A group of South American paediatricians have investigated the use of thalidomide in the continent to finally establish a firm connection between thalidomide and congenital malformations. They found 100% linkage between thalidomide and severe birth-defects. And they suspect a vast number of unknown victims, as their group only covers less than 1% of all births in South America , excluding all rural areas. Here is their testimony.
The photos illustrating this article have kindly been placed at our disposal by Mr James Cutler, a producer at First Tuesday team of Yorkshire Television. He produced the well-known television documentary in 1993, called "Thalidomide: The drug that came back". The programme was the first to reveal to the general public the horrifying fact that the drug thalidomide still causes birth-defects in Brazil . The individuals to be seen on this, and the following photos, have no connection to the text. But they act as hands-on evidence that thalidomide afflicts South America and that the tragedy is on-going story concerning innocent children that deserve all the help they can get — so that they at least will have a chance to live a decent life.
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 it's intake during early pregnancy is very difficult since most pregnancies are unintended, the physicians claim. They are all members of ECLAMC (Latin American Collaborative Study of Congenital Malformations) a network of paediatricians based at maternity hospitals collaborating with the ECLAMC. ECLAMC is a hospital-based birth defects surveillance system, extending over all ten South American countries.
The thalidomide tragedy occurred between 1959 and 1964, and in most countries the drug had been removed from the market by 1965. Nevertheless, thalidomide continued in use for the treatment of leprosy, and in recent years its indications were extended to a wide variety of medical conditions. This situation prompted the Teratology Society Newsletter to publish a warning regarding the possibility that thalidomide would reappear on the market with an expected increase in the frequency of certain types of birth defects.
Survey in South America
The paediatricians decided to do a survey in South America . In the media there had been reported on the availability of thalidomide to women of reproductive age, as well as on the current occurrence of thalidomide embryopathy cases in South America . But the only information on this subject to reach the scientific literature was a prenatal case report from Săo Paulo , Brazil .
This study was based on information provided by the network of reporting maternity hospitals collaborating with the ECLAMC. The availability of thalidomide in each country was investigated through local ECLAMC representatives. The requested information included: availability of thalidomide; names and addresses of manufacturer and distributor; means of obtaining the drug; brand name; pharmaceutical form and dose. This direct inquiry was considered to be more reliable than an official inquiry addressed to local health authorities.
A request for information on thalidomide embryopathy cases born after 1965 was sent to all medical geneticists and paediatricians in the ECLAMC network, as well as to the ABVT (Brazilian Association of Thalidomide Victims).
Thalidomide was found to be available in eight of the ten South American countries, except Chile and Ecuador , through leprosy treatment centres depending on their ministries of health. In Brazil the drug may also be obtained commercially at some pharmacies. Thalidomide is manufactured in Argentina and in Brazil , and exported to other countries (Table below).
TABLE Availability of thalidomide by country, and thalidomide embryopathy cases reported after 1965.
Country Leprosy Birth defects Thalidomide available Registered name Manufacturer Country of origin
Argentina Yes Yes Thalidomide Cassara Argentina
Talidomide Lazar Argentina
Tarisolin Alet Argentina
Brazil Yes Yes Yes Talidomida Brasifa Brazil
Talidomida FUNED Brazil
Bolivia Yes No Yes Talidomida FUNED Brazil
Chile No No No
Colombia Yes No Yes Talidomida Brasifa Brazil
Ecuador Yes No No
Paraguay Yes No Yes Talidomide Lazar Argentina
Peru Yes No Yes Provided by Pan American Health Organization (PAHO)
Uruguay Yes No Yes Talidomide Lazar Argentina
Venezuela Yes No Yes Talidomida Brasifa Brazil
Talidomida Pediat. Pharm. USA
The table above shows the results from all investigated countries in South America . Chile is the only country who not reports any cases of leprosy. In Chile , and in Ecuador , thalidomide is not being used. Where there is leprosy in all other countries, thalidomide is circulated. The paediatrician's found that in Brazil is thalidomide available, not only official channels like health authorities, but is also sold on the open market in pharmacies. The two countries that show cases of thalidomide embryopathy reported after 1965 is Argentina and Brazil . These two countries is also manufacturing, and exporting the drug (three production facilities in Argentina alone).
