How Environmental Effects on Child Health Are Recognized

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How Environmental

Effects

on Child

Health

Are Recognized

Robert

W. Miller,

M.D.

From the Epidemiology Branch, National Cancer Institute, Bethesda, Maryland

There is no doubt that the fetus and child have

special susceptibility to the harmful effects of

chemical pollutants.

EPIDEMIOLOGIC CASE REPORTS

Example 1

“Strange incidents occurred in villages along Minamata Bay in [the] Kyushu district in Japan, in which many cats went mad and died. These incidents were the prelude to

[

an] epidemic of a mysterious disease in human beings.” In this way Japanese scientists began their account of the link between the ailment, now known as Minamata disease, and pollution of water with met.hylmercury.

Initially, a degenerative neurological disease was ob-served only in older children and adults. Apparently no one thought of possible fetal effects. In consequence, they went unnoticed for several years before it was realized that an epidemic of cerebral palsy had paralleled the illness in adults and older children. This was the first evidence that a chemical pollutant could harm the human fetus.

Methylmercury was identified as the cause of the epi-demic by looking back into the histories of affected persons. The frequency and seriousness of the effect was greatest in the families of fishermen. It had been noted that fish in the Bay swam erratically. Fishermen sold their best catch and used the sickest looking fish as food for their families. Twenty-three children developed cerebral palsy after intra-uterine exposure. Six percent of births during the interval were affected, as compared with 0.5% elsewhere in Japan. Although brain damage in the children was severe, only one of their mothers showed signs of the disease.

The methylmercury came from waste flushed into the Bay by a factory that made vinyl plastic. The chemical concentrated in fish and impaired their neurological func-tion as well as that of birds, cats, and people who ate the fish. When a ban was placed on fishing in the Bay, the epidemic disappeared, only to recur when the factory switched its effluent to the river, where people still fished. In all, 121 persons were known to have been affected; 46

of them died. Subsequently, the same disorder occurred hundreds of miles away in Niigata, where 47 people were affected ( one in utero) and six died.

Minamata Bay is a long distance from Western coun-tries. That distance, in part, accounted for some delay in notifying the world of the episode. The first mention of cerebral palsy in a publication outside Japan was in 1965,’ 9 to 10 years after the epidemic occurred. In any event, neither the congenital nor the adult form of the disease seemed related to pollution in other countries. The reports

went largely unnoticed. It is now clear that Japan was at least 10 years ahead of the rest of the world in encounter-ing this pollution problem. Although no illness outside Japan has been traced to fish as a source of methylmercury, another source has been found-right here in the United States.

The first and best account to date was in the New

Yorker magazine.’ It concerned the Huckleby family of Alamogordo, New Mexico. The father, a poor farmer, purchased some seed at bargain prices for his hogs. The grain was stained with a pink warning dye, for it had been coated with a methylmercury-containing fungicide. The hogs became ill, and the family, on eating the pork, suf-fered a catastrophe. Three of the children developed severe brain damage. The mother, who was not affected, was pregnant at the time and later gave birth to a child who had cerebral palsy and mental retardation.”

Example 2

A similar pattern of events occurred with respect to an-other chemical pollutant, polychlorinated biphenyls (PCBs). In Japan an epidemic of chloracne occurred among chil-dren and adults.’ There was marked familial aggregation of

cases. The histories of affected persons revealed that they had used a particular brand of cooking oil. Oil manufac-tured just before the start of the epidemic was analyzed, and showed about 2,000 ppm of PCBs, 48% of which is chlorine. PCBs have long been used as a heat-transfer agent in food manufacturing.

Ten women, who were pregnant at the time they used the cooking oil, gave birth to cola-colored babies.” The color faded during infancy, but the possibility of late-oc-curring effects in the skin or other organs remains. PCBs have since contaminated chicken feed in the United States.’ The contaminant was recognized because of an embryonic effect, reduced hatchability of eggs. The source was the

same as in Japan-the pipes containing the heat-transfer

agent eroded, and pin-hole leaks developed.’

Example 3

Airborne particulates were implicated as a cause of lead poisoning of children in Baltimore in 1933.’ In this instance

a resident from Johns Hopkins Hospital, in seeking the origin of an epidemic among children from a slum, visited

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the area. In the home of one affected child, the mother also

had encephalopathy and referred most questions to a large Negro visitor, Mekose Easter, “whose breath was strong with whiskey.” He thought that burning wooden battery

casings was to blame, because “the smell was bad, even

made the food taste bad.” In this way the cause of the

epidemic was found.

