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Chatter I! THE PLAN WITH the considerations outlined in Chapter I in mind, a plan of attack on the problem was developed which will now be described. 2.1 Pregrzarzcy registration;.-As mentioned earlier, in the post-war years the ration system in Japan was such that pregnant women upon registration of their pregnancy following the completion of the fifth month of gestation could thereby acquire access to certain rationed items. With the cooperation of the city administrators of Hiroshima, Nagasaki, and Kure (a control city), a system was instituted whereby at the time of her registration at the city hall (or dis- trict office) for ration purposes, each pregnant woman or her representative in these three cities completed the first two-thirds of a questionnaire which included such items as identifying in- formation, a brief radiation history of the hus- band and wife, a short summary of the past reproductive performance, and pertinent details concerning the present pregnancy. In the ma- jority of instances the informant for this ques- tionnaire was the pregnant woman herself. Only rarely were both parents available. Accordingly the radiation information on this questionnaire tended to be more reliable for the wife than the husband (cf. Sec. 4.6~. Figure 2.1 is an English translation of this questionnaire, which will be referred to as the "Genetics Short Form." This questionnaire was administered by trained clerks who occupied a special office in the city hall (or district office). The actual collection of data began in Hiro- shima in February, 1948; in Kure in March, 1948; and in Nagasaki in July, 1948. The ques- tionnaire was filled out in duplicate; the original was then given the registrant, while the Com- mission retained the copy. At the time of termination of the pregnancy, the midwife or physician in attendance completed the question- naire by answering certain questions pertaining to the characteristics of the child and delivery. 5 More specifically, information was requested on the following possible indicators of a genetic difference between the children of control and irradiated parents: sex, birthweight, stillbirth, and presence of malformation. In case there was an abnormal termination (e.g., stillbirth, mal- formation), the midwife informed the Com- mission by telephone as soon as possible. If the outcome appeared normal, the questionnaire was held by the midwife until collected by a Commission clerk. Such collections were at first at weekly and later twice weekly intervals. Re- gardless of the type of termination, a Japanese physician in the employ of the Commission or the Japanese National Institute of Health called to examine the child at once, if there was a report of an abnormal termination, or on a somewhat more leisurely schedule if the termination was reported as normal. Midwives received a small fee for each questionnaire they completed. Because of this lag between birth, questionnaire collection, and examination by a physician, it was also possible to obtain rather complete information concerning death during the first 7 days post partum, hereafter referred to as neonatal death. The cooperation both of the mother and of the midwife in this study was of course entirely voluntary. An attempt was made at the time of pregnancy registration to explain the rudiments of the program to the registrants, and, in addi- tion, each mother was given a brief printed description of the program. Figure 2.2 is a translation of this description. Numerous meet- ings were held with the Midwives' Associations of the cities to explain the program and answer questions. Attendance at the meetings was usu- ally excellent, although, the Japanese birth rate being what it was, apt to diminish appreciably between the opening and closing of any given meeting. Approximately a year and a half after the

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6 Genetic Ejec's of Atomic Bombs Chapter II INVESTIGATION SHEET FOR BIRTHS AFTER ATOM BOMB PRINTING OF JULY, 1949 1. Name of city and investigation sheet number 00~000 2. Day, month, and year of registration 3. Expected date of birthO Husband 4. Name (Maiden name in case of wife) 5. Birth dates of husband and wife Age (exact number of g. years and months) Present in Hiroshima or Nagasaki at time of bombing Location at time of bombing (street and number) Distance from hypocenter Indoors 11. Type of building 12. Did you have or not have subcutaneous bleeding- Did you have or not have gingivitis 14. Did you have or not have bloody diarrhea 15. Did you have or not have epilation 16. Did you have or not have fever 17. Did you have or not have burns Wife ~0 00 A a 3 18. Did you have or not have external injuries Date, month, and year of beginning cohabitation Number of months interruption of cohabitation Total number of months cohabitationOOO Number of months cohabitation before August, 1945_C}OO Number of pregnancies before August, 1945ON Number of spontaneous stillbirths before August, 1945O Number of therapeutic abortions before August, 1945O Number of months cohabitation after August, 1945MOO Number of pregnancies after August, 1945 (including present)_ON Number of spontaneous stillbirths after August, 1945 Number of therapeutic abortions after August, 1945a Total number of pregnanciesON Total number of spontaneous stillbirthsO Total number of therapeutic abortionsO Marriage of blood relations (first cousin, one and one-half cousins, second cousins, etc.)O Present address and occupation of husband Day, month, and year of beginning of last menstrual period of wife Day, month, and year of birth expectation (according to calculation sheet) Present month of pregnancy Day, month, and year of termination of birthL:O Number of weeks of pregnancyNO 40. Course of labor: Spontaneous Induced Duration Use of instruments _ ~C:I Live birth after 38 Premature birth under and or more weeks including 38th week Stillbirth 21-29 weeks Stillbirth after 38 weeks 41. Condition of newborn: Miscarriage 20 weeks or under- Stillbirth 30-38 weeks -A

