胎儿生长受限，也称为胎儿宫内生长受限，是一种妊娠的常见并发症，与多种不良的围产期结局有关。目前，胎儿生长受限的专业术语，病因学和诊断标准尚无共识，生长受限的胎儿的最佳管理和分娩时机也缺乏统一标准。另一个挑战是难以区分本质小但能实现其生长潜力的胎儿和由于潜在的病理状况而不能满足其生长潜力的小胎儿。本文旨在于就胎儿生长受限的专业术语、病因学、诊断、监测手段，以及孕期管理和分娩时机的指导作一综述。
背景
专业术语
对于未能达到正常体重的胎儿和未能达到正常出生体重的新生儿分类的术语是不同的。使用定义明确的术语能够促进产科医生和新生儿科医生之间的沟通，这些术语根据给定孕龄的绝对体重或体重百分位数来描述胎儿和新生儿体重 [1-4]。在本文中，“胎儿生长受限”这一术语将用于描述估计胎儿体重小于同胎龄体重的第10百分位的胎儿，而术语“小于胎龄儿（SGA）”仅用于描述出生体重小于同胎龄的第10百分位的新生儿。
发病率
胎儿生长受限的发病率取决于当地采用的的定义。如前所述，在美国，胎儿生长受限使用最广泛的定义是估计胎儿体重小于同胎龄体重的第10百分位数[5]。然而，该定义没有考虑到每个胎儿的个体化生长潜力，并且使用该定义时可能无法识别未达到其生长潜力的较大胎儿，由此可能引起不良的产科结局。相反，这一定义也可能将一些体质上较小的胎儿误诊为胎儿生长受限[6-9]。为了更准确地评估新生儿和胎儿是否正常生长，研究人员设计出了计算个体化生长标准的公式[10,11]。但目前尚未证实使用这些公式能够改善产科结局。
病因
胎儿生长受限的病因大致可以分为母体，胎儿和胎盘因素（见表1）。尽管不同因素引起胎儿生长受限的主要病理生理机制不同，但它们常常（但并非都是）具有相同的最终演变途径：子宫-胎盘灌注不良及胎儿营养不良。
母体疾病
可能导致胎儿生长受限或SGA的母体疾病包括任何与血管疾病相关的慢性疾病[12-14]，如妊娠相关的高血压疾病[12]。抗磷脂综合征是一种获得性免疫介导的血栓形成疾病，也可引起胎儿生长受限[15]。然而，遗传性血栓形成疾病，包括因子V莱顿（Leiden）突变、凝血酶原突变，或亚甲基四氢叶酸还原酶基因突变等，均未被发现与胎儿生长受限或SGA相关[16-18]。
药物的使用和滥用
孕期吸烟可以使SGA风险增加3.5倍，是个可改变的危险因素[12,19]。其它可以引起SGA的因素包括酒精、可卡因和麻醉剂[20-25]。即使每天只摄入一至两杯含酒精的饮料，发生SGA的风险也会增加[21]。
孕期营养
有关饥荒时期妊娠或分娩的妇女的纵向研究表明，母亲的营养不良与SGA之间存在一定联系[26,27]。这些研究显示，妊娠26周前极低的蛋白质摄入量与SGA相关，严重的热量限制（如每天摄入600-900千卡）可以引起出生体重一定程度的下降。但是，当母亲没有营养不良而怀疑合并胎儿生长受限时，没有明确证据表明，额外的增加孕期营养摄入能够增加胎儿体重或改善预后[28]。
多胎妊娠
在美国，双胎妊娠虽然仅占活产儿的2-3％，但发生新生儿不良结局的概率高达10-15％，并且与早产和SGA的发生率增加有关[29-31]。据报道，在多胎妊娠中，双胎妊娠发生SGA的风险高达25％，而三胎和四胎妊娠发生SGA的风险高达60％[32]。此外，单绒毛膜双胎妊娠由于存在胎盘分配不均衡以及双胎输血综合征，较易发生SGA[33]。
致畸剂暴露
某些孕期药物也与胎儿生长受限有关。药物对胎儿的影响取决于药物本身的致畸性、药物作用的时机和持续时间、药物的剂量和药物代谢的个体易感性。某些抗肿瘤药物（如环磷酰胺）、抗癫痫药物（如丙戊酸）和抗血栓药物（如华法林）的使用与胎儿生长受限风险的增加有关[34-38]。
传染性疾病
据估计，约5-10％的胎儿生长受限主要是由于宫内感染引起的[39]。其中，在全世界范围内，疟疾是最主要的病因[40]。其他与胎儿生长受限有关的传染病包括巨细胞病毒，风疹，弓形虫病，水痘和梅毒[39,41-44]。
遗传和结构性疾病
