低剂量阿司匹林联合不同剂量的钙剂预防子痫前期高危孕妇的效果及其对炎症因子的影响.pdf

OSID开放科学标识码Jun.2023年6 月2023Journal of Jinan University(Natural Science&Medicine Edition)第44卷第3期No.3Vol.44暨南大学学报（自然科学与医学版）低剂量阿司匹林联合不同剂量的钙剂预防子痫前期高危孕妇的效果及其对炎症因子的影响韩曦，谢小娟”，张矛1*（陕西省人民医院1.产科；2.临检中心，陕西西安7 10 0 6 8）摘要目的：探讨低剂量阿司匹林(LDA)联合不同剂量的钙剂预防子痫前期高危孕妇的临床效果及其对炎症因子的影响。方法：根据随机数字表法将患者分为对照组、LDA组、LDA+低钙组及LDA+高钙组，对比各组的母婴结局、凝血功能及炎症因子的改变。结果：LDA+低钙组及LDA+高钙组重度子痫前期组的发病率显著低于对照组及LDA组，差异均具有统计学意义（P0.05）。与对照组相比,LDA+低钙组及LDA+高钙组的早产、胎儿生长受限、胎儿窘迫、剖宫产的发生率显著降低，而分娩孕周、新生儿的体质量及身长均显著升高；差异具有统计学意义（P0.05）。与LDA组相比，LDA+低钙组的新生儿体质量显著增高，而LDA+高钙组的分娩孕周、新生儿体质量、身长及1minApgar评分均显著升高，差异均具有统计学意义（P0.05）。与对照组及LDA组相比,LDA+低钙组及LDA+高钙组治疗后的PT、A PT T 及TT明显延长，而Fib、T NF-,IL-6及hs-CRP明显降低，差异均具有统计学意义（P0.05）。结论：阿司匹林联合钙剂可改善患者的凝血及炎症指标,对预防子痫前期发病，改善母婴结局有一定的作用。关键词子痫前期；阿司匹林；大不同剂量；钙；预防效果中图分类号R714.252文献标志码A文章编号1000-9965(2023)03-0274-08D0I:10.11778/j.jdxb.20230039Preventive effect of low-dose aspirin plus different dose of calcium amongwomen with high-risk of preeclampsia and its effects on inflammatory factorsHANXi,XIEXiaojuan,ZHANGMao(1.Department of Obstetrics,2.Shaanxi Center for Clinical Laboratory,Shaanxi Provincial Peoples Hospital,Xian 710068,Shanxi,China)AbstractObjective:To investigate the clinical effect of low-dose aspirin(LDA)plus different dosesof calcium in the prevention of preeclampsia and its influence on inflammatory factors.Methods:According to the method of random number table,the patients were randomly divided into control group,LDA group,LDA+low-dose calcium and LDA+high-dose calcium group.And the maternal and infantoutcomes,coagulation function,and inflammatory factors in each group were compared.Results:Theincidence of severe preeclampsia in the LDA+low-dose calcium group and the LDA+high-dose收稿日期2023-02-22基金项目陕西省自然科学基础研究计划项目（2 0 2 0-JQ937）；陕西省人民医院项目（2 0 2 1BJ-11）作者简介韩曦（0 RCID：0 0 0 9-0 0 0 3-6 317-7 356），女，研究方向：产科危重症；E-mail：h a n x i 1934 16 3.c o m通信作者：张矛（0 RCID：0 0 0 9-0 0 0 0-0 8 2 4-12 37），男，研究方向：妊娠期高血压，E-mail：z