120 i.F VANN: CONGENITAL ABNORMALITIES Canad. Med. Ass. J.July 20, 1963, vol. 89

of Health, for their work in the initial identification ofthe causative organism. The technical assistance of Mr.Paul E. Martineau of the Animal Diseases Research Insti-tute is acknowledged with thanks.

REFERENCES

1. RIcH A. R.: The pathogenesis of tuberculosis, CharlesC 5rhomas, Springfield, Iii., 1944.

2. FELDMAN, W. H. et aL: Amer. J. Path., 25: 1183, 1949.3. KARLSON A G ANDERSEN, H. A. AND NEEDHAM, G. M.:

Di8. dhest, 28: 451, 1955.4. KARLSON, A. G.: Min'aesota Med., 42: 1399, 1959.5. JAHN, R. P.: Amer. Rev. Resp. Dis., 80: 78, 1959.

6, KINCADE, G. F.: Ca'n.ad. Med. A88. ,f., 80: 32, 1959.7. GRIFFITH, F.: Final report of the Royal Commission on

human and animal tuberculosis, pt. 2, IV, 1911. p. 167.8. FELDMAN W H* Avian tuberculosis infections, Williams

& Wilfdns Company, Baltimore, 1938, p. 483.9. RUNYON, E. H., SELIN, M. J. AND HARRIS, H. W.: Amer.

Rev. Tuberc., 79: 663, 1959.10. KUBICA, G. P. AND VESTAL, A. L.: Tuberculosis; labora-

tory methods in diagnosis (Public Health Servicepublications, no. 770), United States Department ofHealth, Education and Welfare, Communicable DiseaseCenter, Atlanta, Georgia, 1960, p. 43.

11. KUBIcA, G. P. AND PooL, G. L: Amer. Rev. Reep. Die.,81: 387, 1960.

12. MEISSNER G Beitr. Kim. Tuberk., 121: 365, 1959.13. NASSAL, ,f.: Det&tsck. Med. WecI&r., 88: 1855, 1961.14. FELDMAN, W. H.: Amer. Rev. Reep. Die., 81: 666, 1960.

Congenital Abnormalities in Children Born in AlbertaDuring 1961: A Survey and a Hypothesis

L. J. le VANN, L.R.C.P.(Edin.), L.R.C.S.(Edin.), L.R.F.P. & S.(Glasg.),*Red Deer, Alta.

A STUDY carried out in Alberta in 1959 by the.author indicated that drugs ingested byexpectant mothers may not be responsible for theincreased incidence of congenital malformationsrecently observed in newborn children. The prob-ability that another factor or factors may be in-volved in this increase became apparent during atwo-year survey of the incidence of congenitalanomalies in children born in Alberta during theyears 1959 and 1961.

In March 1960 the Minister of Health for theProvince of Alberta requested information con-cerning children born with congenital malforma-tions who might eventually require either institu-tional care or special types of therapy.At that time no data of this nature were avail-

able for Alberta or for any other large area inCanada. In order to obtain such an estimate asquickly as possible, the births registered in Albertaduring 1959 were studied.The survey of birth registrations for 1959 re-

vealed that 37,996 infants had been born in Albertaduring that year. Of these, 33,874 were traced andreports were obtained concerning them. Amongthis group, 257 showed some physical abnormality,a rate of 7.76 births per 1000. This seemed to be alow incidence of abnormalities in the light of otherrecent data collected in Japan, Birmingham andSweden.' Further analysis of this group was notcarried out in 1959.

In 1962, when increasing public attention wasfocused on malformations attributable to the useof certain drugs, it was decided to carry out asecond survey to identify children born withphysical deformities during 1961.

In the course of this survey it became apparentthat it is possible to determine only gross physical

*Medical Superintendent, Provincial Training School, RedDeer, Alta., and Lecturer in Psychiatry, University ofAlberta.

ABSTRACTIn Alberta, the provincial average for neo-natal congenital physical abnormalities dis-covered at birth increased from 7.9 per 1000births in 1959 to 13.8 per 1000 births in1961.Drugs taken by mothers during preg-

nancy were tabulated, including the anti-emetic and tranquillizer agents, but norelationship was demonstrated between theiruse and damage to the fetus.A significant relation was apparent, how-

ever, between the incidence of congeni-tal malformations and the extent of precipi-tation in the area concerned. In NorthernAlberta, where precipitation is highest, 15.5per 1000 children born in 1961 showedphysical defects. In Southern Alberta, whereprecipitation is lowest, 11.9 children per1000 births were born with physical defects.