EPIDEMIOLOGIC

METHODS

Retrospective

Studies

In each of the three epidemics cited, the cause

was found by looking back into the histories of

the affected children. This retrospective approach,

sometimes scorned by the uninitiated, has served

medical research well. It has been a first step in

identifying causes of a wide variety of human

dis-ease. It was in this way that an Australian

ophthal-mologist1#{176} recognized maternal rubella as a cause

of congenital cataracts (associated with other

anomalies), Philadelphia obstetricians identified

radiotherapy during early pregnancy as a cause

of small head circumference and mental

retarda-tion in the offspring,1’ and an Australian

obste-trician12 and a West German human geneticist13

related phocomelia to the maternal use of

thalido-mide in pregnancy. More recently, the first

ex-ample of transplacental chemical carcinogenesis in

man was found by the same technique. The

his-tories of seven young women with clear-cell

adeno-carcinoma of the vagina revealed that this rare

neoplasm so early in life was caused by maternal

treatment with stilbestrol during pregnancy.14

Prospective

Studies

The relation between environment and health is

most readily revealed by retrospective studies

con-cerning heavy exposures to specific agents.

Rela-tionships can then be refined through prospective

studies in which cohorts of exposed versus lightly

or nonexposed children are followed over time to

define the frequency of subsequent disease in

rela-tion to a wide dose-range of the agent in question.

This method will also reveal subtle manifestations

of the disease induced and, with respect to

intra-uterine exposures, the interval of maximum

suscepti-biity. Prospective study of the effects of chemicals

on health may be more applicable to occupational

or drug exposures than to the less pure and less

well quantitated pollutants in the general

environ-ment.

EstablIshIng

CausalIty

Demonstrating an association between an

en-vironmental exposure and an increased frequency

of a specific disease is not enough. One must

evalu-ate if the association is causal. Cause is implicated

if the effect disappears when the suspected agent

is removed. A dramatic example occurred in West

Germany when there was a sharp decline in the

occurrence of phocomelia immediately after

thalido-mide was banned.15

Without such a reduction, evaluation of cause

requires integration of concepts from many sources

into an overall estimate of the likelihood that the

association is or is not causal. Important

compo-nents in making this evaluation are

(

1

)

the strength

of the association, i.e., a dose-response effect; (2)

consonance of the results observed with existing

knowledge from experimental, clinical, and other

epidemiological studies; and (3) the exclusion of

other variables which may confound interpretation.

Most of these criteria were met in the examples

cited.

USES

OF EPIDEMIOLOGY

Descriptive Studies

Epidemiology can generate hypotheses-largely

through descriptive studies-by seeking peculiarities

in the occurrence of specific diseases according to

such variables as age, sex, ethnic group, geography,

occupation, preexistent disease, and time. One

looks for marked excesses or deficiencies in

fre-quencies with respect to these and other variables.

Thus, because Hodgkin’s disease has two age-peaks

at 20 and 70 years in all countries evaluated to

date except Japan (which has only the later peak),

it has been proposed that different disease processes

are involved, with overlapping age distributions.1’

Analytical

Studies

Epidemiology can serve to test hypotheses

de-rived from clinical observations, laboratory

find-ings, or previous epidemiologic studies. In doing

so, one must seek accidents of nature that permit

tests of hypotheses to be made. Whenever possible,

use is made of existing data resources such as

hos-pital charts, employment records, special disease

registries and vital certificates. Epidemiologists,

un-like laboratory scientists, must take things as they

are, rather than as they might ideally be.

The discovery that stilbestrol can cross the

pla-centa and induce cancer in the child up to 25 years

later14 has led to hypotheses concerning other

chemicals given during pregnancy that may also

be carcinogenic in the child. For example,

diphenyl-hydantoin given for epilepsy can induce a

Hodg-kin’s-like disease in the patient which can cause

death or is reversible if the drug is discontinued

promptly.17 A transpiacental effect can be evalu..

ated by retrospective study of children with

Hodg-kin’s disease or by prospective studies of children

born of mothers given diphenylhydantoin during

pregnancy, as compared with a similar group of

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Surveillance

Among newborn children, each clinical disorder

may be monitored for changes in frequency over

time or for peculiarities in occurrence. When

aber-rations occur, a search can be made for an

environ-mental change as the explanation. A dramatic

ex-ample was the epidemic of retrolental fibroplasia

among premature infants in the 1950s from

thera-peutic exposure to high concentrations of oxygen.18

In other instances, a change in rates may, of course,

not be attributable to the environment but to

changes in diagnostic practice or reporting.

