Cesar Ghadbane, Elisia Maalouf, Tigresse Boutros, Elie Ghadban
Background
Orofacial clefts (OFCs) are among the most common craniofacial birth defects and have been investigated for possible associations with increased cancer risk in affected individuals and their families.
Method
This narrative review synthesizes current evidence from epidemiological, familial, and genetic studies.
Results
Population-based and registry analyses have reported elevated risks of breast, brain, lung, oral, colorectal, and hematologic cancers, while meta-analyses highlight inconsistent findings and frequent null associations. Familial clustering studies provide stronger support, with excess colorectal and gastric cancers observed in AXIN2- and CDH1-positive pedigrees and an increased prevalence of cancer among relatives of non-syndromic cleft lip and palate patients. At the genetic level, variants in AXIN2, CDH1, FOXE1, BRCA1/2, BRIP1, and E2F1 have been implicated in both craniofacial development and tumorigenesis. Evidence also points to the modifying role of environmental exposures, particularly maternal smoking, which may interact with susceptibility variants to amplify risk. Current research is limited by small sample sizes, subtype heterogeneity, and underrepresentation of late-onset cancers. Larger, subtype-specific studies integrating genomic and environmental data are needed to clarify risk pathways and guide the development of targeted screening strategies for individuals with OFCs and their families.
{"title":"Cancer Risk and Genetic Associations in Individuals With Cleft Lip and Palate and Their Families: A Narrative Review","authors":"Cesar Ghadbane, Elisia Maalouf, Tigresse Boutros, Elie Ghadban","doi":"10.1002/bdr2.2528","DOIUrl":"https://doi.org/10.1002/bdr2.2528","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Orofacial clefts (OFCs) are among the most common craniofacial birth defects and have been investigated for possible associations with increased cancer risk in affected individuals and their families.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>This narrative review synthesizes current evidence from epidemiological, familial, and genetic studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Population-based and registry analyses have reported elevated risks of breast, brain, lung, oral, colorectal, and hematologic cancers, while meta-analyses highlight inconsistent findings and frequent null associations. Familial clustering studies provide stronger support, with excess colorectal and gastric cancers observed in <i>AXIN2</i>- and <i>CDH1</i>-positive pedigrees and an increased prevalence of cancer among relatives of non-syndromic cleft lip and palate patients. At the genetic level, variants in <i>AXIN2</i>, <i>CDH1</i>, <i>FOXE1</i>, <i>BRCA1</i>/2, <i>BRIP1</i>, and <i>E2F1</i> have been implicated in both craniofacial development and tumorigenesis. Evidence also points to the modifying role of environmental exposures, particularly maternal smoking, which may interact with susceptibility variants to amplify risk. Current research is limited by small sample sizes, subtype heterogeneity, and underrepresentation of late-onset cancers. Larger, subtype-specific studies integrating genomic and environmental data are needed to clarify risk pathways and guide the development of targeted screening strategies for individuals with OFCs and their families.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 9","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038419","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}
Wells, B. K., G. K. Garramone, A. Mahomed, and M. Ezin. 2025. “Teratogenic Effects of Serotonin Receptor 2B Disruption on the Migration and Cardiac Derivatives of the Cardiac Neural Crest.” Birth Defects Research 117, no. 7: e2506. https://doi.org/10.1002/bdr2.2506.
The Data Availability Statement for this article has been updated from the originally-published version:
Incorrect:
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Correct:
Data Availability Statement
The data that support the findings of this study are available in the Supporting Information of this article.
The data for this article are available on the publisher's website, and the online version of the article has been updated.
We apologize for this error.
Wells, b.k., g.k. Garramone， A. Mahomed和M. Ezin, 2025。5 -羟色胺受体2B干扰对心脏神经嵴迁移和心脏衍生物的致畸作用出生缺陷研究117，no。7: e2506。https://doi.org/10.1002/bdr2.2506.The本文的数据可用性声明已从原始发布的版本更新：错误：数据可用性声明支持本研究结果的数据可根据通讯作者的合理要求获得。正确：数据可用性声明支持本研究结果的数据可在本文的支持信息中找到。这篇文章的数据可以在出版商的网站上找到，文章的在线版本已经更新了。我们为这个错误道歉。
{"title":"Correction to Teratogenic Effects of Serotonin Receptor 2B Disruption on the Migration and Cardiac Derivatives of the Cardiac Neural Crest","authors":"","doi":"10.1002/bdr2.2519","DOIUrl":"https://doi.org/10.1002/bdr2.2519","url":null,"abstract":"<p>Wells, B. K., G. K. Garramone, A. Mahomed, and M. Ezin. 2025. “Teratogenic Effects of Serotonin Receptor 2B Disruption on the Migration and Cardiac Derivatives of the Cardiac Neural Crest.” <i>Birth Defects Research</i> 117, no. 7: e2506. https://doi.org/10.1002/bdr2.2506.</p><p>The Data Availability Statement for this article has been updated from the originally-published version:</p><p>Incorrect:</p><p>\u0000 <b>Data Availability Statement</b>\u0000 </p><p>The data that support the findings of this study are available from the corresponding author upon reasonable request.</p><p>Correct:</p><p>\u0000 <b>Data Availability Statement</b>\u0000 </p><p>The data that support the findings of this study are available in the Supporting Information of this article.</p><p>The data for this article are available on the publisher's website, and the online version of the article has been updated.</p><p>We apologize for this error.</p>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 9","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdr2.2519","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Traditional observational studies suggest that socioeconomic status (SES) may influence the risk of congenital anomalies; however, an association remains unclear due to residual confounding. This study used Mendelian randomization (MR) to explore the potential causal relationship between SES indicators and specific congenital anomalies.