Increases of radioactive dust containingcesium-137, cerium-144 and strontium-90were associated with above-ground Sovietthermonuclear Arctic explosions during re-cent years. The hypothesis is advanced thatchildren born in Alberta in 1962 will showa greater incidence of physical deformitiesthan those born in 1961, owing to greaterrainfall during 1961 and 1962.

malformations immediately after birth, and evenmany of the gross abnormalities may not be recog-nized for weeks or even years. In this category aresuch disorders as mental retardation, many cardio-vascular abnormalities, endocrine and metabolicdeficiencies such as cretinism, idiopathic hyper-calcemia of infancy, phenylketonuria, Hartnup's dis-ease, also gastrointestinal atresias or hyperplasias,

Canad. Med. Ass. J.July 20, 1963..vol. 89 LE VANN: CONGENITAL ABNORMALITIES 121

and skeletal anomalies. Even so common a condi-tion as mongolism is frequently not diagnosedat birth. Stillbirths constitute another group whichmight contain infants with internal organic mal-formations that are frequently not reported.

Microscopic malformations are rarely discoveredat birth and may only be detected considerablylater in life, if at all. Therefore, it must be borne inmind that even the best records of neonatal mal-formations include only a relatively small propor-tion of such disorders. This consideration lendseven greater significance to the figures concerningmalformation collected during the surveys de.'scribed herein.Of 38,762 births recorded in Alberta in 1961,

reports were received on 38,353. In 1961, theaverage frequency with which children were bornwith congenital abnormalities was 13.8 per 1000births for the province as a whole; there were 528such children. This figure ranged from 15.6 in thenorthern area of the province to 11.9 in thesouthern area. Total deformities (several childrenhad multiple deformities) numbered 18.6 per 1000live births in the northern area compared with 14.0in the south. The records of only 409 births couldnot be traced. The births not recorded in oursurvey were presumed to be those of children bornmainly in the colonies of certain religious sects inwhich mothers are delivered at home rather thanin hospitals, together with some births among theIndian and Metis populations.

CLASsIFICATION OF ABNORMALITIES

For the purpose of this study, "malformation"was taken to mean an anatomical aberration or pre-mature cessation of development of a structure.

In classifying the types of physical malformationsfor this study, we were in a dilemma with respectto the minimum degree of malformation whichshould be considered significant. There is no doubtthat a serious heart lesion constitutes an immediatethreat to the newborn child's life, yet who canpredict the effect of a hemangioma of the face interms of eventual psychoneurosis or psychosis? Forthis reason, it was decided to include all mal-formations, and no attempt was made to gradethem according to their severity. They were alltabulated in accordance with regional anatomicalcategories.

This survey was based largely on questionnaires,although in some few cases where some ambiguityexisted, verbal communication and additionalletters were necessary to ensure that the informa-tion compiled and used in this communication wascorrect.One observation emerging during this study, both

in 1959 and 1961, was the fact that congenitalmalformations were recognized with greater fre-quency in the northern part of the province than inthe southern part. Therefore these deformities wereinvestigated on a regional basis.

GEOGRAPHIC CONSIDERATIONSAlberta is a large province. In length it extends

approximately 850 miles from its northern extremityto the United States boundary. It varies in width:at its northern end it is more than 400 miles wide;at its southern (United States) boundary it tapersto approximately 200 miles.

Its centres of population are separated in such away that they can be divided into three distinctregions: (1) Northern area-demarcated by a trans-verse line drawn on the map immediately belowthe city of Edmonton and including the city andall the area north of it. A total of 18,072 birthsoccurred in. this area. (2) Central area-the totalarea below Edmonton, extending south to (but notincluding) the city of Calgary (6,041 births). (3)Southern area-the city of Calgary and the remain-der of the province south to the United Statesborder (14,240 births). The distribution, by area,of congenital abnormalities that occurred in Albertain 1961 is shown in Table I.

