Amnion nodosum

Amnion nodosum is a placental lesion in which multiple small nodules composed of squamous cells and degenerative debris are deposited on the fetal surface of the amnion.羊膜结节是一种胎盘病变，由鳞状细胞与退变碎屑构成的多发小结节沉积于羊膜的胎儿面。

It is regarded as a placental hallmark of severe and prolonged oligohydramnios and is associated with a high risk of fetal and perinatal mortality.它被视为严重而持续的羊水过少的胎盘标志，并与胎儿及围产期死亡的高风险相关。

Terminology and classification

• The lesion was formerly called Amnionknötchen, meaning amniotic nodules, in the German literature, and the Latin term amnion nodosum has been used in English since the mid-twentieth century.该病变在德语文献中旧称 Amnionknötchen，意为羊膜小结节，二十世纪中叶以后英语文献采用拉丁名（amnion nodosum）。
• The word nodosum refers to the nodular gross appearance and does not imply an inflammatory or neoplastic process, and the lesion is best regarded as a degenerative deposit rather than a tumour.（nodosum）一词指其结节状大体外观，并不意味着炎症或肿瘤性过程，该病变应视为退变性沉积而非肿瘤。
• Amnion nodosum belongs to the group of placental membrane abnormalities, together with amniotic bands, squamous metaplasia of the amnion and amnion rupture sequence.羊膜结节属于胎盘胎膜异常一类，与羊膜带、羊膜鳞状化生及羊膜破裂序列征同组。
• It must be distinguished from true placental tumours such as chorioangioma, from metastatic fetal tumours and from calcified placental infarcts, all of which have different histology.须与绒毛膜血管瘤等真正胎盘肿瘤、转移性胎儿肿瘤及钙化性胎盘梗死相鉴别，后者组织学各不相同。
• In the International Classification of Diseases tenth revision the lesion is usually coded under O43.8 for other placental disorders, because no dedicated code exists for amnion nodosum.在国际疾病分类第十版中，该病变通常归入其他胎盘疾患的 O43.8，因为羊膜结节没有专属编码。
• It is indexed in the Systematized Nomenclature of Medicine under code 71473008, and it has no entry in MONDO or Orphanet because it is a placental finding rather than a Mendelian disease.该病变在医学系统命名法中登记为 71473008，在 MONDO 与 Orphanet 中无条目，因为它属于胎盘所见而非孟德尔遗传病。

History

• The lesion was first described in 1850, according to the historical review by Landing, and early reports focused on its striking gross appearance on the delivered placenta.据 Landing 的历史回顾，该病变最早于 1850 年被描述，早期报告主要关注其在娩出胎盘上的醒目大体外观。^[1]
• Landing published a landmark paper in 1950 that associated amnion nodosum with deficient secretion of fetal urine, linking the placental lesion to renal agenesis and severe oligohydramnios.Landing 于 1950 年发表里程碑式论文，将羊膜结节与胎儿尿液分泌不足相联系，从而把该胎盘病变与肾缺如及严重羊水过少关联起来。^[1]
• Thompson reported a detailed clinicopathological and histological study in 1960, describing the range of nodule sizes and their relationship to the amniotic epithelium.Thompson 于 1960 年发表详细的临床病理与组织学研究，描述了结节大小范围及其与羊膜上皮的关系。^[2]
• Bryans, Balis and Haust published a case series in 1962 that established the characteristic gross description of firm, circumscribed, shiny yellow nodules measuring one to five millimetres.Bryans、Balis 与 Haust 于 1962 年发表病例系列，确立了质硬、界限清楚、有光泽的黄色结节且直径一至五毫米的典型大体描述。^[3]
• Electron microscopy in the late 1960s and 1970s clarified that the nodules consist of densely packed fibrillary material with scattered degenerate cells rather than organised tissue.二十世纪六十年代末至七十年代的电镜研究阐明，结节由致密纤维状物质与散在退变细胞构成，而非有组织的组织块。^[4]
• Salazar and Kanbour published an ultrastructural and histopathogenetic analysis in 1974 that supported a superficial origin from fetal skin elements deposited on the amnion.Salazar 与 Kanbour 于 1974 年发表超微结构与组织发生分析，支持结节起源于沉积于羊膜表面的胎儿皮肤成分。^[5]
• Adeniran and Stanek revisited the entity in 2007 and confirmed that the process is superficial and that the underlying stroma does not participate in nodule formation.Adeniran 与 Stanek 于 2007 年重新审视该病变，确认过程局限于浅层，其下间质并未参与结节形成。^[6]
• Placental pathology reporting has been standardised since the 2016 Amsterdam consensus, which requires lesions of the amniotic membrane such as amnion nodosum to be described systematically.自 2016 年阿姆斯特丹共识以来，胎盘病理报告趋于标准化，要求对羊膜结节这类胎膜病变进行系统描述。

