Pediatrics
VOLUME 30 OCTOBER 1962 NUMBER 4
COMMENTARIES
PRIMUM
NON
NOCERE
I
N THE PAST few months many words havebeen written concerning the hazard of
indiscriminate administration of drugs to
)regnant women and infants. This concern
has simmered in the minds of pediatricians
and obstetricians for some time.15 It is
tragic that the impulse to do something con-stnictive emerged only after an international
disaster. This Commentary is not directed
solely to the specific problem of
thalid-omide, for Taussig, elsewheren and in this
issue, and other u78 have ably
re-rjeved the tragedy in light of scientific
information. I wish to stress some of the
biologic aspects of administering drugs
dur-ing pregnancy and infancy, and more
par-ticularly the responsibility of the physician
to he informed so that he will he able to
protect the health of the public.
Development is a splendid sequence of
molecular events. A congenital anomaly
either may be heritable or can originate
from intervention of some exogenous agent
in the normal gene-enzyme interaction. An
anatomic abnormality will result when an
insult to the succession of developmental
events occurs early in pregnancy, whereas
physiological disturbances are encountered
with later insult. Endogenous sources of
such problems may eventually he
under-stood and possibly prevented, but we can
and must avoid exogenous interference.
The role of the physician is clearly
de-fined by ancient writ and modern law. He
must do everything in his power to avoid
bringing harm to his patient. He must
ex-ercise this influence towards maintenance
of the health of the public to the best of
his ability.
Thalidomide is a useful drug, but its
promiscuous use after obviously inadequate
testing has produced an epidemic of amelia
and phocomelia. Other useful drugs have
a deleterious effect on tile embryo but their
se(Iuelae have not been as quantitatively
tragic. Fortunately, sulfa drugs,
aminop-term, radioactive iodine, thiouracil,
pro-gestins, anticoagulants, x-ray, and other
agents were used for special purposes and
were not initially considered “safe.” In
gen-eral these agents are recommended only
by physicians and are not sold without a
prescription. These agents are used with
discretion and are not subject to the
un-reasoning demand by our contemporary
society for tranquilization nor the avarice
of those meeting these demands. It should
be noted, however, that if these drugs had
been in great demand, then a tragedy
similar to that observed with thalidomide
might have ensued.
Tile mechanism involved in many of these
toxic effects in tile embryo is unknown, as
are the intimate processes involved in tile
production of a malformation. Current
re-search on tile teratogenic mechanism of
thalidomide may yield information of more
general significance.
Development does not terminate in utero,
it continues after birth. Considerable
in-formation is accumulating that tile
me-taholism of time young infant is unique.#{176}’ 10
514 PRIMUM NON NOCERE
In the human infant, sulfa drugs,
acetylsali-cylic acid, chioramphenicol, narcotics,
elec-trolyte solutions, oxygen, and water have
all been associated with singular and
some-times fatal responses. The infant handles
many substances differently from the adult.
Consequently, criteria used for therapy in
the adult must be modified when a drug is
administered to the infant. The usual
for-mulae which involve weight or square
meter of body surface cannot be utilized
arbitrarily. This conclusion can be
sup-ported by: an inability of the infant to
metabolize certain agents; the unique
sensitivity of his receptor organs; and a
general inability for excretion of a drug or
its products.
There is ample evidence of a need for a
pediatric-obstetric pharmacology.
An established procedure is followed
be-fore a drug may appear on the market. It
must first be demonstrated in a series of
animal tests as possibly useful and not
harmful. These observations are usually
made in the laboratories of pharmaceutical
companies or those of associated
universi-ties. Once it is determined that the drug
may be useful and is apparently
non-harm-ful, it can be clinically tested. The next
step is the weakest in the program. All that
is required of a clinical observer is that he
have an M.D. degree, a license to practice
medicine, and that he complete
appropri-ate forms. There is little critical evaluation
of his competence or of the results. A
per-plexing problem is created when the same
drug is offered with merely a different name
resulting from an alteration in an inert side
group. This process is not solely the fault
of the manufacturer. The universities also
share the blame. Most university
depart-ments do not participate in testing
pro-grams although they might if a truly new
to medical practice. Particularly now, when
drugs available for therapy are multiplying
so rapidly, the ability to distinguish
be-tween what’s new and what’s good is
vital.”
Can there be more adequate regulation
of the use of drugs in pediatrics and
ob-stetrics? Many authors, including Dr. Helen
Taussig, have requested that drugs be tested
on pregnant and infant animals. Dr. Morris
Fishbein’s Letter to the Editor in the New
York Times (May 12, 1962) criticized Dr.
Taussig concerning her lack of knowledge
of “drug research, promotion, or in laws
regulating these activities.” He stated that
the testing of drugs in pregnant animals
would lead to increasing costs of
pharma-ceuticals. It is inconceivable that tile exact,
impartial, accurate scrutiny of each and
every drug would impede medical progress.
Medical progress and laissez faire bear no
obligatory relationship to one another. To
quote Dr. Charles May:12
Self-regulation is a myth not likely to be realized outside Utopia. Neither citizens nor nations, pro-fessions nor trades have evolved to this day that deserve such trust, least of all when profit is at
stake. it is actually presumptuous to seek
exemp-tion from that degree of regulation which safe-guards the welfare of all members of society.
Also:
Criticism from individuals submitted privately to drug houses is easily dissipated by polite evasion, but public comment cannot be dealt with so con-veniently. The profession needs to bring its col-lective weight to bear on abuses and poor taste
through pointed criticism in official journals of
medical societies or by some fonn of public ex-pression of pointed opinion from independent
groups of physicians.
I wish to make the following suggestions:
1. That drugs be tested on pregnant
and infant animals when the agent is
eral, it is advisable to avoid the use of
any drugs early in pregnancy.
2. The consideration by government of
the establishment of a central
com-mittee advisory to tile Food and Drug
Administration, consisting of
repre-sentatives from interested Academies
and Colleges, to act in an advisory
capacity concerning the inadequacies
and a means for improving the
clini-cal testing programs. With the
co-operation of manufacturers,
universi-ties, and government, an adequate
protocol could be developed.
3. The formation within the proposed
Institute for Child Health and Human
Development of a section specifically
concerned with neonatal and
obstetri-cal pharmacology. A similar program
has been proposed for the drug
in-dustry.
4. That Departments of Pharmacology
and Experimental Therapeutics
incul-cate in medical students an
appreci-ation for the developmental aspects
of pharmacology and therapeutics.
Also, that clinical teaching services
accept the responsibility for
impress-ing their medical students, house staff,
and attending staff with a deep
skepti-cism for the usefulness of the myriad
of new therapeutic agents.
In addition to scientific inquiry, carefully
considered regulation for the use of
pharma-ceuticals is necessary for the maintenance
and improvement of public health. The
tragedy resulting from the use of
thalid-omide gives us a mandate to prevent a
recurrence.
NORMAN KRETCHMEB, M.D., Ph.D.
Department of Pediatrics
Stanford University School of I’s’ledicine
Palo Alto, California
REFERENCES
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1959.
2. Lucey,
J.
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Med., 94:287, 1961.
4. Nyhan, W. L.: Toxicity of drugs in the ne-onatal period.
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6. Taussig, H. B.: The thalidomide syndrome. Sci. Amer., 207:29, 1962.
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12. May, C. D.: Selling drugs by “educating”