Methods
We performed two-sample MR analyses to explore whether three indicators of SES—educational attainment, household income, and the Townsend Deprivation Index—have a relationship with the risk of major congenital anomalies. Genetic variants associated with these SES indicators were obtained from the MRC Integrative Epidemiology Unit (IEU) OpenGWAS database, based on UK Biobank data. Genetic associations with nine categories of congenital anomalies were sourced from the FinnGen study. The primary MR method was inverse-variance weighted (IVW), with sensitivity analyses and Bonferroni correction applied to account for multiple testing.
Results
Prior to correction for multiple testing, higher educational attainment was associated with reduced risk of congenital heart defects (CHDs) (OR = 0.60, 95% CI: 0.41–0.88; p = 0.001), congenital respiratory system malformations (OR = 0.20, 95% CI: 0.06–0.62; p = 0.005), and musculoskeletal malformations (OR = 0.47, 95% CI: 0.29–0.76; p = 0.002). A lower Townsend Deprivation Index was unexpectedly associated with a higher risk of congenital digestive tract anomalies (OR = 4.53, 95% CI: 1.10–18.63; p = 0.036). However, after Bonferroni correction, only the association between educational attainment and CHDs remained significant (adjusted p = 0.02).
Conclusions
We found limited evidence on the association between SES and congenital anomalies. Only higher educational attainment was significantly associated with reduced risk of CHDs after multiple testing correction. Further research with refined methods is needed to clarify these associations.
传统的观察性研究表明，社会经济地位（SES）可能影响先天性异常的风险；然而，由于残留的混淆，其关联仍不清楚。本研究采用孟德尔随机化（MR）方法探讨SES指标与特定先天性异常之间的潜在因果关系。方法采用两样本磁共振分析，探讨ses的三个指标——受教育程度、家庭收入和汤森剥夺指数——是否与重大先天性异常的风险有关。与这些SES指标相关的遗传变异来自MRC综合流行病学单位（IEU） OpenGWAS数据库，基于UK Biobank数据。与九类先天性异常的遗传关联来源于FinnGen研究。主要MR方法是反方差加权（IVW），采用敏感性分析和Bonferroni校正来解释多重检验。结果在校正多重测试之前，较高的教育程度与先天性心脏缺陷（CHDs） （OR = 0.60, 95% CI: 0.41-0.88; p = 0.001）、先天性呼吸系统畸形（OR = 0.20, 95% CI: 0.06-0.62; p = 0.005）和肌肉骨骼畸形（OR = 0.47, 95% CI: 0.29-0.76; p = 0.002）的风险降低相关。汤森剥夺指数越低，先天性消化道异常的风险越高（OR = 4.53, 95% CI: 1.10-18.63; p = 0.036）。然而，经Bonferroni校正后，只有受教育程度与冠心病之间的关系仍然显著（调整p = 0.02）。结论：我们发现有限的证据表明SES与先天性异常之间存在关联。在多次测试校正后，只有较高的教育程度与降低冠心病风险显著相关。需要用更精确的方法进行进一步的研究来澄清这些关联。
{"title":"Association Between Socioeconomic Status and Major Congenital Anomalies: A Two-Sample Mendelian Randomization Study","authors":"Daniel Linares, Qun Miao, Beatriz Luna","doi":"10.1002/bdr2.2524","DOIUrl":"https://doi.org/10.1002/bdr2.2524","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Traditional observational studies suggest that socioeconomic status (SES) may influence the risk of congenital anomalies; however, an association remains unclear due to residual confounding. This study used Mendelian randomization (MR) to explore the potential causal relationship between SES indicators and specific congenital anomalies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed two-sample MR analyses to explore whether three indicators of SES—educational attainment, household income, and the Townsend Deprivation Index—have a relationship with the risk of major congenital anomalies. Genetic variants associated with these SES indicators were obtained from the MRC Integrative Epidemiology Unit (IEU) OpenGWAS database, based on UK Biobank data. Genetic associations with nine categories of congenital anomalies were sourced from the FinnGen study. The primary MR method was inverse-variance weighted (IVW), with sensitivity analyses and Bonferroni correction applied to account for multiple testing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Prior to correction for multiple testing, higher educational attainment was associated with reduced risk of congenital heart defects (CHDs) (OR = 0.60, 95% CI: 0.41–0.88; <i>p</i> = 0.001), congenital respiratory system malformations (OR = 0.20, 95% CI: 0.06–0.62; <i>p</i> = 0.005), and musculoskeletal malformations (OR = 0.47, 95% CI: 0.29–0.76; <i>p</i> = 0.002). A lower Townsend Deprivation Index was unexpectedly associated with a higher risk of congenital digestive tract anomalies (OR = 4.53, 95% CI: 1.10–18.63; <i>p</i> = 0.036). However, after Bonferroni correction, only the association between educational attainment and CHDs remained significant (adjusted <i>p</i> = 0.02).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We found limited evidence on the association between SES and congenital anomalies. Only higher educational attainment was significantly associated with reduced risk of CHDs after multiple testing correction. Further research with refined methods is needed to clarify these associations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 9","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144998684","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}