胎儿生长受限与某些染色体异常有关：至少有50％的13-三体或18-三体的胎儿合并胎儿生长受限[45]。通过绒毛取样鉴定的限制性胎盘嵌合体也与胎儿生长受限有关[46,47]。
具有多种类型的结构畸形（但不具有染色体或遗传异常）的胎儿，发生胎儿生长受限的风险也会增加[48]。例如，与正常的胎儿和新生儿相比，患有先天性心脏病的胎儿和新生儿发生胎儿生长受限和SGA的风险均增加[49,50]。先天性腹裂是另一种较常引起胎儿生长受限的畸形，约25%的先天性腹裂的胎儿合并胎儿生长受限[51]。
胎盘疾病和脐带异常
胎儿生长受限最常见的病理机制是由于胎盘形成异常导致的胎盘灌注不良（即胎盘功能不全）[52]。某些胎盘疾病（如，胎盘早剥、胎盘梗死、轮状胎盘、血管瘤和绒毛膜血管瘤）和脐带异常（如，脐带帆状附着和脐带边缘插入）与胎儿生长受限的发生也有一定关系[34,53-57]。然而，其他胎盘疾病，如胎盘植入和前置胎盘，与胎儿生长受限无明显关系[58]。
大约有1％的妊娠存在单脐动脉[59]。不伴有其它解剖学或染色体异常时，有研究认为单脐动脉的存在与胎儿生长受限有关，但另外一些研究则认为无相关性[60,61]。
围产期发病率和死亡率
胎儿生长受限会增加胎儿宫内死亡率、新生儿发病率和新生儿死亡的风险[62]。此外，流行病学研究表明，生长受限的胎儿出生后在儿童时期易于出现认知发育迟缓，成年后也容易患病（如肥胖，2型糖尿病，冠状动脉疾病和中风）[63,64]。
胎儿生长受限显著增加死产风险，生长受限程度越严重的胎儿，发生风险越大[65]。胎儿体重低于同孕龄体重的第10百分位时，胎儿死亡的风险约为1.5％，约是正常体重胎儿的两倍。相比之下，低于同孕龄体重第5百分位的胎儿发生死产的风险增长到2.5％[66,67]。合并脐动脉舒张末期血流缺失或者倒置的生长受限的胎儿，发生不良结局的风险增加，新生儿死亡率和发病率亦增加[68]。
小于胎龄儿的新生儿易患以下并发症，包括低血糖，高胆红素血症，体温过低，脑室内出血，坏死性小肠结肠炎，癫痫发作，败血症，呼吸窘迫综合征和新生儿死亡[69-73]。
筛查胎儿生长受限
病史和体格检查
妊娠24-38周，测量的宫底高度（厘米），用于估计孕龄以及筛选低于或超过正常体重第10百分位的胎儿生长[74]。 据报道，妊娠32-34周时，单一宫底高度的测量检出胎儿生长受限的敏感性约为65-85％，特异性约96％[75-79]。宫底高度作为测量工具时，其准确性受到母体肥胖和合并子宫平滑肌瘤等因素的限制，而超声是更好的检查手段。
超声诊断和评估
为了评估胎儿生长受限，通常使用四种生物测量指标：1）双顶径，2）头围，3）腹围，和4）股骨长度。这些测量指标可以组合来估计胎儿体重[80]。95％的胎儿估计体重可能偏离出生体重高达20％，而另外5％的估计体重偏差甚至可能超过20％[78,81-83]。如果超声估计胎儿体重低于同孕龄体重的第10百分位，则应考虑进一步检查，例如羊水评估和脐动脉多普勒血流评估。由于生长受限的胎儿易合并遗传和结构疾病，如果早期未行检查，也建议行胎儿解剖学的超声检查。
胎儿生长受限时，多普勒血流测速，尤其是对脐动脉的评估，其效用已经得到了广泛的研究和回顾分析[84]。脐动脉舒张末期血流缺失或倒置与围产儿死亡风险增加有关[85-88]。胎儿生长受限的标准产前检测中增加脐动脉多普勒血流测速项目，围产儿死亡率降低可多达29％[89,90]。静脉导管中的血流测量也可尝试用于评估胎儿状态，但尚未证实其能够改善产科结局[91-94]。
临床注意事项和建议
孕期应如何筛查胎儿生长受限？
所有孕妇均应回顾产科病史，发现胎儿生长受限的风险因素。妊娠24周后，每次产检均应测量宫底高度。测得宫底高度对应孕周与实际孕周差值大于3者，可能存在胎儿生长受限[74]。母亲肥胖、多胎妊娠及合并子宫肌瘤会影响宫底高度的评估；多次妊娠或宫底高度触诊不满意时，优选超声检查。当存在增加胎儿生长受限风险的母体因素时，也可以使用超声检查。