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The Plan 42. Multiple birth (2, 3, etc.) Order of birth O 43. Sex of newborn 44. Weight (grms.) O BOW 45. Presence or absence of malformation 46. Type of malformation (give details) c :1100~°~ 47. Date of death of newborn child ,OO 48. Date of termination of any pregnancies after January, 19480 49. Remarks 50. Name and address of attendant at birth FIGURE 2.1-English translation of the Japanese-language "Genetics Short Form." program went into operation, an attempt was made to ascertain what proportion of births in Hiroshima were to mothers registered in the Genetics Program, i.e., to determine the com- pleteness of our pregnancy registration. Inas- much as studies by the Public Health and Wel- fare Section, GHQ, SCAP (Mr. L. V. Phelps) had revealed that the official Japanese registra- tion of births by place of occurrence during the period of this study was quite complete, it was felt that the most valid (as well as convenient) approach to this evaluation would be to com- pare the number of terminations recorded by the Genetics Program each month with the number officially registered in the city. The comparison follows: 1948 August ........... September .... October ..... November .... December .... 1949 January . . February March . . . April .... May .... June .... July ......... August . . September . .. . City ABCC % 713 653 91.6 723 674 93.2 602 614 102.0 625 596 95.4 555 577 104.0 1,001 914 759 703 740 675 719 630 707 634 728 711 826 759 762 703 740 685 10,200 9,528 93.4 Percentages greater than 100 are probably best explained by changing city boundaries and iThe actual figures for registration of live births during the years 1948, 1949, and 1950 are 98.1~o, 98.8~o, and 98.9% respectively, while for stillbirths the corresponding figures were 98.7%, 99.4%, and 99.4~% (cf. Public Health & Welfare in Japan, 1948, 1949, 1950, by Public Health & Welfare Section, GHQ, SCAP). monthly carry-overs, especially in the case of the December, 1948 figure, because of the Japa nese custom of delaying registration on a child born in late December. Assuming that termina tions known to the ABCC were also known to the city, this indicates that approximately 7 per cent of the births occurring in the city were to mothers not registered with the Genetics Pro gram. A large proportion of these births to parents not registered with the Genetics Program of the ABCC subsequently came to the attention of the Program in the following two ways: (1) At the time of registration of the birth with the city, the city clerks routinely inquired if the pregnancy was known to the ABCC, and if not, directed the registrant to the Genetics Program offices in the city hall. (2) Private doctors and midwives frequently reported the names of all women whom they attended who were not registered with the Genetics Program. Births coming to the attention of the Program through these channels were placed in an "Unregistered 9~ 3 Series." From time to time, in an effort to im 92 6 prove the coverage of the Program, the reasons 9~.2 were investigated for the failure of the preg 87.6 nancies resulting in these births to be included 897 in the routine registration. One of the more 97179 complete investigations of this type was carried 92 3 out in Hiroshima in October of 1952 and dealt 92 6 with 147 unregistered births occurring in the period of June through September of that year. The reasons for not registering given by the mothers of these 147 children were as follows: Reason for failing to register No. Arrived in city just prior to birth of child. . 20 2. Registered pregnancy at city hall, but failed to visit ABCC office there....... ....... 37 3. Failed to register either with city for ration purposes or with ABCC, although in town during pregnancy Too busy .... Forgot ...... 23 19

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8 First seen by mld~lfe late In pregnant; felt registration wasn't ~ortb bother lng Huh 5 Requested someone else to ranter; that person faded to do so 17 Too hick to reg~ter 4 DldnT know about regl~rabon 12 4. M~ceHaneous causes 10 fir ~ ~/ Or ~ Onto II dlRerences in city admlnlstratlon practices, the percentage of unregistered births was Clays less in Nagasaki tbaD in Hiroshima. The guestlon naturally arose as to imbiber the information collected concerning Bolstered blabs should also be ~t~lned for these unr~- tered births, foll~lng ~bicb the two sets of 47 data would, for analytlca1 purposes, be com TR^NSC^TION Of P^~PHteT D~TRIBuTeD AT THE AGE Of PREGN^NCY ReGISTR^TlON 0 611 Prospe~lve Moths: The ABCC teas ~ request to make of all prospective mothers. I presume you are famlllar with the research project of the ABCC. The AmerlcaR and Japanese doctors work together In ~lvln~ physlca1 exam- lnabons to aU babies born In Hhoshlm~ Ku~ =d ~t and cooperate In call on other shellac researches. Me hope that those who hue encountered the bomb and also those who brave not ~111 respond to our program. ~ comparative study of the pbyslca1 conditions of the persons hobo experienced the bomb and persons go did not loses the sde~lEc aced of our Bump. Ruben you register your pregnant at the cay once AN you kindly 611 out ~ quesHonnalre for ABCC? Our representative ~111 ask you questions and 61I out the queshonnalre You need not be worried about the quesdonnalre for ~ contalos only quetlons ~ncernlng your expected bay, name of par~t`~bl~bdates, date of marclage and history of exposure to the atomic bomb. If you bee any questions to ask, our representative ~1 be happy to assist you. Ibe form, on ~ Bate sheet blab you gin be asked to take home Alto you, MU