In mouse embryos, the body axis typically follows a right-handed helical pattern; however, a definitive orientation in human embryos has not been established. This study aimed to characterize the body axis orientation in human embryos (CS13–CS17) from the Kyoto Collection.
Methods
Embryos were classified as right-helical (RH), left-helical (LH), and middle (M) using MRI-based morphological assessment.
Results
RH orientation was predominant at CS13, whereas it became comparable to LH at CS14. From CS15 to CS17, LH became dominant, nearly doubling the frequency of RH by CS15. The proportion of M-pattern embryos increased with advancing Carnegie Stages, reaching 70% at CS17. As vertebral column chondrification begins at CS17–18, these findings suggest that the helical body axis is established before chondrogenesis, particularly during CS13–CS15. Internal organ laterality (stomach, heart, intestines, and liver) appeared consistent among body axis orientations in CS15–CS17 embryos.
Conclusion
The results demonstrate substantial variability in human embryonic body axis orientation, in contrast to the well-defined pattern in mice, and provide insights into body axis formation in human embryos and their potential role in left–right asymmetry.
{"title":"Helical Body Axis Orientations in Human Embryonic Development","authors":"Sena Fujii, Shigehito Yamada, Tetsuya Takakuwa","doi":"10.1002/bdr2.2527","DOIUrl":"https://doi.org/10.1002/bdr2.2527","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>In mouse embryos, the body axis typically follows a right-handed helical pattern; however, a definitive orientation in human embryos has not been established. This study aimed to characterize the body axis orientation in human embryos (CS13–CS17) from the Kyoto Collection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Embryos were classified as right-helical (RH), left-helical (LH), and middle (M) using MRI-based morphological assessment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>RH orientation was predominant at CS13, whereas it became comparable to LH at CS14. From CS15 to CS17, LH became dominant, nearly doubling the frequency of RH by CS15. The proportion of M-pattern embryos increased with advancing Carnegie Stages, reaching 70% at CS17. As vertebral column chondrification begins at CS17–18, these findings suggest that the helical body axis is established before chondrogenesis, particularly during CS13–CS15. Internal organ laterality (stomach, heart, intestines, and liver) appeared consistent among body axis orientations in CS15–CS17 embryos.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The results demonstrate substantial variability in human embryonic body axis orientation, in contrast to the well-defined pattern in mice, and provide insights into body axis formation in human embryos and their potential role in left–right asymmetry.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 9","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144997895","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}
Paz Ahumada-Droguett, Trinidad Arancibia, Helga Vera, Daniel Martin, Francisco Sánchez, Juan Carlos Bustos
Background
Complete hydatidiform mole with a coexisting fetus (CMCF) is a rare form of twin pregnancy associated with high maternal and perinatal risks, posing complex diagnostic and therapeutic challenges. The standard approach ranges from termination of pregnancy to conservative management to fetal viability. Recent evidence suggests that spontaneous regression of molar tissue may occur, supporting conservative treatment in selected cases. We present a new case and discuss the clinical consequences of this phenomenon.
Case
We report a 29-year-old woman with a history of a previous molar pregnancy who presented with CMCF during her second gestation. The diagnosis was established at 21 weeks' gestation based on ultrasound findings and an elevated beta-hCG level of 454,000 mIU/mL. After multidisciplinary counseling, expectant management was indicated with close clinical, sonographic, and biochemical surveillance. By 30 weeks, significant regression in molar tissue was observed, and by 36 weeks, the appearance on ultrasound was like a normal placenta with decreased beta-hCG levels. At 37 weeks, a cesarean section was performed, resulting in the delivery of a healthy female infant weighing 2585 g. The placenta was normal and small, necrotic-appearing placental tissue. Histopathological analysis confirmed the presence of gestational trophoblastic disease with extensive necrosis.
