Department of Pediatrics, Johns Hopkins University Medical School, and Johns Hopkins Hospital, Baltimore
0
II
0
H
Dr. Taussig’s investigation in Europe was supported by the International Society for Cardiology
Foundation, the Heart Association of Maryland, and the National Institutes of Health, ADDRESS: Johns Hopkins Hospital, Baltimore 5, Maryland.
654
Pmrnzcs, October 1962
SPECIAL
ARTICLE
THALIDOMIDE
AND
PHOCOMELIA
Helen B. Taussig, M.D.
EDITOR’S Nors
The subject of this paper has now been widely
publicized, and Dr. Taussig’s history of the facts as they have unfolded has appeared elsewhere. Nevertheless, so significant an event merits at least one general and introductory article in this journal.
The Editorial Board could thing of no one as well
qualified to prepare it as Helen Taussig. We are
extremely grateful to Dr. Taussig for performing this additional service.
rfHALIDOMIDE [alpha (N-phthalimido)
glutarimide] is a synthetic drug with
the structural formula shown in Figure 1.
Thalidomide was invented by the firm of
Chemie Gr#{252}nenthal as a sedative, but when
tested on animals was found to be
ineffec-tive. Chemie Grunenthal was, however, so
certain that thalidomide must have some
quieting effect on the central nervous
sys-tem that it was then tested on man for its
effect on epilepsy, and promptly reported
to be useless as an anti-convulsant but an
excellent sedative. By 1957, thalidomide,
marketed under the trade-name of
Conter-gan, was widely used as a sedative and
for mental patients. It was considered “safe”
to keep in the home because an overdose
caused a sound sleep but never produced
fatal poisoning. Thalidomide was added to
other preparations for conditions where
se-dation would be beneficial, such as
head-aches (Algosedive, which is aspirin,
phena-cetin, and thalidomine), migraine, cough,
asthma, gastrointestinal disturbances,
grippe, arthralgia, and arthritis. A
prepara-tion with a small amount of thalidomide was
sold as a tranquilizer.
FIG. 1. The stru#{235}tural formula of thalidomide, i.e., alpha (N-phthalimido) glutarimide.
The rights to market the drug were sold
to a number of foreign pharmaceutical firms,
and the drug was exported to many other
countries. Thus, to my certain knowledge,
more than a dozen preparations have been
placed on the market in a minimum of 16
countries, excluding the United States,
where it was distributed to over 1,000
phy-sicians for investigation. Table
I
gives alist of these dgs* which the author has
been able to check. Evidence is steadily
accumulating which indicates that both the
number of preparations and the number of
countries is far in excess of the above
fig-ures.
During 1960 and 1961 the uses and
pop-ularity of thalidomide steadily increased.
Throughout West Germany, thalidomide
was sold without prescription until early in
0 Since this article was sent to the press, a much
Algosedive (;rippex
Peracon-Expectora os Polygripan
Portugal Canada Unitsd States
Softenon Talimol 1eViUloIt*
Kevadon
Asmaval Tensival
Valgis
Valgraine
2 Phocomelia, a mild case (courtesy of Dr.
\v.
Heck and Dr. R#{252}ther, Bremen, Germany).TABLE I
THALIDOMIDE (TRADE NAMES) AND OTHER DRUGS CONTAINING THALIDOMIDE
British
West Germany Commonwealth
_______ (excluding Canada)
Contergan I)istaval
* Never released for sale by F.D.A.
1961 Wilen cases of polyneuritis following its long-continued use began to be reported.
Thereupon the drug was placed on
pre-scription, but its consumption continued to
rise until November, 1961, when its
associ-ation with phocomelia was first suspected.
Phocomelia ilas been long known as a
rare malformationl, 2 in which, typically,
the hands arise from the shoulders as do
the “flippers” of a seal. The essential
ab-normality concerns tile long bones of tile
extremities; the radius is absent, the ulna
and llllmerus are shortened (Fig. 2) or
ab-sent, and tile Ilands or fingers may be
mdi-mentary. Indeed, in some instances tile
ab-normality is so extreme that the extremities
are entirely lacking; such a condition is
known as amelia.
