Thalidomide Risk Summary

Risk Factor: XM
Class: IMMUNOLOGIC AGENTS / Immunomodulators

Fetal Risk Summary

Thalidomide is an immunomodulatory agent used for the acute treatment of erythema nodosum leprosum, a cutaneous manifestation of Hansen's disease (leprosy) (1). The agent was recently approved for use in the United States for the first time, making its debut in 1999. Thalidomide was one of the first drugs that was clearly shown to be a human teratogen and probably has caused more known severe malformations in humans than any other drug.



A large number (>30) of animal (mice, rats, rabbits, and monkeys) reproduction studies conducted with thalidomide were reviewed in a 1976 Reference (2). Embryolethality and teratogenicity (structural and/or functional abnormalities) were noted commonly in some species. Evidence of significant thalidomide teratogenicity was found in monkeys, but in mice and rats, limb- reduction defects were not observed and, in some cases, there was no evidence of teratogenicity. Amelia and micromelia were noted in two mouse fetuses and a limb defect in another that closely resembled the defects observed in humans, but these reports were considered inconclusive (2). In a 1983 study with rats, however, increased rates of both embryolethality and congenital defects involving the skeleton (ribs and spine) and eyes (ophthalmorrhexis and microphthalmia) were observed (3). The authors speculated that the difference in outcome between their study and previous experimental work with rats was possibly due to hydrolysis of the drug before administration, the use of toxic solvents that masked the teratogenic effect of thalidomide, or the low solubility of thalidomide in the solvent that prevented delivery of an effective dose to the target site (3). Experiments in rabbits have consistently revealed fetal limb malformations that are very similar to those seen in human infants exposed in utero to thalidomide (4,5,6,7 and 8). Other anomalies noted in rabbit fetuses included hemangioma of the nose and defects of the skull, nostril, external genitalia, and tail (6). Another study with rabbits observed limb anomalies, arthrogryposis, dysplasia of the kidneys and gallbladder, cleft palate, hernia, and gastric hypoplasia (8). Experiments with chick embryos demonstrated that thalidomide induced cardiovascular anomalies in this species (9).

Several reviews have described the various human systems affected by thalidomide-induced embryopathy (10,11,12,13,14,15,16,17,18 and 19). One of these reviews presented the pregnancy history of two children (twins), born in the United States, who had very different severity of thalidomide embryopathy (10). The first twin, a 2211-g female, was born with duodenal atresia, a rectoperineal fistula, and hypoplastic, dislocated thumbs (right thumb worse than left). The other twin, a 2240-g male, had phocomelia of both upper extremities and a midline hemangioma on the forehead. Missing or hypoplastic digits were noted on both hands (10).

The critical period of fetal exposure to thalidomide is 3450 days after the first day of the last menstrual period (LMP) (20 1 days to 36 1 days after conception) (13,16,17 and 18). Congenital malformations that have been associated with approximate time periods within this 17-day interval include (days after LMP; when two ranges are shown, the References cited disagreed): anotia (3438 days), microtia (3943 days), thumb duplication (3538 days), thumb aplasia (3543 days), thumb hypoplasia (3840 days), thumb triphalangism (4650 days), eye defects (3542 days), cardiovascular defects (ductus, conotruncal defects, and septal defects) (3645 days), duplication of the vagina (3539 days), cranial nerve palsy (3537 days), amelia of the arms (3843 days), phocomelia of the arms (3847 or 49 days), dislocation of the hip (3848 days), amelia of the legs (4145 days), phocomelia of the legs (40 or 4247 days), choanal atresia (4346 days), duodenal atresia (4047 days), anal atresia (4143 days), aplasia of gallbladder (4243 days), pyloric stenosis (4047 days), duodenal stenosis (4148 days), rectal stenosis (4950 days), ectopic kidney and hydronephrosis (3843 days), other genitourinary defects (4547 days), and abnormal lobulation of lungs (4346 days) (13,17).

Perhaps the best description of the spectrum of congenital defects caused by thalidomide was written by Newman (16,17). The limb-reduction defects are bilateral, usually grossly symmetrical, and upper limb anomalies are commonly associated with lower limb defects. Shoulder and hip malformations occur with increasing severity of upper limb defects. Vertebral defects include an increased incidence of progressive ossification of the anterior spinal ligaments that converts the sacral and lumbar vertebral bodies into one bone mass, loss of distal segment of the sacrum, and spondylolisthesis. Spina bifida occulta and meningomyelocele occur with increased frequency. A nonspecific facial asymmetry may occur, as well as tooth hypoplasia and a deficiency in the number of teeth. There may be a hypoplastic nasal bridge with an expanded nasal tip, and choanal atresia can affect one or both nostrils. Laryngeal and tracheal anomalies and abnormal lobulation of the lungs have been observed. Ocular defects include refractive errors, pupillary abnormalities, muscle dysfunction, coloboma, microphthalmos, cataracts, and abnormalities of all three components of the oculomotor nerve. Ear defects are frequently associated with ocular malformations, as is facial nerve palsy. The defects of the ears include external, middle, and internal anomalies and are frequently associated with deafness (either conductive, neural, or both). A midline capillary hemangioma or nevus of the nose and philtrum have been described, but may fade as the child grows older. Cardiac defects, commonly of the conotruncal region, occur frequently and are a major cause of early death (30% at birth, 6% in survivors). Gastrointestinal tract defects include atresia and stenosis, and absence of the gallbladder and appendix. Inguinal hernias may be observed. Genitourinary malformations involve the kidneys (ectopic, horseshoe, hydronephrosis, and double ureter), double vagina, and cryptorchism (16,17).