be filled out by your a~endlng mld~lfe or donor and returned to ABCC. ~hbln ~ month after delved an ABCC donor MU caU on you and make ~ physlca1 examlnabon of your baby. (If unfortunately your pregnant terminates in abortion, sUllbl~b, or any other abnormaUty, an ABCC doctor gin also can on you.) By this =amlnatlon you AH be able to know your baby true physlca1 condlbon and at the same time you AH be making an important contHbutlon to medlca1 science. In the ABCC chnlc the most mourn X-ray Ad other medlca1 equlpm~t are file if Be necessl~ of ~ tboroupb examlnabon of your baby ~ found necessary. In such cases the ABCC ~lHcaH for you and bring you and your bay to the cholc. Abe results of the examlnatlons are stclcHy co~dentla1 but if you desire tam may ~ Callable to your family doctor. All s~lces are performed free of ~e. MOTE: 1. Regardless of Nether or not you experienced the atomic bomb, ~hetber your pregnancy terminates In abortion or stlllbirtb, your cooperation ~111 be appreciated. 2. Please preserve the quesHonnalre that you mere asked to take home and brave the attending Life or doctor 511 ~ out after defied. If you lose the quesHonnalre it AD be issued to you again, if you ~111 present your Expectant other Notebook at the city once. 3. Please inform the ABCC If you change address at any time. Your kind coope~lon is requested In this medlca1 res~rcb program. figure 2.2 EnglLb translation of the Japanese!angiage pamphlet d~td~uted at the time of pregnant reglstrstlon. Reason (1) Spears to represent an uncle loophole in the program, but lnasmucb as mothers falling into this category as ~ rule mere unexposed, this does not represent ~ serious loss of data. Reason (~) also represents an un~old- abIe loophole in ~ program geared as this was to ~ dvlc function. Reason to), on the other hand, reoriented an unnecessary loss of data Unhip could be and ~ resided), due for the most part to the fit that the city clerk failed to glut the reentrant to the ABCC once, either tbro~ forgetfulness or, in the case of new clerks, not o~lng tab this should be dam. Because of bleed. In ale of the extent to filch recent arrivals to the city enter into the co~osibon of He unregistered grog (20/147 in the pre- ceding analysis), it gas felt tab it would better not to combine the Ho series, men tbou~b this involved the loss of ~ certain amount of badly needed data. As mentioned earlier, it gas not necessary that the pregnant Amen ranter in person, ~ bell possible for her designated Restive to ranter for her. ID approximately 4 per cent of all registrations, neither the prospective mother nor the fiber Speared at the city baU,

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The Plan the registration being carried out by some third party. Such individuals of course were unable to answer many of the items on the question- naire. In these instances, a clerk was sent to the home to obtain the necessary data. 2.2 Special studies or; abrzormo~l terminations. In the event that a pregnancy terminated ab- normally, as in a stillbirth or a child with a congenital malformation, a supplementary ques- tionnaire was completed in the patient's home by a doctor in the employ of the ABCC. This ques- tionnaire covered in some detail gynecologic history, maternal disease during pregnancy, past reproductive performance, and economic status. The actual questionnaire is reproduced in Fig- ure 2.3 and will be referred to as the "Genetics Long Form." In addition, in the case of ab- normal terminations, blood was obtained from the mother for a serological test for the presence of syphilis. If the physician charged with completing the supplemental questionnaire encountered an un- usual abnormality, or one concerning whose nature he was unsure, he could, if the parents were willing, arrange for the child to be seen by an American-national pediatrician at the ABCC headquarters, for such diagnostic studies as seemed necessary, as well as photographic documentation of the case. The Japanese physicians concerned with the home examination of these infants were for the most part recent medical school graduates. Many of them were employed on a half-time basis, the remainder of their time being devoted to hospital duties. Each of these men, before he was sent out on home calls, received instruc- tion in the systematic examination of the new- born infant. In addition, from time to time lectures were given on the recognition of the more common congenital abnormalities. Be- tween 30 and 40 full or part-time physicians were employed in this capacity at any one time. For a variety of reasons, personnel turn-over was at first relatively high; this necessitated a constant training program. 2.3 The "10-percent sample." Each woman as she registered received a registration num- ber for her pregnancy, these being assigned in sequence and without respect to radiation history. For every tenth registration, which is to say, all registrations for which the terminal digit in the registration number was zero, the same supplemental questionnaire just described 9 in connection with abnormal terminations was completed in the home. A serological test for syphilis was also carried out on the mother of every tenth termination. In this way a 10 per cent sample was obtained with which to supple- ment the information obtained on the original questionnaire concerning the comparability of control and irradiated parents. In addition, in- formation was obtained of value in analyzing the causation of abnormal pregnancy terminations. 2.4 The accuracy arid reproducibility of the ar~amr~estic data obtained on the Genetics Short Form arid the Genetics Long Form.