Phocomelia in \Vest Germany (liffered
from tile rare previous cases in certain
im-portant aspects.3 No familial ilistory was
obtainable. A facial hemangioma appeared
to he a characteristic feature. In many
in-stances the malformation of the extremities
was combined with abnormalities of the
internal organs, the most common of which
were duodenal stenosis and anal atresia.
Asplenia, abnormality of uterine
muscula-tore, and a wide variety of cardiac
mal-formations also occurred occasionally. In
some instances the external ears were
by-poplastic or absent and the orfices of the
auditory canal were abnormally low. Uni-lateral facial paralysis was also observed,
especially in infants in whom one ear was
abnormal. Tile mentality was usually
nor-mal.
During 1961, as tile incidence of
phoco-melia throughout \Vest Germany trebled,
pediatricians and obstetricians realized that
this unusual type of malformation was
ap-pearing in almost “epidemic” proportions.
It soon became obvious that some
exoge-notis factor must be its cause; thereupon a
number of pediatricians sent out lengthy questionnaires.
On November 8th, 1961, it occurred to
656 THALIDOMIDE AND PHOCOMELIA
cause. He had obtained a 20% positive
his-tory of the ingestion of Contergan in early
pregnancy from mothers of infants with
phocomelia, but on requestioning, so many
women replied that they had considered
Contergan “too innocent” to mention, that
the incidence promptly rose to 50%. On
November 15, Lenz warned the
manufac-turers of the apparent association between
the ingestion of thalidomide and the
oc-currence of phocomelia and advised them
that in his opinion the drug should be
with-drawn.
On November 22, at the 1961 Annual
Meeting of West German Pediatricians,
Lenz5 reported that he suspected a specific
drug as cause of the outbreak of
phoco-melia and had warned the company that
the drug should be withdrawn. He did not
name the drug. Within two days it was
common knowledge that Contergan was
suspected as the cause of phocomelia; on
November 26, the company Witlldrew the
drug. On November 28, the Minister of
Health issued a warning that Contergan
was suspected (but not proven) to cause
phocomelia, and pregnant women were
warned against taking the drug.
At the same time, but on the opposite
side of the world, in Australia, W. G.
Mc-Bride6 suspected Distaval as the cause of
the same malformation. In November, 1961,
he reported his findings to the
manufac-turers and sent a letter to the Lancet.7
Dis-tillers Ltd., in Australia, immediately
ca-bled McBride’s findings to their
headquar-ters in London, who thus received word that
Distaval was suspected on November 27,
one day after Contergan was withdrawn
(and one day before the Minister of Health’s
public warning) in West Germany. The
English company promptly withdrew the
drug, tllough in the spring of 1962,
Dis-tillers Ltd. returned it to the English market
on limited sales to hospitals.
Most English physicians, however, did
not become aware of the situation until
McBride’s note appeared in the Lancet7 of
December 10, stating that its writer had
seen a 0% increase in severe malformations
of the extremities of infants born to women
who had taken Distaval in early pregnancy.
Even then many physicians did not know
that Distaval and Contergan were the same
drug. McBride asked whether Lancet
read-ers had seen anything similar. One of them,
Dr. Speirs of Stirling, Scotland,
immedi-ately realized that Distaval might be tile
cause of phocomelia in 10 infants he had
seen during 1961. Although Stirling is not
a large city, it does have a mental hospital
where Distaval was commonly used. By
early January, 1962, Speirs5 established the
fact that 8 of the 10 women who had given
birth to babies with phocomelia had taken
Distaval in early pregnancy.
