Updating an Overview of Teratology.

In this chapter, the authors aim to update an overview of the principles of teratology, beginning with the definition of teratology, the critical point at which this process occurs, and some of the most common etiological agents that improve our understanding of teratology.Modern teratology has greatly improved in recent years with advances in new methods in molecular biology, toxicology, animal laboratory science, and genetics, increasing our knowledge of ambient influences. Nevertheless, there is a lot to do to reduce the influence of hazardous intervening agents, whether they target our genetics or not, that can negatively affect pregnancy and induce congenital development disorders, including morphological, biochemical, or behavioral defects.Certain agents might indeed be related to certain defects, but we have not been able to identify the cause of most congenital defects, which highlights the importance of finding and testing out new genetics techniques and conducting laboratory animal science to unravel the etiology and pathogenicity of each congenital defect.

Development Features on the Selection of Animal Models for Teratogenic Testing.

Today, the use of animal models from different species continues to represent a fundamental step in teratogenic testing, despite the increase in alternative solutions that provide an important screening to the enormous quantity of new substances that aim to enter the market every year. The maintenance of these models is due to the sharing of similar development processes with humans, and in this way they represent an important contribution to the safety in the use of the compounds tested. Furthermore, the application of advances in embryology to teratology, although hampered by the complexity of reproductive processes, continues to prove the importance of sensitivity during embryonic and fetal development to detect potential toxicity, inducing mortality/abortion and malformations.In this chapter, essential periods of development in different models are outlined, highlighting the similarities and differences between species, the advantages and disadvantages of each group, and specific sensitivities for teratogenic testing. Models can be divided into invertebrate species such as earthworms of the species Eisenia fetida/Eisenia andrei, Caenorhabditis elegans, and Drosophila melanogaster, allowing for rapid results and minor ethical concerns. Vertebrate nonmammalian species Xenopus laevis and Danio rerio are important models to assess teratogenic potential later in development with fewer ethical requirements. Finally, the mammalian species Mus musculus, Rattus norvegicus, and Oryctolagus cuniculus, phylogenetically closer to humans, are essential for the assessment of complex specialized processes, occurring later in development.Regulations for the development of toxicology tests require the use of mammalian species. Although ethical concerns and costs limit their use in large-scale screening. On the other hand, invertebrate and vertebrate nonmammalian species are increasing as alternative animal models, as these organisms combine low cost, less ethical requirements, and culture conditions compatible with large-scale screening. Their main advantage is to allow high-throughput screening in a whole-animal context, in contrast to the in vitro techniques, not dependent on the prior identification of a target. Better knowledge of the development pathways of animal models will allow to maximize human translation and reduce the number of animals used, leading to a selection of compounds with an improved safety profile and reduced time to market for new drugs.

The First Steps on AOPs' Concepts, Development, and Applications in Teratology.

An Adverse Outcome Pathway (AOP) is an analytical model that describes, through a graphical representation, a linear sequence of biologically connected events at different levels of biological organization, causally leading to an adverse effect on human health or the environment. In general, AOPs are constructed based on five central principles: systematic development and review, chemical-agnostic, modular, networks, and living documents. Furthermore, AOPs have the potential to be used, for example, to investigate certain molecular targets; relate the regulation of specific genes or proteins among AOPs; extrapolate biological processes, pathways, or diseases from one species to another; and even predict adverse effects in particular populations. AOPs also emerge as an alternative to animal experimentation in studies of developmental malformations. It's even possible now to develop a quantitative AOP to predict teratogenic effects for some substances. However, the construction of high-quality AOPs requires standardization in the way these models are developed and reviewed, ensuring an adequate degree of flexibility and guaranteeing efficiency. The development of AOPs should strictly be based on the guidance documents developed by the OECD. Nevertheless, an important step for those developing AOPs is the choice of an apical endpoint or an initiating molecular event in order to initiate the construction of the pathway. Another crucial step is a systematic literature review based on the random combination of the blocks of information. With these two fundamental steps completed, it only remains to follow the guidance documents on Developing and Assessing Adverse Outcome Pathways and AOP Developers' Handbook supplement provided by the OECD to organize and construct an AOP. This modern approach will bring radical changes in the field of toxicity testing, regarding the prediction of apical toxic effects using molecular-level effects.