Thalidomide was introduced into clinical medicine in West Germany in 1956 (20). Although a wide range of indications was promoted for the drug, it was primarily used as a sedative and tranquilizer. Because of the concern over birth defects, thalidomide was withdrawn from the market in most countries in late 1961 (21).

In 1961, two cases of congenital defects of the limbs were presented at a German pediatric meeting (22). At the meeting, Lenz proposed that thalidomide was the cause of the defects (23). A brief 1961 correspondence, however, was the first published English language article to describe birth defects that were suspected as being induced by thalidomide (24). McBride had noted an approximate 20% incidence of polydactyly, syndactyly, and limb reduction defects consisting of abnormally short femora and radii in infants exposed in utero to thalidomide (24). In early 1962, Lenz estimated that 2,0003,000 thalidomide-exposed babies had been born in West Germany since 1959 (23).

A number of communications have been published that describe the types of congenital malformations caused by thalidomide (10,15,16,17,18 and 19,23,24,25,26,27,28,29,30,31,32,33,34,35, 36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56, 57,58,59,60,61,62,63 and 64,66,67,68,69,70,71,72,73,74,75,76, 77,78,79,80 and 81,83): Thalidomide Embryopathy Limb Defects upper and lower limbs (bilateral amelia or phocomelia, absence or hypoplasia of radius/ulna and/or tibia/fibula, femoral hypoplasia, preaxial aplasia upper and lower limbs, absence of the fingers and/or toes, thumb defects such as duplication, hypoplasia and triphalangism, duplication of big toe and triphalangism) (10,15,16,17,18 and 19,23,24,25,26,27,28,29, 30,31,32,33,34,35,36, 37 and 38,40,41,45,46 and 47,49,50 and 51,54,55,56,57,58 and 59,61,62,63 and 64,66,67,69,71,72,75,76,77,78,79,80 and 81,83) osteochondritis of femoral head (Legg-Calve-Perthes disease) (possibly a late complication that results from growth disturbance of the upper end of the femur; appeared in early childhood) (51) knee joints (laxity of cruciate ligaments) (16,17,61) Other Skeletal Defects spine (ossification of sacral and lumbar vertebrae, loss of distal segment of sacrum, spondylolisthesis, scoliosis) (15,16,17 and 18,35,36 and 37,40,43,49,50,58,61, 67,72,79,80) shoulder (hypoplasia/dysplasia of glenoid cavity, dysplasia of neck of scapula, altered humeral head) (16,17,19,61) hip/pelvis (dislocation, pelvic girdle hypoplasia) (16,17,19,35,51,59,61,67,79,80) jaw (70,75) Craniofacial eye (refractive errors, pupil, motility, coloboma of the iris, uvea, lens, and choroid, microphthalmos, cataracts, glaucoma, crocodile-tear syndrome) (15,16,17,18 and 19,25,30,33,36,37,40,45,46 and 47,49,50,62,63,66, 67,69,71,72,73,74,75,76,77 and 78) ear (anotia, microtia, low-set, middle and internal ear, deafness) (15,16,17,18 and 19,23,25,26 and 27,29,30,33,35,37,39,41,43,44 and 45,48, 53,56,57 and 58,61,62,63 and 64,66,67,68 and 69,71,74,75,76,77 and 78) face/skull (faceasymmetrical; skullrhomboid shape) (16,17,58,70) tongue (dysplasias of lingual frenulum in the form of an ankyloglossia [tonguetie] or a shortened, sinew-shaped frenulum; grooved point of tongue [bifid tongue]) (16,70) nose (hypoplastic nasal bridge with expanded nasal tip) (16,17,19,58,67) choanal atresia (16,17,18 and 19,29,37,62,66,71,72,76) teeth (hypodontia, hyperdontia, malformed crown, enamel hypoplasia, discoloring, malocclusion, missing teeth) (16,17 and 18,58,60,70,76) midline hemangioma or nevus (nose, upper lip, frontal area) (10,16,17,23,25,30,33,35,45,46,57,58,60,66,67,72) Central Nervous System facial nerve palsy (often associated with eye and ear anomalies) (15,16,17,18 and 19,35,39,43,61,63,69,72,74,76,77,78) hydrocephalus (37,57,66,74) spina bifida occulta (16,17,79,80) meningomyelocele (16,17,35) autism (18,78) epilepsy (15,16,77,78) Marcus Gunn phenomenon or jaw winking syndrome (16,19) Crocodile-tear syndrome (see Eye) Major Organ Systems respiratory system (laryngeal and tracheal abnormalities, abnormal lobulation of lungs) (16,17,19,29,33,36,37,49,62,66,67,75,76) cardiovascular (ventricular septal defect, atrial septal defect, tetralogy of Fallot, cor triloculare, pericardial effusion, hypertrophy of atrium and ventricle, coarctation of aorta, systolic murmurs) (16,17,18 and 19,23,25,30,33,35,36 and 37,39,40,42,43,45,57,61,62,66,67,71,72,76,77) gastrointestinal tract esophageal atresia (23,29,30,37,75) duodenal atresia (10,16,19,23,29,30,33,35,37,49,61,62,67,71) common bile duct atresia (33,67) anal atresia (16,18,19,23,29,30,33,35,37,44,61,62,67,76) rectoperineal fistula (10) malrotation (25,30,33,35,67) stenosis (16,17,18 and 19,25,30,37,40,45,46,53,61,62,66,67,71,77) abnormal lobulation of liver (33,37) aplasia of appendix (16,17,19,23,29,30,33,37,40,46,52,53,59,66, 67) aplasia of cecum (33) aplasia of gallbladder (16,17,19,23,30,33,36,49,57,66,67) rectoperineal fistula (10) genitourinary system unspecified (25,30,33,37 and 76) renal abnormalities (16,17,18 and 19,29,35,36 and 37,46,57,59,61,62,66,67,71,75,76,83) defects and duplication of ureters (16,17,19,37,83) aplasia of fallopian tube (62) defects of uterus and/or vagina (16,17,19,33,37,55,62,66,67,81) penile maldevelopment (66) cryptorchism (16,17,19,25,36,61,66,67) Other excessive sweating (52,54) inguinal hernias (16,17,19,61,67) Cleft lip with or without cleft palate has occasionally been observed in newborns with thalidomide embryopathy (35,44,48,49,66,67,70,71,72), but it is not thought to be related to thalidomide exposure (19).