During the early months of 1962, Lenz
and Knapp9 confirmed Lenz’s original
ob-servations. Furthermore, tiley were able to
limit the “sensitive period,” during which
the embryo was injured, to between the
twentieth-eighth and forty-second day
in-elusive, after conception. A single dose of
thalidomide during that period appears to
be sufficient to cause pllocomeha. How
many women may have taken the drug
dur-ing tile sensitive period and given birth to
a normal child remains unknown. Many
who have taken tile drug during pregnancy
but after tile sensitive period are known to
ilave given birth to a normal infant.
Never-theless, to tile best of my knowledge, less
than a half a dozen instances have been
reported in wilicil a woman was known to
have taken an’ thalidomide during tile
sensitive period and given birth to a
nor-mal infant. All infants, however, are not
equally affected. Some instances are known
in which one dose caused a severe
mal-formation; in others, repeated doses have
only caused a minor one. Nevertheless, tile
incidence of malformation among infants
of women who have taken the drug
dur-ing the sensitive period appears to be high.
It is clear that phocomelia has occurred
where the drug has been available, whereas
the areas where the drug has not been
per-mitted have been spared. The present
es-timation in the British Commonwealth is
ap-SPECIAL ARTICLE
peared, and the number is still rising. At
least 25 cases have been reported in Sweden
with 100% ilistOry of thaliodomide taken in
early pregnancy. Tile number of cases in
Belgium (where Softenon was sold) is
stead-ily rising. Canada has seen phocomelia. Not
only were both Kevadon and Talimol on sale here, but these drugs were not
with-drawn until April 1, 1962, so their toll will
continue to rise longer than in other coon-tries. At least 14 preparations containing
tilalidomide ilave been sold in Italy. On
J
one 18, 1962, a report came from Turinof five cases in 5 weeks. Brazil has Softenon
and has had an epidemic of phocomelia.
To date I have heard nothing of the
situa-tion in Portugal or Japan. Wherever tile
drug was available, tile incidence of
phoco-melia ilas been high among the offspring of
doctors’ wives, and among the wives of
men in tile pharmaceutical firms which
Ilave handled the drug.
Recently, I have learned of at least two
instances of women in West Germany, each
of whom took Contergan early in one
pregnancY, ilad an infant with phocomelia,
was careful not to take Contergan during
tile next pregnancy, and had a normal
in-fant. The reverse situation has been
re-ported, in which a poor woman took
Dis-taval in one pregnancy, gave birth to an
infant \Vitll phocomelia, and accidentally
took thalidomide in her next pregnancy,
because the name of the sedative was not
on the bottle. She gave birth to a second
infant Witil phocomeha. Dr. Sweetman,
\%‘llo reported this instance in the
Man-chester Guardian,b0 urged that the English
law be changed so that the name of the
drug must he given on the label of all
pre-scriptions filled unless the physician
spe-cifically requested that it be withheld. This
would be an e(ually wise precaution for
the United States to adopt.
The inci(lellce in West Germany is
ter-rifle. A recent letter from Dr. Lenz advised
me that as of July, 1962, he had data on
400 cases of phocomelia. The M#{252}nster
In-stitilte for Human Genetics, wilich is in the state of North Rhine-Westphalia, registered
13 sets of twins with phocomelia in 1961,
and therefore estimates that 1,300 infants
should have been born with phocomelia
during the same year. The Minister of
Health of North Rhine-Westphalia has
undertaken to establish a name register of
all cases in that state from doctors and
public ilealth nurses asked to report all
in-fants with abnormalities of the extremities.
The Ministry estimated that approximately
80% of tilese infants would have
phoco-melia. At the end of December, 1961, Vitll
reports from one half of this state, the
Mm-istry had 800 registered cases; thus, tileir
estimated 80% of an expected total of 1,600
deformed children, or 1,280 infants with
phocomelia, tallies closely with tile estimate
of 1,300 from the Institute for Human
Genetics.