Epidemiology

• Amnion nodosum is uncommon in unselected placentas, and no population-based incidence has ever been established because the lesion is diagnosed only when the placenta is examined.羊膜结节在未经选择的胎盘中并不常见，且从未建立基于人群的发病率，因为只有检查胎盘时才能诊断。
• It is found almost exclusively in pregnancies complicated by severe and prolonged oligohydramnios, most often attributable to fetal renal agenesis or renal dysplasia.该病变几乎仅见于合并严重而持续羊水过少的妊娠，最常见原因是胎儿肾缺如或肾发育不良。
• Other settings include prolonged preterm rupture of membranes, severe placental insufficiency, and the oligohydramnios of the donor twin in twin-to-twin transfusion syndrome.其他情形包括早产胎膜早破、严重胎盘功能不全，以及双胎输血综合征中供血儿的羊水过少。
• Fetal and perinatal mortality is high, and death is usually caused by pulmonary hypoplasia and its consequences rather than by the placental lesion itself.胎儿与围产期死亡率高，死亡通常由肺发育不全及其后果导致，而非胎盘病变本身。
• No consistent maternal age, parity, ethnic or seasonal predisposition has been documented, and the distribution simply follows the causes of oligohydramnios.尚未记录到一致的母亲年龄、产次、民族或季节易感性，其分布仅随羊水过少的病因变化。
• Most cases are diagnosed retrospectively at postpartum placental examination, and antenatal detection depends on recognising the associated oligohydramnios and renal anomaly.多数病例在产后胎盘检查时回顾性诊断，产前识别依赖对相关羊水过少与肾脏异常的发现。
• Referral placentas from tertiary centres show a higher proportion of the lesion, which reflects ascertainment rather than a true increase in occurrence.三级中心送检的胎盘显示该病变比例较高，这反映检出偏倚而非真实发生率上升。

Pathophysiology

• The nodules are formed by desquamated fetal squamous cells that accumulate on the amniotic epithelium together with vernix and cellular debris.结节由脱落的胎儿鳞状细胞与胎脂及细胞碎屑一同在羊膜上皮表面聚集而形成。
• Severe oligohydramnios reduces the volume of amniotic fluid available to disperse and clear these cells, so they concentrate and persist on the membrane.严重羊水过少减少了可用于分散与清除这些细胞的羊水量，使其在胎膜上浓缩并滞留。
• Fetal urine is the principal source of amniotic fluid in the second half of pregnancy, which explains why renal agenesis and urinary tract obstruction predispose to the lesion.妊娠后半期胎儿尿液是羊水的主要来源，这解释了为何肾缺如与尿路梗阻易导致该病变。
• Once deposited, the squamous cells undergo secondary degenerative change and become embedded in amorphous eosinophilic debris on the amniotic surface.沉积之后鳞状细胞发生继发性退变，包埋于羊膜表面的无定形嗜酸性碎屑中。
• Nodules may sit on the amniotic epithelium, be embedded in the amniotic mesoderm, or project through the amnion into the spongy layer cleft between amnion and chorion.结节可位于羊膜上皮之上、包埋于羊膜中胚层内，或穿过羊膜突入羊膜与绒毛膜之间的海绵层裂隙。
• Ultrastructurally the nodules contain closely packed electron-dense fibrillary bundles with irregularly dispersed cellular elements, and the underlying basement membrane is often multilaminated.超微结构上结节含致密排列的电子密度纤维束与不规则散布的细胞成分，其下基底膜常呈多层状。
• The process is superficial and the underlying stroma is spared, which supports the theory that the lesion represents surface deposition rather than a primary stromal disorder.病变过程局限于浅层而其下间质不受累，支持该病变为表面沉积而非原发性间质疾病的理论。
• Because the same oligohydramnios that produces the nodules also causes pulmonary hypoplasia, the two findings are linked by a common causal pathway rather than by direct causation.由于产生结节的同一羊水过少也导致肺发育不全，两种表现通过共同病因途径相关联，而非直接因果。