The effectiveness of monitoring the occurrence

of a disease varies with its nature. Surveillance

of congenital malformations is often handicapped

by several problems. Ascertainment will be less

complete when malformations are internal than when

they are external. Individual anomalies are rare,

and effective monitoring is seldom possible within

a single hospital. Experience has demonstrated

that environmental teratogens increase the rates

of specific malformations, but not of total

mal-formations or malformations grouped according to

organ system. Thus, x-irradiation induced a very

specific defect, small head circumference with

men-tal retardation,19 and thalidomide caused reduction

deformities of the limbs, a malformation so rare

that it would have been lost under the catch-all

category “other anomalies of the musculoskeletal

system” in the numerical coding system used at

the time. Detection of these malformations by

rou-tine surveillance would have required registries of

malformations according to specific type in the

right geographic areas at the right time.

Registries specifically created for childhood

can-cer are far less common than those for congenital

malformations. In Manchester, England, the

child-hood tumor registry is population-based and has

excellent review of histologic specimens.2#{176} It serves

as a standard against which comparison can be

made of the relative frequency according to cell

type of childhood cancer in other parts of the

world.21 Comparisons of hospital-based registries

of childhood cancer have shown some marked

geo-graphic or ethnic variations in the occurrence of

specific neoplasms, e.g., the great relative frequency

of acute monomyelocytic leukemia, often with

chloroma of the eye, in Ankara, Turkey, where

40% of all acute leukemias in children were of this

cell type as compared with about

5.5%

2223

Value of Registries

To date, no human teratogen has been identified

by registries of malformations in hospitals, prepaid

medical programs, cities, regions or nations; nor

has any registry confirmed the teratogenicity of an

environmental agent once it has been recognized

or suspected from clinical observations. However,

after a retrospective study identified stilbestrol as

a transplacental cause of a specific cancer,14 the

relationship was quickly confirmed through the

use of data in the New York State Tumor Registry.24

There are four benefits which have been derived

from registries of malformations to date. First, they

have shown that some suspected agents are either

not teratogenic or at best weakly so

(

e.g.,

mecli-zine25 and diphenylhydantoin.26 In this sense,

reg-istries have been used to test hypotheses. Second,

when blood samples were drawn at intervals

dur-ing pregnancy and from the umbilical cord at birth,

serologic observations were related to subsequent

subtle effects of infection during pregnancy.27 In

this way new understanding of such effects has

been achieved. Third, careful examinations at birth

in a large series have provided good data on

oc-currence rates of individual malformations for the

samples under study, as in Birmingham, England.25

These rates can be used cautiously as a “standard”

against which to compare rates observed in other

special series or for international comparisons. It is

well known that normal rates in one region of the

world or ethnic group may be dissimilar from those

in another.29 Fourth, registry data can be used as a

source of study groups for retrospective

investiga-tions.

A New National

Surveillance

The experience from registries for congenital

mal-formations to date point the way to the future. The

need now is for a simple, relatively inexpensive

system that covers a substantial portion of the

United States. One potentially involves the use of

hospital discharge diagnoses collected by the

Com-mission on Professional Hospital Activities

(

CPHA).

In a routine fashion, data are collected from

sub-scribing hospitals on 10 million discharges

annual-ly, about one million of which are newborn

in-fants. The diagnostic code used for congenital

mal-formations is a modified form of the International

Classification of Diseases, Adapted

(

1962) .

Un-fortunately, this coding system places some

diag-noses in groups, making it impossible, for example,

to separate macroglossia which is infrequent from

tongue-tie which may be frequent. Nevertheless,

for the many diagnoses that are not diluted by

grouping with other entities, the surveillance

should prove to be a good early warning system for

new teratogens in the environment. A trial of this

system will be initiated before July 1973 by the

Epidemiology Branch, Chronic Disease Center,

USPHS, with funds provided by the National

Insti-tute for Child Health and Human Development.

