Thalidomide Embryopathy Research Articles

Teratogen update: thalidomide: a review, with a focus on ocular findings and new potential uses.

Thalidomide (a-[N-phthalmido]-glutarimide) was synthesized in 1954, in what was then West Germany, by Chemie Grunenthal under the brand name of Contergan and was subsequently licensed in 46 other countries worldwide, covering all continents. It is an odorless white crystalline compound with low solubility in water (McBride, ’77; Stirling et al., ’97). A number of pharmaceutical companies manufactured thalidomide in various concentrations under several trade names (Stirling et al., ’97).Advertisements for the drug claimed that it was helpful in treating anxiety, insomnia, gastritis, and tension and that it was safe and harmless for pregnant women (Lenz, ’88). Additionally, it was an effective antiemetic in pregnancy (McBride, ’77). Thalidomide was first marketed in Germany in October 1957 as an effective, safe, inexpensive sedative, and production in that country reached 14.58 tons by 1960 (Zwingenberger and Wendt, ’96). A liquid form was available for children, and some compounds were sold without prescriptions (Stirling et al., ’97). Routine screening tests found thalidomide to be nontoxic in rodents, and therefore its potent teratogenicity in humans and higher mammals was not anticipated (Brent and Holmes, ’88). In the early 1960s an increasing number of infants were born with hypoplastic limb defects (Lenz,’85). In fall 1961, Lenz, noting these congenital malformations in the German population, suggested a possible correlation with thalidomide taken during pregnancy. He reported his observations at meetings and in the medical literature (Lenz,’61a,b,’62; Lenz and Knapp, ’62). Similar observations were made in England (Smithells, ’62) and Australia (McBride, ’61). Within a few months of the initially reported cases, the drug was withdrawn from commercial sale by Grunenthal (November 1961), and 9 months later was taken off the market in Japan. It was withdrawn from Great Britain in December 1961 (Kida, ’87). The potent teratogenicity appropriately suppressed other uses of thalidomide, such as for anti-inflammatory effects (Somers, ’60, Miller et al., ’60). The U.S. Food and Drug Administration (FDA) had not approved the drug for unrestricted use because of concerns (primarily about possible peripheral neuropathy) raised by Francis Kelsey, an FDA physician. Thus the number of cases of thalidomide embryopathy in the United States was small (Kelsey, ’88). The teratogenic effects of thalidomide contributed to the passage of new regulatory legislation for pharmaceuticals (Stirling et al.,’97). There are many reviews in the literature of various aspects of the thalidomide story (McBride, ’77; Fraser, ’88; Kelsey, ’88; Lenz, ’88; Warkany, ’88; Lenz, ’88).

The return of thalidomide: can birth defects be prevented?

Thalidomide, the drug that caused a worldwide epidemic of serious birth defects in the late 1950s and early 1960s, was recently approved by the US Food and Drug Administration (FDA) for use in treating the skin disease erythema nodosum leprosum, a complication of leprosy. The drug has also shown promise in the treatment of other serious diseases. If thalidomide is eventually approved for use in the US and other countries for treatment of diseases more prevalent than erythema nodosum leprosum, or if use of the drug for non-approved indications becomes widespread, hundreds of thousands of women with childbearing ability could be treated. If this should happen, can we prevent another epidemic of birth defects? In an effort to prevent fetal exposures to thalidomide, the FDA mandated a comprehensive programme to regulate prescription, dispensing and use of the drug. The programme is designed to require registration of all participating prescribers, pharmacies and patients. It also requires use of effective methods of contraception and periodic pregnancy testing of all patients with childbearing ability during treatment. Prescribers are directed to counsel both female and male patients on the risks, benefits and proper use of the drug, as well as on the proper use of contraceptives during treatment. The patient is required to sign an informed consent form before beginning treatment. Prescription and dispensing of thalidomide will be tightly controlled. Athalidomide registry will monitor prescription. dispensing and use of the drug, and will investigate all reported fetal exposures. This mandatory, but untested, programme promises to be effective at preventing fetal exposures to thalidomide, provided that patients, prescribers and pharmacists comply with all of its provisions. However, even if the programme proves to be successful in the US, there is concern that thalidomide may eventually be widely used in countries that may not require such stringent controls. In Brazil, where thalidomide is commercially available for treatment of leprosy patients, 33 cases of thalidomide embryopathy have already been reported in the literature. Even in countries that may tightly regulate the distribution and use of thalidomide, some patients may obtain the drug through black market sources. Should these events occur, many cases of thalidomide-induced birth defects could appear. Therefore, there is a need to develop nonteratogenic analogues of thalidomide that can provide effective treatment for erythema nodosum leprosum and other serious conditions without increasing the potential for another epidemic of thalidomide-related birth defects.