Clinical features

• The mother is usually asymptomatic, and the lesion produces no maternal systemic symptoms, pain, bleeding or fever.母亲通常无症状，该病变不引起母体全身症状、疼痛、出血或发热。
• On gross examination the fetal surface of the amnion shows multiple firm, circumscribed, round to ovoid, raised, shiny yellow nodules ranging from one to five millimetres in diameter.大体检查可见羊膜胎儿面多发质硬、界限清楚、圆形或卵圆形、隆起、有光泽的黄色结节，直径一至五毫米。
• The nodules may be few and clustered near the cord insertion or widely scattered over the membrane, and they do not invade the underlying placental parenchyma.结节可稀少并聚集于脐带附着处附近，也可广泛散布于胎膜，且不侵入其下胎盘实质。
• The associated oligohydramnios may present clinically as a small-for-gestational-age uterus, reduced fundal height and difficulty in identifying fetal parts.相关羊水过少在临床上可表现为子宫小于孕周、宫底高度偏低以及触诊胎儿肢体困难。
• Fetal consequences include pulmonary hypoplasia, Potter facies, limb deformities and compression-related skin changes, all of which follow from severe oligohydramnios.胎儿后果包括肺发育不全、Potter 面容、肢体畸形与受压所致皮肤改变，均继发于严重羊水过少。
• Amnion nodosum may coexist with amnion rupture sequence or amniotic bands, and the combination worsens the prognosis for the fetus.羊膜结节可与羊膜破裂序列征或羊膜带并存，二者合并使胎儿预后更差。
• When the lesion is found without a history of oligohydramnios, the clinical records and renal imaging of the infant should be reviewed before the finding is dismissed as incidental.若发现该病变而史无羊水过少，在将其视为偶然发现之前应复核临床记录与婴儿肾脏影像。

Diagnosis

• Diagnosis is made by gross and histological examination of the placenta after delivery, because the nodules are too small and non-specific to be detected reliably by antenatal imaging.诊断依靠分娩后胎盘的肉眼与组织学检查，因为结节过小且无特异性，产前影像难以可靠检出。
• Histology shows squamous cells embedded in degenerative amorphous acidophilic debris, with an overlying or intervening amniotic epithelial layer.组织学显示鳞状细胞包埋于退变性无定形嗜酸性碎屑中，其表面或其间可见羊膜上皮层。
• Immunohistochemistry for cytokeratins confirms the squamous nature of the cells and helps to exclude other eosinophilic deposits.细胞角蛋白免疫组化可确认细胞的鳞状性质，并有助于排除其他嗜酸性沉积物。
• Electron microscopy is rarely required but shows dense fibrillary bundles and multilaminated basement membrane, confirming the superficial nature of the deposit.电镜很少需要，但可显示致密纤维束与多层基底膜，证实沉积的浅表性质。
• The differential diagnosis includes amniotic bands, squamous metaplasia of the amnion, placental infarction with calcification, chorioangioma and metastatic tumour.鉴别诊断包括羊膜带、羊膜鳞状化生、伴钙化的胎盘梗死、绒毛膜血管瘤与转移性肿瘤。
• Antenatal ultrasound supports the diagnosis indirectly by showing severe oligohydramnios, an absent fetal bladder and renal agenesis or dysplasia.产前超声通过显示严重羊水过少、胎儿膀胱不显示及肾缺如或发育不良，间接支持诊断。
• Fetal autopsy and postnatal renal imaging are important to identify the underlying renal anomaly and to inform recurrence risk counselling.胎儿尸检与出生后肾脏影像对识别潜在肾脏异常及指导再发风险咨询十分重要。
• No maternal blood or urine test is available, and serum markers of placental function are not diagnostic of amnion nodosum.目前无母体血液或尿液检查可用，胎盘功能血清标志物对羊膜结节无诊断价值。