The surveillance of one million births among

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reveal malformations detected at birth in the areas

covered, recorded on the abstract forms, submitted

to CPHA, and not lost midst a welter of other

diag-noses sharing the same code number. Coverage

does not include malformations that occur in other

areas, or that are not detectable at birth or not

re-ported to CPHA in a retrievable form.

Alert Practitioner Reporting System

These gaps may be filled in part by a selective

reporting system in which peculiarities in the

oc-currence of malformations are referred by alert

prac-titioners to a panel of experts for prompt review,

and action when necessary. This approach is being

evaluated in a pilot study by the American

Acad-emy of Pediatrics. The concept is based on the

his-tory of medicine as it pertains to the discovery of

human teratogens. All have been initially

identi-fled by alert practitioners.3#{176} The pilot study seeks

to encourage reporting of unusual observations,

which would otherwise go unheralded until and

un-less an epidemic occurred. The pilot study

(

with funds from the National Institute of

Environmen-tal Health Sciences, NIH

)

also provides for

indoc-trmnation of selected medical students at three

pediatric centers in obtaining special etiologic

his-tories from parents whose children have

malforma-tions or other illnesses of unknown origin, but

which have some feature

(

as noted by a faculty

supervisor) that warrants a deeper history than

usual. The results are evaluated every 6 months by

the Committee on Environmental Hazards of the

American Academy of Pediatrics.

In the first year of the study, several benefits have

been realized. A pediatrician in practice has notified

the Committee of a child he observed in a hospital

for the mentally retarded whose mother worked

during pregnancy at a factory where she was

ex-posed to chemicals which are known to produce

brain damage among heavily exposed workers and

in experimental animals. The observation has been

referred for further study by the appropriate local

and Federal health agencies.

In the feasibility studies at the medical schools,

the students have realized an advantage over their

classmates in obtaining skillful histories for

diagnos-tic and etiologic purposes. The program was barely

underway when suspicions developed that

proges-tational agents early in pregnancy may be related to

congenital heart disease. Immediately thereafter, an

independent report of the possible relationship

be-tween these drugs and transposition of the great

vessels was published by a group at McGill

Univer-sity.3’

In the feasibility study, parents of newborn

in-fants with malformations have expressed

apprecia-tion for the opportunity to discuss the child’s illness

in detail with a knowledgeable person. The faculty

supervisors have developed their aptitude for

spot-ting cases most likely to yield information of

spe-cial interest. Hopefully, the benefits derived by

participants in the pilot study will spread in the

schools involved as well as elsewhere.

The observations made by alert practitioners or

by medical students represent hypotheses which

can be tested through the use of data in such

re-sources as CPHA, the Metropolitan Atlanta

Con-genital Malformations Surveillance,32 or the

Kaiser-Permanente Perinatal Study.33 When there are no

appropriate existing resources to test hypotheses,

ad

hoc

studies, either retrospective or prospective, may

be appropriate.

Record Linkage

With increased sophistication in computer usage,

the automated linking of records has become an

important tool in epidemiologic research. Great

Britain34 and Canada35 are well ahead of the

United States in this respect. Thus, events during

pregnancy can be linked with the health of the child

at various ages, through the use of data on the

ob-stetric charts; birth and death certificates; and

hos-pital, school, and employment records. In this way

it is possible to study etiology of disease not only in

individuals, but also in families.

Opportunities for such research in the United

States would be enhanced if the child were given

a Social Security number at birth

(

as in Great

Britain), and if on his records (through the school

years at least

)

notations were made of his and the mother’s Social Security numbers. The procedure

is likely to be questioned because it could serve

to invade privacy; but, with proper safeguards, as

exist abroad, its use for scientific research could

reap a rich harvest.

ROLE OF THE AMERICAN

ACADEMY

OF PEDIATRICS

As chemical pollution increases, its adverse

ef-fects on health will increase. Because the fetus and

young child have already displayed unusual

sus-ceptibility, special efforts must be made to identify

environmental effects as promptly as possible. The

American Academy of Pediatrics has played a

lead-ing role in this regard, but it can do more.