m 6 8 0 16 5 16 3.c o m275韩曦，等：低剂量阿司匹林联合不同剂量的钙剂预防子痫前期高危孕妇的效果及其对炎症因子的影响第3期calcium group was significantly lower than that in the control group and the LDA group(P0.05).Compared with the control group and LDA group,the incidence of premature delivery,FGR,fetaldistress and cesarean section in the LDA+low-dose cacium group and LDA+high-dose calcium groupwere significantly reduced,while the gestational weeks of delivery,weight and length of newborns weresignificantly increased,the difference was statistically significant(P0.05).Compared with the LDAgroup,the weight of newborns in the LDA+low-dose calcium group was significantly increased,whilethe gestational week,newborn weight,length,and 1-minute Apgar score of the LDA+high-dose calciumgroup were significantly increased,the difference was statistically significant（P 0.0 5).A f t e rtreatment,compared with the control group and LDA group,PT,APTT and TT in LDA+low-dosecalcium group and LDA+high-dose calcium group were significantly prolonged,while Fib and TNF-,IL-6 and hs-CRP decreased significantly(P0.05).Conclusion:Aspirin combined with calcium canimprove the blood coagulation and inflammatory function,which has a certain role in preventingpreeclampsia and improving the maternal and infant outcomes,and is worthy of clinical promotion.Key wordspreeclampsia;aspirin;different dose;calcium;prevention effect子痫前期（pre-eclampsia,PE）是妊娠期特发性疾病,以高血压及蛋白尿为主要临床表现,若不及时诊治，可进展为多器官功能障碍、子痫，严重者导致孕产妇及围产儿死亡。据报道，PE的发病率为2%8%，每年造成50 0 0 0 0 孕产妇死亡，76000新生儿死亡1，是围产期孕妇及新生儿死亡的主要原因。因此,筛查高危人群,采取积极有效的预防措施，进而降低PE发病，这对改善母婴结局有重要意义。目前，国内外已有研究报道低剂量阿司匹林（l o w-d o s e a s p i r i n,LD A）联合钙剂对子痫前期的预防效果2-3,但对LDA及钙剂的用药剂量及起始孕周仍存在争议(4-51。因此，本研究对筛选出的子痫前期高危孕妇，采用阿司匹林7 5mg/d及钙剂(1或2 g/d)进行干预，以明确阿司匹林联合钙剂对子痫前期的预防效果，并探讨了联合用药对炎症因子的影响，从而为预防子痫前期联合用药方案的制定提供理论依据1材料与方法1.1一般资料选取2 0 2 0 年6 月至2 0 2 1年12 月于陕西省人民医院就诊，且妊娠孕周35岁、初产、肥胖（BMI30kg/m）或子痫前期家族史（母亲或姐妹）及个人病史因素（2 次妊娠间隔 10 年、既往不良妊娠结局、小于胎龄儿或低出生体质量）中任意2 项1。