In 1962, Lenz and Knapp reviewed the fetal effects of thalidomide that were known at the time (62). Of 293 cases known to the authors or from published reports, the approximate percentage of each defect was: arms only (52%), arms and legs (28%), arms, legs, and ears (3%), arms and ears (6%), ears only (7%), legs only (2%), and other malformations (3%). The anomalies observed in the eight infants grouped as other malformations included one case each of a right polycystic kidney with aplasia of the left kidney, aplasia of left fallopian tube and left cornu of the uterus, multicystic kidneys, anal stenosis with hydronephrosis, fistula of the neck, congenital heart disease, choanal atresia, and anal atresia (62). In addition, malformations that accompanied those of the limbs and ears were pyloric stenosis, duodenal stenosis, duodenal atresia, cardiac defect, microphthalmos, anophthalmia, imperforate anus, and choanal atresia (62). Two additional review articles by Lenz, focusing on thalidomide-induced defects, appeared in 1966 (63) and 1971 (64), one with a commentary by Warkany (65).

In 1963, Japanese investigators reported phocomelia and other malformations in 10 cases (5 live infants and 5 stillbirths or early neonatal deaths) (66). Another investigator evaluated 160 cases of thalidomide embryopathy that occurred in Japan (67). Of the 160 cases, 99 had a well-documented history of thalidomide intake in early pregnancy. Of these, 70% had defects of the arms only, 14% of arms and legs, 5% of the arms, legs, and ears, 5% of the ears only, 3% of the arms and ears, and 3% of other organs (67). In 41 of the cases with malformations of the limbs and ears, an autopsy found multiple other defects of various organ systems that were similar to those reported by Lenz and Knapp (see Reference 62) (67).

The importance of early examinations for ear anomalies, especially for resulting hearing impairment, was emphasized in a study published in 1965 (68). The author had observed 14 cases of bilateral congenital meatal atresia in thalidomide-exposed infants at his center, but he was aware of 50 such cases throughout England. Eleven of the cases (three were unsuitable for operation) underwent either bilateral or unilateral surgery to construct a sound conducting mechanism (68). Gross malformations determined by X-ray and tomographic examinations in the 14 cases (28 ears) involved the ossicles (32%), middle ear (21%), and labyrinth (25%).

A later study, published in 1976, evaluated the ear anomalies in 18 children, ages 12 to 16 years, who had thalidomide-induced malformations (69). Hearing impairment and vestibular hypofunction or absence of function were each found in 15 (83%) of the children. External and middle ear anomalies found in 11 of the 18 children included bilateral microtia (N=5), bilateral microtia and bilateral atresia of the auditory canal (N=5), and bilateral microtia and unilateral atresia of the auditory canal (N=1). In one 13-year-old girl, surgical exploration revealed that the stapes and the oval and round windows had not developed, the long process of the incus was shaped like a string, and there was a nearly normal malleus. X-ray examination revealed inner ear malformations in 15 cases (83%) consisting of bilateral inner ear aplasia (N=9), cystic deformity with the shape of the anterior semicircular canal (N=4), large cystic defect of the inner ear (N=1), and a narrow internal auditory canal bilaterally (N=1) (69). In addition to the ear defects, 12 children had eye-movement disturbances consisting of bilateral abducens palsy (N=5), bilateral abducens palsy and bilateral adduction disturbance (N=6), and unilateral abducens palsy (N=1). Bilateral (N=3) or unilateral (N=3) facial palsy, and crocodile-tear syndrome (i.e., abnormal lacrimation that accompanies eating) (N=7) were also observed (69).

A 1968 Reference described the findings that resulted from clinical, orthodontic, and radiologic examinations of the face and jaws of children with thalidomide embryopathy (70). The findings in 127 children (approximate ages 4 to 6 years) with thalidomide embryopathy (group 1) were compared with 57 children with non-thalidomide-induced dysmelia (group 2), and 120 children without malformation of the limbs (group 3). Thalidomide exposure did not disturb either the shape or number of the deciduous or permanent teeth (70). However, in the 103 children of group 1 with complete deciduous dentition, there was an increase in the frequency of abnormalities of the maxilla and/or mandible. The other important findings were malformation at the base of the skull, asymmetry of the skull, and dysplasia of the point of the tongue and the frenum (70).