Thirty-four cases of thalidomide embryopathy born after 1965 were ascertained by a case reference approach. These 34 cases were born between the years 1969 and 1995. One case was born in 1969, 7 cases in the 1970s, 20 in the 1980s, and 6 in the 1990s. One case was born in Argentina (city of Córdoba ), and the remaining 33 cases in 21 cities of 9 different states in Brazil . Their birthplaces are here specified by city, state (standard two-letter abbreviation), and number of cases (in parentheses): Belém, PA (2); Manaus, AM (1); Paulista, PE (2); Salvador, BA (1); Belo Horizonte, MG (4); Itaúna, MG (1); Itaú de Minas, MG (1); Pompeu, MG (3); Ubá, MG ( 1); Nova Iguazu, RJ (1); Niteroi, RJ (1); Săo Paulo, SP (2); Tatuí, SP (1); Campinas, SP (3); Sao José dos Campos, SP (1); Sertaozinho, SP (1); Ribeirao Preto, SP (1); Piraguara, PR (1); Marandero, PR (1); Curitiba, PR (2); Bagé, RS (1).
These birthplaces are plotted on a map of South America in the figure below.
The map show places in South America where the paediatrician's located a thalidomide afflicted child. Every dot represents a child. South America is subdivided by country. These geographical areas have a published prevalence rates for leprosy as follows: High in Brazil (14 per 10,000 inhabitants), intermediate in Colombia , Venezuela , and Paraguay (3 to 5 per 10,000), minimal in Argentina , Bolivia , Ecuador , Peru , and Uruguay (around 1 per 10,000), and close to zero in Chile . As seen; where leprosy is common, the thalidomide-children are more frequent.
One city in Brazil where several children has been found is the industrial city of Belo Horizonte (photo below). Below its poisoness yellow sky lies FUNED (Fundaçăo Ezequiel Dias) located outside of town, South America 's biggest manufacturer of thalidomide. There is also aggravating circumstances of another production facility in the very same city; Tortuga Comphania Zootécnica Agrária.
All cases in leprosy areas
All the cases where reported in areas where leprosy is frequent. In South America, thalidomide accessibility is proportional to the frequency of leprosy which has a maximum prevalence in Brazil (14 per 10,000 inhabitants), intermediate in Colombia , Venezuela , and Paraguay (3 to 5 per 10,000), minimal in Argentina , Bolivia , Ecuador , Peru , and Uruguay (around 1 per 10,000), and close to zero in Chile .
Full descriptions are available only for the ten cases reported by ECLAMC centres, plus the one foetus published by Gollop in 1987. In the article the authors give a summary of these ten cases. This is quite a shocking reading.
Phocomelia is a pattern of severe limb reduction deformities and usually an extremely rare condition. Indeed, a German dysmorphologist in the time of the thalidomide disaster said that before 1961 he had seen more babies with two heads than with phocomelia.The mothers have been prescribed thalidomide as treatment of leprosy. A summary of the cases follow below:
Case 1. Female, born 1971, in Sao José dos Campos, Brazil, from a lepromatous mother, medicated with thalidomide during pregnancy. Limbs: upper right: amelia with remnants of one digit; upper left: hypo plastic hand, with two three-phalangeal digits, articulated on shoulder. No other anomalies.
Case 2. Female, born 1978, in Córdoba , Argentina , from a 36-year-old mother lepromatous, medicated with thalidomide for 2 years, until the 8th month of pregnancy. Limbs: upper: symmetrical bilateral defect with hypo plastic humeri, absent radia and ulnae, hands with three three-phalangeal digits; lower left: hypo plastic femur and tibia. Other anomalies: frontal flat hemangioma, IVSD with pulmonic hypertension. Died at 7 months of age due to cardiac insufficiency.
Case 3. Male, born 1980, in Manaus , Brazil , from a lepromatous mother, medicated with thalidomide during pregnancy. Limbs: upper: bilateral hypo plastic shoulder girdle with hypo plastic glenoids, subluxated ulnas, agenesis of radius and thumbs, syndactyly of fingers 2 and 3, clinodactyly of 5th. No other anomalies.
