癲前症的腫瘤壞死因子-alpha則是明顯高於健康組。利用混和效果模型分析重複測量值，結果顯示妊娠糖尿病的瘦素濃度變化與健康組相比有明顯的差異，且達到統計上的顯著意義。在接收者操作特征曲線的分析並計算曲線下面積的結果顯示，在妊娠糖尿病的組別中，綜合瘦素、脂聯素及白細胞介素-1 beta具有最佳的曲線下面積(AUC=0.93)；在早產的組別中，綜合所有標記具有最佳的曲線下面積(AUC=0.92)；在產前出血的組別中，綜合脂聯素及白細胞介素-1 beta具有最佳的曲線下面積(AUC=0.91)。線性鑑別分析的結果則與接收者操作特徵曲線(ROC)的分析結果一致。
結論
上述結果支持神經發展標記、代謝異常與特定產科併發症之相關性，且在妊娠糖尿病孕婦中，瘦素濃度異常增加，我們將會繼續收案並追縱小孩的發育情形，預期神經發展標記及瘦素濃度可做為鑑別高危險婦女的危險因子且可預測新生兒健康狀態，有益於臨床上用於預防及早期診斷。

Background
Obstetric complications (OCs) are defined as the complicate cases that can happen during pregnancy, birth, and the postpartum period. The published study suggested that preeclampsia and placental insufficiency resulted to vascular damage, enhanced systemic inflammation and increased insulin resistance and caused progressive hypoxemia therefore increased the risk of developmental delay (DD) and autism spectrum disorder (Lim, Wang, & Holtz, 2016). OCs might cause aberrant developmental pathway established early in fetal life by both genetic and environmental factors. A previous report showed that pregnancy obesity is associated with increased risks of infant mortality (Johansson et al., 2014). Adipokines such as leptin and adiponectin, are hormones made by adipocytes and its major function is regulating fat storage. A recent study also showed that preeclampsia is associated with alterations of leptin in maternal blood (Haugen et al., 2006). Moreover, the brain damage in preterm mice is accompanied with increased inflammatory adipokines like TNF-and IL-1 and alternation of other genes expression which are related to brain functions (Elovitz et al., 2011). In spite of these findings, it reminds unknown whether specific metabolic changes in neurodevelopmental disabilities link to a genetic vulnerability for infant neurodevelopment.
Methods
We recruited the prenatal women aged from 20 to 50 years old whose gestational age is 20 weeks or more and conducted the neurodevelopmental evaluation (Minor physical anomalies and Neurological Soft Signs) during pregnancy period. There are 90 women with OCs and 150 women without OCs. In addition, we collected the repeat measurement data in mental status and venous blood samples. Levels of metabolic adipokines such as leptin, adiponectin, IL-1 and TNF- are measured by ELISA kits. The neonatal outcomes were collected from the present pregnancy history and neonatal records in National Cheng Kung University Hospital (NCKUH). A P value of <0.05 is considered statistically significant. A receiver operating characteristic (ROC) curve and linear discriminant analysis was applied to evaluate the diagnostic values of qualitative/quantitative minor physical anomalies and metabolic markers in predicting OCs patients and adverse neonatal outcomes.
Results
Compared qualitative measurements of minor physical anomalies (MPA) scores to healthy controls, PTB and PROM showed the significantly higher odds ratio in hands and total scores. On the other hands, compared quantitative measurements of MPA scores, pooled OCs and GDM showed the significantly higher odds ratio in ears compared to healthy controls. In assessment of adverse neonatal outcomes, group of 1 minute Apgar score ≤ 7 showed the significantly higher odds ratio in hands [OR=1.2; 95%CI=1.0-1.6]. In comparison of quantitative measurements of MPA, fetal distress showed the significantly higher odds ratio in head and eyes. We analyzed the levels of leptin, adiponectin, IL-1 and TNF- at different time points. In comparison of IL-1levels, PTB, PROM and antepartum hemorrhages showed the significantly lower odds ratio in cord blood [OR=0.5; 95%CI=0.2-0.8; OR=0.8; 95%CI=0.5-1.0; OR=0.6; 95%CI=0.4-0.9]. The results of TNF- levels in preeclampsia and healthy controls showed the significantly higher odds ratio in the blood sample collected before delivery [OR=1.1; 95%CI=1.0-1.2]. In addition, the results of mixed effect model showed that there is a significant difference in changes of leptin levels between patients with GDM and controls. In ROC curves of GDM, the AUC for the 3 adipokines (leptin, adiponectin and IL-1) in second trimester was 0.93 and the ROC analysis of IL-1 was 0.92, close to the former. Adiponectin at third trimester showed the better ability of classification (AUC=0.73) and combined all markers had the highest AUC (AUC=0.92) in PTB. Combined adiponectin and IL-1 showed the highest AUC (AUC=0.91) at second trimester and MPA with leptin and TNF- showed the highest AUC (AUC=0.86) at third trimester in antepartum hemorrhage. Linear discriminant analysis (LDA) was applied to determine the linear combination of variables for classifying patients and healthy control. The results were similar with ROC curves.
Conclusion
These findings support the association between neurodevelopmental markers, metabolic signals and specific OCs. The neurodevelopmental marker and serum levels of adipokines could be useful biomarkers for helping to distinguish the ‘high-risk’ women during early period. In addition, the abnormal expression of adipokines in specific OCs and adverse neonatal outcomes probably contribute to the occurrence of diseases. We look forward to construct a superior guideline for identifying the women at high risk and predict adverse neonatal outcomes.

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