Birth Defects Research最新文献_第3页

Folate Interaction With Genetic Risk for Neural Tube Defects Among Infants in Bangladesh 叶酸与孟加拉国婴儿神经管缺陷遗传风险的相互作用。

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-12-11 DOI: 10.1002/bdr2.70007

Enrique Mondragon-Estrada, Xingyan Wang, Michael D. Uhler, Afifah Farooque, Kelly Liu, Sudipta Kumer Mukherjee, Sheikh Muhammad Ekramullah, D. M. Arman, Joynul Islam, Hafiza Sultana Suchanda, David C. Christiani, Benjamin C. Warf, Maitreyi Mazumdar, Sarah U. Morton

Background

Neural tube defects such as spina bifida (SB) are congenital anomalies associated with significant morbidity and mortality worldwide. Environmental factors, particularly folate, modify SB risk. Based on recurrence rates of SB within families, genetic risk also contributes to SB development. However, the effect of maternal folate intake on genetic risk for SB in Bangladesh has not been quantified.

Methods

Genetic variants were imputed from array data of 112 infants with SB and 116 infants without SB. After quality filtering, genome-wide association was performed on 91 infants with SB and 97 without. Maternal folate intake and maternal nail arsenic concentration were included as covariates and interaction terms (SNP × Folate, SNP × Arsenic) along with maternal age, infant sex, and 10 principal components as covariates.

Results

Two loci had variants nominally associated with SB: one within the coding region of WWOX, including rs7184417 (odds ratio [OR] = 6.20, p = 2.22E-06), and a second in the coding region of ISOC2 (rs4801638; OR = 0.24, p = 5.75E-06). With the gene-folate interaction, a locus in CNTN5 was associated with SB. After including the gene-arsenic interaction, the gene-folate interaction effect was nominally associated with a locus in CTNNA2.

Conclusions

Inclusion of maternal folate intake as a covariate and interaction term identified three genomic loci that could impact the risk for SB. A fourth locus was identified when maternal arsenic level was included. These nominal associations should be assessed in additional cohorts with larger sample sizes. Novel genes impacted by these loci may interact with previously reported genes for SB.

背景：神经管缺陷如脊柱裂（SB）是一种先天性畸形，在世界范围内具有很高的发病率和死亡率。环境因素，尤其是叶酸，会改变SB风险。根据家族内SB的复发率，遗传风险也有助于SB的发展。然而，在孟加拉国，母亲叶酸摄入量对SB遗传风险的影响尚未被量化。方法：对112例SB婴儿和116例未患SB婴儿的基因序列数据进行遗传变异推算，并对91例SB婴儿和97例未患SB婴儿进行质量筛选和全基因组关联。包括母亲叶酸摄入量和母亲指甲砷浓度作为协变量和相互作用项（SNP ×叶酸，SNP ×砷），以及母亲年龄，婴儿性别和10个主成分作为协变量。结果：两个基因座在名义上与SB相关：一个在WWOX编码区，包括rs7184417（比值比[OR] = 6.20, p = 2.22E-06），另一个在iso2编码区（rs4801638; OR = 0.24, p = 5.75E-06）。在基因-叶酸相互作用中，CNTN5中的一个位点与SB有关。在包括基因-砷相互作用后，基因-叶酸相互作用效应在名义上与CTNNA2中的一个位点有关。结论：将母体叶酸摄入量作为协变量和相互作用项，确定了可能影响SB风险的三个基因组位点。当母体砷水平包括在内时，确定了第四个位点。这些名义上的关联应该在更大样本量的其他队列中进行评估。受这些基因座影响的新基因可能与先前报道的SB基因相互作用。

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引用次数: 0

A Case of a Fetus With SETD5 Mutation: Prenatal Phenotype and Literature Review 一例胎儿SETD5突变：产前表型和文献复习。

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-12-10 DOI: 10.1002/bdr2.70003

Jiaqi Fan, Hairui Sun, Huan Jiang, Siyao Zhang, Hongmei Xia, Yihua He

Background

Pathogenic variants in the SETD5 gene cause autosomal dominant intellectual developmental disorder 23. The limited number of published clinical case reports has hindered a comprehensive understanding of the associated phenotypic spectrum and mutational landscape.

Methods

We report a fetal case identified by cardiac ultrasound with an ostium primum atrial septal defect and a suspected high ventricular septal defect.