尽管还有其他筛查胎儿生长受限的方法（包括孕晚期系统超声筛查、子宫动脉多普勒血流测速，以及妊娠相关血浆蛋白A的分析测量），但没有证据表明上述这些筛查手段能够改善产科结局[95-102]。
如何评估有前次小于胎龄儿分娩史的孕妇？
SGA出生的复发风险约为20％[9]。任何有前次SGA分娩史的孕妇都应回顾其既往病史，以发现风险因素，尤其是可纠正的风险因素。尽管尚未确定最佳监测方案，但对于这类孕妇有必要进行连续的超声检查来评估胎儿生长情况。如果孕妇此次妊娠的胎儿生长情况正常，前次SGA分娩史则不是进行产前胎心率测试，胎儿生物物理评分或脐动脉多普勒血流测速的指征[103]。
其他与SGA相关的母体因素亦需要被评估。抗磷脂综合征的一个诊断标准是前次妊娠于34周前分娩形态学正常的生长受限的胎儿。然而，没有足够的证据表明在随后的妊娠中进行筛查和治疗可以改善产科结局[104]。遗传性血栓形成倾向的杂合性（如因子V莱顿（Leiden）突变和凝血酶原突变）并未始终与胎儿生长受限相关，且并不推荐对母亲进行血栓形成倾向的相关检测[17,104]。
胎儿生长受限如何预防？
现已有较多方法来预防胎儿生长受限。许多营养和膳食补充策略已被研究，尽管尚无一种有效。这些方法包括个体化营养咨询[105]；增加鱼类，低脂肪肉类，谷物，水果和蔬菜的摄入量[106]；低盐饮食[107]；补充铁[108]，锌[109]，钙[110]，蛋白质[111]，镁[112]和维生素D[113]。因此，营养和膳食补充策略不能预防胎儿生长受限，故不推荐。
同样，尚无一致的证据表明住院或门诊卧床休息可以预防胎儿生长受限或降低SGA的出生率[114]。对于有SGA分娩史的孕妇，一些专家建议使用阿司匹林来预防胎盘功能不全。但是，没有足够证据证明这种治疗预防胎儿生长受限的常规手段[115-118]。
胎儿生长受限发生时，应何时进行遗传咨询和产前诊断检测？
尽管单独的胎儿生长受限可能与非整倍体胎儿相关，但如果存在胎儿结构异常，非整倍体的风险也会增加。因此，胎儿生长受限和结构缺陷同时存在时，患者应进行胎儿异常类型咨询，并考虑进行产前诊断测试。另外，由于妊娠早期发现的胎儿生长受限更多见与非整倍体的发生相关[119]，因此孕中期发现的胎儿生长受限是进行遗传咨询和产前诊断检测的指征。
如何评估和管理妊娠合并胎儿生长受限？
超声检查仍然是评估生长受限胎儿的最佳方法。监测胎儿生长受限的方法包括胎儿生物测量和羊水量的连续超声测量。考虑到围产期利益，脐动脉多普勒血流测速和分娩前监测（如非应激试验或或者胎儿生物物理评分）建议在达到可以分娩的孕周进行[30,31,120-124]。评估胎儿生长的最佳间隔时间和最佳产前监测方案尚未确定。大多数生长受限的胎儿可以通过每3-4周的连续超声监测得到充分评估。由于超声测量本身的固有误差会影响最胎儿阶段生长的准确评估，因此超声评估胎儿生长的时间间隔不应小于2周[125,126]。
多普勒血流测速仪在评估妊娠合并胎儿生长受限方面有何作用？
脐动脉多普勒血流测速在妊娠合并胎儿生长受限的诊断和管理中起重要作用。它与标准胎儿监测（如非应激试验，生物物理学概况，或两者结合）的联合使用，可以改善已确诊生长受限胎儿的出生结局[90]。多普勒评估可以发现胎儿生长受限的病因，因为脐动脉血流阻力增加表明妊娠合并潜在的胎盘功能不全。此外，脐动脉舒张末期血流缺失或倒置与围产期胎儿死亡增加相关[86-88,127]，并且可以影响胎儿生长受限的分娩时机[84]。多普勒血流测速对胎儿其他血管，包括对大脑中动脉和心前区静脉系统的评估也被用来研究胎儿生长受限的发生。在欧洲脐带和胎儿血流的随机试验（TRUFFLE）研究的2年随访中，研究人员发现，与孕期多普勒追踪胎儿心率变化分娩的胎儿相比，尽管孕期多普勒监测静脉导管晚期变化可能导致围产期胎儿和婴儿的死亡率增加，但其与儿童2岁时发生神经发育缺陷的减少有关[128]。因此，这些血流测量尚未被证实能够改善围产期结局，并且它们在临床中的作用仍不确[91,92,127,129-131]。