-The in- formation accumulated in the course of this study is of two types: anamnestic, and observa- tional. The accuracy of both types of informa- tion was of course a matter of vital concern. During the period covered by this investigation, many women in the study cities had several pregnancies. Each pregnancy of a given woman was registered independently of any others. Discrepancies in the answers to particular ques- tions in the course of multiple registrations by a given woman provide some insight into the reliability of the material. In addition, because of overlaps in the various segments of the ABCC program, the same information might be obtained independently in different studies. The information obtained on the Genetics Short Form is of three main types: (1) radia- tion history, (2) history of past reproductive performance, and (3) observations by midwives and physicians on the outcome of the current pregnancy. The reliability of information of types (1) and (3) will be examined in detail in Chapters IV, VIII, IX, and X. The attempt to obtain information of type (2) was moti- vated by the possibility of detecting an increase in the proportion of abortions and miscarriages among conceptions occurring in the period im- mediately following the bombing. However, a preliminary analysis of repeat registrations by the same mother, in May of 1951, suggested that the error in the reporting of abortions and miscarriages was such that any attempt to utilize these data would be ill-advised. This study thus utilizes only direct observations col- lected under supervision during the years 1948- 1954. The material sought on the Genetics Long Form was collected with three purposes in mind: (1) the description in some detail of congenital defect, (2) the recording of certain

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Diagnosis: 10 Genetic Effects of Atomic Bombs Chapter II SPECIAL BIRTH QUESTIONNAIRE Date of investigation 1. Sex and full name of baby: M F (Ronzaj:, K``n~i, Fa,~gana) 2. Name of place of birth ; Home Hospital 4. Date of birth 5. Attendant at birth: Dr. Mw. Nan e: Address: Name of ir~vestigating Doctor 3. Questionnaire Number 1' 1 1 1 1 1 1 1 ' ;! 4 ., ~ fi. Diagnosis of defects of child and details: Mm. Sun. Blood then Y N Birth weight Gms. Birth length In. Seen by ABCC doctor Y N Specimen taken Y N CircuTr~ferer.ce: Head In. Chest In. Photo or X-ray taken Y N [] sac 1-1 1 1 1-1 1 °7 °S °9 -0 .t ,.2 [ 1 1~ 1 ,. 1 1 1 .^,X ,^~. .^, ~:' ~:'.7 .~S 1 ..9 1 40 1 411 42 1 4,, 1 44 1 7. Place of death: Age: NEONATAL I I I Ilome Hospital I I 45 4~; a. Attendant at death: Dr. Mw. Name: Address: 9. Autopsy: Yes No- Unknown Place of autopsy 3.nd Doctors name: Poe 1 of 2 p.nges Date: ABCC Form No. GE~'-2 (OCT 50 R3) BIRTH QUESTIONNAIRE FIGURE 2.3 The Genetics "Long Form." Explanation in text.

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The Plan 10. Nan~e of father: (Ron,aji, Kanji, Fvri,,gana) 12. Date of birth: 11. Address: 13. Ape: yes. mans. 14. Does the father have the same defect as this child? Yes No Unknown Details: Does the f:ttl~er have any ·,ther defect ? Details: ir ~To lJnknn~vn J)ces any of the father's relatives have the same defect as this child ? Details: Does any of the fatl~er's relatives haste any other ~lefect ? \' es Nc> IJnt;nown Details: 15. Blood relatiorusl~ip: I;3ther and brother Yes No Unknown Details: 16. Ecor.omic status of family Very Nor O'er 17. Hame of another: (}~n~a,,2i, Kan,,i, I Wry) 19. Date of birth: 21. Does the mother lI.3Ye the satire defect as this child ? Ves No Unknown Details: Does the metier have any other defect ? Details: 11 47 4S 48 Yes No Unknown Materr=1 (;rand~>arents Ares No Unknown Avenge U'ell-to~do Very rich Paternal (;randl~3rents Yes into Unknown 18. Address: . _ 20. Age: yrs. mans. Yes No Unknown l:>oes any of the mother's relatives haste the same defect as this child ? Yes Ad> Unknown Details: [toes any of the motherts relatives have any other defect? Details: Yes No Unknown 22. Menstruation: Age of onset Duration in days Interval in days 23. Irregularities menstruation: Yes To Unknown Details: FIGURE 2.3 Continued F561571~I 1 1 58 do ~1 ABCC Borne No. GEN-9 (OCT 50 R3) ElIRTH QUESTIONNAIRE

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12 Genetic Ejects of Atomic Bombs Chapter II 2` Pelvic ol>erations, diseases, or treatn~e.ats prior to >resent pregnancy: (Part~culcrly D& C) Yes Hame of host>. 8; Dr.: Date: Address of hosp. & Dr.: Details: RECORD OF THIS PREGNANCY pro Unkno`` n 63 "fi. (;ener31 diseases and sur~i=~1 o~cratio.as (particularly of afebrilc Arc): Yes Ho Vnkr~own Date: n Details: Fever: Onset Duration I;asl~: Yes Ho Unknown Details: "a. Uterine bleeding in the first six months of pregnancy: Yes No Unknown. Onset Hours of duration: 27. Prese;~tatlon of fetus At delivery: Occil>ut Face Breech Foot Arm Caesarean Unknown SEROLOGY 38. Mother: J. Infant: 30. Remarks: ! , . ~ DATE TEST RF,SUl,'! PLACE DATE ABCC ABCC ABCC ABCC ~ ~ ~ ~ ABCC TEST |RESULT! l WASSER MANN MURATA IDE HOKKEN MF,INICKE ., INDICATE; POSITIVE as DOUBTFUL as i NEGATIVE as - TEST RESULT PLACE DATE TFST RESULT| PLACE ~ DUSTS ABCC WASS}:: RMANN ABCC MURATA ABCC IDE . ABCC HOKKEN ABCC MEINICKE Page 2 of 2 >es FIGURE 2.3 Corzti?~ned ABCC Form No. GEN-2 (OCT 50 R3) BIRTH aUESrlONNAIRE