One investigator categorized the malformations found in 154 children with thalidomide embryopathy using a classification system of principal defects that he had designed (71). The types of defects were the same as those listed above for thalidomide embryopathy. In eight groups, limb defects were dominant but other defects were often present, whereas in two groups, limb defects were absent or minimal. The defect classifications and the number and approximate percentage of children in each group were: upper limb amelia or phocomelia with normal legs (N=60, 39%); upper limb amelia or phocomelia with other leg defects (N=18, 12%); forearm defects with normal legs (N=17, 11%); four-limb phocomelia (N=15, 10%); anomalies of the ears (N=16, 10%); severe lower limb defects with less severe upper limb defects (N=10, 6%); other limb defects (N=9, 6%); forearm defects with defects of the lower limbs (N=5, 3%); lower limb defects with normal upper limbs (N=3, 2%); and other anomalies (N=1, <1%). A discussion of the disabilities caused by the defects in each group was also included in the text (71).

The focus of eight studies was on thalidomide-induced ocular malformations (18,46,47,72,73,74,75 and 76). Four children with ocular defects and typical thalidomide embryopathy were described in a 1964 report (46). The eye defects thought to be thalidomide related were: left optic disc with a very deep physiologic cup; bilateral coloboma of the iris, unilateral coloboma of the choroid and retina involving the optic disc, and unilateral microphthalmos; unilateral coloboma of the choroid and retina; and bilateral coloboma of the iris, choroid, and retina, involving the optic disc on one side, and unilateral microphthalmos (46). At one ophthalmology center, minor ocular abnormalities were found in some children consisting of pigmentary retinopathy, a high refractive error, and reduced visual acuity (47). A 1963 study evaluated 20 children with known or suspected thalidomide-induced limb malformations for ocular anomalies (72). Thirteen of the children had anatomically normal eyes with apparently normal function and seven (35%) had visual defects. Five of the seven had structural defects consisting of either unilateral or bilateral coloboma of the iris, choroid, or lens, sometimes involving the macular areas or the disc, and microphthalmos. The other two had anatomically normal eyes but abnormalities in visual function. The visual prognosis was rated as good in three cases, poor in two, and uncertain in two (72). A 1966 study from Sweden examined 38 children for ocular malformations who had thalidomide-induced defects (73). Abducens paralysis was found in 17 children, bilateral in 13 and unilateral in four. Bilateral oculomotor paralysis was present in two of these cases and unilateral in one (73). Other conditions, often concomitant with additional defects, included strabismus, unequal pupils (both reactive to light), nonreactive pupil, microphthalmos (both bilateral and unilateral), anophthalmos on one side and severe microphthalmos on the other, coloboma of the choroid, bilateral aplasia of macula with nystagmus, and bilateral epiphora (with free tear ducts and grossly normal drainage system) (73). Of note, more than half of the children had hearing impairment of varying severity. A 1967 report reviewed the previously published cases of ocular abnormalities induced by thalidomide and presented additional data on 21 Canadian children (ages 3 to 4.5 years) exposed in utero to the drug (74). Only four of these children had ocular malformations and none had a coloboma.

Ocular abnormalities associated with thalidomide embryopathy were reported in a 1991 study of 21 Swedish patients, ages 28 to 29 years (75). Horizontal incomitant strabismus, usually of the Duane syndrome type, was the most common ocular motility abnormality, but other motility abnormalities were also noted (75). Abnormal tearing, facial nerve (7th cranial nerve) palsy, and ear anomalies were also present in some cases. Citing previous studies, facial nerve palsy and ear anomalies were thought to have occurred from thalidomide exposure on days 2029 after conception (75). This time period is consistent with the time intervals (3443 days after LMP) given earlier. Two years later, these same authors reported the results of an ophthalmologic study conducted in 86 of 100 Swedes with documented thalidomide embryopathy (76). The subjects, 49 males and 37 females, ranged in age from 27 to 30 years. Forty-six (54%) had one or more abnormal eye signs. The ocular abnormalities included the following: (a) motility defects (N=43, 50%), including 37 with horizontal incomitant strabismus (26 with Duane syndrome, 4 with marked limitation of abduction, and 7 with gaze paresis), and 6 with horizontal comitant strabismus (all esotropia); (b) facial nerve palsy (N=17, 20%); (c) abnormal lacrimation (N=17, 20%); (d) coloboma of uvea and optic disc (N=1, 1%) or optic disc only (N=2, 2%); (e) microphthalmos (N=2, 2%); and (f) one each of congenital glaucoma, conjunctival lipodermoid, and hypertelorism (76).

