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Saturday 3 November 1984

OBSTETRIC ULTRASOUND AND CHILDHOODMALIGNANCIES

L. M. KINNIER WILSON J. A. H. WATERHOUSE

Cancer Epidemiology Research Unit, Queen Elizabeth MedicalCentre, Birmingham B15 2TH

Summary The mothers of 1731 children who died ofcancer in the United Kingdom between

1972 and 1981, together with the mothers of 1731 matchedcontrols, were asked about exposure to diagnostic ultrasoundduring the relevant pregnancy. The claims of 103 casemothers and 103 control mothers were verified by hospitalrecords. Exposure to ultrasound in utero did not differbetween cancer and control children. It is concluded thatultrasound is safe as regards the risk of cancer and leukaemia.The observed difference between cases and controls exposedduring the earlier years of ultrasound use may be due to theselective application of this technique to abnormal

pregnancies at that time.

Introduction

ULTRASOUND produces adverse biological effects in vivoand in vitro both thermally and by cavitation. In pregnantmice and rats these effects include weight reduction andreduced litter size,’ delayed neuromuscular development,altered emotional behaviour, and fetal abnormalities.’ Cellsin suspension undergo changes in appearance and motilitywhen exposed to ultrasound. These changes includealterations in DNA, unscheduled DNA synthesis, and in-vitro morphological transformation;2 a rise in sisterchromatid exchanges;3 and morphological changes in thesurface membrane of cultured cells.4 In most of the

experiments higher doses were used for longer periods thanthe normal doses used in human diagnostic ultrasound.There is also some evidence of increased fragility in theerythrocytes of women continuously exposed to Dopplerultrasound monitoring for more than 7 h.5Early epidemiological studies of possible hazards to the

human fetus from diagnostic ultrasound were directed todiscovering effects on abortion rates, premature births, andcongenital deformities and have so far failed to reveal anysuch effects.6,7 Two large prospective epidemiologicalstudies are continuing. One in Canada, begun in 1975, is

following 10 000 women and their children and 2000controls for evidence of altered risk of fetal death,

abnormalities, familial disorders, and cancer; and

preliminary results are reassuring.8 The second study, inDenver, has investigated 425 children exposed to diagnosticultrasound and 381 matched controls for adverse effects atbirth and for effects on hearing, visual acuity, cognitivefunction, and behaviour at age 7-12 years.9 No significantdifferences between exposed and unexposed children werefound. However, because childhood cancers are rare, neitherof these investigations is sensitive enough to detect changes inthe incidence of these diseases. We have looked instead at the

exposure of children with cancer to diagnostic ultrasound inutero.

Methods

The Oxford Survey of Childhood Cancers (OSCC) is a

retrospective study of children who died of cancer and leukaemia inthe United Kingdom during the past 30 ears and of living controlsmatched for sex, age, and locality. Records of the use ofultrasound during the relevant pregnancy have been collected fromcase and control mothers and confirmed through reference togeneral practitioners and hospital records. Information collected bythe OSCC should therefore reveal whether there is any relationshipbetween obstetric ultrasound and childhood cancers.The use of diagnostic ultrasound was initiated in the United

Kingdom about 1970 but has been widely used only since 1975. TheOSCC first included questions on ultrasound to mothers andhospitals, for children who died in 1972. The longest intervalbetween exposure and death in this study is 9 years, and the numberof children at risk of cancer for 6 years following exposure is stillrelatively small. Both diagnostic pulsed ultrasound and continuous-wave Doppler ultrasound used for monitoring during labour havebeen included in this study. Details of dosage, timing of exposures,and types of machine used were noted, but no difference hasemerged here between case and control mothers.

Results and Discussion

Table I shows numbers and percentage of ultrasound

investigations claimed by case and control mothers and thenumbers and percentage verified by contemporary records,by year of birth of the child, together with total numberssurveyed. These figures relate to children who were bornbetween 1970 and 1980 and who died between 1972 and 1981

(though figures for the final year are not yet complete). TableI shows the increasing use of ultrasonic tests during the studyperiod. Table 11 shows the number of claims and verifiedclaims by case and control mothers by age at death of the casechild and also by diagnosis (leukaemia or solid tumour). Onlyin the figures relating to children aged over 6 years at the time

998

TABLE I-OBSTETRIC ULTRASOUND USE BY YEAR OF BIRTH

TABLE 11-OBSTETRIC ULTRASOUND USE BY DIAGNOSTIC CATEGORY AND AGE AT DEATH

*All cases and controls were born between 1970 and 1980 and all cases died between 1972 and 1981.