（2)近1月未服用抗凝血药物、钙剂等药物；（3)在陕西省人民医院常规产检并分娩；（4)临床资料完整，依从性好。排除标准：（1)合并精神疾病者；（2)中途退出研究者；（3）过敏体质；（4）阿司匹林抵抗者。本研究获得陕西省人民医院医学伦理委员会批准。根据随机数字表法将患者随机分为对照组、LDA组、LDA+低钙剂组及LDA+高钙剂组。对照组患者给予围产期保健，按时产检，饮食及运动指导等；LDA组患者自妊娠12 周开始，每日给予阿司匹林7 5mg，直到孕36 周停药；LDA+低钙组患者自妊娠12 周开始，每日给予阿司匹林75mg和钙剂1g，直到孕36 周停药；LDA+高钙组患者自妊娠12 周开始，每日给予阿司匹林7 5mg和钙剂2 g，直到孕36 周停药。1.2评价指标（1）临床指标：包括各种类型子痫前期（早发型子痫前期、轻度子痫前期及重度子痫前期）的发病率和母婴结局两方面。子痫前期及重度子痫276暨南大学学报（自然科学与医学版）第44卷前期的诊断标准采用2 0 2 0 年中华医学会妇产科学分会妊娠期高血压疾病学组制定的妊娠期高血压疾病诊治指南中的定义4。早发型子痫前期指需要在34周前终止妊娠者。母婴结局指标包括早产、胎盘早剥、胎儿生长受限、分娩方式、终止妊娠孕周、产后出血、胎儿窘迫及新生儿室息的发病率，新生儿出生体质量，1min及5min的Apgar评分。（2）实验室指标：在干预前及孕36 周，孕妇晨起空腹采血5mL,采用全自动凝血分析仪测定活化部分凝血活酶时间（activated partial thromboplastintime，A PT T）、凝血酶原时间（prothrombintime，PT）、凝血酶时间（thrombin，T T）及纤维蛋白原（f i b r i n o g e n,Fi b）；采用酶联免疫吸附法测定肿瘤坏死因子（tumor necrosis factor-，T NF-）、白介素-6（interleukin-6，I L-6）及超敏C反应蛋白(Hypersensi tive C reactive protein,hs-CRP)1.3统计分析采用SPSS25.0软件进行数据统计分析，计数资料采用平均值标准差（xs）表示，多组间比较采用单因素ANOVA方差分析，组间两两比较采用LSD-t检验；计数资料采用百分比（%）表示,采用检验或Fisher确切概率检验。P0.05），具有可比性，见表1。表1各组妊娠孕妇的基线情况比较Table 1 Comparison of basic data of pregnant women in each groupn(%)孕前BMI/产次组别年龄/岁孕次/次(kg m*2)初产经产对照组9030.69 4.4824.38 3.522.48 1.2139(43.33)51(56.67)LDA组9029.58 4.0925.30 4.422.27 1.2438(42.22)52(57.78)LDA+低钙组9029.72 4.6424.45 3.762.23 1.3436(40.00)54(60.00)LDA+高钙组9030.83 4.7925.01 3.422.30 1.2838(42.22)52(57.78)2/F值1.8541.2310.6640.217P值0.1370.2980.5740.980纳人人群并发症组别n糖尿病高血压高龄初产妇肥胖不良孕产史对照组902(2.22)10(11.11)33(36.67)39(43.33)29(32.22)42(46.67)LDA组903(3.33)10(11.11)29(32.22)38(42.22)31(34.44)39(43.33)LDA+低钙组904(4.44)12(13.33)35(38.89)36(40.00)28(31.11)43(47.78)LDA+高钙组903(3.33)17(18.89)31(34.44)38(42.22)33(36.67)40(44.44)值0.6903.0950.9700.2170.7340.448P值0.8760.3770.8090.9800.8650.9302.2各组子痫前期发病情况比较与对照组相比,LDA+高钙组的早发型子痫前期、轻度子痫前期及重度子痫前期的发病率显著降低，差异均具有统计学意义（P0.05）。同时，与对照组相比,LDA组及LDA+低钙组的早发型子痫前期及重度子痫前期率显著降低（P0.05），而轻度子痫前期的发病率无明显改变（P=0.15;P=0.0 57）。