"The Logic of Monsters:" Pere Alberch and the Evolutionary Significance of Experimental Teratology.

This paper offers an historical introduction to Pere Alberch's evolutionary thought and his contributions to Evo-Devo, based on his unique approach to experimental teratology. We will take as our point of reference the teratogenic experiments developed by Alberch and Emily A. Gale during the 1980s, aimed at producing monstrous variants of frogs and salamanders. We will analyze his interpretation of the results of these experiments within the framework of the emergence of evolutionary developmental biology (or "Evo-Devo"). The aim is understand how Alberch interpreted teratological anomalies as highly revealing objects of study for understanding the development of organic form, not only in an ontogenetic sense-throughout embryonic development-but also phylogenetically-throughout the evolution of species. Alberch's interpretation of monsters reflects the influence of a long tradition of non-Darwinian evolutionary thought, which began in the nineteenth century and was continued in the twentieth century by people such as Richard Goldschmidt, Conrad H. Waddington, and Stephen Jay Gould. They all proposed various non-gradualist models of evolution, in which embryonic development played a central role. Following this tradition, Alberch argued that, in order to attain a correct understanding of the role of embryological development in evolution, it was necessary to renounce the gradualist paradigm associated with the Darwinian interpretation of evolution, which understood nature as a continuum. According to Alberch, the study of monstrous abnormalities was of great value in understanding how certain epigenetic restrictions in development could give rise to discontinuities and directionality in morphological transformations throughout evolution.

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.

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.

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.

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 ).

Medications prescriptions in COVID-19 pregnant and lactating women: the Bergamo Teratology Information Service experience during COVID-19 outbreak in Italy.

Objectives The severe acute respiratory syndrome coronavirus 2 (COVID-19) outbreak in Italy, especially in Lombardy and Bergamo city, represented probably nowadays one of the first major clusters of COVID-19 in the world. The aim of this report is to describe the activity of Bergamo Teratology Information Service (TIS) in supporting the public and health-care personnel in case of drug prescriptions in suspected/confirmed COVID-19 pregnant and lactating patients during COVID-19 outbreak in Italy. Methods All Bergamo TIS requests concerning COVID-19 pregnant and lactating women have been retrospectively evaluated from 1 March to 15 April 2020. Type of medications, drug's safety profile and compatibility with pregnancy and lactation are reported. Results Our service received information calls concerning 48 (9 pregnant, 35 lactating) patients. Among pregnant and lactating women, the requests of information were related to 16 and 60 drugs prescriptions respectively. More than half concerned drugs prescriptions during the first and second trimester (13/16) and during the first six months of lactation (37/60). Hydroxychloroquine and azithromycin were the most involved. Conclusions Hydroxychloroquine and azithromycin at dosages used for COVID-19 may be considered compatible and reasonably safe either in pregnancy and lactation. Antivirals may be considered acceptable in pregnancy. During lactation lopinavir and ritonavir probably exhibit some supportive data from literature that darunavir and cobicistat do not. Tocilizumab may be considered for COVID-19 treatment because no increased malformation rate were observed until now. However caution may be advised because human data are limited and the potential risk of embryo-fetal toxicity cannot be excluded.

Approach to evaluating pregnancy safety of anti-rheumatic medications in the OTIS MotherToBaby pregnancy studies: what have we learned?

For the last 30 years, pregnancy exposure studies, with varying methodologies, have been the mainstay of post-marketing surveillance for new drugs likely to be used by women of reproductive age. While they provide valuable data to inform use during pregnancy, they have limitations that render them necessary but not sufficient in supplying timely information to patients and prescribers. The Organization of Teratology Information Specialists MotherToBaby Pregnancy Studies' collaborative research group operates to help fill this gap. This paper provides an overview of the research that has been and is currently being conducted, as well as best practices determined over the past two decades. The Organization of Teratology Information Specialists MotherToBaby studies can provide earlier signaling with regard to concerns following possible teratogenic exposures, which when examined in conjunction with larger database studies and case-control designs, can move us closer to developing a fuller picture of drug safety for women of reproductive age.