Effects of thallium ion on cellular components of the skin.

Thallium salts have been employed by dermatologists to cause depilation, and dermatologic features are prominent in thallium overdose. These features include alopecia and follicular hyperkeratosis. Administration of thallium to pregnant animals results in limb deformities, similar to those seen after thalidomide embryopathy. These findings suggest that thallium may act on keratinocytes, melanocytes, and endothelial cells. We show that thallium exerts pleiotropic effects on proliferation, cell shape and motility of multiple cell types. These findings may help explain the clinical findings of thallotoxicosis.

Thalidomide, a current teratogen in South America

Thalidomide, employed for the treatment of leprosy, is a current teratogen in South-America, and it is reasonable to assume this situation is at present affecting many babies in the underdeveloped world. Furthermore, the potential remarketing of thalidomide for the treatment of a large variety of diseases makes the problem global. When available, the control of drug intake during early pregnancy is very difficult since most exposed pregnancies are unintended, which are as frequent as 60% in the US and much more than that in underdeveloped countries. By a case-reference approach, the ECLAMC: Latin-American Collaborative Study of Congenital Malformations, registered 34 thalidomide embryopathy cases born in South America after 1965. A thalidomide-like phenotype (TLP), to be monitored for the ongoing surveillance of thalidomide teratogenic effect is proposed, including bilateral forms of preaxial limb reduction defects plus phocomelia, either isolated or associated with other congenital anomalies. In South America, this TLP has a birth prevalence rate of 1/20,000, with a stable secular trend and a homogenous geographic distribution.

Follow-up Study on Mental Health in Patients with Thalidomide Embryopathy

Follow-up Study on Mental Health in Patients with Thalidomide Embryopathy

Reconstruction of absent fingers and hands

The author described his personal experiences for more than 30 years in treating absent fingers and/or hands due to congenital condition or trauma. His initial interest in this subject was aroused by the thalidomide incident occurred in Japan around 1960, when he encountered many children with the tragic thalidomide embryopathy. In the first part of the paper, he described his experience in the research and development of electric arms. He obtained an opportunity visiting the Pediatric Amputee Clinic at Michigan Crippled Children Commission (MCCC) in Grand Rapids headed by late Dr. G. T. Aitken and Dr. C. Frantz in 1968. This prompted him to organize a study group to develop electric arms for the thalidomide victims in Japan responding a big social demand to create a reasonable artificial arm for them. He and his group developed arms with three-degree of freedom (motion) incorporated with a microcomputer system. But its heavy weight, weak power and complicated mechanism prevented the children from daily and practical use of the arm. Frankly, the author and his group ended up only to realize the extreme difficulty in simulating a living human arm and hand. In the second part of the paper, the author described surgical managements for absent fingers and/or hands, demonstrating the photographs of his own cases. The reconstructive methods included digital transfer, toe transplantation, bone lengthening, digital reconstruction, interdigitation and Krukenberg procedure. Digital transfer was especially useful for the total thumb defect. Microvascular toe transfer using the second toe was successful in a child with monodactylic form of symbrachydactylia. Sometimes, thumb reconstruction with a wrap-around flap from a big toe yielded a good cosmetic and functional result. He also described reconstruction of floating thumbs with iliac bone grafting and/or vascularized metatarsophalangeal joint transplantation associated with an abdominal flap. As for the bone lengthening procedure, he mentioned that recent knowledge in callotasis improved the results and expanded its indications. Finally for long forearm amputees, especially bilateral ones, he mentioned that the value of Krukenberg procedure still exists in view of its good postoperative functional capacity.

Thalidomide, a current teratogen in South America

Thalidomide, mainly used for the treatment of leprosy, is a current teratogen in South America, and it is reasonable to assume that at present this situation is affecting many births in underdeveloped countries. Moreover, the potential re-marketing of thalidomide for the treatment of a large variety of diseases may extend the problem to the developed world. When the drug is available, the control of its intake during early pregnancy is very difficult since most pregnancies are unintended. The ongoing occurrence of thalidomide embryopathy cases went undetected by the ECLAMC, due to several factors: (1) low populational coverage through this monitoring system; (2) pre-existence of the teratogen with its effects present in both baseline (expected) and monitored (observed) materials; and (3) lack of a defined phenotype to be monitored. Thus, if thalidomide re-enters the market throughout the world, due to the wide range of new applications, occurrence of phocomelia alone might not be sufficient to detect its effects. By a case-reference approach, the ECLAMC registered 34 thalidomide embryopathy cases born in South America after 1965 whose birthplaces correspond to endemic areas for leprosy. Phocomelia was found in five of eleven fully described cases. Thus, phocomelia alone is neither specific nor sufficient to serve as a suitable phenotype to survey the teratogenic effects of thalidomide. Therefore, a thalidomide-like phenotype, defined as any bilateral upper and/or lower limb reduction defect of the preaxial and/or phocomelia types, should be included in the routine surveillance of birth defects in all programmes.