TABLE 1.-CONGENITAL MALFORMATIONS PER 1000 LIvE BIRTHS INALBERTA, BY AREA. 1961

StandardNumber of error

mal- Births S EArea formations Number of births rate per 1000 .

Provinceasawhole.... 631

Northern area... 337Central area.... 94

294Southern area... 200

38.35318.0726041

20,28114,240

16.518.615.6

14.514.0

0.651.011.59

0.840.98

The incidence of congenital malformations isshown in the three areas. The difference in mal-formation rate between the northern and centralarea is not statistically significant, largely becausebirths in the central area were 1/3 those of thenorth. The difference between the northern andsouthern areas is statistically significant, to a 1%confidence level. When the malformations in thecentral and southern areas are combined andcompared with those of the northern area thereis also a difference significant to a 1% confidencelevel.

Association Between the Drugs Ingested byPregnant Women and Congenital Malformations,by RegionsThere seems to be a great human need to at-

tribute the disabilities of mankind to some malign,intervening fate. Drugs have, for many obviousreasons, recently been incriminated in the causa-tion of fetal abnormalities. During the survey itwas established that 143 different drugs had beeningested during their pregnancy by women whosubsequently gave birth to children with physicaldeformities. Information concerning all types ofdrugs was requested in the questionnaire-not onlythose in the antiemetic group.One important fact emerged during the present

survey: every type of deformity appeared withequal frequency among "unmedicated" mothersas among those mothers who had been "medicated".

122 LE VANN: CONGENITAL ABNORMALITIES

TABLE 11.-NUMBER OF MALFORMED INFANTS BORN TO MOTHERS WHOTooa DRUGS DURING PREGNANCY, COMPARED WITH THOSE BORN TO

MOTHERS WHO DID NOT, ALBERTA, 1961

No drugs taken during pregnancy

Rate ofmalformed

Number of infantsmalformed (per 1000 Standard

Area infants born No. of live births live births) error

Provinceas a Whole....

Northern area...Central area....

Southern area...

34419755

14792

Drugs taken during pregnancy

Provinceas a whole....

Northern area...Central area....

Southern area...

The antiemetic drugs were the subject of specialinvestigation. Of a total of 55 children with harelipand/or cleft palate, classified under the category"Head and Neck", 11 were born to mothers who hadingested some type of antiemetic* medication.However, the births of 44 other infants with harelipand cleft palate were recorded; the mothers ofthese infants had taken no (antiemetic) medication.The relationship of amelia and phocomelia to

drug ingestion was also considered. Two motherswho had taken thalidomide during pregnancy gavebirth to children with these deformities. On theother hand, 65 malformations of the same or of asimilar type relating to the upper and lower limbswere recorded among mothers who had taken nomedication of any kind. Indeed, one mother whohad taken thalidomide throughout her pregnancygave birth to a normal child.

*The antiemetics whose ingestion by pregnant women wasrecorded during this study were as follows: meclizine hydro-chloride (Bonamine), trifluoperazine dihydrochloride (Stela-zine), dicyclomine, pyridoxine hydrochloride, doxylamine(Bendectin), dimenhydrinate (Gravol), cyclizine hydro-chloride (Marzine) and prochlorperazine (Stemetil).

Canad. Med. Ass. 3.July 20, 1963, vol. 89

In Table II, the number of malformed infantsborn to mothers who ingested drugs during preg-nancy is compared with those born to motherswho did not ingest drugs.There is a significant difference between malform-

ations occurring among children born to motherswho had taken no drugs and those occurring amongchildren of mothers who had taken drugs, whenthe central and southern areas are combined. Thereason that the signfficance of drug ingestion dis-appears when comparing the northern area andthe central area is again largely due to the facttht the births in the central area were consider-ably lower than in the northern and southern areas.Table III indicates the types of abnormalities

noted among the births reported in each area.Almost without exception, mothers who took nomedication gave birth to an equal number of de-formed children, or in the case of some anomalies,a greater number, than mothers who had drugs pre-scribed for them. The higher incidence of mal-formations per 1000 births in the northern part ofthe province than in the southern part is alsoapparent in this table.Table IV indicates the geographic distribution-

that is, the percentage of the various types of de-formities and their regional occurrence per 1000births. Here again the numbers of malformationsare, with few exceptions, higher in the north thanin the south.