In a subsequent paper, the authors again reviewed the above ocular findings but also included the multiple other thalidomide-induced defects that were found in the 86 subjects (18). The defects and the number of cases for each were (note that all cases had more than one defect): thumbs (triphalangeal, absent, misplaced, hypoplastic, or extra digit) N=70 (81%), upper limb excluding thumb N=59 (69%), lower limb N=21 (24%), ears/hearing N=33 (38%), facial nerve palsy N=17 (20%), kidney (absent, horseshoe, hydronephrosis, dysfunctional) N=12 (14%), cardiovascular (VSD, arrhythmia, ductus botalli, murmur) N=7 (8%), chest/lung (cardiovascular defects, pulmonary atresia, enlarged chest wall or structural anomaly) N=4 (5%), genitalia (absent uterus and vagina, double vagina) N=3 (3%), anal atresia N=4 (5%), choanal atresia N=2 (2%), dental anomalies N=4 (5%), mental retardation (moderate to severe) N=5 (6%), and autism (all had mental retardation) N=4 (5%) (18). The authors also expanded the type of ocular malformations listed in their previous study (Reference 74) to include two cases of myelinated nerve fiber, two cases of ptosis, and one additional case each of coloboma (uveal or optic disc) and microphthalmos (18).

Neurologic complications of thalidomide embryopathy include epilepsy. In a study that appeared in 1976, the incidence of epilepsy was determined from a database that included all surviving children (N=408) with documented thalidomide embryopathy in the United Kingdom (77). Seven children (1.7%) met established criteria for the diagnosis of epilepsy and were classified into two groups: (a) children with normal ears (four had upper limb defects, two had mental impairment, and one had ocular anomalies, facial palsy, and high intelligence) (N=4); and (b) children with abnormal ears (in addition, one had ocular defects and facial palsy, one had defects of the thumbs, and one had facial palsy and bilateral sixth nerve palsies) (N=3) (77). In a third group, those with cardiac abnormalities, the diagnosis of epilepsy was uncertain. The two children in this group also had other defects consisting of amelia of the upper limbs, pyloric stenosis, and ocular and ear defects in one, and upper limb defects in the other. These two cases were apparently excluded from the prevalence rate calculations below. The prevalence rates of epilepsy calculated for various ages were significant when compared to published rates in the population as a whole: active epilepsy5 cases, 12.5/1000 vs. 2.7/1000 (p<0.01); epilepsy between birth and 9 years of age7 cases, 17.2/1000 vs. 2.42/1000 (p<0.0001); and new cases in first 7 years of life6 cases, 2.1/1000 vs. 0.43/1000 (p<0.01) (77). The types of epilepsy in the first group (normal ears) were thought to be consistent with structural defects of the cerebral cortex (77). Moreover, two of the children in this group had severe refractory epilepsy, a prevalence of 5/1000 vs. 0.5/1000 in the general population. The unlocalized or generalized seizures in the second group (abnormal ears) suggested abnormalities in the brainstem (77).

Five subjects, suspected of having a severe learning disorder (IQ scores <20 to 7084), were identified from a group of 100 patients previously studied for ocular malformations (78). The five cases were then evaluated for the presence of autism. The ages of the subjects (three males, two females) ranged from 30 to 31 years. All had physical stigmata (i.e., ocular motility defects, other cranial nerve disorders, ear and upper-limb anomalies) characteristic of thalidomide embryopathy that had occurred from drug exposure approximately 2024 days after conception (3438 days after LMP). Four of the cases (two males, two females) met the criteria for autism. Based on an incidence of 4%, compared to a prevalence of about 0.08% in the general population, the investigators estimated that there was a 50-fold higher rate of autism in those with thalidomide embryopathy (78).

A 1977 report evaluated the spinal deformities in 28 children, ages 1014 years, who had thalidomide embryopathy (79). The children's spinal defects had been first studied at 48 years of age (80), and the current study was part of a continuing evaluation of their status. The initial group contained 32 cases, but 4 were either lost to follow-up or had died. All of the subjects had characteristic limb defects. In both studies, the spinal abnormalities were classified into five types. The initial and current (shown in italics) findings for each group were: (i) local anomalies of bone development (spina bifida, N=3; fusion of adjacent spinous processes, N=2), neural arch defect more obvious, increased number of minor changes; (ii) scoliosis (N=18), 20 children now had scoliosis; (iii) wedge deformity of solitary vertebral bodies (N=4), worsened in four cases; (iv) disc space calcification (N=3); and (v) end-plate and disc defects (N=16), two additional cases of vertebral fusion, extension of fusion in two others, reduction in lumbar lordosis in 10 cases (79).

The pregnancy outcomes of women with thalidomide embryopathy were presented in a 1988 publication (81), and also discussed in 1989 (82). The pregnancy of one woman was described in detail (81). This case involved a 24-year-old primigravida with upper limb amelia and lower limb phocomelia. Although there were many technical difficulties (e.g., blood pressure determination, blood sampling, and obesity), she eventually delivered a term, 3.4-kg healthy female infant without any apparent abnormalities. The baby was doing well at the first postnatal check. During the cesarean section, a left rudimentary uterine horn was noted that did not communicate with the uterine cavity (81). Supplementing their case history, the authors described the outcomes of 70 pregnancies in 35 women (includes the case history) who were living in England and who had thalidomide embryopathy (8 with absent upper and/or lower limbs; 27 with minor disabilities of the upper limbs and ears). Six miscarriages (9%) had occurred, but there were no congenital malformations in the 64 live births (81).