Appendage abnormalities in spiders induced by an alternating temperature protocol in the context of recent advances in molecular spider embryology.

In the literature there are numerous reports of developmental deformities in arthropods collected in their natural habitat. Since such teratogenically affected individuals are found purely by chance, the causes of their defects are unknown. Numerous potential physical, mechanical, chemical, and biological teratogens have been considered and tested in the laboratory. Thermal shocks, frequently used in teratological research on the spider Eratigena atrica, have led to deformities on both the prosoma and the opisthosoma. In the 2020/2021 breeding season, by applying alternating temperatures (14 °C and 32 °C, changed every 12 h) for the first 10 days of embryonic development, we obtained 212 postembryos (out of 3,007) with the following anomalies: oligomely, heterosymely, bicephaly, schistomely, symely, polymely, complex anomalies, and others. From these we selected six spiders with defects on the prosoma and two with short appendages on the pedicel for further consideration. The latter cases seem particularly interesting because appendages do not normally develop on this body part, viewed as the first segment of the opisthosoma, and appear to represent examples of atavism. In view of the ongoing development of molecular techniques and recent research on developmental mechanisms in spiders, we believe the observed phenotypes may result, at least in part, from the erroneous suppression or expression of segmentation or appendage patterning genes. We consider "knockdown" experiments described in the literature as a means for generating hypotheses about the sources of temperature-induced body abnormalities in E. atrica.

Teratology research in the shadow of the Dobbs decision.

Following the 2022 US Supreme Court decision in Dobbs vs. Jackson Women's Health Organization, numerous states have passed laws banning or severely restricting abortion. The consequences of the decision stretch beyond abortion contexts, including progress on developing a more robust evidence base for care in pregnancy. In this Robert L. Brent lecture, I explore the impact of the Dobbs decision on teratology research, arguing that it is of importance even and perhaps especially for those concerned about the moral complexities of ending a pregnancy. For as abortion restrictions threaten teratology research, they also threaten its life-affirming aims. First, I show how teratology research and abortion are intertwined, highlighting the stories of Sherri Finkbine and Frances Kelsey, two courageous women whose lives intersected with both. Second, I describe how restrictions on abortion make teratology research more difficult and ethically complex, highlighting additional risks to research participants and staff, as well as new challenges to scientific validity and feasibility. And third, foregrounding yet another story of courage (and heartbreak), I highlight how abortion restrictions make teratology research more important than ever. Honoring Dr. Brent's legacy requires addressing-rather than avoiding-the ethical challenges of pregnancy-related research, especially now in the post-Dobbs era.

History and highlights of the teratological collection in the Narrenturm, Vienna (Austria).

The collection of the Narrenturm in Vienna houses and maintains more than 50,000 objects including approximately 1200 teratological specimens; making it one of the biggest collections of specimens from human origin in Europe. The existence of this magnificent collection-representing an important resource for dysmorphology research, mostly awaiting contemporary diagnoses-is not widely known in the scientific community. Here, we show that the Narrenturm harbors a wealth of specimens with (exceptionally) rare congenital anomalies. These museums can be seen as physical repositories of human malformation, covering hundreds of years of dedicated collecting and preserving, thereby creating unique settings that can be used to expand our knowledge of developmental conditions that have to be preserved for future generations of scientists.

An update on teratogens for pediatric healthcare providers.

PURPOSE OF REVIEW: To review updates regarding teratogens and give pediatric healthcare providers insight into the prevention of teratogenic exposures. RECENT FINDINGS: Application of the principles of teratology can help to assess the potential for exposures to be teratogenic. Identification of Zika virus as a teratogen, the most recent teratogenic agent identified, allowed public health measures to be put in place to mitigate its spread. Risk management strategies for teratogenic medications have resulted in a decrease but often not elimination of prenatal exposures. The failure to include pregnant persons in clinical trials results in their being less likely to receive needed medications and vaccines in a timely manner. SUMMARY: Pediatricians play an important role in the prevention of teratogenic exposures. Ensuring optimal management of patients with chronic illnesses that might increase their risk of birth defects during pregnancy due to the illness itself or its treatment is essential. For patients with pregnancy potential who are on teratogenic medications, ensuring effective contraception is also important. Inclusion of pregnant persons in clinical trials and research studies will be critical to advancing our knowledge of the safety of medications and other exposures during pregnancy.