Its scientists and their consultants can open

broad new areas of understanding by calling

at-tention to recently developed screening procedures

and resources for detecting the influence of

chemi-cal pollutants on child health. The next presentation

at this symposium is in this category. It concerns

mass screening for environmental

mutagenesis-ger-minal or somatic, an area toward which the

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ex-ample concerns a new resource of potentially great

value in studies of human teratogenesis : a data

bank

(

developed by the Stanford Research Institute

under contract with the National Cancer Institute)

with details on 30,000 chemicals in the

environ-ment which may have impact on human health.

The Academy, as its interest enlarges, may well

emerge as the center in the United States to which

questions concerning environmental effects on

children will be referred, evaluated, and acted

upon.

REFERENCES

1. Study Group of Minamata Disease: Minamata Disease. Kumainoto, Japan: Kumamoto University

Publica-tion, 1968.

2. Matsumoto, H., Koya, G., and Takeuchi, T. : Fetal Minamata disease: A neuropathological study of two cases of intrauterine intoxication by a methyl-mercury compound. J. Neuropath. Exp. Neurol., 24:563, 1965.

3. Rouech#{233}, B. : Annals of medicine: Insufficient evidence. New Yorker, August 22, 1970.

4. Pierce, P. E., Thompson, J. F., Likosky, W. H., Nickey, L. N., Barthel, W. F., and Hinman, A. R. : Alkyl mercury poisoning in humans: Report of an

out-break. JAMA, 220: 1439, 1972.

5. Snyder, R. D. : Congenital mercury poisoning. New Eng. J. Med., 284:1014, 1971.

6. Kuratsune, M., Yoshimura, T., Matsuzaka, J., and Yama-guchi, A.: Epidemiologic study on Yusho, a

poison-ing caused by ingestion of rice oil contaminated

with commercial brand of polychlorinated bi-phenyls. Environ. Health Perspect., 1 : 1 19, 1972.

7. Yamaguchi, A., Yoshimura, T., and Kuratsune, M. : A

survey on pregnant women having consumed rice

oil contaminated with chlorobiphenyls and their

babies. Fukuoka Acta Med., 62: 117, 1971. 8. Kolbye, A. C., Jr.: Food exposures to polychiorinated

biphenyls. Environ. Health Perspect., 1 :85, 1972. 9. Williams, H., Schulze, W. H., Rothschild, A., Brown,

S., and Smith, F. R., Jr. : Lead poisoning from the

burning of battery casings. JAMA, 100: 1485, 1933.

10. Gregg, N. : Congenital cataract following German

mea-sles in the mother. Trans. Ophthal. Soc. Aust., 3:35, 1941.

11. Goldstein, L., and Murphy, D. P. : Etiology of the

ill-health in children born after maternal pelvic

ir-radiation: II. Defective children born after

post-conception pelvic irradiation. Amer. J. Roentgen., 22:322, 1929.

12. McBride, W. G. : Thalidomide and congenital abnor-malities. Lancet, 2: 1358, 1961.

13. Lenz, W. : Diskussionsbemerkung zu dem Vortrag von R. A. Pfelffer und K. Kosenow: Zur Frage der

exogenen Entstehung schwerer

Extremit#{228}tenmiss-bildungen, Tagung der Rheinisch-Westf#{228}lischen

Klnderarztevereinfgung in D#{252}sseldorf,19: 11, 1961.

14. Herbst, A. L., Ulfelder, H., and Poskanzer, D. C.:

Adenocarcinoma of the vagina. New Eng. J. Med.,

284:878, 1971.

15. Lenz, W.: Epidemiologic von Missbildungen. P#{228}dlat.

P#{228}dol.,1:38, 1965.

16. MacMahon, B.: Epidemiology of Hodgkin’s disease. Cancer Res., 28:1189, 1986.

17. Anthony, J. J.: Malignant lymphoma associated with

hydantoin drugs. Arch. Neurol., 22:450, 1970.

18. Patz, A. : Retrolental fibroplasia. Survey Ophthal., 14:1,

1969.

19. Miller, R. W., and Blot, W. J. : Small head size after in utero exposure to atomic radiation. Lancet, 2:784, 1972.

20. Marsden, H. B., and Steward, J. K. : Problems of chil-dren’s tumours in Britain. In Recent Results in Cancer Research: Tumours in Children. New York: Springer-Verlag, 1968.

21. Miller, R. W. : Interim report: UICC international study of childhood cancer.

mt.

j. Cancer, 10:675, 1972. 22. Cavdar, A. 0., Arcasoy, A., Gozdasoglu, S., and

Demi-rag, B. : Chloroma-like ocular manifestations in

Turkish children with acute myelomonocytic

leu-kemia. Lancet, 1:680, 1971.