Conclusions
This is the third reported case of spontaneous regression of molar tissue in CMCF, with resolution occurring in the third trimester. This finding opens a new perspective for the management of these complex pregnancies, suggesting that conservative strategies may be justified in selected patients under close surveillance.
{"title":"Spontaneous Resolution of Molar Tissue in Complete Hydatidiform Mole With a Coexisting Fetus","authors":"Paz Ahumada-Droguett, Trinidad Arancibia, Helga Vera, Daniel Martin, Francisco Sánchez, Juan Carlos Bustos","doi":"10.1002/bdr2.2525","DOIUrl":"https://doi.org/10.1002/bdr2.2525","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Complete hydatidiform mole with a coexisting fetus (CMCF) is a rare form of twin pregnancy associated with high maternal and perinatal risks, posing complex diagnostic and therapeutic challenges. The standard approach ranges from termination of pregnancy to conservative management to fetal viability. Recent evidence suggests that spontaneous regression of molar tissue may occur, supporting conservative treatment in selected cases. We present a new case and discuss the clinical consequences of this phenomenon.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Case</h3>\u0000 \u0000 <p>We report a 29-year-old woman with a history of a previous molar pregnancy who presented with CMCF during her second gestation. The diagnosis was established at 21 weeks' gestation based on ultrasound findings and an elevated beta-hCG level of 454,000 mIU/mL. After multidisciplinary counseling, expectant management was indicated with close clinical, sonographic, and biochemical surveillance. By 30 weeks, significant regression in molar tissue was observed, and by 36 weeks, the appearance on ultrasound was like a normal placenta with decreased beta-hCG levels. At 37 weeks, a cesarean section was performed, resulting in the delivery of a healthy female infant weighing 2585 g. The placenta was normal and small, necrotic-appearing placental tissue. Histopathological analysis confirmed the presence of gestational trophoblastic disease with extensive necrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This is the third reported case of spontaneous regression of molar tissue in CMCF, with resolution occurring in the third trimester. This finding opens a new perspective for the management of these complex pregnancies, suggesting that conservative strategies may be justified in selected patients under close surveillance.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 9","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935358","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}
Sharon Ng, Jeremy P. Brown, Loreen Straub, Brian Bateman, Kathryn J. Gray, Krista F. Huybrechts, Sonia Hernández-Díaz
Background
Birth defect surveillance can help identify temporo-spatial clusters and teratogenic signals to inform subsequent investigations or interventions. In the United States, state surveillance systems exist but collect limited information, prompting a complementary use of health insurance claims data to describe national birth defect prevalence trends and investigate signals.
Methods
The Merative MarketScan Commercial Claims and Encounters (MarketScan) database was used to identify liveborn infants from 2016 to 2022, with linkage to maternal health care records during pregnancy. Birth defects were identified using ICD-10-CM codes recorded in the first 3 months of life, and prevalence estimates with 95% confidence intervals were generated for birth defect categories and select birth defects.
Results
The study population included 943,855 liveborn infants. From 2016 to 2022, the prevalence increased for cardiac, central nervous system, ear, genital, urinary, musculoskeletal, and limb birth defect categories. Stable prevalence over the study period was observed for chromosomal, oral cleft, respiratory, gastrointestinal, vascular, and eye defects. For specific defects, we observed an increased prevalence of both ankyloglossia and lip-tie over the study period and a transient higher prevalence of omphalocele over 2017 and 2018. Within genital birth defects, we observed increasing prevalence trends for congenital malformations of the penis, while hypospadias and cryptorchidism remained relatively stable.
Conclusion
Health care utilization databases can complement existing surveillance systems by generating, confirming, or refuting signals based on ecological trends or clusters. The availability of patient information in claims databases can allow for further investigation of signals to inform birth defect etiology.