of death is there any noteworthy difference between cases (14)and controls (4, but 1 happened also to be a control matchedto 1 of the cases); ie, with relative risk of 4 ° 33 (95%confidence limits 1’ 38 to 13. 58).Table III shows the percentage of all children who had

confirmation of ultrasound and estimates for relative risk. Forall ages together approximately 6% of both cases and controlshad ultrasound exposure. Leukaemia and solid tumours are

compared with controls to provide estimates of relative riskand to permit comparison in this respect between theleukaemias and solid tumours. There is virtually no

difference between these diagnostic categories except in theoldest age group; here both ratios are raised and the ratio forleukaemia is higher than that for solid tumours.We conclude that diagnostic ultrasound is safe with regardto the risk of cancer and leukaemia between birth and the 6th

year of life but that an unresolved question remains regardingonsets and deaths after this age. It is possible that ultrasoundin the older children carried out in the earlier years was

selectively related to abnormal pregnancies, to which other

TABLE III-TESTS OF CASE/CONTROL DIFFERENCES

*Equivalent to relative risk.

cancer hazards, such as radiation, might be attached. 6 of the14 case children over 6 years but none of the 4 controls hadalso had obstetric X-rays taken; there were 3 twin birthsamong the cases to none in the controls; 3 cases with

congenital defects to none in the controls; and 6 difficultbirths leading to forceps delivery or caesarean section amongthe cases to only 1 in the controls. 8 case mothers were agedover 30 (mean age 30 - 2), and no control mothers were over 30(mean age 22-3).These findings of slight case preponderance among the

children who were exposed in the early 1970s have not beencorroborated by the Inter-Regional Epidemiological Study ofChildhood Cancers (IRESCC)." The difference may be dueto the fact that that study is confined to three large regions,whereas the present study (though by no means

comprehensive) draws cases and controls from all areas of theUnited Kingdom, including many centres where ultrasoundis rarely used. Our study may have collected a larger numberof cases which were selected for abnormal pregnancies, asdescribed above. Data for the onsets and deaths during thenext 5-10 years, based on ultrasound exposures incurred onless selective clinical criteria, might resolve the issue. Wemust certainly hope so because, in the longer term, universaluse might deprive us altogether of the necessary comparativebasis for attacking the question.We thank Prof George Knox and Dr Alice Stewart for their help and advice

We also thank all the general practitioners, hospital consultants, and health-authority personnel who have supported the survey for many years. This workwas supported by a contract with the Bureau of Radiological Health, Food andDrug Administration, USA, contract number 223/78/6017, and a grant fromthe Medical Research Council.

Correspondence should be addressed to J. A. H. W.

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L. M. KINNIER WILSON AND J. A. H. WATERHOUSE: REFERENCES

1 Stratmeyer ME. Research in ultrasound bioeffects: A public health view. Birth Fam J1980; 7: 92-100.

2 Liebskind D, Bases R, Elequin F, et al. Diagnostic ultrasound Effects on the DNA andgrowth patterns of animal cells. Radiology 1979; 131: 177-84.

3 Liebskind D, Bases R, Mendes F, et al Sister chromatid exchanges in humanlymphocytes after exposure to diagnostic ultrasound. Science 1975; 205: 1273-75.

4 Liebskind D, Bases R, Koenigsberg M, et al. Morphological changes in the surfacecharacteristics of cultured cells after exposure to diagnostic ultrasound. Radiology1981; 138: 419-23.

5 Bause GS, Niebyl JR, Sanders RC. Doppler ultrasound and maternal erythrocytefragility. Obstet Gynaecol 1983, 62: 7.

6 Bernstine RL. Safety studies with ultrasonic doppler technique. Obstet Gynaecol 1969;34: 704-09.

7 Hellman LM, Duffus GM, Donald I, et al. Safety of diagnostic ultrasound in obstetrics.Lancet 1970; i: 1133-35.

8 Bolsen B Question of risk still hovers over routine prenatal use of ultrasound JAMA1982, 247: 2195-97.

9 Stark CR, Orleans M, Haverkamp AD, et al. Short and long-term risks after exposure todiagnostic ultrasound in utero Obstet Gynaecol 1984, 63: 194.