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14 Genetic Efects of Atomic Bombs Chapter II supplementary technical observations of possible pertinency to pregnancy outcome such as eco- nomic status and maternal luetic infection (as revealed by serological testing), and (3 ~ the re- cording of considerable background information of possible relevancy to the manner in which a given pregnancy terminated, with particular reference to the problem of congenital defect. This included a brief family history of both father and mother, a detailed reproductive his- tory of the mother, disease during pregnancy, etc. The reliability of the material collected under headings (1) and (2) will be discussed in Chapters V and VIII. The reliability of anam- nestic data mentioned under heading (3) will be briefly considered here. This material is in the strict sense not relevant to the problem of radiation effects, the questions having been in- troduced because of the opportunity of adding to existing knowledge concerning the etiology of congenital defect. Unfortunately, particularly with reference to the occurrence of congenital defect in other members of the family, several analyses have raised serious doubts as to whether these histories are of sufficient reliability for research purposes. There is in general less major congenital defect reported in family histories than would be expected on the basis of the ob- servations made during the course of this in- vestigation. This may in part be due to lack of information and forgetfulness, but is probably in no small measure due to the social stigma connected with congenital defect, and the conse- quent efforts to conceal it. 2.5 The autopsy program. As the over-all program of the ABCC developed, and particu- larly after a Department of Pathology was established, it became possible to initiate the performance of autopsies on deceased or still- born infants falling within the scope of the program. Because of the greater concentration of Commission personnel in Hiroshima than in Nagasaki, infant autopsies were begun in Hiroshima in December, 1948, but not in a methodical fashion in Nagasaki until several years later. A request to perform an autopsy was rou- tinely made of the parents of each stillborn infant and of each infant dying during the neonatal period coming to the attention of the Commission. If permission was granted, the contactor brought the cadaver to the ABCC pathology laboratory. A complete autopsy was performed in all cases save where maceration made this impossible. Photographs and X-rays were taken when indicated. A copy of each autopsy protocol was ultimately filed with the appropriate Genetics Long Form. The cadaver was then carried to a crematorium in an ABCC vehicle. Ashes were returned to the family in a suitable receptacle on request. Cost of the coffin and cremation fee were borne by the ABCC. When the autopsy program was well under way in the two cities, some 50 per cent of the total available material came to autopsy. For instance, an analysis of 300 consecutive regis- trations terminating in stillbirths or neonatal deaths, beginning January, 1950 in Hiroshima, revealed that out of the total of 311 infants in- volved, 158 (50.870) came to autopsy. Of the remaining 153, 46 (14.8~o) were seen by an ABCC physician but did not come to autopsy. There were 107 (34.4~o ~ who were not seen by an ABCC physician, and concerning whose ap- pearance at birth there is only the statement of the mother and attending midwife. This repre- sents the most serious potential loss of informa- tion in the entire program, since a certain amount of congenital malformation could well go unrecognized or concealed. However, these unexamined infants can introduce bias into the findings only if there is a difference in report- ing on the part of exposed and unexposed parents. We shall examine the latter possibility in Chapter XIII. 2.6.The collection of data on infants aged 9 rnor~ths. Japanese homes are not always well lighted and, because of their construction and the fuel shortage, are decidedly cold in winter. These conditions are not favorable for an adequate physical examination of a newborn child. The possibility had to be recognized that for these reasons, as well as diagnostic over- sights, some malformations were not being ob- served at birth. Furthermore, certain defects, such as congenital dislocation of the hip, spastic paraplegia, deafness, blindness, congenital heart disease, or mental defect are not always readily diagnosable at birth. Accordingly, in January of 1950, the earliest date at which the over-all development of the ABCC permitted such ac- tion, a program was inaugurated to bring into the central clinical facility at age 9 months as many of the children examined shortly after birth as possible, both as a check on diagnostic

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The Plan oversights at the time of the first examination and on supplementary diagnoses. Certain an- thropometric measurements were also obtained as an index of general physical development. Furthermore, because of the possible relation- ship between genetic damage and death during the neonatal period of infancy, information as to time and manner of death was obtained for deceased children. The age for this study was set at 9 months rather than, e.g., one year, because of the relative ease with which a 9- month-old infant may be examined. The form on which the data were recorded is reproduced as Figure 2.4, and will be referred to as the Genetics 9-Months Follow-up. Since it was not possible to conduct studies of all the babies examined at birth who were still alive 9 months later, a system of obtain- ing a random sample had to be set up. This was done by the simple expedient of calling in babies for examination according to the terminal registration digit of the pregnancy. Each month all babies with certain specified terminal regis- tration digits were seen, the number of children seen being regulated by the other demands on the clinical facility and the personnel available. In this fashion, a random 10, 20, 30, etc. per cent of the original group could be called in for examination. Parental cooperation was usu- ally excellent. Where a child who was included in the sample could not be examined, an attempt was made to establish why, in an effort to detect possible sources of bias. A comparison of the recorded findings on a series of infants examined shortly after birth and again at 9 months provides a check on both the clerical and medical efficiency of the pro- gram. Such a comparison was carried out in 1952, based on 4,578 pregnancy