{"title":"Leveraging Health Insurance Claims Data to Complement the Centers for Disease Control and Prevention Surveillance System for Birth Defects","authors":"Sharon Ng, Jeremy P. Brown, Loreen Straub, Brian Bateman, Kathryn J. Gray, Krista F. Huybrechts, Sonia Hernández-Díaz","doi":"10.1002/bdr2.2523","DOIUrl":"https://doi.org/10.1002/bdr2.2523","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Birth defect surveillance can help identify temporo-spatial clusters and teratogenic signals to inform subsequent investigations or interventions. In the United States, state surveillance systems exist but collect limited information, prompting a complementary use of health insurance claims data to describe national birth defect prevalence trends and investigate signals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The Merative MarketScan Commercial Claims and Encounters (MarketScan) database was used to identify liveborn infants from 2016 to 2022, with linkage to maternal health care records during pregnancy. Birth defects were identified using ICD-10-CM codes recorded in the first 3 months of life, and prevalence estimates with 95% confidence intervals were generated for birth defect categories and select birth defects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The study population included 943,855 liveborn infants. From 2016 to 2022, the prevalence increased for cardiac, central nervous system, ear, genital, urinary, musculoskeletal, and limb birth defect categories. Stable prevalence over the study period was observed for chromosomal, oral cleft, respiratory, gastrointestinal, vascular, and eye defects. For specific defects, we observed an increased prevalence of both ankyloglossia and lip-tie over the study period and a transient higher prevalence of omphalocele over 2017 and 2018. Within genital birth defects, we observed increasing prevalence trends for congenital malformations of the penis, while hypospadias and cryptorchidism remained relatively stable.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Health care utilization databases can complement existing surveillance systems by generating, confirming, or refuting signals based on ecological trends or clusters. The availability of patient information in claims databases can allow for further investigation of signals to inform birth defect etiology.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 9","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144927445","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}
Eydie L. Moses-Kolko, Loreen Straub, Kelly Fung, Krista F. Huybrechts
We thank the authors for their positive feedback on our recent publication “Synthesizing cohort study results to promote knowledge transfer of safety data regarding gestational antidepressant exposure and offspring congenital anomalies: A test of concept” (Moses-Kolko et al. 2025). We appreciate the commendation for our test-of-concept fact box that we used to illustrate a strategy to facilitate prescriber-patient communication regarding potential benefits and risks of use of antidepressants during pregnancy. The idea of a layered fact box is intriguing. Because many patient encounters are virtual, technology could indeed be harnessed to create and display digital image layers during a risk discussion (Tsai et al. 2025).
The authors raise the important point that we mention in our discussion; that presenting pooled relative risks for overall major congenital anomalies and cardiac anomalies can obscure specific risk data regarding individual drugs as well as anomalies in specific organ systems and subsystems. As the manuscript title implies, we presented the example of gestational antidepressant exposure and the risk of major congenital malformations overall and cardiac malformations as a test of concept. We agree that it would be meaningful to extend the example we provided in the manuscript to organ-specific malformations as well as specific drugs. Ideally, there would be ample studies which minimize confounding and misclassification bias available to generate pooled risk estimates on specific drug exposure-organ malformation outcomes for use in a fact box. As we mention in the manuscript, a current challenge for summarizing data for specific drugs, for new drugs, or for rare anomalies is the paucity of high-quality evidence (Covington et al. 2004).
The authors cite several studies they believe provide clinically actionable signals. One study is misquoted. The Huybrechts study (Huybrechts et al. 2014) did not report an organ-specific and agent-specific increase in risk. They reported an adjusted RR of 0.94 (95% CI 0.73–1.21) for the association between paroxetine and cardiac anomalies and an adjusted RR of 0.73 (95% CI 0.49–1.09) for the association with ventricular septal defects and 1.07 (95% CI 0.59–1.93) for the association with right ventricular outflow tract obstruction, specifically.
An important direction of pharmacoepidemiology research is the harmonization across studies of exposure and outcome definitions as well as methods to address confounding and bias (Richardson et al. 2025) to make replication and meta-analysis possible in future research. We eagerly anticipate such research advances that will generate greater confidence in drug and organ-specific signals that can be incorporated into clinical risk discussions as well as into clinically useful fact boxes.