Investigation of Environmental FactorsAssociated with the Regional Variation inIncidence of Congenital Alalformations inAlbertaDuring this survey it became apparent that a

relationship existed between the incidence of con-

'TABLE 111.-INCIDENCE OF CONGENITAL MALFORMATIONS AMONG CHILDREN OF MOTHERS WHO DID NOT RECEIVE ANYMEDICATION, COMPARED WITH THE TOTAL ABNORMALITIES OF EACH AREA

Northern area Central area Southern area Total

Total Total TotalSite or nature No mal- No mal- No mal- No Mal-

of malformation drugs formations drugs formations drugs formations drugs formations

Upper limbs.12 23 3 7 5 14 20 44Lower limbs.33 65 4 15 8 26 45 106Head and neck (includes facial, oral

and nasal deformities).20 37 8 12 15 36 43 85Central nervous system (islcludes

hydrocephalus, microcephalus,spina bifida).28 51 6 9 13 37 47 97

Cardiovascular system.18 27 2 6 9 21 29 54Urogenital system.28 44 0 5 10 24 38 73Gastrointestinal system.21 26 4 5 4 7 29 38Respiratory system.6 7 1 6 1 2 8 15Blood dyscrasias.2 5 3 3 0 0 5 8Mongolism.12 28 5 8 5 18 22 54Others.12 24 11 18 8 15 31 57

Totals.192 337 47 94 78 200 317 631Rate of malformations per 1000 live births--among mothers who receivedno drugs.

-among mothers who receiveddrugs.

5.7 5.0 3.9 5.0

4.3 5.0 6.1 4.9

Canad. Med. Ass. J.July 20, 1963, vol. 89 LE VANN: CONGENITAL ABNORMALITIES 123

TAFILE IV. GEOGRAPHIC DISTRIBUTION OF MALFORMATIONS

Site or nature of 'malformation

Upper limbs .Lower limbs.Head and neck (includes facial, oral

and nasal deformities).Central nervous system (includes

hvdrocephalus, microcephalus,spina bifida).

Cardiovascular system.Urogenital system.Gastrointestinal system.Respiratory system.Blood dyscrasias.Mongolism.Others.

Total malformations per area 337

Total malformations per 1000births per area.

rthern Rate per Central Rate per Southernarea 1000 births area 1000 births area

23 1.2 7 1.1 1463 3.5 15 2.4 26

37 2.0

51 2.827 1.444 2.426 1.47 0.35 0.228 1.524 1.3

Rate per Rate per1000 births Total 1000 births

0.9 44 1.11.8 106 2.7

12 1.9 36 2.5 85 2.2

96SS63818

94

18.6

1.40.9080.80.90.41.32.9

3721247201815

2.o1.41.60.40.10.01.31.0

200

15.6 14.0

97547338158

5457

2.51.41.90.90.30.21.41.4

631

16.5

genital deformities and the region of the provincein which the affected child was born. In the ex-amination of possible environmental factors, whichmight have a different effect in the northern sectionsof the province, the factor of precipitation waschosen for initial investigation.

Precipitation as a FactorIn Alberta, precipitation (rainfall, snowfall, etc.)

and its runoff are quite different from many otherareas in Canada. There is more precipitation in theprovince's northern regions than in the south.Also, precipitation occurring during the last threemonths of the year usually accumulates during thewinter months, remaining for a further three orfour months of the subsequent year as ice or snow,until its runoff in the spring. This usually occursas much as six weeks later in the northern partof the province than in the south.The precipitation for the years 1960 and 1961

(a period during .vhich the conception, gestationand birth of the babies studied would have oc-curred) was compiled, and the average precipita-tion of these two years was calculated for eachgeographical area. During each of the years itwas higher in the northern than in the southernarea.

Fig. la indicates the average regional rainfall ininches for the years 1960 and 1961. This figure forprecipitation was compared with that for the in-cidence of malformations per 1000 births (Fig.ib) in each respective area. This comparison indi-cated that there was a marked relationship be-tween the extent of precipitation and the frequencyof congenital malformations.