LD A+低钙组的重度子痫前期的发病率显著低于LDA组（P=0.03）,而早发型子痫前期及轻度子痫前期的发病率两组间无显著降低（P=0.06,P=0.68）;LD A+高钙组的早发型子痫前期及重度子痫前期的发病率显著277韩曦，等：低剂量阿司匹林联合不同剂量的钙剂预防子痫前期高危孕妇的效果及其对炎症因子的影响第3期低于LDA组，差异具有统计学意义（P=0.01，P=0.03）,而轻度子痫前期的发病率两组间无显著差异（P=0.121）。同时,LDA+低钙组及LDA+高钙组之间早发型子痫前期、轻度子痫前期及重度子痫前期的发病率差异无统计学意义(表2)。表2 名各组子痫前期的发病率比较Table2Comparison of the incidence of preeclampsia ineach groupn(%）早发型轻度重度组别子痫前期子痫前期子痫前期对照组16(17.78)9(10.00)19(21.11)LDA组7(7.78)1)4(4.44)8(8.89)1)LDA+低钙组1(1.11)1)2(2.22)1(1.11)1)2)LDA+高钙组0(0)1)2)0(0)1(1.11)1)2)值28.9647.58P值0.0010.0011)与对照组比较,P0.05;2)与LDA组比较,P0.05。1)Compared with control group,P0.05;2)Compared with LDAgroup,P0.05.2.3各组母婴结局情况比较如表3所示，各组间早产、胎儿生长受限、血小板减少、剖宫产、胎儿窘迫及新生儿室息发生率差异有统计学意义（P0.05）。两两比较分析发现,与对照组相比,LDA组、LDA+低钙组及LDA+高钙组的早产、FCR、剖宫产、胎儿窘迫的发生率显著降低(P0.05);LDA+低钙组及LDA+高钙组的血小板减少、新生儿室息的发病率较对照组显著降低（P0.05);LDA+高钙组早产及FCR发病率显著低于LDA组（P=0.009,P=0.014）,而两组之间血小板减少、剖宫产、胎儿窘迫及新生儿室息率差异无统计学意义（P0.05）。不仅如此,LDA+低钙组及LDA+高钙组之间早产、胎儿生长受限、血小板减少、剖宫产、胎儿窘迫及新生儿室息均差异无统计学意义（P0.05）。表3各组母婴结局比较Table 3Comparison of maternal and infant outcomes among groupsn(%)指标对照组LDA组LDA+低钙组LDA+高钙组x/F值P值早产23(25.56)9(10.00)1)2(2.22)1)2)1(1.11)1)2)39.090.001胎儿生长受限20(22.22)7(7.78)1)1(1.11)1)0(0)12)39.350.001胎盘早剥2(2.22)1(1.11)0(0)0(0)3.700.30血小板减少8(8.89)2(2.22)0(0)1)1(1.11)1)14.540.002宫产33(36.67)17(18.89)1)12(13.33)13(14.44)1)19.180.001产后出血5(5.56)2(2.22)1(1.11)2(2.22)3.700.30胎儿窘迫9(10.00)2(2.22)1)1(1.11)1)0(0)17.240.001新生儿室息5(5.56)1(1.11)0(0)1)0(0)11.530.009分娩孕周36.52 3.1337.91 2.141)38.33 1.451)38.68 1.311)2)17.660.001新生儿体质量/kg2749.06521.892964.56 496.84 1)3154.97 418.561)2)3223.17 415.45 1)2)18.820.001新生儿身长/cm47.41 2.2148.54 2.13 1)49.05 2.091)49.52 1.43 1)2)18.810.0011minApgar评分9.09 1.289.260.919.21 0.819.63 0.6111)2)3)5.700.0011)与对照组比较,P0.05;2)与LDA组比较,P0.05;3)与LDA+低钙组比较,P0.05。1)Compared with control group,P0.05;2)Compared with LDA group,P0.05;3)Compared with LDA+low-dose Calcium group,P0.05.278第44卷暨南大学学报（然科学与医学版）此外,与对照组相比,LDA组、LDA+低钙组及LDA+高钙组的分娩孕周、新生儿的体质量及身长均显著升高（P0.001）;LD A+高钙组的1minApgar评分显著升高（P0.05）。