Renal failure complicated the fifth pregnancy of a 26-year-old woman with upper limb phocomelia and kidney and ureter malformations secondary to thalidomide (83). At 11 years of age, bilateral refluxing megaureters with dilated calices and thinning of the renal cortex were diagnosed because of chronic urinary tract infections and she underwent a bilateral antireflux procedure. Her first pregnancy, 7 years previously, had been normotensive but complicated by proteinuria, hematuria, and premature labor thought to have been precipitated by a urinary tract infection. She had delivered a 660-g female infant who was currently alive and well. Her next three pregnancies resulted in a spontaneous abortion and two elective terminations. At 24 weeks' gestation in the index pregnancy, complications included normochromic normocytic anemia, hypertension, proteinuria, hematuria, urinary tract infection, and renal failure (creatinine clearance 11 mL/minute). A renal ultrasound revealed small kidneys with diffuse caliceal clubbing, a very thin parenchyma, and dilated ureters to the bladder (83). Peritoneal dialysis, in addition to antihypertensive, antibiotic, and iron therapy, was initiated with ritodrine tocolysis. Two weeks later, however, ultrasound confirmed that no fetal growth had occurred and her hypertension and renal failure had worsened. A cesarean section was performed to deliver a 460-g male infant who died 6 hours after birth. Because of her continued renal failure, the patient eventually received a kidney transplant (83).

The mechanism of thalidomide-induced malformations is still unknown. The findings of many investigations have been discussed in reviews published in 1988 (84) and 2000 (85,86). Four other References (87,88,89 and 90) have developed additional hypotheses to explain how thalidomide causes structural defects.

A review published in 1988 listed 24 proposed mechanisms for thalidomide teratogenesis (84). Eight of the proposals were rejected by the author for various reasons. The remaining 16 proposed mechanisms were classified as those involving biochemical or molecular mechanisms (N=9), cellular mechanisms (N=2), or tissue-levels mechanisms (N=5) (84). The absence of solid experimental evidence for the proposed mechanisms, however, led the author to the conclusion that none of the proposals could adequately account for thalidomide teratogenicity (84).

The role of a toxic arene oxide metabolite was thought to be involved in thalidomide teratogenicity according to a 1981 study (87). In an in vitro experiment, the human lymphocyte toxicity of a thalidomide metabolite was enhanced in the presence of epoxide hydrolase inhibitors and abolished by addition of the pure enzyme. The toxic thalidomide metabolite was not produced by rat liver microsomes, but was produced in hepatic preparations from maternal rabbits, and fetal rabbits, monkeys, and humans. These results were consistent with the lack of sensitivity to thalidomide teratogenesis in the rat versus the sensitivity of rabbits, monkeys, and humans (87). A decrease in ascorbic acid (vitamin C) levels has been suggested as a mechanism of thalidomide teratogenesis (88). Two important consequences of ascorbic acid deficiency in the fetus would be inhibition of collagen synthesis and disruption of the development of nerve ganglia innervating limb buds (88).

A 1996 research study used developing chick embryos to test the hypothesis that elimination of the mesonephros, in the absence of scarring, would produce limb abnormalities similar to those observed with thalidomide (89). Tantalum foil barriers were used at various levels of the intermediate mesoderm to prevent caudal elongation of the mesonephros. Limb-reduction defects were produced when the mesonephros was prevented from forming caudal to somite 14. The types and percentage of limb defects in the chick embryos were: upper limb only (57%), upper and lower limb (31%), and lower limb only (12%). In comparison, the corresponding percentages of limb-reduction defects in 1,252 human cases of thalidomide embryopathy were 64%, 34%, and 2%, respectively (89). Based on these results and previous studies, the investigators concluded that disruption of the mesonephros (or factors produced in the mesonephros) results in limb-reduction defects and that the mechanism of thalidomide-induced limb anomalies probably also involves disruption of the mesonephros (89).

Whole embryo culture was used in a study directly comparing thalidomide-resistant rats and thalidomide-sensitive rabbits (90). Various concentrations of thalidomide were shown to significantly decrease the concentration of glutathione in rabbit visceral yolk sacs, but not in the rat. Cysteine concentrations were not affected in either species, but the cysteine levels in control rabbits were 65% lower than those in control rats. Thus, a possible role for glutathione was suggested by the results (90).

In a study published in 1996, a highly teratogenic derivative of thalidomide (EM12) was used in an experiment with nonhuman primates (marmosets) (91). EM12 was chosen because it is a more potent teratogen than thalidomide, is more stable to hydrolysis, and produces a teratogenic incidence close to 100% in the marmoset. Moreover, the pattern of malformations produced in the marmoset are identical to those seen in humans after in utero exposure to thalidomide (91). The data indicated that thalidomide produced a statistically significant down-regulation (in some cases, complete disappearance) of several surface adhesion receptors found on early limb bud cells and other organs. The adhesion receptors identified were receptors of the integrin family (b1-integrins, b2-integrins, and b3-integrins), the immunoglobulin family, and the selectin family. These receptors are involved in the development of the limbs, heart, head, and body. The down-regulation of these receptors, which was most pronounced in those involved with limb development, was expected to alter cell-cell and cellextracellular matrix interactions (91).

A 1998 communication proposed that the mechanism of limb-reduction anomalies induced by thalidomide was related to the inhibition of mesenchymal proliferation in the limb bud (92). In the progress-zone model, the proximal and distal structures of the limb are specified sequentially by a continuous signal (thought to be fibroblast growth factor [FGF]) from the apical ectodermal ridge (92). The mesenchyme at the tip of the limb bud is respecified by FGF to produce distal structures, whereas those not receiving a continuous FGF signal develop into proximal structures. If thalidomide blocks mesenchymal cell growth, all of the progress-zone cells remain under the influence of FGF and are programmed only to form the distal most elements (i.e., a phocomelia) (92).