Management

• There is no specific treatment for the nodules themselves, and management is directed at the pregnancy complicated by oligohydramnios and at the underlying fetal anomaly.结节本身无特异性治疗，处理针对合并羊水过少的妊娠及潜在胎儿畸形。
• Pregnancy surveillance includes serial ultrasound for amniotic fluid volume, fetal growth, bladder visualisation and renal anatomy.妊娠监测包括系列超声评估羊水量、胎儿生长、膀胱显示与肾脏解剖。
• Delivery should be planned in a centre with neonatal intensive care and paediatric nephrology support when severe oligohydramnios or a renal anomaly is suspected.疑有严重羊水过少或肾脏异常时，应安排在具备新生儿重症监护与儿童肾脏病支持的中心分娩。
• Neonatal resuscitation and respiratory support may be needed for pulmonary hypoplasia, and the paediatric team should be present at delivery.肺发育不全可能需要新生儿复苏与呼吸支持，分娩时应有儿科团队在场。
• Genetic counselling and postnatal renal imaging are indicated because renal agenesis and dysplasia carry a recurrence risk and may be part of a syndrome.因肾缺如与肾发育不良具有再发风险且可能属于某综合征，应进行遗传咨询与出生后肾脏影像检查。
• Infants with bilateral renal agenesis require renal replacement therapy, and those with less severe dysplasia need long-term nephrological follow-up.双侧肾缺如婴儿需肾脏替代治疗，发育不良较轻者亦需长期肾脏病随访。
• Placental histology should be communicated to the clinical team, because it documents the severity of oligohydramnios and supports counselling for future pregnancies.胎盘组织学结果应告知临床团队，因为它记录羊水过少的严重程度并支持未来妊娠的咨询。
• Prevention is limited to identifying and managing the causes of oligohydramnios, such as urinary tract obstruction, placental insufficiency and preterm membrane rupture.预防仅限于识别并处理羊水过少的病因，如尿路梗阻、胎盘功能不全与早产胎膜破裂。

Research and controversies

• The precise pathogenesis remains uncertain, and the relative contribution of fetal skin desquamation, amniotic epithelial injury and reduced fluid clearance is still debated.确切发病机制仍不确定，胎儿皮肤脱屑、羊膜上皮损伤与液体清除减少的相对贡献仍有争议。
• Whether the amniotic epithelium participates actively in nodule formation or is merely a passive surface is unresolved, and ultrastructural studies give conflicting emphasis.羊膜上皮是主动参与结节形成还是仅作为被动表面尚未明确，超微结构研究的侧重相互矛盾。
• No molecular marker or immunohistochemical panel has been validated to distinguish amnion nodosum from other squamous deposits in the membrane.尚无分子标志物或免疫组化组合经验证可用于区分羊膜结节与胎膜其他鳞状沉积物。
• Prenatal diagnosis remains indirect, depending on the detection of oligohydramnios and renal anomalies, and the nodules themselves are not imaged.产前诊断仍为间接性，依赖对羊水过少与肾脏异常的检出，结节本身无法成像。
• Population data are scarce because cases are collected in placental pathology archives, and multicentre registries would be needed to estimate frequency and outcomes.由于病例集中于胎盘病理档案，人群数据稀缺，需多中心登记才能估计发生频率与结局。
• The long-term renal and respiratory outcomes of surviving infants with amnion nodosum have not been systematically studied, and follow-up studies are needed.存活羊膜结节婴儿的长期肾脏与呼吸结局尚未被系统研究，需要随访研究。