North Rhine-Westphalia is only one state
in West Germany, and the above figures
are only for 1961. During tile first ilaif of
1962 the incidence of phocomelia will
steadily rise because the use of Contergan
was steadily increasing during the summer
of 1961. Wesphalia has approximately 200
deformed children registered in the first 2
months of 1962. Therefore, the estimate for
all West Germany of 3,500 cases is a
mini-mum estimate. The final count may well
be over 5,000; two-thirds of these children
are expected to live and be of normal
men-tality. \Vest Germany is now planning
spe-cial orthopedic clinics and special schools
throughout the country for
tue
care of thesechildren. When the parents learn tilat help
is available, more deformed children will be brought to medical attention.
The hospitals of the United States Army
of Occupation have acted as control areas
througilout West Germany. Dr. T. W.
Im-mon11 of tile U. S. Army Headquarters
states that 16,000 babies were born to tile
wives of American soldiers in West
Ger-many in 1961, and no case of pilocomelia
had occurred. Use of drugs not passed by
our Food and Drug Administration is not
permitted in Army hospitals, but recently
U. S. Military Hospitals have seen several
THALIDOMIDE AND PHOCOMELIA
American soldiers whose German wives
had taken Contergan at home.
The refusal of the Food and Drug
Ad-ministration to permit the sale of Kevadon
in the United States has saved our country
from a tremendous catastrophe.
Neverthe-less, had the drug been invented in this
country (by no means a remote possibility,
as we have many keen pharmaceutical
com-panies), the drug would in all probability
have passed the Food and Drug
Adminis-tration as it appeared to be an excellent
sedative. It is widely and gratefully realized
that the credit for the refusal to permit the
sale of thalidomide in this country is due
to Dr. Frances Oldham Kelsey. The initial
application was delayed because the papers
were found “incomplete.” During the next
few months, while William S. Merrel
Corn-pany was gathering the necessary
informa-lion, the first reports of polyneuritis
ap-peared in the German and British medical
press. Dr. Kelsey read these, and she also
notedl2 that Merrell’s proposed label
recom-mended the drug as anti-emetic for the
nausea of early pregnancy. Therefore, she
requested proof that the drug was safe for
the fetus as well as for the mother. While
tile manufacturers were seeking this,
re-ports came from Germany and England
that thalidomide was suspected as the cause
of phocomelia, a complication so
unex-pected that many did not at first believe it.
Indeed, it was not until the end of March,
1962, that William S. Merrell Co. finally
withdrew their application for permission
to market thalidomide in the United States.
Thus, for nearly one year and a half, Dr.
Kelsey withstood the pressure to “make
thalidomide available to American
physi-cians,” and thereby she has saved the
United States from one of the greatest
tragedies of modem medicine.
Thalidomide has opened up not only the
new problem of harm from drugs to the
unborn child, but also a new avenue of
in-vestigation. Chemie Gr#{252}nenthal
immedi-ately tried to test the effect of thalidomide
on pregnant anunals. The only positive
in-formation1 they obtained was that the drug
passed through the placenta of rabbits.
Somers,14 f Distillers Ltd., fed large doses
of thalidomide to rabbits between the
twelfth and twentieth days of pregnancy
and thereby has repeatedly produced litters
of offspring many of which had
abnormal-ities of the limbs similar to phocomelia.
Murphy15 has produced the malformation
in fetuses of a pregnant rat by the
intra-peritoneal injection of an enormous dose
of thalidomide on the twelfth day of
preg-nancy.
Somers’ work has been criticized because
of the enormous doses of thalidomide which
he used. However, h&6 has recently
re-ported that although 75 times the
thera-peutic dose for man must be fed to the
maternal animal, the blood level of
thalido-mide in such rabbits is only three times
that obtained in man after a therapeutic
dose.
The disastrous effect of thalidomide on
the unborn child has brought to light many
problems. The Food and Drug
Administra-tion has no control over a drug until the
manufacturing company makes application
for its sale. If the Food and Drug
Adminis-tration fails to act, the application is
auto-matically granted in 60 days. Moreover, the
Administration has jurisdiction only over
safety, none concerning efficacy.