Results

Whole-exome sequencing revealed a novel, previously unreported frameshift variant in SETD5 (NM_001080517.3; exon21: c.3601_3605del, p. Trp1201GlufsTer2). Segregation analysis confirmed it to be a de novo variant.

Conclusion

This case expands the known mutational spectrum of SETD5. A review of the literature allows for a synthesis of the characteristic clinical features of this rare disorder. Congenital heart defects, including atrial and ventricular septal defects, can serve as early diagnostic indicators. Fetal cardiac ultrasound represents a valuable tool for early screening, underscoring the critical importance of prenatal whole-exome sequencing in such cases.

背景：SETD5基因的致病变异导致常染色体显性智力发育障碍23。已发表的临床病例报告数量有限，阻碍了对相关表型谱和突变景观的全面理解。方法：我们报告一个胎儿病例确定的心脏超声与原心房间隔缺损和怀疑高室间隔缺损。结果：全外显子组测序揭示了SETD5中一个新的、以前未报道的移码变异（NM_001080517.3；外显子21:c.3601_3605del, p. Trp1201GlufsTer2）。分离分析证实它是一种新的变异。结论：本病例扩展了已知的SETD5突变谱。回顾文献，可以综合这种罕见疾病的临床特征。先天性心脏缺陷，包括心房和室间隔缺陷，可以作为早期诊断指标。胎儿心脏超声是早期筛查的一种有价值的工具，强调了在这种情况下产前全外显子组测序的重要性。

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引用次数: 0

Utility of Electronic Case Reporting for Case Identification in Texas Birth Defects Surveillance 电子病例报告在德克萨斯州出生缺陷监测中用于病例识别的效用。

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-12-10 DOI: 10.1002/bdr2.70004

R. P. Allred, C. Yantz, H. Jeon, R. Howell, M. Kilburn, C. Shumate

Background

The utility of electronic case reporting (eCR) in birth defects surveillance is unknown. This evaluation assessed whether electronic initial case reports (eICRs) can serve as a potential case identification source and how eICRs compare to electronic health records (EHRs) in capturing demographic and diagnostic information.

Methods

Cases were identified from the Texas Birth Defects Registry's eCR data stream. Upon case confirmation, the EHR was requested and abstracted following routine abstraction processes. Next, the eICR html file was abstracted. The number, range, and mean of coded birth defects, as well as pre- and postnatal procedures were calculated for both data sources. Concordance between abstracted variables from the EHR and the eICR was evaluated for non-missing data using weighted kappa agreement statistics in SAS.

Results

There were many missing data from the eICR. Fewer birth defects and pre- and postnatal procedures were reported in the eICR compared to the EHR. Most variables had low concordance, while a few variables had high concordance (e.g., infant sex [kappa = 0.95], infant birthdate [kappa = 0.99], primary defect code/diagnosis [kappa = 0.83 using 6-digit British Pediatric Association [BPA] codes; kappa = 0.92, 4-digit BPA codes]).

Conclusions

eCR may be a viable source for timely potential case identification and may also facilitate timelier referral to social services among eligible cases. eCR data files are not standardized across facilities, lack critical variables permitting examination of birth defect risk factors, and are generally not a comprehensive resource for all pertinent data related to a birth defect case.

背景：电子病例报告（eCR）在出生缺陷监测中的应用尚不清楚。该评估评估了电子初始病例报告（eICRs）是否可以作为潜在的病例识别来源，以及eICRs与电子健康记录（ehr）在获取人口统计和诊断信息方面的比较。方法：从德克萨斯州出生缺陷登记处的eCR数据流中确定病例。在病例确认后，请求EHR并按照常规提取流程提取。接下来，对eICR html文件进行抽象。对编码出生缺陷的数量、范围和平均值以及产前和产后程序进行了计算。从EHR和eICR中提取的变量之间的一致性使用SAS中的加权kappa协议统计来评估非缺失数据。结果：eICR数据缺失较多。与EHR相比，eICR报告的出生缺陷和产前和产后手术较少。大多数变量具有低一致性，少数变量具有高一致性（如婴儿性别[kappa = 0.95]，婴儿出生日期[kappa = 0.99]，原发性缺陷编码/诊断[kappa = 0.83，使用6位英国儿科协会[BPA]编码；kappa = 0.92，使用4位BPA编码]）。结论：eCR可能是及时发现潜在病例的可行来源，也可能有助于将符合条件的病例及时转介到社会服务机构。eCR数据文件没有跨设施标准化，缺乏允许检查出生缺陷风险因素的关键变量，并且通常不是与出生缺陷病例相关的所有相关数据的综合资源。