23. Fraumeni, J. F., Jr., Manning, M. D., and Mitus, W. J.: Acute childhood leukemia: Epidemiologic study by

cell type of 1,263 cases at the Children’s Cancer

Research Foundation in Boston, 1947-65. J. Nat.

Cancer Inst., 46:461, 1971.

24. Greenwald, P., Barlow, J. J., Nasca, P. C., and Burnett, W. S. : Vaginal cancer after maternal treatment with synthetic estrogens. New Eng. J. Med., 285: 390, 1971.

25. Wilson, J. G. : Present status of drugs as teratogens in man. Teratology, 7:3, 1973.

26. Lowe, C. R. : Congenital malformations among infants born to epileptic women. Lancet, 1 :9, 1973. 27. Sever, J. L. : Perinatal infections affecting the

develop-ing fetus and newborn. In National Institute of Child Health and Human Development Confer-ence on the Prevention of Mental Retardation Through Control of Infectious Diseases. Washing-ton, D. C., PHS Publ. 1692, 1966.

28. Leck, I., Record, R. G., McKeown, T., and Edwards,

J. H. : The incidence of malformations in Binning-ham, England, 1950-1959. Teratology, 1 :263, 1968. 29. Ned, J. V. : A study of major congenital malformations

in Japanese infants. Amer. J. Hum. Genet., 10:398, 1958.

30. Miller, R. W. : Teratology in 1970: The national scene:

President’s report to the Teratology Society.

Tera-tology, 3:223, 1970.

31. Levy, E., Cohen, A., and Fraser, F. C. : Hormone treat-ment during pregnancy and congenital heart de-fects. Lancet, 1:611, 1973.

32. Flynt, J. W., Jr. : Trends in surveillance of congenital malformations. In Janerich, D. T., Skalko, R. C., and Porter, I. H. ( eds. ) : The Problem of Congen-ital Defects, 1972. New York: Academic Press,

Inc., to be published.

33. van den Berg, B. J., and Yerushaliny, J. : The relation-ship of the rate of intrauterine growth of infants of low birth weight to mortality, morbidity, and congenital anomalies. J. Pedlat., 69:531, 1988.

34. Acheson, E. D. : The Oxford Record Linkage

Study-The first five years. In Acheson, E. D. (ed.):

Record Linkage in Medicine. Edinburgh: E. and S. Livingstone, Ltd., 1987.

35. Newcombe, H. B. : Record linkage-Its role in congenital defect research. In Janerich, D. T., Skalko, R. C.,

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General

Discussion

DR. J. R0BBIN5. With respect to Minamata disease in

Japan, you alluded only to gross observations. What

about minimal and perhaps avoidable damage?

DR. WEIss. According to Japanese health officials in

Minamata, some of the children from exposed families

who had previously shown no overt signs of

methyl-mercury poisoning now in their teens display some

de-ficits in athletic abilities. There are, however, no

quan-titative data of subtle neurological impairment.

The Rochester Mercury Research Group has studied

an even wider epidemic in Iraq, a consequence of feed

grain from Mexico, Algeria, and California treated with

a methylmercury fungicide (Bakir, F., at cii.: Science, 181:230, 1973) . The grain was distributed to the

peasant population and baked into bread. The number

of deaths may have been grossly underestimated, and

as many as 50,000 people may have been affected with illness.

The levels of methylmercury in breast milk cone-sponded to about 3% of blood levels. It was thought at

one time that the fetus was a sort of sink for the

methyl-mercury in the mother, thus explaining why almost none

of the mothers in Minamata developed symptoms

dur-ing pregnancy. The other possibility is that they

dis-played no symptoms because the blood levels were not

high enough. The offspring could have been affected

not only because of greater susceptibility, but also be-cause they received additional methylmercury via the

mothers’ milk. A considerable cumulative effect,

there-fore, may have occurred in the developing

organism-an effect that would not have been seen if the exposure

were limited to intrauterine life.

DR. HOLLAND. Dr. Miller mentioned registry data to obtain information on the hazards of environmental

ex-posures. How do you cope with the ethics of this?