Further-more, the Food and Drug Administration
has no supervision during the investigational
period. How much experimental work is
done, how the drug is initially tried on
man, how widely it is distributed for
in-vestigational purposes, are left entirely to
the discretion of tile pharmaceutical firms
who are subject to the bias of commercial
interest. The records submitted by
physi-cians are concerned with the immediate
effect of the drug; inadequate attention has
been paid to the possibility of late
ill-effects.
The catastrophe of phocomelia has
stim-ulated attempts in Germany, England, and Canada to correct this obvious defect in
central regulatory control. Physicians are
urging that careful records be kept on all
659
these records, together with a report of the
infants’ condition, be sent to a central
corn-puting office. Common sense requires that
careful records be kept on all new drugs
which may conceivably have constitutional
effects upon anyone to whom they are
ad-ministered, and that all such records should
be submitted to some detached control
agency for analysis and future reference.
Not only must the present haphazard
system of the control of drugs be revised,
but a great deal of difficult investigation
will be needed for adequate methods for
the detection of teratogenic effects of drugs
and chemicals. In the last analysis, all
ani-mals do not react alike. What is safe for
many animals need not be safe for man.
For this reason, no matter how good the
animal studies, careful surveillance of drugs
when they first are tried on man must have
paramount importance.
Finally, it is clear that the indiscriminate
use of drugs by women of the child-bearing
age should be avoided. Not infrequently
the fetus may be injured before the
exist-ence of pregnancy is recognized. Certainly
a pregnant woman should not take any
medicament without consulting her
physi-cian, and he should be content to prescribe
only these drugs which have been
well-tested. This is especially important during
the first trimester when the embryo is
de-veloping. Nevertheless, it should be borne
in mind that even though malformations
only occur during early pregnancy, injury
to the normally formed but rapidly
grow-ing organs of the fetus could certainly occur
at any time after the fetus is formed. It
must, therefore, be concluded that women
should abstain from all unnecessary drugs
throughout the total period of pregnancy.
REFERENCES
1. Kosenov, W., and Pfeiffer, R. A. : Micromelia, haemangioma and duodenal stenosis exhibit.
German Pediatric Society, Kassel, 1960.
Re-ported by title in Mschr. Kinderheik., 109:
227, 1961.
2. Taussig, H. B. : A study of the German out-break of phocomelia. J.A.M.A., 180:1106, 1962.
3. Wiedemann, H. R., and Aeissen, K: Zur Frage der derzeitigen Haufung von Gliedmassen-Fehlbiklungen. Med. Mschr., 12:816, 1962. 4. Pfeiffer, R. A., and Kosenow, W. : Zur Frage
einer exogenen Verursachung von schweren
Extremitatenmissbildungen. Muench. Med. Wschr., 104:68, 1962.
5. Lenz, Klindliche Missbildungen nach Medika-ment w#{228}hrend der Gravidit#{228}t. Deutsch. Med. Wschr., 86:2555, 1961.
6. McBride, W. G. : Personal communication from Distillers, Ltd., London.
7. McBride, \V. G. : Thalidomide and congenital abnormalities. Lancet, 2:1358, 1961. 8. Speirs, A. L. : Thalidomide and congenital
abnormalities. Lancet, 1 :303, 1962. 9. Lenz, W., and Knapp, K. : Die
Thalidomid-Embryopathie, Deutsch. Med. Wschr., 87:
1232, 1962.
10. Sweetman, W. P. : Note on the labelling of drug containers. Manchester Guardian, June 14th, 1962.
11. Immon, T. W. : Personal communication to the author.
12. Kelsey, F. 0. : Personal communication to the author.
13. v. Schroder-Beielstein, H. W., from Chemie Gr#{252}nenthal: Personal communication to the author.
14. Somers, G. F. : Lancet, April 28, 1962; per-sonal communication to the author, Brown and Somers of Distillers Ltd., London.
15. Murphy, M. L.: Reported at meeting of Amen-can Pediatric Society, Atlantic City, May 10, 1962.