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引用次数: 0

Imbalance of Fetal Growth Factor Levels in Congenital Heart Disease Pathology: A Systematic Review 先天性心脏病病理中胎儿生长因子水平失衡：系统综述。

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-12-09 DOI: 10.1002/bdr2.70006

Yazdan Ghandi, Samira Zakeri Shahvari, Negar Poor Ahmadian, Mahbod Soltani, Seyed Amir Hossein Musavi, Mohammad Satarzadeh

Background

Vascular endothelial growth factor (VEGF) is a factor that is responsible for cell proliferation, growth of vascular endothelial cells, and angiogenesis. Changes in the level of this factor are associated with the pathology of structural disorders such as CHD. This systematic study assesses previous studies in order to find the VEGF influences on congenital heart disorders.

Method

This systematic review was written based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, and the principle of non-bias was respected. All the articles from 2014 to 2024 were extracted from Web of Science, PubMed, and Scopus databases. We investigated the role of VEGF in the pathology of cardiovascular structural disorders, the therapeutic and diagnostic effects of VEGF, and related factors that are influenced by this factor.

Results

Studies assessed based on PRISMA search steps and 22 were included in our study. Any disturbance in the production and functioning of VEGF is known as a genetic disorder in tetralogy of Fallot (TOF). VEGF caused abnormal elongation of the heart tubes, as well as disproportionate growth of cardiovascular tissue just before full formation. The increase of Hypoxia-inducible factor (HIF) with the increase of VEGF function precedes the development of the fetal heart. HIF also mediates endothelial formation through endothelial nitric oxide synthases (eNOS); HIF in children with cyanotic CHD (CCHD) and acyanotic CHD (ACHD) is significantly higher than in the control group, and its value is higher in complex CHD children than in the other groups. EGFR, inducible NOS (iNOS), and ET-1 were more in ACHD than in CCHD, and their amounts showed a positive correlation with HIF.

Conclusion

The increase in the level of VEGF and HIF before the completion of the heart tissue is the main cause of CHD pathology; after the completion of the heart tissue, these factors help in the regeneration of the heart tissue. The regulation of VEGF and HIF levels during the fetal period is of great importance for the diagnosis and pathological aspect of CHD.

背景：血管内皮生长因子（Vascular endothelial growth factor， VEGF）是一种与细胞增殖、血管内皮细胞生长和血管生成有关的因子。该因子水平的变化与结构性疾病（如冠心病）的病理有关。本系统的研究评估了以往的研究，以发现VEGF对先天性心脏病的影响。方法：本系统评价采用系统评价和meta分析首选报告项目（PRISMA）标准，遵循无偏倚原则。2014 - 2024年的所有文章均摘自Web of Science、PubMed和Scopus数据库。我们研究了VEGF在心血管结构疾病病理中的作用，VEGF的治疗和诊断作用，以及受其影响的相关因素。结果：基于PRISMA检索步骤和22的研究被纳入我们的研究。VEGF的产生和功能的任何障碍都被称为法洛四联症（TOF）的遗传疾病。VEGF引起心管的异常伸长，以及心血管组织在完全形成之前的不成比例的生长。缺氧诱导因子（Hypoxia-inducible factor， HIF）随血管内皮生长因子（VEGF）功能的增加而升高，在胎儿心脏发育之前。HIF还通过内皮型一氧化氮合酶（eNOS）介导内皮形成；紫绀型冠心病（CCHD）和无绀型冠心病（ACHD）患儿的HIF值明显高于对照组，复杂型冠心病患儿的HIF值高于其他组。EGFR、诱导NOS （iNOS）和ET-1在ACHD中高于CCHD，且其含量与HIF呈正相关。结论：心肌组织完成前VEGF、HIF水平升高是冠心病病理发生的主要原因；在心脏组织完成后，这些因素有助于心脏组织的再生。胎儿期VEGF和HIF水平的调节对冠心病的诊断和病理方面具有重要意义。

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引用次数: 0

Spatial and Temporal Analysis of Hospital Discharges due to Congenital Malformations in Argentina 阿根廷先天性畸形患者出院的时空分析

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-12-01 DOI: 10.1002/bdr2.70001

Marcelo I. Figueroa, Lautaro D. Andrade, Jorge S. López-Camelo, Hernán J. Dopazo, José E. Dipierri

Background

Hospital discharges (HD) provide population data that can be used to define specific epidemiological profiles.