Mesonephros has a role in limb development and is related to thalidomide embryopathy.

Recent studies have demonstrated a link between limb reduction defects and mesonephros removal [Geduspan and Solursh, 1992) Dev. Biol., 151:242-250]. However, there is some question as to whether the limb-reduction defects seen in that study resulted from the removal of mesonephros or from the formation of scar tissue medial to the limb territory. The current study was conducted to test the hypothesis that elimination of the mesonephros without producing scar tissue adjacent to the limb will adversely affect limb morphogenesis. The hypothesis was tested by the insertion of tantalum foil barriers into various levels of the intermediate mesoderm of developing chick embryos to prevent the caudal elongation of the mesonephros. Limb reduction defects were obtained when the mesonephros was prevented from forming caudal to somite 14. No limb defects were seen when a foil barrier was placed into the intermediate mesoderm at the level of somite 21 or 25. Our results support the notion that a signal from the mesonephros is necessary for normal limb development. In addition, it appears that a craniocaudal factor emanating from the mesonephros plays a role in limb development. The limb reduction defects obtained in this study were also compared to the pattern of thalidomide embryopathy in humans. There is a close correspondence between the types of limb reduction anomalies seen with thalidomide and mesonephric blocks and between the severity of defects vs. the timing of thalidomide intake or mesonephric blockage. A model for possible thalidomide embryopathy is presented.

アザラシ肢症を伴った両側性唇顎口蓋裂の１例

Phocomeliais characterized by hypoplasty of the upper limbs and is known to be a complication of thalidomide embryopathy. Robert's syndrome may also be associated with phocomelia but is often accompanied by other serious malformations.We report a patient with bilateral cleftlip, cleft palate, and phocomelia that were idiopathic and could not be classified into any known category of malformations.

Thalidomide embryopathy: revisited 27 years later.

A prospective ophthalmological study was done in 86 out of a total of 100 Swedes with established thalidomide embryopathy. Forty-six (54%) of all examined individuals had eye findings, which made the eye the second most commonly affected organ in thalidomide embryopathy only surpassed by upper limbs (81%). Forty-three patients (50%) had ocular motility defects, mostly incomitant strabismus. Facial palsy and abnormal lacrimation each occurred in 17 (20%) individuals. One patient had coloboma of the uvea and optic disc and another two had coloboma of the optic disc. Infrequent anomalies were microphthalmos, congenital glaucoma, lipodermoid, and large refractive errors. The observed ocular motility defects, facial palsy and abnormal lacrimation occurred with early induced defects in thalidomide embryopathy, but not with isolated late occurring anomalies. This suggests that thalidomide exerts its effects on the development of these structures early in the teratogenic period, probably mainly during the fourth week of development.

Embryotoxic interactions between a hydrolysis product of thalidomide and the surfactant Tween 20 in mice

N,N-phthaloyl-L-glutamic acid (NPLG), a hydrolysis product of thalidomide, and the surfactant Tween 20 were co-administered intraperitoneally to pregnant NMRI mice on days 9 and 8 2/3 p.c. at doses where the hydrolysis product as well as the surfactant alone induce minimal embryotoxicity. The combined substances (350 mg/kg NPLG + 1.0 ml/kg Tween 20) caused a potentiative teratogenic and an additive embryolethal response. Enhancement of the amount of Tween 20 in the combinations to 2.5 ml/kg led to the same potentiative teratogenic and, in addition, potentiative embryolethal response. Distribution studies using 14C-NPLG showed a strongly increased NPLG content in the maternal plasma under the influence of 2.5 ml/kg Tween 20 but not after co-administration with 1.0 ml/kg Tween 20. The malformations obtained were of the same type in all groups and mostly located in the vertebrae and ribs. These axial and paraxial defects were frequently more severe and included more affected elements after application of the combined than of the single substances. Extension of our experiments with the combined substances to treatment days 8 1/2 and 9 1/2 p.c. revealed that the first affected segment shifts in caudal direction depending on an increasing embryonal age at treatment. Limb malformations occurred at a low frequency; most of them were of the same type as described in cases of human thalidomide embryopathy.