Fig. 2a indicates the total number of malforma-tions per 1000 births in the three largest cities inAlberta, each of which had over 1000 births duringthe year. This figure is significant because it givesthe yearly average precipitation in these threecities. There is a direct relationship between levels

of precipitation and numbers of malformations per1000 births in these three major Alberta cities.

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124 I.E VANN: CONGENITAL ABNORMALITIESCanad. Med. Ass. J.July 20, 1963, vol. 89

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or other structure showing a developmental fault), for the northern, central and southernareas of Alberta. Black bar-graph represents the number *of children per 1000 births bornwith malformations. Transverse striated bar-graph represents the number of children per1000 births born with more than one malformation. Vertical striated bar-graph representstotal malformations per 1000 births.

Since rain water itself is inert and harmless, andcannot be regarded as the factor producing fetalmaldevelopment, a search for other related factorswas extended into other scientific fields. In thisrespect it was recalled that Wiles2 reported thatmany plants in Canada have a specific affinity forcertain minerals during their growth. Many plantscontain so much cesium-137 that they give a highcounting rate on prospectors' portable Geigercounters. Because these instruments are not suffi-ciently sensitive to other types of radiation, theydo not distinguish between the y rays emitted byuranium and those emitted by other radioactivey-emitters. In this respect Wiles commented:"Certainly it is important to note that radioactivity

during or after a rain or snowstorm is to be viewed(by the prospector) with suspicion and may welldisappear when the rain or snow runs off. Further-more, radioactivity which appears only on the sur-face and does not persist to a depth of more thana few inches, is more than likely attributable tofallout."The most recent publication3 of the United

Nations Scientific Committee reporting on atomicradiation states: "Although more information is re-quired before firm conclusions can be drawn, thereis evidence indicating that embryos are more sus-ceptible to radiation injury than adults, and evenlow doses may induce both developmental disordersand malignant changes in embryos. Further studies

Canad. Med. Ass. J.July 20, 1963, vol. 89

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LE VANN: CONGENITAL ABNORMALITIES 125

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Fig. 2a.-Total congenital malformations per 1000 births for the three largest cities inAlberta. Fig. 2b.-Average precipitation (snow and rainfall) for 1960-1961 in Alberta.

on the effects of radiation on fetuses exposed inutero are therefore crucial."Among the variety of man-made isotopes pro-

duced in increasing amounts as a result of the largenumber of above-ground explosions of thermo-nuclear devices are certain isotopes which, by vir-tue of their long half-life, present serious biologicalhazards. Of these, strontium-90, cesium-137 andcerium-144 are particularly dangerous. The affinityof strontium-90 for calcium is well known. Cesiumhas the ability to act as an active metabolite in

cellular metabolism, behaving in much the sameway as potassium. These elements and cerium arestrong gamma emitters.Because of their long half-lives, these isotopes

(strontium-90, 28 years; cesium-137, 33 years, andcerium-144, 282 years) represent a great radiationhazard. It is not unreasonable to assume that anyfurther atomic or thermonuclear explosions carriedout above ground will add these isotopes to thestratosphere from whence they can re-enter theatmosphere. They will be carried to earth by

126 LE VANN: CONGENITAL ABNORMALITIES Canad. Med. Ass. J.July 20, 1963, vol. 89

clouds, rain and snow and will increase the presentgenetic hazard.The Department of National Health and Welfare

is aware of this danger and has recently started totest previous and present samplings of precipitationand other substances in order to determine thepresence of cesium-137. The Department has beenmost co-operative in making available to us all ofthe information in their possession that is pertinentto this study.

DISCUSSION

During this survey, the only constant factorsrecognized to have a relationship to abnormal birthswere (1) the geographic area where the childwas born and (2) the precipitation levels of thatarea. The hypothesis is advanced that because ofthe higher levels of rainfall in 1961 and its con-tamination by radioactive dust, more babies mayhave been subjected to dangerous man-made radio-active elements in utero. Births in 1962 .vill, if ourprojection is valid, show even higher rates of ab-normalities per 1000 births because of an increasedconcentration of radioactive dust in the strato-sphere, the result of intensive above-ground ex-plosions in the Soviet Arctic and sub-Arcticthroughout 1959 and 1962.