Objectives

To quantify the prevalence of CM among all hospital discharges and its spatiotemporal patterns across Argentina. Furthermore, the study will benchmark these estimates against RENAC to contextualize agreement and discrepancies.

Methods

HD data (2005–2020) from the National Ministry of Health were analyzed at national, regional, and provincial levels. We estimated the proportion of HD due to CM (HDCM; ICD-10 Q00–Q99) overall and by age (< 1 year, 1–5 years, > 5 years). For infants < 1 year, CM prevalence per 100 live births (LB) was computed and compared with RENAC. Temporal trends were assessed with Joinpoint regression.

Results

HDCM represented 0.71% of all HD; 63.4% occurred in children ≥ 1 year, indicating substantial CM-related care beyond infancy. Spatial differences were directionally consistent across sources: nationally and in the Center, RENAC estimates were higher than HDCM; Cuyo showed higher HDCM throughout; NWA shifted to higher HDCM from mid-decade; NEA/Patagonia displayed small gaps with occasional crossovers. Temporally, Joinpoint analyses revealed heterogeneous regional trends without a common timing of inflections: HDCM increased in NWA, the gap widened in Cuyo toward the late decade, while national and Center trajectories were relatively stable; RENAC series remained more tightly clustered around the national pattern. In infants < 1 year, structural cardiac malformations were the leading HD diagnoses.

Conclusion

HD-based metrics and RENAC provide complementary views of the CM burden; their systematic divergence with regional heterogeneity indicates that HD can robustly contextualize spatiotemporal differences where birth-surveillance alone is insufficient.

背景：医院出院（HD）提供可用于定义特定流行病学概况的人口数据。目的：量化CM在阿根廷所有医院出院中的患病率及其时空模式。此外，该研究将根据RENAC对这些估计进行基准测试，以确定一致性和差异。方法：分析国家卫生部2005-2020年的HD数据，包括国家、地区和省级数据。我们估计了CM引起的HD的比例（HDCM; ICD-10 Q00-Q99）总体和年龄（5岁）。结果：HDCM占所有HD的0.71%；63.4%发生在≥1岁的儿童中，表明婴儿期之后有大量与cm相关的护理。不同来源的空间差异在方向上是一致的：在全国和中心，RENAC的估计值高于HDCM；Cuyo全期HDCM增高；NWA从十年中期开始转向更高的HDCM；NEA/巴塔哥尼亚表现出偶尔交叉的小差距。从时间上看，Joinpoint分析揭示了不同区域的不同趋势，没有共同的变化时间：NWA的HDCM增加，Cuyo的差距在近十年中扩大，而全国和中部的轨迹相对稳定；RENAC系列仍然更紧密地聚集在全国范围内。结论：基于hd的指标和RENAC提供了CM负担的互补观点；它们与区域异质性的系统性差异表明，在仅靠出生监测是不够的情况下，HD可以强有力地将时空差异置于背景中。

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引用次数: 0

FGFR1 Tyrosine Kinase Domain Variant p.Val561Met in Caudal Dysraphism: A Case Report FGFR1酪氨酸激酶结构域变异p.Val561Met与尾侧书写障碍的关系：1例报告。

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-11-17 DOI: 10.1002/bdr2.70000

Himanshu Goel, Victoria Yachmenikova, Tanya Mckenny, Hannah Klucknow, Sheridan O'Donnell

Background

Neural tube defects (NTDs) are complex congenital malformations with both environmental and genetic contributions. Monogenic causes of NTDs are increasingly recognized, particularly those involving genes that regulate key morphogenetic pathways. FGFR1, a receptor tyrosine kinase, is crucial for axial and neural development; however, its role in caudal dysraphism remains unclear.

Methods

We report a female fetus delivered at 25 weeks of gestation following prenatal diagnosis of severe lumbosacral spina bifida. Comprehensive postmortem and genetic investigations, including trio exome sequencing, were performed to identify potential causal variants.

Results

Postmortem examination revealed Chiari II malformation, dysmorphic features, bilateral talipes, and a large caudal spinal defect. Trio exome sequencing identified a de novo heterozygous FGFR1 variant (c.1681G>A; p.Val561Met) affecting the conserved tyrosine kinase domain. This variant has been reported in somatic and developmental contexts, where it may modulate FGFR1 signaling, although evidence for constitutive activation remains limited and context-dependent. The variant has not been previously associated with NTD.