History and highlights of the teratological collection in the Museum Anatomicum of Leiden University, The Netherlands.

The anatomical collection of the Anatomical Museum of Leiden University Medical Center (historically referred to as Museum Anatomicum Academiae Lugduno-Batavae) houses and maintains more than 13,000 unique anatomical, pathological and zoological specimens, and include the oldest teratological specimens of The Netherlands. Throughout four centuries hundreds of teratological specimens were acquired by more than a dozen collectors. Due to the rich history of this vast collection, teratological specimens can be investigated in a unique retrospective sight going back almost four centuries. The entire 19th century collection was described in full detail by Eduard Sandifort (1742-1814) and his son Gerard Sandifort (1779-1848). Efforts were made to re-describe, re-diagnose and re-categorize all present human teratological specimens, and to match them with historical descriptions. In the extant collection a total of 642 human teratological specimens were identified, including exceptional conditions such as faciocranioschisis and conjoined twins discordant for cyclopia, and sirenomelia. Both father and son Sandifort differed in their opinion regarding the causative explanation of congenital anomalies. Whereas, their contemporaries Wouter Van Doeveren (1730-1783) and Andreas Bonn (1738-1817) both presented an interesting view on how congenital anomalies were perceived and explained during the 18th and 19th centuries; the golden age of descriptive teratology. Although this enormous collection is almost 400 years old, it still impresses scientists, (bio)medical students, and laymen visiting and exploring the collections of the Museum Anatomicum in Leiden, The Netherlands.

Dinosaurs, Chameleons, Humans, and Evo-Devo Path: Linking Étienne Geoffroy's Teratology, Waddington's Homeorhesis, Alberch's Logic of "Monsters," and Goldschmidt Hopeful "Monsters".

Since the rise of evo-devo (evolutionary developmental biology) in the 1980s, few authors have attempted to combine the increasing knowledge obtained from the study of model organisms and human medicine with data from comparative anatomy and evolutionary biology in order to investigate the links between development, pathology, and macroevolution. Fortunately, this situation is slowly changing, with a renewed interest in evolutionary developmental pathology (evo-devo-path) in the past decades, as evidenced by the idea to publish this special, and very timely, issue on "Developmental Evolution in Biomedical Research." As all of us have recently been involved, independently, in works related in some way or another with evolution and developmental anomalies, we decided to join our different perspectives and backgrounds in the present contribution for this special issue. Specifically, we provide a brief historical account on the study of the links between evolution, development, and pathologies, followed by a review of the recent work done by each of us, and then by a general discussion on the broader developmental and macroevolutionary implications of our studies and works recently done by other authors. Our primary aims are to highlight the strength of studying developmental anomalies within an evolutionary framework to understand morphological diversity and disease by connecting the recent work done by us and others with the research done and broader ideas proposed by authors such as Étienne Geoffroy Saint-Hilaire, Waddington, Goldschmidt, Gould, and Per Alberch, among many others to pave the way for further and much needed work regarding abnormal development and macroevolution.

Thomas H. Shepard, M.D., pioneer in embryology and teratology.

Dr. Thomas H. Shepard died on October 3, 2016 at the age of 93. He was a major figure in the fields of teratology, embryonic and fetal pathology, and pediatrics. He was beloved by his colleagues as he was by the many students and fellows whom he taught, mentored and befriended. His contributions to teratology are extraordinary and he is greatly missed. © 2017 Wiley Periodicals, Inc.

Exploring the effects of acid mine drainage on diatom teratology using geometric morphometry.