terminations studied at birth and followed up again at age 9 months in Hiroshima in 1951. The compari- son involved the findings coded on the IBM cards used for the final analysis (see below) rather than on a matching of the two original forms, since the IBM cards are of course the basis for the final tabulations. Particular atten- tion was directed towards the occurrence of across malformation in the two series. A total of 38 clerical errors came to light. Approximately half of these arose in the fol- lowing manner: a tentative diagnosis of major malformation made when a child was seen in the home was not confirmed when the child 15 was brought into the central facility for ex- amination a short time thereafter. When this same child was seen at age 9 months and the defect again not observed, this was erroneously coded as a refutation of an earlier diagnosis, when in fact no actual diagnosis had been reached. This error did not affect the actual analysis of the data. The other 20 clerical errors were of a more serious nature, involving for the most part an error in the use of the 6-digit code developed in connection with this study for the classification of congenital malformation. From the medical standpoint, the comparison of the two sets of records brought out the unre- liability, under the conditions of this study, of the diagnosis shortly after birth of congenital heart disease and congenital torticollis. This finding led to omitting these two diagnoses from the "at birth" data, although both were included in the "9 months" data.2 Excluding these two diagnoses, there were 48 instances of major defect listed among the 4,578 terminations studied shortly after birth. The follow-up ex- amination at age 9 months increased the number of diagnosed major defects (exclusive of con- genital heart disease) to 122. On the face of it, this amounts to a 154 per cent increase. How- ever, analysis of the data revealed that three diagnoses contributed disproportionately to the 9-months total, as follows: No. of times No. of times made on made on first second examination examination 26 22 19 Diagnosis Dysplasia of acetabulum 3 Pilonidal sinus 5 Inguinal hernia (females only). 5 13 67 Exclusive of these three diagnoses, there were 35 diagnoses of major defect at the time of the first examination (all confirmed later), as con- trasted to 55 at the second examination, an in- crease of 57 per cent. It was apparent from this that the 9-months examination not only served as a valuable check on the "at birth" program but significantly increased the amount of con- genital disease recognized in these children, although the bulk of this contribution was due 2 The diagnosis of congenital heart disease was based on one or more of the following criteria: per- sistent cyanosis, a grade III or IV apical systolic mur- mur, a precordial thrill, or cardiomegaly in the ab- sence of another adequate explanation.

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16 Genetic EJects of Atomic Bombs ATOMIC BOMB CASUALTY COMMISSION PeOl~TRIG FOLLOW-UP (Initial Record) | Kanji l Chapter II Gem . _ Master File Num her - Location: H O K ~ N O Exposed | | | Control O Day Month Year Sex: M ~ Fad Birth Date: Day Month Year (Era Year) Genetics pro. Dept. No. Address: Source of Info. l Year of Birth Reliability Narne (Romaji) Mother: Family History: Consanguinity Diseases: Date of Birth Health (G'F'p'D) Sex Date of Birth General Health (Good, Fair, Poor) (Good, Fair, Poor) Health (G,F,P,D) 1. Tuberculosis: 4. Venereal Disease: 2. Blood 5. Endocrine: . . , 3. Nervous: 6. Other: Mother:_ Prenatal Care Pregnancy Complications: ~'here Para Delivery Midwife, doctor, other) (normal, abnormal) Details if abnormal: Condition at birth (and first 14 days) (Good. Fair, Poor) Details if Poor: Birth Weight: Nutrition: Age Begun Terminated Illnesses: Breast hlilk Other Milk Solid foods 1. 2. 3. Vitamin Supplements: Motor DevetoPment: Sat (age in months) Walked Talked Remarks: Immunizations: Gravida No. Months Date Reaction History Taken By Examining Physician Ped Follow.Up I. FIGURE 2.4 The form used for recording pediatric information at age 9 months. Explanation in text.

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The Plan ATOMIC BOMB CASUALTY COMMISSION PEDIATRIC FOLLOW-UP (art - at 17 Aromas) Family none Given na:ne (Bsn,Il Naster tile no. Furleana) | location: }I ~ K ~ N O Exposed | | | Control O | Sex: M C F O Day Mooth Year l Day Month Yes. (Era Year) Age (mom) Dept. No. Birth Date: ., 1 Interval History: Bowel movements Feedir~gs per day . Vomiting or regurgitation Sleep _ . . i, I ~ Measurements: Weight | Ibs. oz. |1 Abdomen `~m' Height (cm) l l Pelvis (cm) Health (cm) l Chest (cm) Physical Examination: Temp: (O) (R) Pulse: . ~,)>,~,,,~ .,_ I'm;, .¢,>.~ >, 2 ~3~:~: ,'. : it: ~ I::: ~ :, ~ ~ ~ I:: : ~ :. : ~. ~ it:: : :~: ~ ~ ~ i: ~,~ :,~: ~ ~' ~::. ~:~:~:~:~ ~ ~.~:~'~'~:~'~,~.~'~'~'~.~:~: :~:~:~:~:~ ~:~'~ ~, :~ ::':'' ~:~ :~,~':~':':~ Teeth: Present (X) Erupting (O) Right Left ~ ~v ~ m ~I I 1 ~m ~_| . 1 Motor Development: (good, fair, poor) Muscles: (good, fair, poor) Subcutaneous tissues: (good fair, poor) , , Menu 1 : Laboratory" _(X) Examination Completed; (A) Abnormal Finding i. - Hematology Urine l Serology l Stool -is l X-ray (hand) X-ray (chest) : ~- Remarks: _ 1 Examining Physician ABCC Fonn No. PED-6 (FEB 51) PED FOLLOWER INr. FIGURE 2.4 Con cl ad ed