Conclusion

This single case raises the possibility that altered FGFR1 signaling may contribute to defective neurulation and warrants further investigation in larger cohorts. Our findings support considering FGFR1 in the differential diagnosis of complex or syndromic spinal dysraphism, though additional evidence is required before recommending its inclusion in routine panels for isolated cases.

背景：神经管缺陷（NTDs）是一种复杂的先天性畸形，与环境和遗传因素有关。人们越来越认识到被忽视热带病的单基因原因，特别是那些涉及调节关键形态发生途径的基因的原因。FGFR1是一种酪氨酸激酶受体，对轴和神经发育至关重要；然而，它在尾侧书写障碍中的作用尚不清楚。方法：我们报告一名女性胎儿在妊娠25周分娩后产前诊断为严重腰骶脊柱裂。全面的死后和遗传调查，包括三重奏外显子组测序，进行了确定潜在的因果变异。结果：尸检显示Chiari II型畸形，畸形特征，双侧taltales和大的尾椎缺损。三人外显子组测序鉴定出一种新的杂合FGFR1变异（c.1681G >a; p.Val561Met），影响保守的酪氨酸激酶结构域。该变体在体细胞和发育环境中已被报道，它可能调节FGFR1信号，尽管构成激活的证据仍然有限且依赖于环境。以前没有发现这种变异与NTD有关。结论：这一单一病例提出了FGFR1信号改变可能导致神经发育缺陷的可能性，值得在更大的队列中进一步研究。我们的研究结果支持在复杂或综合征性脊柱异常的鉴别诊断中考虑FGFR1，尽管在推荐将其纳入孤立病例的常规检查之前需要额外的证据。

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引用次数: 0

Effects of Pre-Conception Stress and Dracocephalum moldavica Extract on Sperm Parameters and Sex Hormones in Parents and Offspring 孕前应激和龙头提取物对亲代和子代精子参数和性激素的影响。

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-11-17 DOI: 10.1002/bdr2.2545

Leila Ghassemifard, Hajar Ramezanikhah, Parisa Jafari, Fatemeh Amiri, Ehsan Saboory

Background

Stress is one of the causes of fertility weakness in both females and males and herbal approaches may reduce this harmful effect. This study aimed to investigate the effect of Dracocephalum moldavica (DM) on the reproductive system in parental pre-pregnancy stress.

Material and Methods

In this experimental study, male and female rats were divided into four groups as follows: control, stress (restraint stress daily for 50 and 15 days for male and female, respectively), extract, and stress + extract. After treatment, the control and experimental rats were mated. Pregnant females were kept undisturbed until delivery and weaning. Offspring were divided into four groups according to the parents’ treatment: McFc, McFc+EX, MsFs, MsFs+EX (M: male, F: female, C: control, S: stress, and EX: extract). Epididymis and vagina were dissected from adult rats; sperm parameters, the thickness of vaginal epithelium, vaginal pH, sex hormone levels were assessed; in pups, testosterone/estradiol, litter size and sex ratio were investigated.

Results

DM extract significantly reduced immotile, dead, and abnormal sperms (p < 0.001) and led to increased levels of testosterone/estradiol in parents and offspring (p < 0.01); the sex ratio was changed among the groups (p = 0.036); the highest number of female pups belonged to the MsFs group. Stress led to a decrease in vaginal thickness and pH while DM extract increased them (p < 0.01).

Conclusion

The results indicate that DM extract may have a beneficial effect on some reproductive parameters affected by pre-conception stress. Notably, it was associated with improvements in sperm quality, hormone levels in parents and offspring, and certain vaginal health measures. Further research is needed to confirm these effects and better understand the underlying mechanisms.

背景：压力是女性和男性生育能力低下的原因之一，草药疗法可以减少这种有害影响。本研究旨在探讨孕前应激对母本生殖系统的影响。材料与方法：本实验将雄性和雌性大鼠分为4组，分别为对照组、应激组（雄性和雌性分别为限制性应激，每天50和15 d）、提取物组和应激+提取物组。治疗后，对照大鼠与实验大鼠进行交配。怀孕的雌性在分娩和断奶前都不受打扰。按亲本处理将子代分为McFc、McFc+EX、MsFs、MsFs+EX 4组（M：雄性，F：雌性，C：对照组，S：应激组，EX：提取物组）。解剖成年大鼠附睾和阴道；评估精子参数、阴道上皮厚度、阴道pH值、性激素水平；对幼犬进行睾酮/雌二醇、产仔数和性别比的研究。结果：DM提取物可显著降低不动、死亡和异常精子(p)。结论：DM提取物可能对孕前应激影响的某些生殖参数有有益作用。值得注意的是，它与精子质量、父母和后代的激素水平以及某些阴道健康措施的改善有关。需要进一步的研究来证实这些影响，并更好地了解潜在的机制。