LD A+高钙组的分娩孕周、新生儿的体质量、身长及1minApgar评分均显著高于LDA组，差异具有统计学意义（P0.05)。2.4各组凝血功能比较治疗前各组之间PT、A PT T、T T 及Fib差异无统计学意义（P0.05）。各组治疗前后比较可见,对照组治疗后Fib显著下降，而TT、PT 及APTT无明显改变；LDA组、LDA+低钙组及LDA+高钙组的PT、A PT T 及TT均显著延长，而Fib明显降低，差异均具有统计学意义（P0.001,表 4)。治疗后各组间凝血功能进行比较，显示与对照组相比，LDA、LD A+低钙组及LDA+高钙组的PT、A PT T 及TT明显延长，而Fib明显降低，差异均具有统计学意义（P0.001）。与LDA组相比,LDA+低钙组及LDA+高钙组的PT、APTT及TT均显著延长，而Fib明显降低，差异均具有统计学意义（P0.05）。LD A+高钙组的PT较LDA+低钙组显著延长（P0.05，表4）。表4名各组凝血功能比较Table 4Comparison of coagulation function in each groupPT/sAPTT/s组别值P值值P值用药前用药后用药前用药后对照组10.50.510.3 0.52.000.0527.0 1.928.9 2.30.890.38LDA组10.4 0.511.4 0.81)4)10.350.00127.5 1.731.0 3.61)4)8.270.001LDA+低钙组10.4 0.511.7 0.71)2)4)12.930.00127.5 2.132.1 2.91)2)4)12.260.001LDA+高钙组10.50.612.10.61)2)3）4)19.730.00127.4 1.932.1 2.61)2)4)13.820.001F值0.309124.4641.20924.778P值0.8190.0010.3060.001TT/sPrib/(g L-1)组别值P值值P值用药前用药后用药前用药后对照组14.6 0.914.5 0.80.890.385.2 0.84.90.74)2.200.03LDA组14.50.817.4 1.11)4)19.790.0015.30.74.3 0.81)4)9.140.001LDA+低钙组14.50.918.4 0.91)2)4)30.400.0015.30.84.1 0.71)2)4)10.900.001LDA+高钙组14.51.018.5 0.51)2)4)33.340.0015.30.84.1 0.81)2)4)9.920.001F值0.293457.2000.70726.874P值0.8310.0010.5490.0011)与对照组相比,P0.05;2)与LDA组相比,P0.05;3）与LDA+低钙组比较,P0.05;4)与治疗前比较,P0.05。1)Compared with control group,P0.05;2)Compared with LDA group,P0.05;3)Compared with LDA+low-dose Calcium group,P0.05;4)Compared with pre-treatment,P0.05）。治疗前后比较可见,对照组治疗后的hs-CRP显著升279第3期韩曦，等：低剂量阿司匹林联合不同剂量的钙剂预防子痫前期高危孕妇的效果及其对炎症因子的影响高，而TNF-及IL-6无明显改变。LDA组治疗后的TNF-显著降低,hs-CRP明显升高,而IL-6呈下降趋势，但差异无统计学意义。LDA+低钙组及LDA+高钙组治疗后TNF-及IL-6显著下降，而hs-CRP明显升高，差异均具有统计学意义(P0.05)。对治疗后各组间进一步分析可见，与对照组相比，LDA、LD A+低钙组及LDA+高钙组的TNF-,IL-6及hs-CRP明显降低,差异均具有统计学意义（P0.05）。进一步分析发现，LDA+低钙组及LDA+高钙组的TNF-,IL-6及hs-CRP较LDA组明显下降，差异均具有统计学意义（P0.05)。