子痫前期为妊娠特发的疾病，以孕20周之后出现血压升高，蛋白尿为主要临床表现，由于全身小动脉痉挛可造成多系统受累，如心、肝、肾功能不全，血小板减少、脑水肿等，同时可导致胎盘早剥、胎死宫内等诸多不良妊娠结局，严重时会突发抽搐、发生子痫，可危及生命。子痫前期在妊娠期妇女中发病率约为5%～10%，严重威胁母儿安全。有学者对美国国内的数据进行分析认为，子痫前期的患者胎盘早剥、血小板减少、弥散性血管内凝血、肺水肿、肺部感染发生率较正常孕妇增加3～25倍[1]。轻度子痫前期及重度子痫前期患者新生儿死亡率为2%及4%[2]。子痫前期还可导致新生儿低出生体重，并对新生儿远期学习能力及智力发育有不良影响。子痫前期发病机制复杂，涉及免疫异常，胎盘或滋养细胞缺血，氧化应激及遗传因素[3]。目前，分娩是已知的唯一治愈手段，因此子痫前期的剖宫产率和早产率远高于正常人群[4]。
同型半胱氨酸(Homocysteine，Hcy)是蛋氨酸脱甲基代谢中产生的一种含硫氨基酸，Hcy的代谢途径需要叶酸、维生素B12及N5、N10-亚甲基四氢叶酸还原酶(Methylene Tetrahydro Folate Reductase，MTHFR)的参与。因此，富含维生素B6、维生素B12和叶酸的饮食和Hcy呈负相关。而Hcy水平升高被认为能够提示这种代谢途径(一碳代谢)的紊乱[5-6]。而MTHFR是Hcy叶酸循环途径代谢过程的关键酶，它的基因碱基对突变将导致MTHFR活性下降，其中目前研究已明确与高同型半胱氨酸血症相关的MTHFR基因位点有677位点及1298位点等。MTHFR基因突变导致N5、N10-亚甲基四氢叶酸还原酶活性下降，进而引起Hcy升高[7-8]。此外，肾功能减退、长期大量饮酒、吸烟、营养缺乏等均可导致Hcy升高。以下对Hcy与子痫前期及叶酸的相关研究进行综述。
图1 叶酸代谢途径
一、Hcy与子痫前期
子痫前期的发病机制复杂，涉及胎盘植入异常、遗传、免疫、环境等。遗传易感性方面，凝血与纤溶系统异常参与子痫前期发病，病理检查发现，子痫前期患者的胎盘绒毛血管中存在微小血栓的形成。有很多针对凝血与纤溶系统遗传学特征的研究，集中在凝血因子V(coagulation factor V，FV)，凝血因子II(coagulation factor II,FII)，亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase，MTHFR)，纤溶酶原激活物抑制剂(plasminogen activator inhibitor,PAI-1)等。MTHFR是Hcy及叶酸代谢途径中的关键酶，MTHFR基因突变位点与MTHFR的活性及血液中Hcy水平密切相关，目前研究比较成熟的两个多态性位点是MTHFR 677C/T多态及1298A/C多态，有很多学者在针对这两个位点的基因突变与子痫前期发病进行相关性研究，但尚未得到一致结论[9-11]。
其他方面，包括肾素-血管紧张素-醛固酮系统、血管生成相关因子、氧化应激、脂质代谢、炎症反应，这些参与子痫前期发病的机制均存在相关的基因多态性病理基础。
Sorensen等[12]测定3 042例15～22周妊娠期妇女血浆Hcy水平，从中选取发展为妊娠期高血压妇女52例，健康对照组56例，发现病例组血浆Hcy≥5.5 μmol/L者占29%，而对照组仅13% ，经过年龄、性别、胎次、BMI指数的校正，孕中期Hcy水平升高增加3.2倍子痫前期的风险(校正OR=3.2，95% CI ：1.1～9.2，P=0.030)，提示血浆Hcy水平升高可能会促进子痫前期发展。而2005年一项涉及25项研究的meta分析对3 649例孕妇进行血浆Hcy的测定发现，在子痫前期出现临床表现之前，血浆Hcy水平已较血压正常的孕妇有所升高[13]。2015年西班牙学者对252例孕20周以前的孕妇进行随访观察，发现其中49例发展为子痫前期，在发展为子痫前期之前一个月，血浆Hcy水平明显升高(P=0.001)，而无合并症组孕期血浆Hcy水平维持在稳定的水平[14]。同时，多位学者发现，血清Hcy水平过高将导致子痫前期，高Hcy血症预测子痫前期，但与其严重程度无明显关系[15-16]。因此，妊娠中期血浆Hcy水平可作为早期预测妊娠期高血压疾病的指标。Zeng等[17]认为，Hcy水平升高导致血管内皮细胞损伤，内皮素-1升高，最终导致妊娠期高血压疾病的发生。
