Recurrent Constellations of Embryonic Malformations (RCEM): Teratogenicity Linked to Transient Hypoxia and Hormone Pregnancy Tests Agrees With RCEM and Suggest a Reactive Oxygen Species Pathogenesis

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research Pub Date : 2026-03-04 DOI:10.1002/bdr2.70036

Aaron P. Adam, Helen E. Ritchie, Margaret P. Adam, Bengt R. Danielsson

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Abstract

Background

No consistent genetic etiology has been found for a group of six different conditions in humans with multiple malformations called “recurrent constellations of embryonic malformations” (RCEM). Recent studies indicate hypoxia/reoxygenation and generation Reactive Oxygen Species (ROS) as an underlying mechanism for RCEM with the specific manifestations related to the timing, severity and duration of the ROS exposure.

Methods

Medical literature was evaluated in relation to a hypoxia/ROS related mechanism for RCEM. Special attention was paid to investigate if the reported spectrum of multiple human malformations for Hormone Pregnancy Tests (HPTs), which have been associated with embryonic hypoxia due abnormal uterine contractions in early pregnancy, agrees with the RCEM spectrum.

Results

The pattern of human multiple and single malformations associated with HPTs in 44 case reports with multiple defects, 86% (38/44) were consistent with RCEM spectrum, the most common was VACTERL. There was also a high consistency with regards to increases in single HPT malformations within the RCEM spectrum in a large case report study (> 225 cases) and in more than 25 human epidemiological studies evaluating HPT teratogenicity. The RCEM spectrum is also consistent with reported malformations when the embryo has been exposed to periods of transient embryonic hypoxia/ROS in animal studies and when exposed to drugs associated with embryonic hypoxia/ROS (e.g., cocaine) and in some genetic diseases with malformations (e.g., NAD+ deficiency) when ROS overwhelms the antioxidant defense.

Conclusions

This review shows that HPTs are associated with human teratogenicity and ROS to be the proximate teratogen underlying RCEM.

Abstract Image

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胚胎畸形复发星座（RCEM）：致畸性与短暂缺氧和激素妊娠试验一致，并提示活性氧的发病机制。

背景：没有一致的遗传病因的一组六种不同的条件下，人类与多种畸形称为“复发性星座的胚胎畸形”（RCEM）。最近的研究表明，缺氧/再氧化和活性氧（ROS）的产生是RCEM的潜在机制，其具体表现与ROS暴露的时间、严重程度和持续时间有关。方法：对与RCEM的缺氧/ROS相关机制相关的医学文献进行评价。特别注意的是，如果报告的多种人类畸形的频谱激素妊娠试验（HPTs），这已经与胚胎缺氧有关，由于在妊娠早期子宫异常收缩，与RCEM频谱一致。结果：44例HPTs多发和单发畸形报告中，86%（38/44）与RCEM谱一致，以VACTERL最常见。在一项大型病例报告研究（bbbb225例）和超过25项评估HPT致畸性的人类流行病学研究中，关于RCEM谱中单个HPT畸形的增加也有高度一致性。在动物研究中，当胚胎暴露于短暂的胚胎缺氧/活性氧时，当暴露于与胚胎缺氧/活性氧相关的药物（如可卡因）时，以及当活性氧破坏抗氧化防御时，某些遗传疾病（如NAD+缺乏症）伴有畸形时，RCEM谱也与报道的畸形一致。结论：本综述显示HPTs与人类致畸性有关，ROS是RCEM的近似致畸原。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Birth Defects Research Medicine-Embryology

CiteScore

3.60

自引率

9.50%

发文量

153

期刊介绍： The journal Birth Defects Research publishes original research and reviews in areas related to the etiology of adverse developmental and reproductive outcome. In particular the journal is devoted to the publication of original scientific research that contributes to the understanding of the biology of embryonic development and the prenatal causative factors and mechanisms leading to adverse pregnancy outcomes, namely structural and functional birth defects, pregnancy loss, postnatal functional defects in the human population, and to the identification of prenatal factors and biological mechanisms that reduce these risks. Adverse reproductive and developmental outcomes may have genetic, environmental, nutritional or epigenetic causes. Accordingly, the journal Birth Defects Research takes an integrated, multidisciplinary approach in its organization and publication strategy. The journal Birth Defects Research contains separate sections for clinical and molecular teratology, developmental and reproductive toxicology, and reviews in developmental biology to acknowledge and accommodate the integrative nature of research in this field. Each section has a dedicated editor who is a leader in his/her field and who has full editorial authority in his/her area.