Two 2000 reviews by the same group of investigators evaluated 30 mechanistic hypotheses of thalidomide embryopathy (85,86). Fourteen of the proposals were rejected because they were either unsubstantiated or had been proven not to be viable. The 16 remaining hypotheses were grouped into six categories with thalidomide affecting: (a) DNA synthesis or transcription, synthesis and/or function of (b) growth factors (insulin-like growth factor and FGF) or (c) integrins (a subunit type v and b subunit type 3), (d) angiogenesis, (e) chondrogenesis, or (f) cell death or injury (85,86). The hypotheses were not thought to be necessarily mutually exclusive, but could eventually be fitted into a unified model (85,86). Citing evidence from the literature, they proposed that thalidomide, or a metabolite, intercalates into the DNA of specific promoter regions of genes that code for proteins involved in normal limb development. The binding of thalidomide would inhibit the transcription of these genes, resulting in interference with the development of new blood vessels and leading to truncation of the limb (85,86).

Although thalidomide was withdrawn from England and the European markets in late 1961, the agent has continued to be available in 8 of 10 South American countries for the treatment of leprosy (56,93). Thalidomide is manufactured in Argentina and Brazil and is available either through pharmacies (Brazil) or government health agencies (Brazil and Argentina) (93). A 1987 case report from Brazil described a 17-week-old fetus that was diagnosed by prenatal ultrasound with malformations secondary to thalidomide (56). After pregnancy termination, an autopsy revealed upper limb phocomelia, absent tibiae and fibulae (both feet connected directly to the femora), missing toes on both feet, and absent external ears (56). This case was apparently the first to report a prenatal diagnosis of thalidomide syndrome (56). In a second report, 34 children with thalidomide embryopathy who were born in South America after 1965 were identified by the Latin American Collaborative Study of Congenital Malformations (ECLAMC) in endemic areas for leprosy (93). Specific details of the typical thalidomide-induced malformations in 11 of these cases (including the case in Reference 56) were presented.

A study published in 1988 reviewed the history of thalidomide embryopathy and cited 4,336 cases that had been identified in various countries (20). The number of cases was considered a minimal estimate, however, because stillborns and early deaths were underrepresented and the ascertainment of surviving cases in many countries was thought to be incomplete (20). The countries and the number of affected fetuses/infants are shown below. Note that none of the cases from the United States (resulting from thalidomide obtained elsewhere) were included.

Australia

  • Mexico 4 Austria 7 Netherlands
  • Belgium
  • Norway
  • Brazil
  • Portugal 8 Canada
  • Spain 5 Denmark
  • Sweden
  • Finland 8 Switzerland
  • Ireland
  • Taiwan
  • Italy
  • United Kingdom
  • Japan
  • West Germany

3,049 Seventeen years before the above report, a review on the medicolegal implications of the thalidomide tragedy estimated that a total of 5,000 to 6,000 babies had been affected, about 4,000 of these in West Germany (94).

In summary, thalidomide is a potent teratogen in rats, rabbits, nonhuman primates, and humans. In humans, the severe malformations induced by thalidomide may involve defects of the limbs, axial skeleton, head and face, eyes, ears, tongue, teeth, central nervous, respiratory, cardiovascular, and genitourinary systems, and the gastrointestinal tract. The neurologic complications may include severe mental retardation secondary to sensory deprivation. The critical period of exposure is 3450 days after the LMP (20 1 days to 36 1 days after conception). The critical maternal dose is at least 100 mg (96). However, normal pregnancy outcomes have occurred, even when thalidomide was taken during the critical period (45,95). In addition, other causes of limb reduction defects and heart defects, such as Holt-Oram syndrome, may mimic thalidomide-induced malformations (19).

The risk of congenital malformations after exposure during the critical period has been estimated to be between 20% and 50% (17). The large degree of uncertainty in the estimated risk is a result of the lack of epidemiologic studies and any organized attempt to determine the number of normal, yet exposed children (17). Just as uncertain, because it is based on only four reports, the frequency of specific malformations is thought to be in the following order: arms only > arms and legs > ears only > arms and ears arms, legs, and ears > legs only (62,67,71,89,. The frequencies of the other malformations associated with thalidomide are unknown, partially because many of them were determined at autopsy, were only recognized later in life and in specialized groups, or have not been fully analyzed.

Although thalidomide had not been approved for use in the United States when thalidomide embryopathy was discovered, at least 17 such cases were delivered in this country, apparently from women who had received the drug elsewhere (10,94). Fortunately, thalidomide did not receive approval in the United States because of the alertness of the FDA (94,97).

Thalidomide is indicated (FDA approved) for the treatment of a leprosy skin complication (erythema nodosum leprosum) (1), but it may also have eventual application in other serious conditions, such as chronic graft-versus-host disease, rash due to systemic lupus erythematosus, Behet's syndrome, inflammatory bowel disease, prostate cancer, metastatic breast cancer, rheumatoid arthritis, uremic pruritus, severe atopic erythroderma, weight loss in tuberculosis, and in the complications of acquired immunodeficiency syndrome (aphthous ulcers, microsporidioses diarrhea, macular degeneration, wasting, Kaposi's sarcoma, and human immunodeficiency virus replication) (85,98,99). The mechanism of action of thalidomide teratogenesis is unknown, but recent investigations have suggested that it involves disruption of specific genes involved in normal limb development. If the mechanism can be fully understood, development of nonteratogenic derivatives that retain the ability to treat disease may be possible (85,86).