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引用次数: 0

Understanding Clubfoot: Integrating Historical Origins, Embryologic Foundations, Epidemiology and Etiology—A Review 了解内翻足：整合历史起源、胚胎学基础、流行病学和病因学综述

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-11-15 DOI: 10.1002/bdr2.2543

J. S. R. G. Saran, Varun Devdass, Durai Anand

Purpose

Congenital talipes equinovarus (CTEV) or idiopathic clubfoot, is a common yet complex congenital musculoskeletal deformity characterized by cavus, adductus, varus and equinus components. Despite advances in conservative and surgical management, recurrence and long-term functional limitations remain unresolved challenges. This review aims to provide an integrative synthesis of the historical evolution, embryological basis, etiological theories and clinical implications of idiopathic clubfoot.

Methods

A narrative literature review was conducted, synthesizing data from historical records, embryological studies, genetic and developmental biology research and clinical reports. Key theories of etiology, including embryological, genetic, vascular, neuromuscular, environmental and structural mechanisms, were critically examined to highlight converging and divergent perspectives.

Results

The evidence suggests that idiopathic clubfoot arises from a multifactorial interplay of genetic predisposition, aberrant embryological signaling pathways, vascular dysgenesis, and environmental influences. While molecular studies implicate PITX1–TBX4 pathways and extracellular matrix remodeling, developmental hypotheses highlight disruptions in muscle patterning, connective tissue organization and vascular development. Clinically, even well-corrected cases demonstrate persistent sequelae such as restricted ankle mobility, muscle weakness and altered biomechanics, predisposing to early degenerative joint changes.

Conclusions

CTEV should be considered a systemic developmental dysplasia rather than an isolated foot deformity. The persistence of recurrence and long-term morbidity underscores the need for multidisciplinary research integrating genetics, developmental biology, biomechanics and rehabilitation. Improved understanding of the etiological mechanisms may enable earlier detection, targeted interventions and ultimately better long-term outcomes for affected individuals.

先天性马蹄内翻（CTEV）或特发性内翻足，是一种常见但复杂的先天性肌肉骨骼畸形，其特征是腔窝、内收、内翻和马蹄成分。尽管保守和手术治疗取得了进展，但复发和长期功能限制仍然是未解决的挑战。本文综述了特发性内翻足的历史演变、胚胎学基础、病因学理论和临床意义。方法综合历史文献、胚胎学研究、遗传与发育生物学研究及临床报告等资料，进行文献综述。病因学的关键理论，包括胚胎学，遗传学，血管，神经肌肉，环境和结构机制，严格审查，以突出趋同和分歧的观点。结果有证据表明特发性内翻足是遗传易感性、胚胎信号通路异常、血管发育不良和环境影响等多因素相互作用的结果。虽然分子研究涉及PITX1-TBX4通路和细胞外基质重塑，但发育假说强调肌肉模式，结缔组织组织和血管发育的破坏。临床上，即使矫正良好的病例也会出现持续的后遗症，如踝关节活动受限、肌肉无力和生物力学改变，易发生早期退行性关节变化。结论CTEV应被认为是一种全身性发育不良，而不是孤立的足部畸形。复发的持久性和长期发病率强调需要多学科研究整合遗传学，发育生物学，生物力学和康复。提高对病因机制的了解可能有助于早期发现、有针对性的干预，并最终为受影响的个体带来更好的长期结果。

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引用次数: 0

Pregnancy Outcomes Following Paternal Methotrexate Exposure: A Systematic Review and Meta-Analysis 甲氨蝶呤暴露后的妊娠结局：一项系统回顾和荟萃分析

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-11-14 DOI: 10.1002/bdr2.2542

Nusret Uysal, Hüseyin Yilmaz, Mesut Gungor, Ahmet Ozyurek, Tijen Kaya-Temiz, Baris Karadas, Yusuf C. Kaplan

Objective

Evidence guiding the management of pregnancies fathered by men exposed to methotrexate (MTX) remains limited. This systematic review and meta-analysis evaluated whether paternal MTX exposure before or at conception is associated with major congenital malformations or other adverse pregnancy outcomes.