Metal pollution of aquatic habitats is a major and persistent environmental problem. Acid mine drainage (AMD) affects lotic systems in numerous and interactive ways. In the present work, a mining area (Roșia Montana) was chosen as study site, and we focused on two aims: (i) to find the set of environmental predictors leading to the appearance of the abnormal diatom individuals in the study area and (ii) to assess the relationship between the degree of valve outline deformation and AMD-derived pollution. In this context, morphological differences between populations of Achnanthidium minutissimum and A. macrocephalum, including normal and abnormal individuals, were evidenced by means of valve shape analysis. Geometric morphometry managed to capture and discriminate normal and abnormal individuals. Multivariate analyses (NMDS, PLS) separated the four populations of the two species mentioned and revealed the main physico-chemical parameters that influenced valve deformation in this context, namely conductivity, Zn, and Cu. ANOSIM test evidenced the presence of statistically significant differences between normal and abnormal individuals within both chosen Achnanthidium taxa. In order to determine the relative contribution of each of the measured physico-chemical parameters in the observed valve outline deformations, a PLS was conducted, confirming the results of the NMDS. The presence of deformed individuals in the study area can be attributed to the fact that the diatom communities were strongly affected by AMD released from old mining works and waste rock deposits.

A core syllabus for the teaching of embryology and teratology to medical students.

Clinical relevance in the teaching of biomedical sciences within health care courses presupposes that there is internationally agreed core material within the curricula. However, with the exception of a syllabus for neuroanatomy and gross anatomy of the head and neck for medical students, core syllabuses within many of the specialized anatomical sciences have yet to be developed. The International Federation of Associations of Anatomists aims to formulate internationally accepted core syllabuses for all anatomical sciences disciplines initially using Delphi Panels that comprise anatomists, scientists, and clinicians who evaluate syllabus content. Here, the suggestions of a Delphi Panel for embryology and teratology are presented prior to their publication on the website of the International Federation of Associations of Anatomists. Hence, to obtain a more definitive syllabus, it is required that anatomical and embryological/teratological societies, as well as individual anatomists, embryologists and clinicians, freely comment upon, elaborate and amend, this draft syllabus. The goal is to set internationally recognized standards and thereby provide guidelines concerning embryological and teratological knowledge when involved with course development. Clin. Anat. 30:159-167, 2017. © 2016 Wiley Periodicals, Inc.

Markov counting models for correlated binary responses.

We propose a class of continuous-time Markov counting processes for analyzing correlated binary data and establish a correspondence between these models and sums of exchangeable Bernoulli random variables. Our approach generalizes many previous models for correlated outcomes, admits easily interpretable parameterizations, allows different cluster sizes, and incorporates ascertainment bias in a natural way. We demonstrate several new models for dependent outcomes and provide algorithms for computing maximum likelihood estimates. We show how to incorporate cluster-specific covariates in a regression setting and demonstrate improved fits to well-known datasets from familial disease epidemiology and developmental toxicology.

Separating Family-Level and Direct Exposure Effects of Smoking During Pregnancy on Offspring Externalizing Symptoms: Bridging the Behavior Genetic and Behavior Teratologic Divide.

Maternal smoking during pregnancy (MSDP) has been robustly associated with externalizing problems and their developmental precursors in offspring in studies using behavioral teratologic designs (Wakschlag et al., Am J Public Health 92(6):966-974, 2002; Espy et al., Dev Psychol 47(1):153-169, 2011). In contrast, the use of behavior genetic approaches has shown that the effects commonly attributed to MSDP can be explained by family-level variables (D'Onofrio et al., Dev Psychopathol 20(01):139-164, 2008). Reconciling these conflicting findings requires integration of these study designs. We utilize longitudinal data on a preschool proband and his/her sibling from the Midwest Infant Development Study-Preschool (MIDS-P) to test for teratologic and family level effects of MSDP. We find considerable variation in prenatal smoking patterns both within and across pregnancies within families, indicating that binary smoking measures are not sufficiently capturing exposure. Structural equation models indicate that both conduct disorder and oppositional defiant disorder symptoms showed unique effects of MSDP over and above family level effects. Blending high quality exposure measurement with a within-family design suggests that it is premature to foreclose the possibility of a teratologic effect of MSDP on externalizing problems. Implications and recommendations for future studies are discussed.

Comparison of a modified mid-coronal sectioning technique and Wilson's technique when conducting eye and brain examinations in rabbit teratology studies.