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18 Genetic Effects of Atomic Bombs Chapter II to a relatively few diagnoses. The question of whether these three common diagnoses "un- balance" the 9-months data will be examined later. On the basis of these findings, the de- cision was made to conduct separate analyses on the malformation findings "at birth" and the additional findings at the later examination. It should perhaps be emphasized at this point that although we have presented the above analysis in terms of specific defects, the unit in the statistical analysis to be presented later of the relationship between radiation history and congenital defect was the malformed child rather than specific defects, i.e., for analytic purposes each child is scored only once regard- less of the number of major defects present. 2.7 The processing of the data. All of the questionnaires employed in this study were checked for completeness by trained clerks. In the event of an omission or an obvious error, the individual concerned was queried either by mail or by a "contactor." Where a discrepancy ap- peared between the information obtained on a first registration and on a subsequent registra- tion by the same couple, an attempt was made to determine which of the two statements was correct and the reason for the discrepancy. When the questionnaires were completed, the data necessary to the projected analyses were coded, and the coded results transferred to standard 80-column machine tabulation cards. The codes used for the Genetics Short Form, the Genetics Long Form, and the Genetics 9-Months Follow-up are reproduced in Ap- pendix 1. 2.fS The study of spontaneous abortions. Early in the planning of the study, the possi- bility presented itself that a significant fraction of the detectable genetic effects of the atomic bombs on the first post-bomb generation would be in the form of dominant lethals which would find expression during the early stages of preg- nancy. Although some of these dominant lethals might manifest themselves prior to implanta- tion, others might not be en ective until a month or two after implantation. Theoretically, the occurrence of dominant lethals in any number might be detectable through an increase in early spontaneous abortions. In the fall of 1949 an attempt was initiated i'n Hiroshima to obtain as many records as pos- sible of pregnancies terminating spontaneously prior to the twentieth week of gestation. Data were collected through the personal contact of one physician with the practicing obstetricians and gynecologists of the city. Radiation histories were obtained on each couple involved, with the intent of determining whether these histories differed significantly from those obtained from parents when the pregnancy was of twenty or more weeks' duration. In the fall of 1950, the physician originally responsible for the collection of these data sev- ered his association with the ABCC; the collec- tion of the data was continued by two younger men. The collection of data was discontinued in early 1952. Data on 1,053 early spontaneous terminations were obtained during the first por- tion of this study, and information on 638 dur- ing the latter portion. Many problems were anticipated in the col- lection of data on early spontaneous termina- tions; most of these anticipations were realized. During the spring of 1952, a preliminary analy- sis of these data was carried out. This analysis clearly revealed heterogeneity within the data, in terms of differences between the findings of the first and second portions of the program. Because of the impossibility of determining the source of these differences, as well as continu- ing difficulty in the collection of such data, this aspect of the program was abandoned, and will not be referred to again. 2.9 Cytogerzetic effects of the atomic bombs. -As one facet of the over-all Genetics Pro- gram, the possibility has been explored of de- tecting by cytological methods chromosomal damage among the survivors of the bombings. Testicular material obtained either at the time of surgery, by biopsy, or at autopsy was ex- amined, using appropriate methods. These stud- ies, which will be described in detail elsewhere by Dr. M. Kodani, revealed an unsuspected amount of chromosomal polymorphism among normal Japanese, a finding which has served as a serious drawback in the use of this material as originally envisioned. 2.10 The decision to discor~tir~e work in Kare. At the outset of the study, when satis- factory information was not available concern- ing the composition in terms of irradiation ex- perience of the population of the cities of Hiro- shima and Nagasaki, an effort was made to collect control data in the city of Kure, located some 18 miles from Hiroshima. Preliminary analyses of the year-to-year data quickly revealed

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The Plan that a considerable proportion of the inhabitants of the cities of Hiroshima and Nagasaki during the years 1948 through 1953 had not been there at the time of the atomic bomb explosions. Thus there existed in these two cities a source of in- ternal controls which appeared to obviate the necessity for a separate control city. Accordingly, in September, 1950, after data had been col- lected on some 8,391 pregnancy terminations, work was discontinued in Kure. 2.11 The termination of the program ir; January, 1954. At the time that the program which has just been described was initiated, Japanese birth rates were at record levels. How- ever, in 1948 and 1949 the Japanese govern- ment, as one of a series of measures designed to reduce the disparity between population num- ber and available food resources, liberalized the legal indications for the performance of "thera- peutic" abortions by physicians. Although exact figures are impossible to obtain, in 1951 ap- proximately 300 pregnancies were being inter- rupted each month in Hiroshima alone. In consequence of this and possibly other measures, the birth rate in Japan, including, of course, Hiroshima and Nagasaki, underwent one of the most spectacular declines ever recorded in a civilized country (Koya, 1953, 1954; Popula- tion Reference Bureau, 1953~. The decline in actual number of births registered with the Genetics Program in the two study cities is shown in Table 2.1. In addition, during