K.F.H. reports being an investigator on grants to her institution from UCB, GSK, and
我们感谢作者对我们最近发表的“综合队列研究结果以促进妊娠期抗抑郁药暴露和后代先天性异常安全数据的知识转移：概念测试”（Moses-Kolko et al. 2025）的积极反馈。我们感谢对我们的概念测试事实盒的赞扬，我们用它来说明一种策略，以促进医生和病人就怀孕期间使用抗抑郁药的潜在益处和风险进行沟通。分层事实盒的想法很有趣。由于许多患者的接触是虚拟的，技术确实可以用来在风险讨论期间创建和显示数字图像层（Tsai et al. 2025）。作者提出了我们在讨论中提到的重要观点；总体主要先天性异常和心脏异常的综合相对风险可能会模糊个别药物以及特定器官系统和子系统异常的具体风险数据。正如论文标题所暗示的那样，我们提出了妊娠期抗抑郁药暴露与主要先天性畸形和心脏畸形风险的例子，作为概念的检验。我们同意将我们在手稿中提供的例子扩展到器官特异性畸形以及特定药物将是有意义的。理想情况下，应该有充分的研究，尽量减少混淆和错误分类偏差，以产生特定药物暴露-器官畸形结果的综合风险估计，用于事实框。正如我们在论文中提到的，当前总结特定药物、新药或罕见异常数据的挑战是缺乏高质量的证据（Covington et al. 2004）。作者引用了几项研究，他们认为这些研究提供了临床可操作的信号。一项研究被错误引用。Huybrechts研究（Huybrechts et al. 2014）没有报告器官特异性和药物特异性的风险增加。他们报道帕罗西汀与心脏异常相关的校正RR为0.94 (95% CI 0.73 - 1.21)，与室间隔缺损相关的校正RR为0.73 (95% CI 0.49-1.09)，与右室流出道梗阻相关的校正RR为1.07 （95% CI 0.59-1.93）。药物流行病学研究的一个重要方向是协调暴露和结果定义的研究，以及解决混淆和偏倚的方法（Richardson et al. 2025），以便在未来的研究中进行复制和荟萃分析。我们热切地期待着这样的研究进展，这将对药物和器官特异性信号产生更大的信心，这些信号可以纳入临床风险讨论以及临床有用的事实箱。报告称她是UCB， GSK和武田向她的机构提供资助的研究员，与这项工作无关。L.S.报告说，她是葛兰素史克向她的机构提供的一项拨款的研究员，与这项工作无关。E.L.M.-K。和K.F.没有商业或财务利益冲突。
{"title":"Reply to Correspondence “Beyond Aggregate Risk: Drug- and Organ-Specific Nuances in Counseling on Antidepressant Teratogenicity” (Tsai et al. 2025)","authors":"Eydie L. Moses-Kolko, Loreen Straub, Kelly Fung, Krista F. Huybrechts","doi":"10.1002/bdr2.2522","DOIUrl":"https://doi.org/10.1002/bdr2.2522","url":null,"abstract":"<p>We thank the authors for their positive feedback on our recent publication “Synthesizing cohort study results to promote knowledge transfer of safety data regarding gestational antidepressant exposure and offspring congenital anomalies: A test of concept” (Moses-Kolko et al. <span>2025</span>). We appreciate the commendation for our test-of-concept fact box that we used to illustrate a strategy to facilitate prescriber-patient communication regarding potential benefits and risks of use of antidepressants during pregnancy. The idea of a layered fact box is intriguing. Because many patient encounters are virtual, technology could indeed be harnessed to create and display digital image layers during a risk discussion (Tsai et al. <span>2025</span>).</p><p>The authors raise the important point that we mention in our discussion; that presenting pooled relative risks for overall major congenital anomalies and cardiac anomalies can obscure specific risk data regarding individual drugs as well as anomalies in specific organ systems and subsystems. As the manuscript title implies, we presented the example of gestational antidepressant exposure and the risk of major congenital malformations overall and cardiac malformations as a test of concept. We agree that it would be meaningful to extend the example we provided in the manuscript to organ-specific malformations as well as specific drugs. Ideally, there would be ample studies which minimize confounding and misclassification bias available to generate pooled risk estimates on specific drug exposure-organ malformation outcomes for use in a fact box. As we mention in the manuscript, a current challenge for summarizing data for specific drugs, for new drugs, or for rare anomalies is the paucity of high-quality evidence (Covington et al. <span>2004</span>).</p><p>The authors cite several studies they believe provide clinically actionable signals. One study is misquoted. The Huybrechts study (Huybrechts et al. <span>2014</span>) did not report an organ-specific and agent-specific increase in risk. They reported an adjusted RR of 0.94 (95% CI 0.73–1.21) for the association between paroxetine and cardiac anomalies and an adjusted RR of 0.73 (95% CI 0.49–1.09) for the association with ventricular septal defects and 1.07 (95% CI 0.59–1.93) for the association with right ventricular outflow tract obstruction, specifically.</p><p>An important direction of pharmacoepidemiology research is the harmonization across studies of exposure and outcome definitions as well as methods to address confounding and bias (Richardson et al. <span>2025</span>) to make replication and meta-analysis possible in future research. We eagerly anticipate such research advances that will generate greater confidence in drug and organ-specific signals that can be incorporated into clinical risk discussions as well as into clinically useful fact boxes.</p><p>K.F.H. reports being an investigator on grants to her institution from UCB, GSK, and","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdr2.2522","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ventral body wall defects (VBWDs), including omphalocele and gastroschisis, result from failed embryonic midline closure and contribute to high neonatal morbidity. While thyroid hormones (THs) are essential for morphogenesis, their role in VBWD pathogenesis is not well defined.
Aim
To investigate the impact of TH deficiency on ventral body wall development in chick embryos and evaluate levothyroxine as a therapeutic intervention.
Materials and Methods
Hypothyroidism was induced on embryonic day 3 using thiourea (2.5 mg/50 μL), a thyroid peroxidase inhibitor. A rescue group received levothyroxine (2.5 μg/50 μL) on day 5.5. Embryos were harvested on days 6 and 10 for analysis of thyroid peroxidase activity, morphology, skeletal patterning, and expression of morphogenetic (SHH, MYOD, MSX1/2), epithelial/mesenchymal (CDH1/2, VIM, TGFβ1), and apoptotic (Cleaved CASPASE 3) markers.