Case 4. Male, born 1980, in Sertaozinho , Brazil , from a 32-year-old lepromatous mother, medicated with thalidomide for 8 years and throughout pregnancy. Limbs: upper: hypo plastic glenoids, stiff shoulders, bilateral absent radia, and thumbs. Other anomalies: flat hemangioma on glabela.
Case 5. Unknown sex, born 1986, in Săo Paulo , Brazil from a 24-year-old lepromatous mother, medicated with thalidomide for 1 year preconception until the 35th day of pregnancy. After ultrasonographic diagnosis, pregnancy was interrupted at 17th weeks of gestation. Limbs: upper: bilateral phocomelia; lower: bilateral absent tibia and fibula. Other anomalies: bilateral anotia (Gollop et al., '87).
Case 6. Male, born 1988, in Săo Paulo , Brazil , from a lepromatous mother, medicated with thalidomide until the 2nd month of pregnancy, when she realized she was pregnant and stopped medication. Limbs: upper: symmetrical bilateral defect with absent radia, short ulnae; lower right: short femur, dislocated knee, absent tibia, duplicated hallux; lower left: absent femur, hypo plastic tibia. Other anomalies: Bulging philtrum; fused C1-C2 vertebrae.
Case 7. Female, born 1988, in Itaú de Minas , Brazil from a lepromatous mother, medicated with thalidomide for 2 years and throughout gestation. Limbs: upper: bilateral absent thumbs and small pedunculated tag on proximal phalanx of 2nd right finger. Other anomalies: bilateral microtia grade III, A-V canal, gastroesophageal reflux.
Case 8. Female, born 1991, in Campinas , Brazil , from a 32-year-old lepromatous mother, medicated during first trimester of pregnancy, presumably with thalidomide. Limbs: upper left: hypo plastic radius; bilateral triphalangeal thumbs. Other anomalies: flat hemangiomas on eyelids, face, and glabella; A-V canal; septated cysts in right lobe of liver, hamartoma of bile ducts.
Case 9. Male, born 1994, in Bagé , Brazil , from a 28-year-old lepromatous mother, medicated with thalidomide during 7 years, and in the first trimester of pregnancy. Limbs: bilateral tetra-phocomelia, oligodactyly of both hands, preaxial polydactyly (7 toes) of left foot; duplicated hallux of right foot. Other anomalies: bilateral undescenderd testes.
Case 10. Male, born 1994, in Campinas , Brazil , from a 22-year-old lepromatous mother, medicated with thalidomide preconceptionally and during the first 16 weeks of pregnancy: 300 mg, 3 times a week. Limbs: tetramelic preaxial defect. Upper: radius absent at right and hypo plastic at left; both thumbs pedunculated with absent metacarpals; lower: bilateral absent tibiae. Other anomalies: bilateral transverse grooves on ear lobes; right hydrocele.
Case 11. Female, born 1995, in Campinas , Brazil from a 22-year-old lepromatous mother, medicated with thalidomide and dapsona on alternate days for 5 years, at the time of conception she was taking thalidomide "prn" for pain relief. Foetus with bilateral renal agenesis diagnosed by ultrasonog-raphy at 16 gestational weeks, interrupted at week 21. Autopsy revealed a 16-18-week female foetus with partial agenesis of left tibia, curved fibula, duplication of right thumb. Other anomalies: bilateral renal agenesis, bilateral talipes equinovarus.
As is the case with many other birth defect monitoring systems and registries, ECLAMC was founded as an aftermath to the thalidomide pandemic, starting data collection in 1967. Nevertheless, thalidomide itself was used more as a model than as an actual issue, since this teratogen had supposedly been removed from the market before the ECLAMC system started. In spite of this, thalidomide continued to be used in South America , unnoticeably causing severely malformed babies.
Covers less than 1% of all births
Several factors may be invoked to explain the failure of the ECLAMC monitoring system to identify this teratogen in the population. One is that thalidomide was already present when the system started, so that its effects were included in the expected prevalence rates and thus went unnoticed. Another more important factor is that ECLAMC is a hospital-based and not a population-based system. Thus the system covers less than 1% of all births in South America , excluding all rural areas, of which leprosy is endemic in many such areas.