There is also a major problem in this regard

concern-ing record linkage. Unless one has the various suspected

agents recorded at the time of registration, the investi-gator must go to the individual or the parents to

de-termine if they have been exposed. The same procedure

must be followed with respect to the control group. In Great Britain, if one registers the details of an

mdi-vidual, these data are confidential and no investigator

may approach that individual directly to ask about exposure to particular agents. To do so would breach

the rules of confidentiality of the registry. In the

United Kingdom, follow-back may only be done if the

investigator obtains the cooperation of the private

physi-clan. This underlines the crucial role that the individual practitioner plays in these investigations. How do you

cope with this problem in the United States?

DR. OAKLEY. We follow the same procedure. We

have been ascertaining all newborn infants with birth defects in metropolitan Atlanta through hospital

nurs-eries and obstetrical units. The registry contains

identi-fying information, including the physician’s name. We

learned in November 1972, from a physician in an-other city, of a child born with reduction deformities of

the limbs after the mother received a mild tranquilizer first marketed in the United States in 1967. A similar

case had been reported in the French literature about 6 years ago. We obtained permission from the private

physicians to interview at home 26 of the 31 mothers

who had given birth to children with this malformation in the Atlanta area since 1970. The medication was

shown to the mothers, and none of them recalled having taken it during the first trimester.

DR. HOLLAND. You cannot really conclude from this

study that there was no hazard.

DR. OAKLEY. I agree. Our concern was that the

clinical reports could be the first cases of a major new

epidemic of a drug-induced embryopathy. Our results

merely suggested that we were not sitting on a catas-trophe. They in no way show that the drug is safe for

use in pregnancy.

DR. J. ROBBINS. Dr. Miller, you said that registries have not unearthed teratogens, and the few that are known were rather quickly discovered by clinicians. Do

you think that occurred because human malformations

in the main are not caused by environmental agents, or

might it be because the surveillances were inadequate?

DR. MILLER. The surveillances have been fine. It is

difficult to recognize environmental agents as causes of

malformations. Apparently there are not many clear-cut environmental causes that can be identified by simple surveillance data. One problem is that the surveillance

must be made in the right place at the right time. A

registry in New York in 1961 could not have detected

phocomelia from thalidomide in West Germany, or a

surveillance in West Germany in 1965 would have been

4

years too late. The problem is that a teratogen may be introduced anywhere in the world, and monitoring

simply cannot be maintained in all countries at all

times. The resource developed by CPHA is already in

existence. It may be informative because it covers al-most one third of the births in the United States

annual-ly.

DR. J. ROBBINS. Can you conceive of a questionnaire

for the parents to complete at the time the malformed

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10

10’

10

10’

a-.01

I

.0001

.001

.01

.05

a- .05

:

p-s

D* .0001

,3 .001

102 .01

.05 10

2 3 4 5 #{149} 7 8910

Fdd icr*as k abnormty icidsnce

Fic. 1. Sample size required for detecting various magni-tudes of increase in incidence when the probability of false positives is 1 : 100 (a = .01 ) and of false negatives is 1:20

( p

= .05). The dotted lines indicate disease incidence,

e.g., .001 = 1 new case per 1,000 subjects at risk.

DR. MILLER. Yes, that is one purpose of the Alert

Practitioner Program. It is concerned, however, not only

with congenital malformations, but also with other

diseases of unknown etiology. Beginning in 1959, the

Collaborative Perinatal Research Program of the

Na-tional Institute of Neurological Diseases and Stroke

attempted to collect prospectively a huge catalog of

data from about 50,000 mothers during pregnancy. The

purpose was to relate these observations to abnormal

outcomes of pregnancy. No teratogens have yet been

revealed by the histories obtained in this large and

ex-I0

2 3 4 5 S 1 p910 Fold iiaas. iiabnovmalty iicidsnc.

Fic. 2. Sample size required for detecting various magni-tudes of increase in incidence when = .05 and p = .5.

pensive study, but the blood samples collected from the mothers during pregnancy and from the cord blood

have substantially added to our knowledge of the

sub-tie effects of a variety of microorganisms, including

rubella virus, toxoplasmosis, and cytomegalovirus.

MR. SULLIvAN. I should like to make a fundamental

point concerning much of this discussion. Someone

asked if we can detect human teratogens through

sur-veiliance. That is not a proper question. The correct

question is, how teratogenic must a compound be before

we can detect its effect? We must also ask, how often

are we willing to incriminate a compound which is

harmless, on the one hand, and how certain do we

want to be to pick up a teratogen, on the other.