Thalidomide is contraindicated during pregnancy and in women of childbearing age who are not receiving two reliable methods of contraception for 1 month prior to starting therapy, during therapy, and for 1 month after stopping therapy (1). In addition, it is contraindicated in women who do not meet the specific requirements of the STEPS program (System for Thalidomide Education and Prescribing Safety). The STEPS program was developed by the manufacturer to limit the prescribing and use of thalidomide to tightly controlled situations and to prevent inadvertent exposure of pregnant women (1,99). Any suspected fetal exposure to thalidomide should be reported to the FDA (Medwatch Program at 1-800-FDA-1088) and/or to the manufacturer (1).

Breast Feeding Summary

No reports describing the use of thalidomide during lactation have been located. The molecular weight (about 258) is low enough, however, that excretion into milk should be expected. Moreover, nothing is known about the excretion of thalidomide metabolites into breast milk. Women who are taking thalidomide should not breast feed because the effects on a nursing infant from exposure to thalidomide and its metabolites in breast milk are unknown.

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Questions and Answers

Thalidomide?, What was Thalidomide given for in the 1960s?

To help prevent morning sickness.

are their any second generations or improved molecules of thalidomide?, I have heard that there is a newer molecule called Lerolomide. It is considered to be the second generation of Thalidomide.

I haven't heard anything about this. I know thalidomide was recently apporved by the FDA to treat multiple myeloma, which is plasma cell cancer, but I'm pretty sure it's the same old thalidomide that produces dolphin babies in pregnany women.

How do you know if someone had Thalidomide overdose before his death?, What are the symtoms you can look for during the autopsy?

You'd probably have to analyze blood, etc for the drug.

What are some of the birth defects caused by the drug Thalidomide?, What was the drug used for?

What can I say? Diamond Lil beat me to it. But I'll be she didn't know it was used for morning sickness on women in South America, as early as the forties, with few to no problems. It started in England where they first used it for morning sickness. The doctors there have a different standard then we have.

Couldn't you just see the doctors here giving thalidomide to thousands of American woman, like the English doctors did without the proper tests.

Many of the babies were born with "flippers" like Diamond Lil said, and some without legs.
The appendages didn't develop normally in the womb, the drug stopped the normal development while he fetus was developing, the mothers took it for "morning sickness" I did hear they were using it, or trying it here, on men for morning sickness after drinking. That's a fact. I can't give you any details about it though.

What is the problem with thalidomide in relation to congenital malformation?,

I saw what thalidomide did when I was a boy. That was tough. See ref 1 for a very good discussion. Ref 2 has pictures that show what happened.

What I saw were people with very short, deformed arms. This tragedy was more common in Europe since thalidomide had not been approved for use in the US. In my school (I live in the US near the Canadian border) I believe the kids had parents who had been in Europe or Canada for a time.

When was the first thalidomide baby born in the UK?, Was it 1959 or 1960?
The only information I could find was September 1960 but I have been told that babies were born the previous year, does anyone know if this is right?

Thalidomide is a sedative, hypnotic, and multiple myeloma medication. The drug is a potent teratogen in primates, i.e. leads to severe malformations of the unborn child when taken during pregnancy.
Thalidomide, 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole... was developed by German pharmaceutical company Grünenthal. It was sold from 1957 to 1961 in almost 50 countries under at least 40 names, including Distaval, Talimol, Nibrol, Sedimide, Quietoplex, Contergan, Neurosedyn, and Softenon. Thalidomide was chiefly sold and prescribed during the late 1950s and early 1960s to pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep. Before its release, inadequate tests were performed to assess the drug's safety, with catastrophic results for the children of women who had taken thalidomide during their pregnancies.
From 1956 to 1962, approximately 10,000 children were born with severe malformities, including phocomelia, because their mothers had taken thalidomide during pregnancy. In 1962, in reaction to the tragedy, the United States Congress enacted laws requiring tests for safety during pregnancy before a drug can receive approval for sale in the U.S. Other countries enacted similar legislation, and thalidomide was not prescribed or sold for decades.

What is the significance of chiral in birth defects by thalidomide?,

The thalidomide molecule has a chiral carbon and can exist as one of a pair of optical isomers, or stereoisomers. One of the isomers was found to cause birth defects - the other was safe. Inadequate testing of the drug didn't pick this up.

Either: (a) a method of stereo-specific synthesis should have been used which formed only the safe isomer, or (b) the two isomers should have been separated, although separating two stereoisomers can be a very difficult process.

How do you pronounce thalidomide?, Some people say tha-lid-omide
And that's how I thought it was pronounced
But a lot of people say fa-lid-omide
And the term flid comes from thalidomide.

How is it correctly pronounced?

Pronounce it with the TH sound, not F. It's true that "flid" comes originally from "thalidomide," but the original was never pronounced with an F sound.

how did jenner discover the vaccine?what are the risks in using thalidomide & how did it treat morning sicknes?, need an answer! fast!

I'm not going to answer the first one cuz I don't know but the thalidomide I do know: Babies were born with flipper like appendages and the mothers were attempting to use it as a sleeping aid.

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