the first five years of the study, there was not only an absolute decline but in Hiroshima, the largest source of data, there was also a tendency toward a relative decrease in the numbers of infants born to more heavily irradiated parents. The reasons for this are not entirely clear. In part the finding is undoubtedly due to emigration from the city and completion of reproductive span on the part of older exposed individuals, without proportional replacement by younger age groups, but other factors may also be involved. In the original planning of the program, the anticipated duration had been approximately ten years. By 1952 the annual decline in the amount of data becoming available had reached the point where it was apparent that a serious reconsideration of the duration of the program was indicated. Accordingly, on July 10-11, 1953, a Second Genetics Conference met to con- sider the results of a preliminary analysis of the 19 data, and to reach recommendations concerning the future conduct of the work. The members of this conference were Dr. G. W. Beadle, Dr. D. R. Charles, Dr. C. C. Craig, Dr. L. H. Snyder, and Dr. Curt Stern (chairman) with Drs. W. I. Schull and J. V. Neel functioning ex officio. In view of the relatively small ex- pected return, in terms of reducing the sampling variances of possible differences, from observa- tions extending over an additional four years, and in the light of the very real problems and the expense involved in maintaining the pro- gram at a satisfactory level of efficiency, it was the unanimous recommendation of the Con- ference that the program be terminated in the near future. This recommendation was accepted Year 1 ... 2 ... 3 ... 4 ... 5 ... 6 ... TABLE 2.1 PER CENT OF ALL REGISTRATIONS ~ IN CLUDING THOSE INVOLVING PARENTAL CON SANGUINITY ~ WITH AT LEAST ONE PARENT HEAVILY EXPOSED (RADIATION CATEGORIES 4, 5) Nagasaki Hiroshima ,. . ~ MorF, 4 or 5 Total ..31 778 ..269 8,736 ..259 7,621 ..226 7,093 ..222 6,664 ..158 5,348 1,165 36,240 MorF, % 4Or5 4.0 356 3.1 593 3.4 488 3.2 393 3.3 360 3.0 317 3.22 2,507 Total % 3,805 9.4 8,064 7.4 6,878 7.1 6,064 6.5 5,239 6.9 4,723 6.7 34,773 7.21 by the Committee on Atomic Casualties; actual data collection was suspended in February of 1954. 2.12 Acknowledgments. It is obvious that a program of this complexity and magnitude depends for its success on the efforts of many people in addition to the authors of this mono- graph. In particular, our heartfelt appreciation is due Lt. Col. Carl F. Tessmer, Dr. Grant Taylor, Dr. John Morton, and Dr. F. H. Con- nell, who, as successive directors of the Com- mission faced with the difficult task of balancing many demands on limited facilities and person- nel, were always most generous in their treat- ment of the Genetics Program. Without the staunch, long-time support of the Committee on Atomic Casualties of the National Research Council and the Division of Biology and Medi- cine of the U.S. Atomic Energy Commission, this program could not have been undertaken nor continued. In particular, we are indebted to Drs. Max Belle, Harold Plough, and Earl

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20 Genetic Efects of Atomic Bombs Chapter II Green, who, during their tenure as geneticists with the Division of Biology and Medicine of the Atomic Energy Commission, gave freely of their time and advice, and to Dr. A. E. Brandt, who, as biometrician to the Health and Safety Division of the New York Operations Office of the U.S. Atomic Energy Commission, offered a number of helpful suggestions. Turning now to Japan, it is a pleasure to mention the support received from various members of the Public Health and Welfare Section, GHQ, SCAP, and in particular from Brigadier General C. F. Sams, Chief of the Section, Col. Harry Johnson, Chief, Medical Service Division, and Mr. L. V. Phelps, Chief, Health Statistics Division. Dr. Harry C. Kelley, Deputy Chief, Scientific and Technical Division, Economic and Scientific Section, GHQ, SCAP, was an important link with Japa- nese science. Our special thanks are due Dr. M. Tsu~uki, who, as Chairman of the Medical Section of the Special Committee for the Investi- gation of the Effects of the Atomic Bombs of the Japanese National Research Council, assisted the work in many ways during the early days of the study. Later, when the Japanese National Institute of Health entered into the picture, Dr. R. Kobayashi, Director of the Institute and Dr. I. Nagai, Chief of the Atomic Bomb Section, were most helpful. Dr. H. Maki, as Director of the National Institute of Health staff in Hiro- shima and Nagasaki, was an unfailing source of counsel in meeting local problems as they arose. Dr. Taku Komai served as a frequent and greatly appreciated source of contact with Japa- nese geneticists. The statistical analysis profited greatly from discussions and correspondence with Dr. C. R. Rao, Dr. H. L. Lucas, Dr. Robert Krooth, Dr. Martin Kastenbaum, and Mr. Donald E. Lamphiear. Mrs. Betty Hsiao pro- vided invaluable assistance in the computations. In addition the following persons have been so kind as to read and criticize all or part of the manuscript: Dr. H. Fairfield Smith, Dr. I. Olkin, Dr. C. C. Craig, Dr. P. S. Dwyer, Dr. Joseph Ullman, Dr. Curt Stern, Dr. L. S. Pen- rose, Dr. Bradford Hill, and Dr. P. Armitage. The burden of preparing the manuscript has been substantially lightened by the conscientious assistance of Miss Frances Davidson, Mrs. Jane Schneidewind, Mrs. Barbara Seijas, and Miss Grace Yesley. We are grateful to the Rockefeller Foundation for defraying publication expenses through a grant to the National Academy of Sciences. Finally, to the literally hundreds of other people, American and Japanese employees of the Commission and local Japanese, who have contributed so much to whatever success this program may have enjoyed, our sincerest thanks.