From a purely statistical viewpoint, I wondered how

easy it would be to pick up a teratogen in a real-life

situation. In collaboration with my colleague, Mr. Frank

House, we estimated the number of patients who

would have to be studied to detect various-fold

increas-es in the incidence of congenital abnormalities, if the

control incidence was already known. This is a

hi-nomiai problem, but the proportions are so small that

it can be considered as a Poisson distribution. The

square root transformation makes it nearly normal with

known variance.

In preparing the graphs, we calculated the sample

size needed to provide for a specified probability (/3) of

detecting an effect of a particular magnitude in a

sig-nificance test at specified confidence level(a) , assuming

a normal distribution. In other words, to create the series of curves we had to specify values for a (i.e., the

Type I error) , which refers to the chance of designating

a compound as “teratogenic” when in fact it is not (i.e., false positives) ; and values of p (i.e., the Type II

er-ror) , which is the chance of failing to pick up a

corn-pound which really is teratogenic (i.e., false negatives).

Figure 1 shows the situation where one is prepared

to incriminate harmless compounds one in a hundred

times (a0.01) and have a 5% chance of failing to detect an active teratogen (f3=O.O5) . The number of

patients who would have to be studied is plotted

against the fold increase in malformation rate which

the compounds would produce. The control incidences

for different malformations are denoted by the different

curves.

‘To detect a teratogen that doubled the incidence of

a defect, such as anencephaly with an incidence of one

in one thousand (0.001), would require study of

23,000 newborn infants whose mothers had actually

taken the drug in question during the first trimester. It

does not seem feasible to make such a study.

Suppose instead, we were willing to incriminate 1 in 20 harmless drugs instead of 1 in 100, and we wanted

only a 50% chance of picking up a harmful one (a very

slack situation) . The curves in Figure 2 show that, to

detect a twofold increase in incidence, one would still

have to study the offspring of 4,000 women who took

the drug during pregnancy. From these figures it can

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terato-gens at only double or treble the natural incidence of a

defect.

In the case of thalidomide, the natural incidence of

limb-reduction deformities was 1 in 100,000 to 1 in 1 million, whereas perhaps half of the embryos exposed

during the critical period were affected. The increase,

thus, was 50,000 to 500,000 times greater than normal. With this example in mind, one can see that

surveii-lances or the Alert Practitioner Program are unlikely

to detect increases unless they are thousands of times

greater than normal.

An important point is that one should not conceive of

a compound simply in terms of whether or not it is

teratogenic; one should instead consider how teratogenic the compound is. Any surveillance system must take

account of how big an effect has to be before it will be detected.

DR. OAKLEY. It seems to me fatalistic to say that there

is no way to pick up human teratogens without

mas-sive studies. We know that the malformation rates in

metropolitan Atlanta have not changed in the past 5

years. These data indicate it is unlikely that major

teratogens have been introduced in that time. The sur-veillance system revealed a doubling in frequency of

cleft palate in 1971 that was not detected by clinicians.

We do not know what the increase means, but the ex-perience illustrates the potential benefits of routine

monitoring as compared to selective reporting by alert practitioners.

DR. BATTAGLIA. Dr. Oakley, on statistical grounds,

how did you decide that a jump from say two cases

reported to four cases in a time-interval is too much?

How do you know that you are not tracking something

that is unreal?

DR. OAKLEY. We used a 4-year average background

rate for each of 120 malformations. The computer, based

on the number of births in the last 1, 2, 4, 6, and 12

months, calculated the expected number of cases and

compared them with those observed. Most variations were

statistical artifacts that disappeared with time. We saw 25 cases of cleft palate in a year versus 15 expected

(P < .01 ), which seemed enough of an increase to

justify the interviews we undertook.

MR. SULLIVAN. The thalidomide experience is a good

example of the situation we face. If any teratogen were

to attract attention, it is one such as this. Thalidomide

produced a rare defect in high frequency and was easily

recognized at birth. Yet, it took 4,000 to 5,000 cases in Germany and from 1956 until 1961 to relate the effect

to the drug. If the relationship in this instance could

not be made quickly, how can one detect less apparent

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1974;53;792

Pediatrics

Robert W. Miller