Further investigation along the lines suggestedby this hypothesis may be impeded by the reaction,within the profession and among the general public,to the sensational treatment given to this compli-cated subject in the popular press. For example, oncertain occasions the author encountered some re-ticence on the part of the patient's doctor whenhe was asked for information about the patient'singestion of certain drugs. Although the fact ofthe child's deformity, the date of birth and thearea of birth were recorded, some physicians re-fused to give any information concerning the medi-cations that had been prescribed for their patients.They gave as the reason for this refusal the "badpublicity" that might arise.Comparable studies on the incidence of con-

genital malformations in our other provinces shouldbe carried out, so that more extensive comparisonscan be made. Sequential (yearly) studies wouldalso help to establish trends occurring in the inci-dence of congenital abnormalities. It is a matter ofregret that long-range studies, such as were con-ducted in Birmingham, England,' have not yetbeen carried out in Canada.

In Canada, studies of this nature are made moredifficult because most Provincial Committees onPerinatal Mortality do not yet list all physical mal-formations on their questionnaires, but confine theirrecords to those inimical to the life of the child.

It is recommended that every birth record shouldincorporate a tabulation of all the physical ab-normalities of the child and that a Central Prov-incial Register of these anomalies be maintained.A suitable form for this information should ac-

company all initial requests for birth registration.With modern recording methods such as microfilm-ing, the difficulties experienced previously in carry-ing out projects of this sort should be largely over-come.

SUMMARY

The incidence of congenital malformations in chil-dren born in Alberta in 19(31 was 13.8 per 1000 births;this was considerably higher than in 1959 (7.6 per1000 births).The ingestion of drugs by the mother during preg-

nancy does not appear to have made any regular contri-bution to these malformations.The direct association between geographic location,

high precipitation levels, and the incidence of con-genital malformations appears to have 'been established.

More complete birth records should be kept by allprovinces so that a continuing study of the incidenceof congenital malformations can be carried out forsequential years, to identify whatever genetic hazardsmay exist.

The author would like to extend thanks to the Honour-able Dr. J. Donovan Ross, Minister of Health for theProvince of Alberta, who suggested the initial study in1960; Dr. Randall R. MacLean, Director of the Divisionof Mental Health for the Province of Alberta, who actedin a consultant capacity on many occasions; Dr. W. B.Parsons, who read the manuscript and made many valuablesuggestions; Dr. S. Orford Smith, who was responsible fororganizing the mathematical work which included standarderrors as well as the statistical confidence levels; and Mrs.Gail Blades who, in the capacity of research assistant,worked assiduously on the many statistical tables andcharts to advance the completion of this study by severalmonths.

REFERENCES

1. Ciba Foundation for the Promotion of International co-operation in Medical and Chemical Research: CibaFoundation Symposium on congenital malformations,edited by Ciba Foundation, by G. E. W. Woistenholmeand C. M. O'Connor, J. & A. Churchill, Ltd., London,1960.

2. WILEs. D. R.: Canadian Mining Journal, 81: 61, May1960.

3. Unitea Nations, Secretariat: Report of the United NationsScientific Committee on the effects of atomic radiation,General Assembly Official Records. Seventeenth session,supplement No. 16 (A/5216), 1962.

PAGES OUT OF THE PAST: FROMTHE JOURNAL OF FIFTY YEARS AGO

The great physician and surgeon must depend for hisdiagnosis upon the physical examination and the evidencehe extracts, sifts, and weighs in the patient's history.Laboratory methods are of only occasional use, viz, tosupport or not support clinical findings . . It is hopelesslyfutile to attempt anything more than the most elementaryteaching in the primary subjects of medicine today. Thetried-out subjects of the ages, anatomy, physiology, andchemistry, should have preference as to the length of in-struction hours. A student's most precious possessions arehis time, his vitality, and a clear mind at the age when themind is most supple, its curiosity most alert, and its naturemost impressionable. It is only by cutting down the timeallotted to laboratory subjects that we will be able to finda place to instruct students in all the physical, mental, andnutritional forms of healing. It is high time that there wasa readjustment of the programme, and a place, if not aprofessorship, given to these important subjects.-H. A.McCallum: President's Address to The Canadian MedicalAssociation, London, Ont., June 1913; Canad. Med. Ass. I.,3: 548, 1913.