=urrsnt Eommsnts” EUGENE GARFIELD INSTITUTE FOR SCIENTIFIC INFORMATION” 3501 MARKET ST PHILADELPHIA PA 19104 Teratology Literature and the Thalidomide Controversy Number 50 December 15, 1986 The prospect of bearing an abnormal or studies the action, detection, and treatment deformed child has long been a chilling fear of toxins. Although interrelated, each of of all expectant mothers. Of the estimated these disciplines has its own language. In 130 million children born each year world- the near future we will study the develop- wide, ] at least 2 to 3 percent are born with mental biology journals. some type of birth defect.z It has only been A major challenge to teratologists, there- within the last 150 years that doctors have fore, is to establish and expand links with attempted to interpret birth defects, or the varied disciplines contributing to the congenital malformations, in a scientific field. The multidisciplimry aspect of tera- manner. The term “teratology” was first tology makes it an excellent field to dem- coined in 1832 by the French physician onstrate the value of citation analysis. The Isidore Geoffroy Saint-Hilaire to define a cognitive and social ties between scientific field of science dedicated to studying devel- papers and authors can be determined by opmental anomalies. The term is derived analyzing direct citation links, co-citation, from the Greek term ‘‘terato, ” meaning or bibliographic coupling. The relationships monster. He also described and classified between teratology and other areas carsthen the known abnormalities of his day. 3 be ascertained. ISI@is using similar proce- While teratology had its origins in the de- dures in a project concerning toxicology for scriptive anatomy of congenital malforma- the National Library of Medicine. We are tions, Richard W. Smithells, Department of using bibliometric methods to determine Pediatrics and Child Health, University of how well the current TOXLINE database Leeds, UK, points out that today teratolo- covers the relevant literature. gy includes any birth defect—morphologi- Figure 1 is a map showing how research cal, biochemical, or behavioral-induced by fronts from the various fields of teratology an embryotoxic agent at any stage of gesta- are related. The higher-level front on’ ‘Ter- tion.’$This wider definition inevitably in- atogenic activity of various chemicals” cludes the involvement of many disciplines. (#85-0540) shows the links between smaller For example, teratology is considered an fronts on environmental medicine, the ef- offshoot of developmental biology. While fects of chemicals on fetal development, and developmental biology is the study of the the neurological effats of chemicals. Table overall development of the individual dur- 1 is a list of six 1985 research fronts direct- ing gestation, teratology is primarily con- ly concerning teratology. We will review cerned with factors that interfere with de- some of these research fronts, pointing out velopmental differentiation. These factors those areas that have made the most impact are often considered embryotoxins requir- in the science community. We will also dis- ing the expertise of a toxicologist who cuss some of the established principles of 404 Figure 1: Higher-1evel map for C2 research front #r?5-0540, ‘‘Teratogenic activity of varioua chemicals, ” showing li between Cl research fronts. The numbers of core/citing items are given in parentis foUowingthereaearch- from name on the map. 8482 Teratogeniceffncts to monomathylether, Chemicalfactorsaffecting mouse of chemicalagents ether, ethylene glycol, sperm-headmorphology(2/21 ) on embryonic and other chemicalson development(2/19) reproductivesystemsin I male mrimels(2/20) 7 / 136! Male reproductive dysfunction (2/1 7) Neurologicalmanifestationsof chlordnconein humens(3/26) \ Evaluationof teratogenicectivity of variousagentsand their effects on fetal developmmt (2/28) teratology as well as the obstacles prevent- A preliminary journal list was developed ing certain quegtions from being answered. using keywords, concepts, and prominent In addition, to show the complexities in- authors in an online and manual literature volved in the mechanisms of teratogenesis, search. We also examined the Journal Cita- we will discuss the drug thalidomide. This tion Reports@ for journal titles. The jour- dmg was taken off the market 25 years ago nals that appeared most often from these after it was established as a cause of congen- sources were added to the preliminary list. ital malformations. Controversy still exists The final list was reviewed by subject spe- concerning this tragedy-which allegedly cialists to provide an inclusive representa- caused over 10,000 children to be born with tion of all facets of teratogenesis. severe