BACKGROUND: There are two methods used when examining fetal rabbit eyes and brain in teratology studies. One method employs prior fixation before serial sectioning (Wilson's technique) and the other uses fresh tissue (mid-coronal sectioning). METHODS: We modified the mid-coronal sectioning technique to include removal of eyes and brain for closer examination and to increase the number of structures that can be evaluated and compared it to the Wilson's technique. We found that external examination of the head, in conjunction with either sectioning method, is equally sensitive in identifying developmental defects. We evaluated 40,401 New Zealand White (NZW) and Dutch-Belted (DB) rabbit fetuses for external head alterations, of which 28,538 fetuses were further examined for eye and brain alterations using the modified mid-coronal sectioning method (16,675 fetuses) or Wilson's technique (11,863 fetuses). The fetuses were from vehicle control or drug-treated pregnant rabbits in embryo-fetal development studies conducted to meet international regulatory requirements for the development of new drugs. RESULTS: Both methods detected the more common alterations (microphthalmia and dilated lateral cerebral ventricles) and other less common findings (changes in size and/or shape of eye and brain structures). CONCLUSIONS: While both methods are equally sensitive at detecting common and rare developmental defects, the modified mid-coronal sectioning technique eliminates the use of chemicals and concomitant fixation artifacts that occur with the Wilson's technique and allows for examination of 100% intact fetuses thereby increasing potential for detecting eye and brain alterations as these findings occur infrequently in rabbits.

Toxicology and teratology of the active ingredients of professional therapy MuscleCare products during pregnancy and lactation: a systematic review.

BACKGROUND: The rates of muscle aches, sprains, and inflammation are significantly increased during pregnancy. However, women are afraid to use systemic analgesics due to perceptions of fetal risks. Thus, topical products are important alternatives to consider for those women. Of interest, Professional Therapy MuscleCare (PTMC) has shown to be effective in alleviating the myofascial pain as reported in a randomized, placebo-controlled double-blinded comparative clinical study of five topical analgesics. However, to date, there is no complete review or long-term safety studies on the safety of these products during pregnancy and lactation. Thus, the aim of this article was to review toxicological, developmental, and reproductive effects associated with the use of PTMC products. METHODS: We performed a systematic review on safety of PTMC from all toxicological articles investigating the effects of PTMC's ingredients. This search was conducted through medical and toxicological databases including, Web of Science, EMBASE, Medline, and Micromedix. Both reported and theoretical adverse effects were extensively reviewed. RESULTS: Of the 1500 publications reviewed, 100 papers were retrieved and included in the review. Although some ingredients in PTMC products might cause adverse reproductive effects at high systemic doses, these doses are hundreds to thousands fold greater than those systemically available from topical use at the recommended maximum dose (i.e. 10 g/day). CONCLUSIONS: This study provides evidence that, when used as indicated, PTMC is apparently safe for pregnant women and their unborn babies as well as for breastfed infants.

Effect of feeding graded doses of Citrinin on clinical and teratology in female Wistar rats.

Citrinin is the one of the well-known mycotoxins, which is possibly spread all over the world. The graded doses of citrinin (1, 3 and 5 ppm CIT in feed) in female Wistar rats 10 weeks prior to mating, during mating and during organogenesis resulted in resorptions and post implantation losses, decreased fetal body weights and crown-rump lengths in fetuses of all groups. Various developmental anomalies recorded in fetuses of treated rats included gross (wrist drop, curled tail, stretched forelimb, subcutaneous haematoma), skeletal (incomplete ossification of skull bones, incomplete fusion of vertebral bodies, complete and partial agenesis of sternaebrae, metacarpals, metatarsals and phalanges, fused ribs and swing out ribs) and visceral (internal and external hydrocephalus, cerebellar hypoplasia, microphthalmia, roundening of heart, contracted kidneys, dilated renal pelvis and cryptorchid testes). The results suggest that CIT has adverse effects on fetal development which may be due to the longer bioavailability of citrinin in the animals.