サリドマイドによる頭頚部奇形とえん下障害

サリドマイドによる頭頚部奇形とえん下障害

Response to “Comments on Proposed Mechanisms of Action in Thalidomide Embryopathy”

TeratologyVolume 41, Issue 2 p. 245-246 Letters Response to “Comments on Proposed Mechanisms of Action in Thalidomide Embryopathy” Trent D. Stephens, Trent D. Stephens Department of Biological Sciences Idaho State University Pocatello, ID 83209Search for more papers by this author Trent D. Stephens, Trent D. Stephens Department of Biological Sciences Idaho State University Pocatello, ID 83209Search for more papers by this author First published: February 1990 https://doi.org/10.1002/tera.1420410219Citations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume41, Issue2February 1990Pages 245-246 RelatedInformation

Comments on “Proposed Mechanisms of Action in Thalidomide Embryopathy”

Comments on “Proposed Mechanisms of Action in Thalidomide Embryopathy”

Response to comments on “Proposed Mechanisms of Action in Thalidomide Embryopathy”

Response to comments on “Proposed Mechanisms of Action in Thalidomide Embryopathy”

Comments on “Proposed Mechanisms of Action in Thalidomide Embryopathy”

Comments on “Proposed Mechanisms of Action in Thalidomide Embryopathy”

Proposed mechanisms of action in thalidomide embryopathy.

Proposed mechanisms of action in thalidomide embryopathy.

A Quarter Century of Thalidomide Embryopathy*

Abstract Some 137 patients with thalidomide embryopathy have been registered. Of them, 65 were male and 72 female. The age of patients who had a medical examination from 1976 to 1983, ranged from 7 to 22 years. The mean age was 17.0 ± 2.3 (mean ± SD) years. The number of hearing impairments were 35 (25.6%), limb defects were 55 (40.1%) and combined defects were 47 (34.3%). In order to determine the mutual relationships of 34 abnormal symptoms, the correlation coefficient was calculated, and cluster analysis was carried out by utilizing the result. There was a strong inverse correlation between deformities and hearing impairments. The 34 symptoms were divided into three groups. In the first group 11 symptoms were included, but there was little mutual relationship. Fifteen symptoms belonged to the second group, which evidenced strong mutual relationships. The 8 symptoms belonging to the third group were central to all of the symptoms.

Monitoring for multiple malformations in the detection of epidemics of birth defects.

Although most known human teratogens often produce a combination of birth defects in an affected infant, surveillance programs aimed at detecting epidemics of birth defects usually only monitor rates of individual defects. A drawback to this approach is that an increase in the rate of infants affected with a specific combination of defects may lead to little or no increase in the rates of component defects. Using the Poisson distribution, we show that, compared with monitoring for individual defects, monitoring for combinations of two and three defects may require fewer numbers of births to detect an epidemic. In general, an increase can be detected more rapidly by monitoring the rates of defect combinations than by monitoring the rates of individual defects if most affected infants have combinations of defects rather than isolated defects. For example, in the case of Congenital rubella syndrome (CRS), monitoring for the combination of cataracts with deafness and/or patent ductus arteriosus could have led to earlier detection of an epidemic than could monitoring for cataracts alone. In contrast, in the case of thalidomide embryopathy, monitoring for reduction defects of upper limbs in combination with reduction defects of lower limbs and/or microtia/anotia would not have led to earlier detection of an epidemic than would monitoring for reduction defects of upper limbs alone. This is due mainly to the low frequency of defect combinations among affected cases. When used with regular monitoring for individual defects, surveillance of defect combinations can enhance the ability of monitoring programs to detect epidemics of birth defects.

Electroencephalographic study of 137 patients with thalidomide embryopathy.

EEG examinations were carried out on 137 patients with thalidomide embryopathy aged between 7 and 22 with a mean age of 17.0. Waking and sleep EEGs were normal in 82 (59.9%), and abnormal in 55 (40.1%). The incidence of abnormal EEG was significantly high in the patients associated with mental retardation, and it increased in proportion to the severity of mental retardation. The most frequent abnormal EEG finding was slowing of the basic activity (35/137; 24.8%). The incidence of slowing was significantly higher in the patients with a sensorineural hearing impairment (26/74; 35.1%) than in those with dysmelia (9/62; 14.5%). Slowing appeared frequently in the patients with various cranial nerve symptoms (30/84; 35.7%). The incidence of slowing was found significantly high in the patients with borderline or subnormal intelligence (8/16; 50.0%), and it correlated with the severity of mental retardation. Many patients (48/84; 57.1%) showed unilateral or asymmetrical neurological symptoms. However, asymmetry or focal abnormality in EEG was shown in only 8 patients. Positive spikes appeared frequently in the patients with gonadal dysplasia. Other somatic symptoms, past medical history and family history were not related to the incidence of abnormal EEGs. Eight patients had had epileptic seizures prior to this examination. Another 2 patients had nocturnal enuresis and showed epileptic EEG abnormalities in this examination. The incidence of epilepsy was significantly higher in the patients we examined than among the general population. It is concluded that ingestion of thalidomide during pregnancy affected not only the morphological development of the limbs of the fetus, but the functions of its central nervous system, causing hearing impairment, other cranial nerve symptoms, mental retardation or epilepsy.