physical defects—and whether it The earliest teratology studies began ap- could have been averted. @g ~ the late1800s, when the emphasis shifted from classifying malformations to experimentally inducing them in animals. In Early Teratology Studies 1855 Camille Dareste applied heat, cold, The earliest scientific human teratology shaking, and chemicals to chicken eggs. studies are found in a wide range of jour- These treatments artificially induced devel- nals, such as the American Journal of Oph- opmental abnormalities in chicks and pro- dsaimdogy, the American Joumul of Roent- vided the first proof that extrinsic factors gendogy, and the Biochenskal Journal. This could cauge abnormal embryonic develop- is an indication of the diverse fields contrib- ment. $ uting to the origin of modem teratology. The first report of experimentally induced Table 2 is a selected list of the current jour- congenital malformations in mammals was nals publishing articles on teratology. These in 1921. Sylvester S. Zilva, Biochemical journals cover many disciplines, including Department, Lister Institute, London, UK, gynecology, obstetrics, embryology, and and colleagues fed a pregnant sow a fat- mutagenesis. deficient diet. Eight piglets were stillborn 405 TaMe 1: Tk 1985 SCf9SSCPrcrearch fronts on teratology and thalidomide. A= research-front number. B= reacarch- front name. C= numk of core items. D= number of citing items. A B CD 85-1 S03 Uac of thalidomide therapy in leprosy 2 14 85-2250 Teratogenicity of retinoic acid and vitamin A analogs 4 35 85-4632 Evaluation of teratogenic activity of various agents and their effects on fetal development 2 28 85-6306 Maternal drug use in early pregnancy snd bkth defects 9 75 85-7692 Intrauterine factors affecting normaf fetal growth and development 2 18 85-8348 Teratogenic effects of chemical agents on embryonic development 2 19 Tabte 2: Sekted tiatof journals reporting on teratology Etiology of Congenital Malformations and embryology. A=titfe and first yea of publication, B= 1985 impact factor. Wilson estimated that about 20 to 25 per- A B American JLNJmzdof Obstetrics and 1.78 cent of all birth defects are the result of ge- Gynecology ( 1920) netic transmission and chromosomal abnor- Anatomy and Embryology (1892) 1.62 malities, while 5 to 10 percent have been Arzneimittel-Forachung/Dmg Research (195 l) 0.87 Cell Differentiation (1972) 1,39 attributed to known environmental factors. Development, Growth & Differentiation 0.98 The remaining 65 to 75 percent of birth de- (1950) fects arise from unknown causes but may Developmental Biology (1959) 3.58 Differentiation (1973) 1.79 be caused by an interplay of multiple envi- Journal of Embryology and Experimental 2.46 ronmental agents with genetic factors. 10 Morphology ( 1953) Mutation R-ch (1964) 2.28 Alcohol is an example of an environmen- Teratogenesis, Carcirrogenesis, and 0.99 tal factor acting as a teratogen. There is evi- Mutagenesis (1980) dence that habitual or even occasional drink- Teratology (1%8) 1,76 Toxicology (1973) 1.03 ing by an expectant mother can endanger the Toxicology and A@ied f%SITIMCOlOgy ( 1959) 1.93 health of the fetus. A baby of a heavy drirtk- Toxicology Mters (1977) 0.76 er may be born with fetal alcohol syndrome Rouxs Archives of Developmental Biology 1.93 (1894) (FAS), characterized by a small head, defec- tive joints in the hands and feet, a cleft or died very soon afler birth. Four of these palate, heart abnormalities, or mental im- piglets were born with rudimentary liibs.h pairment. 11There is a large literature on In 1929 Leopold Goldstein and Douglas P. FAS that will not be reviewed here, but the Murphy, Gynecean Hospital Institute of research fronts have been identified in the Gyne.cologic Research, University of Penn- historiograph (see Figure 2). sylvania, Philadelphia, showed that X rays can affect human embryonic development.T Determinants of Drug Teratogenicity And in 1941 Sir Norman M. Gregg, Royal Alexandra Hospital, Sydney, Australia, de- Our review focuses on the mechanisms in- termined that the dreaded virus of rubella, volved in drug-inducd malformations since or German measles, is a teratogen. BJames this is the topic involved with thalidomide. G. Wilson, Children’s Hospital Research The potential for drug teratogenicity is de- Foundation and Department of Pediatrics, pendent upon at least four variables, accord- University of Cincinnati, Ohio, observed ing to Marcus A. Khngberg and colleagues, that an interest in the teratogenic potential Department of Preventive and Social of drugs and other biologically active chem- Medicine, Saclder school of Medicine, Tel- icals virtually exploded during the 1950s. Aviv University, Israel. The first of these But despite the notoriety associated with the is the