Development and validation of a machine-learning algorithm to predict the relevance of scientific articles within the field of teratology.

The Dutch Teratology Information Service Lareb counsels healthcare professionals and patients about medication use during pregnancy and lactation. To keep the evidence up to date, employees perform a standardized weekly PubMed query where relevant literature is identified manually. We aimed to develop an accurate machine-learning algorithm to predict the relevance of PubMed entries, thereby reducing the labor-intensive task of manually screening the articles. We fine-tuned a pre-trained natural language processing transformer model to identify relevant entries. We split 15,540 labeled entries into case-control-balanced train, validation, and test datasets. Additionally, we externally validated the model prospectively with 1288 labeled entries obtained from weekly queries after developing the model. This dataset was also independently labeled by a team of six experienced human raters to evaluate our model's performance. The validation of our machine learning model on the retrospectively collected outheld dataset obtained an area under the sensitivity-versus-specificity curve of 89.3 % (CI: 88.2- 90.4). In the prospective external validation of the model, our model classified relevant literature with a sensitivity versus specificity curve area of 87.4 % (CI: 85.0-89.8). Our model achieved a higher sensitivity than the human raters' team without sacrificing too much specificity. The team of human raters showed weak to moderate levels of agreement in their article classifications (kappa range 0.40-0.64). The human selection of the latest relevant literature is indispensable to keep the teratology information up to date. We show that automatic preselection of relevant abstracts using machine learning is possible without sacrificing the selection performance.

The role of the University of Padua medical school in the study of conjoined twins between 18th and early 19th century.

The Medical School of Padua (Italy) contributed profoundly to the study of teratology. Many famous physicians and professors of medicine, such as Liceti, Vallisneri, Morgagni, and Malacarne, have studied and investigated these anomalies to better understand the causes and to find a potential explanation, often preserving the specimens for future studies. The present study highlights some historical cases of conjoined twins and a conjoined triplet preserved at the Morgagni Museum of Human Anatomy to show the development of medical theories in the teratological field between the 18th and early 19th century. This approach will provide insights into different study methods and ideas of some of the most famous scholars working in Padua at that time. The current article focuses on rare cases, both human and animal, that were encountered by physicians who worked in the Veneto area in the late 18th and early 19th century. Their detailed descriptions are not only of historical but also of contemporary dysmorphological value.

The forelimbs of Alvarezsauroidea (Dinosauria: Theropoda): Insight from evolutionary teratology.

Alvarezsauroidea (Tetanurae) are nonavian theropod dinosaurs whose forelimb evolution is characterised by the overdevelopment of digit I, at the expense of the other two digits, complemented by a drastic forelimb shortening in derived species (Parvicursorinae). These variations are recognised as evolutionary developmental anomalies. Evolutionary teratology hence leads to a double diagnosis with (1) macrodactyly of digit I and microdactyly of digits II and III, plus (2) anterior micromelia. The teratological macrodactyly/microdactyly coupling evolved first. Developmental mechanisms disturbing limb proportion are thought to be convergent with those of other Tetanurae (Tyrannosauridae, Carcharodontosauridae). As for the manual anomalies, both are specific to Alvarezsauroidea (macrodactyly/microdactyly) and inherited (digit loss/reduction). While considering the frame-shift theory, posterior digits develop before the most anterior ones. There would therefore be a decrease in the area devoted to digits II (condensation 3) and III (condensation 4), in connection with the Shh signalling pathway, interacting with other molecular players such as the GLI3 protein and the Hox system. Developmental independence of digit I (condensation 2) would contribute to generating a particular morphology. Macrodactyly would be linked to a variation in Hoxd-13, impacting Gli3 activity, and increasing cell proliferation. The loss/reduction of digital ray/phalanges (digits II and III), would be associated with Shh activity, a mechanism inherited from the theropodan ancestry. The macrodactyly/microdactyly coupling, and then anterior micromelia, fundamentally changed the forelimb mechanical function, compared to the 'classical' grasping structure of basal representatives and other theropods. The distal ossification of the macrodactylian digit has been identified as physiological, implying the use of the structure. However, the debate on a particular 'adaptive' use is pointless as the ecology of an organism is interactively complex, being both at the scale of the individual and dependent on circumstances. Other anatomical features also allow for compensation and different predation (cursorial hindlimbs).