胎儿生长何时终止妊娠？
胎儿生长受限的最佳分娩时机取决于发生胎儿生长受限的潜在病因（如果已知），估计胎龄和其他产前检查的结果，例如，改变染色体非整倍体胎儿或合并先天性感染的胎儿的分娩时机可能无法改善预后。此外，在某些情况下，孕妇可能会选择不干预，例如，即使胎儿死亡风险增加，一些孕妇也可能选择放弃严重生长受限的胎儿，而在25周时分娩。可以通过个性化和多学科的方法加强产前管理。当妊娠干预是围产期受益的首选方案时，产前胎儿监测可能有助于指导分娩时机。单独的胎儿生长受限不是剖宫产分娩的指征，分娩方式的选择应基于其他临床条件。
胎儿生长受限干预试验是目前唯一发布的，用来评估生长受限的早期早产儿（小于34周）分娩时机的随机试验。在这项试验中，当对于妊娠合并胎儿生长受限的孕妇，产科医生不确定分娩是否有益时，孕妇则被随机分配到早期分娩组（48小时内分娩）或期待治疗组（进行产前监测，直到不再需要延长孕周时分娩）。两组的倍他米松给药率相同。结果显示，两组的围产儿存活率相似，并且在6-12岁的随访中发现，两组孕妇分娩的胎儿在认知、语言、行为或运动能力方面没有差异[132-134]。在长期不成比例宫内生长干预试验中，单胎妊娠36或以上的怀疑胎儿生长受限（定义为估计胎儿体重低于第10百分位）的孕妇被随机分配到分娩组或者期待治疗组（当出现其他指征时终止妊娠）[135]。尽管该队列研究样本量太小，不足以确定个体结局（如围产儿死亡）是否受到不同处理方法的影响，但这两组之间的新生儿整体结局没有差异。
目前没有足够有力的随机试验来确定孕周为34-36周的生长受限的胎儿的最佳分娩时机。根据有关分娩时机的现有数据和专家共识，尤尼斯·肯尼迪·施莱佛国立儿童健康与人类发展研究所、美国母婴医学学会和美国妇产科学院的联合会议针对已确诊的胎儿生长受限，给出以下两种分娩时机策略：1）妊娠仅合并胎儿生长受限时，建议妊娠38 0/7周-39 6/7周分娩；2）胎儿生长受限合并其他引起不良产科结局的危险因素（如羊水过少，脐动脉多普勒血流测速结果异常、产妇自身因素，或有其他合并症）时，建议妊娠32 0/7周至37 6/7周分娩。在某些严重情况下，如脐动脉舒张末期血流倒置，在此孕周范围内也应提前终止妊娠[136-138]。
胎儿生长受限的孕妇，估计在妊娠34周之前分娩时，应在新生儿重症监护室中心进行分娩，最好咨询母婴专家后进行分娩。估计在妊娠33 6/7周之前分娩时，糖皮质激素由于与改善新生儿早产结局有关，建议在分娩前使用。此外，孕妇估计在妊娠34 0/7周至36 6/7周之间分娩时，若孕妇可能在7天内分娩，或未使用过糖皮质激素，也建议分娩前使用糖皮质激素[139-143]。对于可能在妊娠32周前分娩的孕妇，应使用硫酸镁用于胎儿和新生儿的神经保护[144-147]。
总结和结论
以下建议和结论基于良好和一致的科学证据（A级）：
脐动脉多普勒血流测速与标准胎儿监测（如非应激试验、生物物理评分，或两者结合）的联合使用，可以改善已诊断生长受限的胎儿的产科结局。
如果估计在妊娠33 6/7周之前分娩，糖皮质激素由于与改善早产新生儿结局有关，推荐分娩前使用。此外，此外，孕妇估计在妊娠34 0/7周至36 6/7周之间分娩时，若孕妇可能在7天内分娩，或未使用过糖皮质激素，也建议分娩前使用糖皮质激素。
估计在妊娠32周前分娩，应推荐使用硫酸镁用于胎儿和新生儿的神经保护。
营养和膳食补充策略不能预防胎儿生长受限，不推荐使用。
以下建议和结论基于共识和专家意见（C级）：
单独的胎儿生长受限不是剖宫产分娩的指征。
胎儿生长受限的最佳分娩时机取决于发生胎儿生长受限的潜在病因（如果已知），估计胎龄和其他产前检查的结果。
建议的绩效衡量
怀疑合并胎儿生长受限的孕妇，如果在确诊后没有进行分娩，则启动评估和监测胎儿生长和健康的计划，并统计（这一部分孕妇所占的）比例。
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