Data Sources

PubMed, Web of Science, and Reprotox were searched from inception to May 2025, supplemented by manual reference screening.

Study Eligibility Criteria

Eligible studies were cohort or case–control designs assessing paternal MTX exposure during preconception or conception period with an unexposed control group. Reviews, editorials, animal studies, case reports, and overlapping datasets were excluded.

Methods

Study selection and data extraction were conducted independently. Risk of bias was assessed with ROBINS-I, quality with the Newcastle-Ottawa Scale, and certainty of evidence with GRADE. Adjusted odds ratios (aORs) were used for random-effects meta-analysis; outcomes lacking sufficient data were narratively synthesized. The primary outcome was major congenital malformations following paternal MTX exposure. Secondary outcomes included cardiac malformations, spontaneous abortion, live birth, elective termination, stillbirth, and preterm birth.

Results

No increased risks were observed for congenital malformations (aOR 1.00; 95% CI 0.62–1.61; I² = 0%), stillbirth (OR 0.85; 95% CI 0.11–6.45; I² = 0%), or preterm birth (OR 0.95; 95% CI 0.59–1.53; I² = 26%). In the qualitative review of case reports, case series, and noncomparable cohort data, no consistent or recurring patterns of malformations were identified.

Conclusions

Paternal MTX exposure was not associated with increased risks of congenital malformations, stillbirth, or preterm birth, nor with a consistent or recurrent pattern of anomalies. These findings provide reassurance regarding fetal safety following paternal MTX exposure.

客观证据指导管理的男性接触甲氨蝶呤（MTX）的怀孕仍然有限。本系统综述和荟萃分析评估了父亲在怀孕前或怀孕时接触甲氨蝶呤是否与主要先天性畸形或其他不良妊娠结局有关。数据来源PubMed， Web of Science和Reprotox从成立到2025年5月进行检索，并辅以人工参考筛选。符合条件的研究是队列或病例对照设计，评估父亲在孕前或受孕期与未暴露对照组的甲氨蝶呤暴露。综述、社论、动物研究、病例报告和重叠数据集被排除在外。方法独立进行研究选择和资料提取。偏倚风险采用ROBINS-I评估，质量采用Newcastle-Ottawa量表评估，证据确定性采用GRADE评估。随机效应荟萃分析采用调整优势比（aORs）；缺乏足够数据的结果被叙述合成。主要结果是父亲接触甲氨蝶呤后的主要先天性畸形。次要结局包括心脏畸形、自然流产、活产、选择性终止妊娠、死产和早产。结果先天性畸形（aOR 1.00; 95% CI 0.62-1.61; I2 = 0%）、死产（aOR 0.85; 95% CI 0.11-6.45; I2 = 0%）和早产（aOR 0.95; 95% CI 0.59-1.53; I2 = 26%）的风险均未增加。在病例报告、病例系列和不可比较的队列数据的定性回顾中，没有确定一致或反复出现的畸形模式。结论：父亲甲氨蝶呤暴露与先天性畸形、死产或早产的风险增加无关，也与持续或复发的异常模式无关。这些发现为父亲接触甲氨蝶呤后胎儿的安全提供了保证。

{"title":"Pregnancy Outcomes Following Paternal Methotrexate Exposure: A Systematic Review and Meta-Analysis","authors":"Nusret Uysal, Hüseyin Yilmaz, Mesut Gungor, Ahmet Ozyurek, Tijen Kaya-Temiz, Baris Karadas, Yusuf C. Kaplan","doi":"10.1002/bdr2.2542","DOIUrl":"https://doi.org/10.1002/bdr2.2542","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Evidence guiding the management of pregnancies fathered by men exposed to methotrexate (MTX) remains limited. This systematic review and meta-analysis evaluated whether paternal MTX exposure before or at conception is associated with major congenital malformations or other adverse pregnancy outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Data Sources</h3>\u0000 \u0000 <p>PubMed, Web of Science, and Reprotox were searched from inception to May 2025, supplemented by manual reference screening.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Study Eligibility Criteria</h3>\u0000 \u0000 <p>Eligible studies were cohort or case–control designs assessing paternal MTX exposure during preconception or conception period with an unexposed control group. Reviews, editorials, animal studies, case reports, and overlapping datasets were excluded.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Study selection and data extraction were conducted independently. Risk of bias was assessed with ROBINS-I, quality with the Newcastle-Ottawa Scale, and certainty of evidence with GRADE. Adjusted odds ratios (aORs) were used for random-effects meta-analysis; outcomes lacking sufficient data were narratively synthesized. The primary outcome was major congenital malformations following paternal MTX exposure. Secondary outcomes included cardiac malformations, spontaneous abortion, live birth, elective termination, stillbirth, and preterm birth.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>No increased risks were observed for congenital malformations (aOR 1.00; 95% CI 0.62–1.61; <i>I</i><sup>2</sup> = 0%), stillbirth (OR 0.85; 95% CI 0.11–6.45; <i>I</i><sup>2</sup> = 0%), or preterm birth (OR 0.95; 95% CI 0.59–1.53; <i>I</i><sup>2</sup> = 26%). In the qualitative review of case reports, case series, and noncomparable cohort data, no consistent or recurring patterns of malformations were identified.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Paternal MTX exposure was not associated with increased risks of congenital malformations, stillbirth, or preterm birth, nor with a consistent or recurrent pattern of anomalies. These findings provide reassurance regarding fetal safety following paternal MTX exposure.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 11","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145522171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Infant Mortality due to Congenital Diaphragmatic Hernia, United States 2007–2021 美国2007-2021年先天性膈疝导致的婴儿死亡率。