Information Needs and Counseling Preferences among Potential Users of the Future Teratology Information Service in Belgium: A Cross-Sectional Study Involving the Public and Healthcare Professionals.

A Teratology Information Service (TIS) does not exist in Belgium yet but will hopefully be established soon. To prepare for this, we aimed to provide insight into the information needs and counseling preferences of the Belgian public and healthcare professionals (HCPs) regarding medication use in pregnancy and breastfeeding. A cross-sectional study using two anonymous, online surveys disseminated via social media, websites, and newsletters addressing Dutch and French-speaking individuals (≥18 years) and licensed HCPs was performed between June and September 2020. Ethics approval and informed consent were obtained. In total, 1508 public survey respondents (98% women) and 702 HCPs participated. Information needs on perinatal medication use were ubiquitous among both groups, and for which they often relied on patient information leaflets or the product information and online fora. Conflicting information on this topic regularly occurs and complicates HCPs' duties. Women and HCPs assigned an important role to a TIS, both in terms of providing evidence-based information (via a website or app) and being accessible to be contacted in case of questions (by phone or via e-mail or chat). In conclusion, a TIS would be warmly welcomed by women and HCPs in Belgium and should ideally be established soon to address current information needs regarding perinatal medication use and to contribute to research in this field.

Current activities between the DevTox Berlin workshops and the Japanese Teratology Society Terminology Committee in harmonizing the terminology for classifying anomalies in laboratory animals in developmental toxicity studies: Report from the Satellite Workshop of the 60th Annual Meeting of the Japanese Teratology Society.

In recent years, the Japanese Teratology Society has worked with the DevTox Berlin Workshops project to provide internationally consistent terminology for teratogenic effects. This paper summarizes a satellite workshop of the 60th Annual Meeting of the Japanese Teratology Society, which was entitled "Current activities between DevTox Berlin Workshops to develop a harmonized terminology for classifying anomalies in laboratory animals in developmental toxicity studies." The Japanese Teratology Society - Laboratory Animal Terminology Project (JTS-LATP) reviewed "gray zone" anomalies and focused on developing criteria for reclassifying a large number of gray zone anomalies to clarify them and to make it easier to judge fetal categories. This effort will lead to international agreement, based on shared conceptions. The present article aimed to provide the reader with a summary of the issues discussed at the 2020 satellite meeting, which included discussions on open issues from the DevTox Berlin Workshops, ongoing work by the JTS-LATP on gray zone (GZ) anomalies, current industrial concerns, and future challenges.

[The Role of Pharmacists as Seen from the Japan Teratology Information Center].

The Japan Drug Information Institute in Pregnancy (JDIIP) was established in 2005 as a project of the Ministry of Health, Labour and Welfare with the aims of providing information on drug safety to women who are worried about drug use during pregnancy and creating evidence through epidemiological studies based on counseling cases. Since being established, JDIIP has made many contributions to the wellness of mothers and children by promoting the proper use of drugs during pregnancy. However, some studies have shown that this alone is not enough to meet potential needs. From now on, it is hoped that the hub hospitals in the 47 prefectures will take the lead in promoting regional pharmaceutical cooperation and striving for equalization in this field. Pharmacists will play an important role in this effort. In particular, many women consult pharmacists during lactation because they are out of touch with their obstetricians. If the wording of the section on lactating women in the package insert is faithfully explained, breastfeeding and drug therapy become incompatible. However, in most cases, it is possible to achieve both if the benefits of breastfeeding and the amount of drug transfer into milk are taken into consideration. Counseling on drug treatment during lactation is a field where pharmacists who are skilled in reading package inserts and pharmacokinetics should play an active role. The newly established the Japan Drug Information in Pregnancy Society aims to provide a place for pharmacists who do not have many opportunities to learn about this field.

Can non-responding mask or mimic drug effects on pregnancy outcome? Evaluation of case characteristics based on the national Embryotox cohort.