Results
Thiourea-treated embryos exhibited incomplete ventral closure, skeletal abnormalities, impaired myogenesis, and disrupted epithelial–mesenchymal transition. Gene profiling showed downregulation of SHH, MYOD, and MSX1/2, with concomitant upregulation of CDH1, VIM, TGFβ1, and Cleaved CASPASE 3. Levothyroxine administration partially restored thyroid activity, improved wall integrity, and normalized developmental gene expression.
Discussion
TH deficiency perturbs morphogenetic signaling, leading to defective mesodermal differentiation, epithelial–mesenchymal imbalance, and enhanced apoptosis. Partial rescue with levothyroxine underscores the hormone's developmental role and therapeutic relevance.
Conclusion
TH insufficiency contributes to VBWDs by disrupting key pathways in myogenesis and tissue remodeling. Early levothyroxine supplementation may offer a strategy to mitigate endocrine-related congenital malformations.
{"title":"Thyroid Hormone Deficiency Disrupts Embryonic Ventral Body Wall Development and Myogenesis With Partial Recovery Following LevothyroxineTherapy","authors":"Juhi Vaishnav, Suresh Balakrishnan","doi":"10.1002/bdr2.2520","DOIUrl":"https://doi.org/10.1002/bdr2.2520","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ventral body wall defects (VBWDs), including omphalocele and gastroschisis, result from failed embryonic midline closure and contribute to high neonatal morbidity. While thyroid hormones (THs) are essential for morphogenesis, their role in VBWD pathogenesis is not well defined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To investigate the impact of TH deficiency on ventral body wall development in chick embryos and evaluate levothyroxine as a therapeutic intervention.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and Methods</h3>\u0000 \u0000 <p>Hypothyroidism was induced on embryonic day 3 using thiourea (2.5 mg/50 μL), a thyroid peroxidase inhibitor. A rescue group received levothyroxine (2.5 μg/50 μL) on day 5.5. Embryos were harvested on days 6 and 10 for analysis of thyroid peroxidase activity, morphology, skeletal patterning, and expression of morphogenetic (SHH, MYOD, MSX1/2), epithelial/mesenchymal (CDH1/2, VIM, TGFβ1), and apoptotic (Cleaved CASPASE 3) markers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Thiourea-treated embryos exhibited incomplete ventral closure, skeletal abnormalities, impaired myogenesis, and disrupted epithelial–mesenchymal transition. Gene profiling showed downregulation of SHH, MYOD, and MSX1/2, with concomitant upregulation of CDH1, VIM, TGFβ1, and Cleaved CASPASE 3. Levothyroxine administration partially restored thyroid activity, improved wall integrity, and normalized developmental gene expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>TH deficiency perturbs morphogenetic signaling, leading to defective mesodermal differentiation, epithelial–mesenchymal imbalance, and enhanced apoptosis. Partial rescue with levothyroxine underscores the hormone's developmental role and therapeutic relevance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>TH insufficiency contributes to VBWDs by disrupting key pathways in myogenesis and tissue remodeling. Early levothyroxine supplementation may offer a strategy to mitigate endocrine-related congenital malformations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144894262","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}
Lorenzo D. Botto, Matthew R. Reeder, George K. Lui, M. Jill Glidewell, Wendy M. Book, Tessa L. Crume, Jesse M. DeLaRosa, Alfred d'Ottavio, Karrie F. Downing, Marcia L. Feldkamp, Daphne T. Hsu, Amber D. Khanna, Sergey Krikov, Nelangi M. Pinto, Cheryl L. Raskind Hood, Fred H. Rodriguez III, Aida S. Soim, Kevin J. Whitehead, Karen Chiswell, Jennifer S. Li
Background
Survival of individuals with congenital heart disease (CHD) has improved, leading to a growing and aging population of adults living with these conditions. Over their lifetime, they often face an array of comorbidities that affect outcomes and complicate medical management. However, population-based information on such comorbidities is scarce, reducing opportunities for prevention.
Methods
This population-based, cross-sectional study assessed comorbid conditions in adults with CHD residing in five geographic areas in the United States (in Colorado, Georgia, New York, North Carolina, and Utah). The study included 18,672 adults aged 19 to 64 years who had a healthcare encounter between 2011 and 2013 associated with ≥ 1 CHD-related diagnosis code. Data were derived from linked clinical and administrative sources, reflecting inpatient, outpatient, and emergency department encounters.