10 Stewart AM, Webb J, Hewitt D. A survey of childhood malignancies. Br Med J 1958, i:1495

11 Cartwright RA, McKinney PA, Hopton PA, Birch JM, Hartley AL, Mann JR,Waterhouse JAH, Johnston HE, Draper GJ, Stiller C. Ultrasound examinations in

pregnancy and childhood cancer. Lancet 1984; ii: 999-1000

ULTRASOUND EXAMINATIONS IN PREGNANCYAND CHILDHOOD CANCER

R. A. CARTWRIGHT P. A. MCKINNEYP. A. HOPTON

Department of Epidemiology, Yorkshire Regional CancerOrganisation, Cookridge Hospital, Leeds LS16 6QB

J. M. BIRCH A. L. HARTLEY

Department of Epidemiology and Social Research, Christie Hospitaland Halt Radium Institute, Manchester M20 9BX

J. R. MANNChildren’s Hospital, Ladywood Middleway, Ladywood, Birmingham

B16 8ET

J. A. H. WATERHOUSE H. E. JOHNSTONWest Midlands Cancer Registry, Queen Elizabeth Medical Centre,

Birmingham B15 2TH

G. J. DRAPER C. STILLER

University of Oxford Childhood Cancer Research Group, RadcliffeInfirmary, Oxford OX2 6HE

FOR THE INTER-REGIONAL EPIDEMIOLOGICAL STUDY OFCHILDHOOD CANCER GROUP*

Summary Analysis of information obtained in an inter-regional epidemiological study by

interviewing the parents of 555 children with malignancydiagnosed between 1980 to 1983 and the parents of 1110control children did not reveal any significant associationbetween exposure to ultrasound examination in pregnancyand risk of childhood cancer.

Introduction

CONCERN has been expressed in the media that there maybe an association between imaging ultrasonography duringpregnancy and a subsequent increased risk of malignantdisease in the examined fetus. This suggestion is based onexperimental evidence from in-vitro studies,’ I for

*0ther members of the IRESCC Group: Dr C. C. Bailey, Dr A. H. Cameron,Dr R. H. A. Campbell, Dr S. C. Cartwright, Mr J. J. Corkery, Dr D. Deakin,Mr P. Gornall, Dr H. B. Marsden, Dr P. H. Morris Jones, Dr D. Pearson, A4rR. Swindell, and Mrs J. Williams.

TABLE I-ULTRASOLTND SCANS IN PREGNANCY

epidemiological studies have indicated that prenatalultrasound has no measurable biological effect.2 The presentreport describes the preliminary results of an inter-regionalepidemiological study of childhood cancer with regard toin-utero ultrasound exposure.

Methods

Between 1980 and 1983 members of the Inter-regionalEpidemiological Study of Childhood Cancers (IRESCC), based inBirmingham, Leeds, and Manchester, interviewed parents ofchildren with newly diagnosed cancer on a wide range of topics,many associated with events during the index pregnancy. Identicalquestions were asked of two sets of parents of control childrenwithout malignant disease, of the same sex and age, chosen fromhospital admissions and general-practitioner lists. Medicalinformation obtained at interview was confirmed whenever possibleby cross-checking with NHS records.The study contains information on 555 cases, each with two

matched controls. The cases represent the full range of childhood

malignant disease, the single largest group being the acute

lymphoblastic leukaemias (ALL) (149 cases), followed by central-nervous-system tumours (CNS) (77 cases).We present here the results of an initial analysis of the effects of

antenatal diagnositic pulsed ultrasound based on data frominterview reports confirmed by medical/obstetric records.

Results

There was little difference between cases and controls in

the number of children exposed to ultrasound in utero(26% cases, 27% controls) or in the number of examinations(table I).The proportion of women scanned rose steeply from 3%

(cases) and 2% (controls) in 1972 and before to 70% (cases)and 79% (controls) in (table II).The age of the case child at diagnosis was the next factor to

be considered while allowing for. three diagnosticcategories-ALL, CNS, and "other malignancies". Theestimated relative risks are not significantly raised either forchildren aged 0-4 years at diagnosis or those diagnosed age 5years and above (table III). In fact, there appears to be asignificantly reduced risk for exposed children diagnosedbetween the ages 0 and 4 years in the "other malignancies"group, a finding that is difficult to explain.The risk ofultrasonography in pregnancy was examined by

comparing children who received one or more scans withthose who received none, by means of a matched-triplet case-control analysis, allowing for the three diagnostic categoriesof cases. The estimated relative risks were not significantlydifferent from unity for any of these groups (table IV).