Women and their health care provider (HCP) often seek advice for drug safety in pregnancy at Teratology Information Services (TIS). In turn, TIS ask for details of drug exposure and pregnancy outcome. These data constitute a valuable basis for research on prenatal drug risks in many countries. Non-response to follow-up questionnaires, however, may cause biased study results. To assess the potential of non-response bias, this study based on the German Embryotox cohort compares maternal and HCP characteristics of responders and non-responders. Change in loss of follow-up rates over time is investigated using logistic regression. From 2010 until the end of 2020, 48,410 pregnant women and/or their HCP consented to participation in follow-up. Of these, 25.0 % did not return follow-up questionnaires. Loss rates were similar for patients and HCP but increased over time. Participants from semi-dense populated areas had a smaller loss rate (20.4 %) than those from rural (28.4 %) or urban areas (25.6 %). Responding women were older than non-responders, had a lower BMI, a more positive attitude towards pregnancy, a higher educational level, a lower number of previous pregnancies, smoked less, and indicated alcohol consumption more but social drugs less often. Non-response bias cannot be ruled out in studies based on observational data on drug use in pregnancy as those collected by TIS. However, differences between the complete and lost-to follow-up cohort do not suggest a particularly high or low risk profile for one of the cohorts that might substantially confound study results or even mask or mimic potential drug toxicity.

Protocol of a prospective and multicentre China Teratology Birth Cohort (CTBC): association of maternal drug exposure during pregnancy with adverse pregnancy outcomes.

BACKGROUND: As reported, 27-93 % of pregnant women take at least one drug during pregnancy. However, drug exposure during pregnancy still lacks sufficient foetal safety evidence of human origin. It is urgent to fill the knowledge gap about medication safety during pregnancy for optimization of maternal disease treatment and pregnancy drug consultation. METHODS AND ANALYSIS: The China Teratology Birth Cohort (CTBC) was established in 2019 and is a hospital-based open-ended prospective cohort study with the aim of assessing drug safety during pregnancy. Pregnant women who set up the pregnancy health records in the first trimester or who seek drug consultation regardless of gestational age in the member hospitals are recruited. Enrolled pregnant women need to be investigated four times, namely, 6-14 and 24-28 weeks of gestational age, before discharge after hospital delivery, and 28-42 days after birth. Maternal medication exposure during pregnancy is the focus of the CTBC. For drugs, information on the type, name, and route of medication; start and end time of medication; single dose; frequency of medication; dosage form; manufacturer; and reason for medication is collected. The adverse pregnancy outcomes collected in the study include birth defects, stillbirth, spontaneous abortion, preterm birth, post-term birth, low birth weight, macrosomia, small for gestational age, large for gestational age and low Apgar score. CTBC uses an electronic questionnaire for data collection and a cloud system for data management. Biological samples are collected if informed consents are obtained. Multi-level logistic regression, mixed-effect negative binomial distribution regression and spline function regression are used to explore the effect of drugs on the occurrence of birth defects. DISCUSSION: The findings of the study will assist in further understanding the risk of birth defects and other adverse pregnancy outcomes associated with maternal drug exposure and developing the optimal treatment plans and drug counselling for pregnant women. TRIAL REGISTRATION: This study was approved by the Research Ethics Committee of the West China Second Hospital of Sichuan University and registered at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx , registration number ChiCTR1900022569 ).

A teratology information system in vernacular: Closing an information gap.

BACKGROUND: Leading Teratology Information Systems (TIS) arose in major industrial nations and are mostly in English. The prevalence of anglophone speakers in Ukraine is among the lowest in Europe. A TIS in Ukrainian (UTIS) seeks to diminish an information gap concerning teratogens. The process and results related to UTIS are applicable to formulations of other TIS in vernacular languages. METHODS: Implementation of a free-access UTIS and analysis of utilization patterns. UTIS provides access to articles in Ukrainian (AU) which are summaries extracted from leading international TIS and other sources. AU are revised at least tri-annually. RESULTS: UTIS provides access to over 1,100 AU accrued since 2016 to the present. The number AU views increased from nearly 30,000 (2016) to over 80,000 (2020); the number of visitors increased from 3,500 to 58,000 during the same periods. The highest percent of users per urban population (2.09, 1.77, and 1.72) was in Ternopil, Ivano-Frankivsk, and Kyiv (capital), respectively; the lowest was in Odesa (0.17). CONCLUSIONS: UTIS reduced an information gap in Ukraine concerning teratogenic risk factors. The process can be implemented elsewhere relying on generally available local resources.