Results
Most adults with CHD experienced at least one (88.5%) and usually multiple (76%) comorbidities. Overall, noncardiac comorbidities exceeded cardiac comorbidities. The most frequent noncardiac comorbidities were endocrine/metabolic conditions (e.g., diabetes, hyperlipidemia, hypothyroidism), hypertension, and neuropsychiatric conditions (e.g., anxiety, depression). The presence and number of comorbidities varied in different sociodemographic groups. Men and older individuals experienced higher rates of many comorbidities, cardiac and noncardiac, regardless of CHD type.
Conclusions
Preventable and treatable comorbidity and multimorbidity are common in adults with CHD, with patterns shaped by sociodemographic factors and CHD type. Reducing preventable mortality in this growing population will require sustained tracking of health metrics and coordinated, data-driven, and lifelong care.
{"title":"Comorbidity and Multimorbidity in Adults With Congenital Heart Disease: Findings From a Multi-Site Population-Based Study","authors":"Lorenzo D. Botto, Matthew R. Reeder, George K. Lui, M. Jill Glidewell, Wendy M. Book, Tessa L. Crume, Jesse M. DeLaRosa, Alfred d'Ottavio, Karrie F. Downing, Marcia L. Feldkamp, Daphne T. Hsu, Amber D. Khanna, Sergey Krikov, Nelangi M. Pinto, Cheryl L. Raskind Hood, Fred H. Rodriguez III, Aida S. Soim, Kevin J. Whitehead, Karen Chiswell, Jennifer S. Li","doi":"10.1002/bdr2.2515","DOIUrl":"https://doi.org/10.1002/bdr2.2515","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Survival of individuals with congenital heart disease (CHD) has improved, leading to a growing and aging population of adults living with these conditions. Over their lifetime, they often face an array of comorbidities that affect outcomes and complicate medical management. However, population-based information on such comorbidities is scarce, reducing opportunities for prevention.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This population-based, cross-sectional study assessed comorbid conditions in adults with CHD residing in five geographic areas in the United States (in Colorado, Georgia, New York, North Carolina, and Utah). The study included 18,672 adults aged 19 to 64 years who had a healthcare encounter between 2011 and 2013 associated with ≥ 1 CHD-related diagnosis code. Data were derived from linked clinical and administrative sources, reflecting inpatient, outpatient, and emergency department encounters.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Most adults with CHD experienced at least one (88.5%) and usually multiple (76%) comorbidities. Overall, noncardiac comorbidities exceeded cardiac comorbidities. The most frequent noncardiac comorbidities were endocrine/metabolic conditions (e.g., diabetes, hyperlipidemia, hypothyroidism), hypertension, and neuropsychiatric conditions (e.g., anxiety, depression). The presence and number of comorbidities varied in different sociodemographic groups. Men and older individuals experienced higher rates of many comorbidities, cardiac and noncardiac, regardless of CHD type.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Preventable and treatable comorbidity and multimorbidity are common in adults with CHD, with patterns shaped by sociodemographic factors and CHD type. Reducing preventable mortality in this growing population will require sustained tracking of health metrics and coordinated, data-driven, and lifelong care.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdr2.2515","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Whole-genome sequencing (WGS) has been studied increasingly as a genetic testing technology in clinical applications, and its clinical validity has been preliminarily verified. In recent years, WGS has been employed in prenatal diagnosis.
Methods
This review synthesizes the current research and existing guidelines on the use of WGS for prenatal diagnosis. The methods, diagnostic scope, diagnostic rate, clinical usefulness, feasibility, limitations, and ethical issues of WGS in prenatal diagnosis are also presented.
Results
After reviewing the relevant studies, evidence indicated that WGS can improve the diagnostic rate for fetuses with abnormal development. At the same time, WGS also has significant challenges, such as a higher detection rate of variants of uncertain significance.
Conclusion
WGS has great potential in prenatal diagnosis, but more research is needed to advance its clinical application.
{"title":"Progress, Challenges, and Prospects of Short-Read Genome Sequencing in Prenatal Diagnosis","authors":"Yanfei Wang, Xiaofan Zhu, Zhi Gao, Kong Xiangdong","doi":"10.1002/bdr2.2516","DOIUrl":"https://doi.org/10.1002/bdr2.2516","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Whole-genome sequencing (WGS) has been studied increasingly as a genetic testing technology in clinical applications, and its clinical validity has been preliminarily verified. In recent years, WGS has been employed in prenatal diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This review synthesizes the current research and existing guidelines on the use of WGS for prenatal diagnosis. The methods, diagnostic scope, diagnostic rate, clinical usefulness, feasibility, limitations, and ethical issues of WGS in prenatal diagnosis are also presented.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>After reviewing the relevant studies, evidence indicated that WGS can improve the diagnostic rate for fetuses with abnormal development. At the same time, WGS also has significant challenges, such as a higher detection rate of variants of uncertain significance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>WGS has great potential in prenatal diagnosis, but more research is needed to advance its clinical application.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144869179","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}
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