表5各组炎症因子比较Table 5Comparison of inflammatory factors in each group(元s)PTNF-/(g L-1)PIL-6/(pg mL-1)Phs-CRp/(mg L-1)组别用药前用药后值P值用药前用药后值P值用药前用药后值P值对照组1.80.61.80.60.290.7765.1 0.75.1 0.80.770.4412.3 0.6 4.2 0.84)17.420.001LDA组1.80.51.6 0.31)4)2.190.0305.10.74.8 0.81)1.870.0632.3 0.8 3.8 0.91)4)11.650.001LDA+低钙组1.80.61.5 0.41)2)4)3.890.0015.1 0.74.6 0.61)2)4)5.200.0012.4 0.7 3.5 1.01)2)4)9.020.001LDA+高钙组1.7 0.61.5 0.51)2)4)2.890.0015.1 0.74.5 0.61)2)4)6.21 0.0012.3 0.83.5 1.11)2)4)8.090.001F值0.19511.4340.11918.7730.04610.250P值0.9000.0010.9490.0010.9870.0011)与对照组相比,P0.05;2)与LDA组相比,P0.05;3)与LDA+低钙组比较,P0.05;4)与治疗前比较,P0.05。1)Compared with control group,P0.05;2)Compared with LDA group,P0.05;3)Compared with LDA+low-dose Calcium group,P0.05;4)Compared with pre-treatment,P 35岁、初产、肥胖（BMI30kg/m）或子痫前期家族史及个人病史因素（2 次妊娠间隔10年、既往不良妊娠结局、小于胎龄儿或低出生体质量）中任意2 项者。对于筛选的高危人群，可采用阿司匹林作为子痫前期的预防药物。同280暨南大学学报（自然科学与医学版）第44卷时，WHO指南12 推荐阿司匹林7 5mg作为子痫前期的预防剂量，而我国阿司匹林剂型以50 和100mg为主，因此，本研究采用了阿司匹林7 5mg作为子痫前期的预防剂量，同时并对比了联合不同剂量(1或2 g/d)钙剂的预防疗效。本研究结果提示与对照组及单用阿司匹林组相比，联用钙剂组子痫前期、早产、胎儿生长受限、胎儿窘迫的发病率显著降低，而终止妊娠孕周、新生儿体质量、身长及1minApgar评分显著升高。但是，阿司匹林联合低剂量钙剂（1g/d）与联用高剂量钙剂(2 g/d)两组之间子痫前期发病率及母婴结局均差异无统计学意义，这提示阿司匹林联合钙剂对降低子痫前期及其相关并发症如早产、FGR及产后出血的发病率，适当延长孕周，改善母婴结局具有重要临床意义。相关研究揭示免疫系统的过度激活及微血管的异常痊挛与子痫前期的发病密切相关13-15。IL-6、h s-C RP及TNF-是炎症反应的标志物,在子痫前期中的表达显著升高16-18 ,且与疾病的进展密切相关。阿司匹林是乙酰水杨酸类药物，其在机体内可发挥抑制炎症及抗凝反应，还可对血管内皮形成保护作用；而钙剂补充可解除低钙导致的血管痉挛,从而预防子痫前期的发病。本研究揭示采用阿司匹林联合钙剂组的IL-6、T NF-及hs-CRP水平明显下降,且治疗后hs-CRP、T NF-及IL-6水平低于对照组及单用阿司匹林组，提示阿司匹林组联合钙剂可显著降低机体炎症免疫反应。本研究创新性地对比了阿司匹林联合不同剂量钙剂对子痫前期的预防效果，结果表明阿司匹林联合高、低剂量钙剂组之间母婴的临床结局、凝血功能及炎症因子均无显著性差异。这可能与研究对象的基础钙摄人量不同有关，在今后的研究中可进一步评估基础钙摄人量从而个性化制定钙剂补充量。本研究的不足之处：首先，样本量较小，可能存在统计偏差；其次，研究未设置不同孕周应用阿司匹林联合钙剂治疗组，以便观察最优开始及结束孕周；最后，未收集氧化应激等相关指标。有待于后续进一步扩大样本量并制定严谨治疗方案以验证结论。作者贡献声明韩曦：提出研究思路，论文书写及修改；谢晓娟：数据收集；张矛：统计分析数据。利益冲突声明本研究未受到企业、公司等第三方资助，不存在潜在利益冲突。参考文献1AHMAD A,KOHLI M,MALIK A,et al.Role ofthromboelastography versus coagulation screen as a safetypredictor in pre-eclampsia/eclampsia patients undergoinglower-segment caesarean section in regional anaesthesiaJ.J Obstet Gynaecol India,2016,66(Suppl 1):340-346.2SOUZA E V,TORLONI M R,ATALLAH A N,et 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