二、Hcy与胎盘血管疾病及胚胎发育
有研究表明，合并子痫前期的孕妇胎盘检测C677T基因TT型的比例更高[18]。还有学者对165例胎盘血管疾病(胎盘梗死，胎盘早剥)及139例健康妊娠期妇女进行分析，发现病例组血浆Hcy水平显著高于对照组，叶酸水平低于对照组，病例组中MTHFR基因纯合突变率为12%，而对照组为5%[19]。因此，学者们推断，血浆Hcy水平与胎盘血管疾病发生也是具有相关性的[20]。
Eskes等[21]研究认为，高Hcy水平与胎盘早剥相关，是胎盘血管疾病的独立危险因素。Murphy等观察发现孕早期孕妇的血清Hcy达到8.44 umol/L以上时，新生儿低体重的发生率比血清Hcy水平在8.44 umol/L以下的孕妇高3倍[22]。但也有部分学者认为，血清Hcy水平与妊娠结局没有必然的联系[23]。
Hcy与胚胎发育方面的相关性方面，有研究者发现，向培养基添加额外的Hcy可以抑制动物模型的胚胎发育[24]。还有学者对236名孕早期的妇女(包括97例辅助生殖及139例自然受孕的妇女)进行分析发现，血浆Hcy水平与上述两亚组的孕早期顶臀长均呈负相关，并且高Hcy水平(+2SD)与低Hcy水平(-2SD)相比，在孕7周平均降低胚胎体积0.10 m3(-33.3%)，在孕11周平均降低胚胎体积1.65 m3(-16.1%)[25]。而孕早期的胚胎生长和孕中晚期的胎儿发育和出生体重密切相关。孕早期顶臀长水平偏低的孕妇和正常孕妇相比，早产、低出生体重儿、子代心血管疾病的风险都将明显增加[26-29]。
三、叶酸对Hcy及子痫前期的影响
高Hcy血症的治疗可通过抑制Hcy生成，促进代谢来实现。目前普遍接受的最经济和有效的手段是补充叶酸[30]。Sudchada等[31]于2012年对符合纳入标准的4项RCT研究进行的meta分析得出，连续服用叶酸5 mg(4周～6个月)可降低2型糖尿病患者的Hcy水平，甚至改善血糖控制水平。
有学者对246名孕妇分为两组[32]，自妊娠早期至分娩全程使用叶酸5 mg/d或0.8 mg/d，探讨不同剂量叶酸对妊娠期高血压疾病发生率及血浆同型半胱氨酸水平的影响，发现两组均未发生妊娠期高血压疾病，但补充叶酸5 mg/d组血浆Hcy水平下降更为显著，并且新生儿体重大于补充叶酸0.8 mg/d组。后续的研究中该学者在2016年扩大样本量至460例，得出同样的结论。同时，该学者研究表明，整个孕期服用大剂量叶酸(叶酸5 mg/d)未导致孕妇出现不良反应[33]。MTHFR基因型对叶酸降Hcy是有影响的，TT基因型由于酶活性降低，Hcy水平较高，但服用叶酸后血浆Hcy下降程度较CT型和CC型更为明显，但目前尚未得出一致性结论[34]。
Wen等[35]对2 951名孕妇进行研究发现，服用含叶酸的复合维生素可提高血清叶酸含量(平均10.51mmol/L)、降低血浆Hcy水平(平均0.39 mmol/L)，可降低子痫前期的发生率(校正OR=0.37；95% CI ：0.18～0.75)。该团队2016年发表对7 669名妊娠期妇女的前瞻性队列研究结果，研究认为补充叶酸可以降低子痫前期风险，但是由于对照组，即未补充叶酸的孕妇占总样本量的不足5%，样本计算把握度较小，叶酸剂量对子痫前期风险的影响差异无统计学意义[36]。
Kennedy等[37]研究认为，整个孕期服用大剂量叶酸(叶酸5毫克/日)并不增加结肠癌等肿瘤风险。2007年及2015年加拿大妇产科协会针对孕前妇女预防NTD应用叶酸联合复合维生素相关指南[38]反复强调，对于合并1型或2型糖尿病的NTD风险为高危的患者，建议孕前3个月至孕10～12周服用叶酸5 毫克/日以降低NTD风险；同时，该指南认为，服用叶酸5 毫克/日并不增加母儿风险，人体对叶酸的吸收是按需摄入，可根据需要量调节摄入量。此外，有研究对硬化的患者给予口服叶酸15 毫克/日治疗观察头颅MRI变化，其中68名患者服用达到2年，患者血浆Hcy水平均较治疗前下降，且患者表现出良好的依从性，未出现不良反应[39]。
因此，目前研究广泛认为Hcy与子痫前期具有相关性，可以作为子痫前期的血清学预测指标之一，应用叶酸可降低Hcy水平，但是否可以同时降低子痫前期发生率，尚待进一步研究。
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