A third factor contributing to this failure in monitoring, which is not limited to South America , is the lack of an appropriate type of birth defect to be monitored. The clinical defination of the thalidomide embryopathy syndrome seems to be so difficult. Only three experts on the subject is to be found; for example, in the U.K. Phocomelia may be neither sensitive nor specific enough to identify the effect of thalidomide. Phocomelia is an ill-defined condition not to mention that some cases of thalidomide embryopathy did not present with phocomelia, but instead were characterized by preaxial limb defects or other anomalies. The pediatricians call for a definition of a thalidomide-like phenotype to be included in the routine surveillance of birth defects.
Given thalidomide for 8 years
Fourth, there is another alarming conclusion to be made from the cases referred by the South American ECLAMC network: The women suffering from leprosy had been medicated with thalidomide constantly for very long periods of time, in some cases 7-8 years. The WHO standard therapy of MDT (Multi Drug Therapy), against in leprosy is a 24 month duration of the treatment, recently the recommendation is lowered to only 12 months. This implicates that the need for treatment of ENL (Erythema Nodosum Leprosum, a side-effect of MDT-treatment of Lepromatous leprosy) with thalidomide should be equally limited in time; thus reducing the risk for thalidomide embryopathy to an absolute minimum. When of MDT-treatment is completed, then any patient showing ENL-symptoms should recover from ENL too.
WHO arguments weak
But, on the contrary, thalidomide is prescribed for years; clearly showing that WHO arguments can not stand a confrontation with hard realities. Obviously physicians are willing to prescribe thalidomide to patients despite the fact that thalidomide is a well-known human teratogen. In-fact it's not seldom that the patient himself is the driving-force in a prescription situation. Thalidomide acts as a tranquilizer. The patient gets addicted to the drug and wants more, and more.
The ongoing occurrence of thalidomide embryopathy cases is limited to the underdeveloped world, where leprosy is more common, and drug control measures are more relaxed. However, new applications for thalidomide are being tested in clinical trials, and ECLAMC believes it's reasonable to suspect that the stage may be set for a new catastrophe as great as that of the early sixties.
Incitements of a new disaster
The incitements for a new disaster are alarming. A low production cost of thalidomide, the drug's potential for widespread use for many common diseases, the high rate of unintended pregnancies in many countries, and the difficulties inherent in enforcing drug control regulations in many countries, as shown by the leprosy-thalidomide-malformation chain of events in South America . But this second disaster threats also the developed world as ECLAMC noticed the permission requests to commercialise thalidomide on their way in various developed countries.
Therefore, if a new epidemic is anticipated, there is a need for birth defects monitoring systems to ascertain increases in the frequency of congenital anomalies attributable to thalidomide. However, physicians first need to define what to look for. Based on the observation that only five of the eleven cases reported by ECLAMC presented phocomelia or some type of intercalary transverse limb reduction defect, the South American paediatricians propose a definition for a thalidomide-like phenotype to be included in the routine surveillance of birth defects: any bilateral upper and/or lower limb reduction defect of the preaxial and/or phocomelia types.
In spite of all the progress made in birth defects surveillance during the past 30 years, the world is still in the same situation as in the early sixties when it comes to thalidomide embryopathy. Thus, the clinical case-reference approach provides more information to the present situation than an epidemiologic monitoring of a still undefined thalidomide-like phenotype.
If you want to contact ECLAMC and the authors of the article ”Thalidomide, a Current Teratogen in South America", please write to: Dr. Eduardo E. Castilla, Dept. Genética, Fiocruz, CP 926, Rio de Janeiro 20001-970, Brazil .
Reference: E.E. Castilla, P Ashton-Prolla, E. Barreda-Mejia, D. Brunoni, D.P Cavalcanti, J. Correa-Neto, J.L. Delgadillo, M.G. Dutra, T. Felix, A. Giraldo, N. Juarez, J.S. Lopez-Camelo, J. Nazer, I.M. Orioli, J.E. Paz, M.A. Pessoto, J.M. Pina-Neto, R. Quaddrelli, M. Rittler, S. Rueda, M. Saltos, O. Sánchez, , L. Schüler. Thalidomide, a Current Teratogen in South America . Teratology 54: 273-277 (1996). If you want to read the article in full text, please click on this hyper-link
"Thalidomide, a Current Teratogen in South America " Tillbaka till toppenTillbaka till toppen