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-11-12 DOI: 10.1002/bdr2.2544

Ramesh Vidavalur, Kanekal S. Gautham

Objective

To analyze temporal trends and geographic variations in infant mortality rate associated with congenital diaphragmatic hernia (CDH-IMR) in the United States.

Methods

From 2007 to 2021, we used CDC-WONDER linked birth/death data to identify CDH-related infant deaths (ICD-10 code: Q79 as the underlying cause of death), analyze annual CDH-IMR trends, and explore associations with sex, gender, gestational age (GA), and U.S. state of birth. Descriptive statistics were derived, and bivariate analyses were conducted to discern differences in CDH-IMR by gender, race, and GA. CDH-IMR was expressed per 100,000 live births with Poisson-modeled 95% confidence intervals, and trends were assessed through joinpoint regression to extrapolate annual percent change (APC).

Results

Between 2007 and 2021, 59,117,761 live births and 3391 CDH-related infant deaths were recorded. CDH infant deaths accounted for 0.96% of all infant deaths and occurred in 0.006% of live births. The mean CDH-IMR was 5.7 (95% CI: 5.5–5.9) per 100,000 live births, with a significant downward trend (APC: −1.3%, [95% CI: −2.0, −0.5, p < 0.01]). Asian infants had a lower risk of mortality (RR 0.66 [95% CI: 0.55, 0.79]) compared to White infants, and higher GA at birth correlated with better survival. Regional analysis revealed a median CDH-IMR (IQR) of 5.9 (4.7, 7.2), with a three-fold variation across U.S. states.

Conclusion

In this national population-based U.S. study, we observed a decreasing trend in CDH-IMR. However, significant variation in CDH mortality persists by region, gender, and race. Despite evidence of current CDH care is associated with a decreasing trend in mortality, there remain many opportunities for equitable improvement in outcomes across race, gender and by geographic region.

目的：分析美国先天性膈疝（CDH-IMR）相关婴儿死亡率的时间趋势和地理差异。方法：从2007年到2021年，我们使用CDC-WONDER相关的出生/死亡数据来确定与cdh相关的婴儿死亡（ICD-10代码：Q79作为潜在死亡原因），分析年度CDH-IMR趋势，并探讨与性别、性别、胎龄（GA）和美国出生状态的关系。导出描述性统计数据，并进行双变量分析，以辨别性别、种族和遗传基因在CDH-IMR中的差异。用泊松模型的95%置信区间表示每10万活产婴儿的CDH-IMR，并通过联点回归来推断年百分比变化（APC）来评估趋势。结果：2007年至2021年期间，记录了59,117,761例活产和3391例与冠心病相关的婴儿死亡。婴儿死亡占所有婴儿死亡的0.96%，占活产婴儿的0.006%。平均CDH-IMR为每10万例活产5.7例（95% CI: 5.5-5.9），呈显著下降趋势（APC: -1.3%, [95% CI: -2.0, -0.5, p]）。结论：在这项基于美国全国人群的研究中，我们观察到CDH-IMR呈下降趋势。然而，CDH死亡率在地区、性别和种族之间存在显著差异。尽管有证据表明，目前的CDH护理与死亡率下降趋势有关，但仍有许多机会可以公平地改善跨种族、性别和地理区域的结果。

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引用次数: 0