Maternal Interview Reports of Family History ofBirth Defects: Evaluation From a Population-BasedCase-Control Study of Orofacial Clefts

Paul A. Romitti,1* Trudy L. Burns,2 and Jeffrey C. Murray1

1Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa2Department of Preventive Medicine and Environmental Health, University of Iowa College of Medicine,Iowa City, Iowa

Accurate family histories of birth defectsare critical for risk assessment and etiologicinvestigations. Typically, information aboutfamily history of birth defects is ascertainedfrom interviews with birth mothers of indexchildren; however, the quality of these in-terviews is rarely assessed. We evaluatedfamily history information provided by case(n = 28) and control (n = 29) mothers whoparticipated in a population-based, case-control study of orofacial clefts. Interviewresponses from mothers were compared toquestionnaire reports collected by mailfrom first- and second-degree parental rela-tives. A total of 345 case and 380 controladult relatives completed questionnaires.These relatives also provided reports for 130case and 169 control offspring. To examinethe quality of birth defect reports, the sen-sitivity and specificity of birth mother re-sponses were calculated. Sensitivity forpresence (yes/no) of a birth defect was 31%for case mothers and 9% for control moth-ers. Specificity for case and control motherswas 98% and 97%, respectively. Interview re-sponses from mothers who participate infamily genealogy were more likely to be con-cordant with relative reports than were re-sponses from mothers who do not partici-pate in family genealogy. Case mother re-sponses were more likely to be concordantthan control mother responses. These re-sults suggest that reliance on interview re-ports from birth mothers may lead to an un-derestimation of the occurrence of birth de-fects in relatives. Future investigations

should explore methods to improve thequality of informant reports about familyhistories of birth defects. One alternativeapproach is discussed. Am. J. Med. Genet.72:422–429, 1997. © 1997 Wiley-Liss, Inc.

KEY WORDS: congenital anomalies; epide-miology; family history; hu-man genetics; validation

INTRODUCTION

Birth defects contribute substantially to infant mor-tality and childhood disability in the United States[Sever et al., 1993]. Reduction of this burden of mor-tality and morbidity requires identification of factorsassociated with these malformations. Clues to recur-rence risks and etiologic determinants of birth defectscan be identified in part by the collection and analysisof family history information.

Typically, the initial step in acquiring family historyinformation is to have an informant (e.g., an index sub-ject or their birth parent) identify the disease status ofrelatives. Ideally, each identified relative would thenbe interviewed independently]; however, the use of di-rect interviews with relatives, the family study method[Weissman et al., 1986], is limited by the availabilityand consent of relatives and by cost [Khoury et al.,1993]. Instead, indirect reports of disease occurrenceprovided solely by the informant, the family historymethod [Andreasen et al., 1986], are often used.

Family history reports of birth defects are typicallyobtained from birth mothers of index children. Unfor-tunately, little study has been given to evaluating thequality of such reports. Past investigations [Axelssonand Rylander, 1984; Rasmussen et al., 1990] only ex-amined maternal reports of birth defects among theiroffspring; therefore, we evaluated information obtainedfrom family history interviews collected from partici-pants in a population-based case-control study of oro-facial clefts. Previously, we contacted relatives of theseparticipants to assess their willingness to provide self-reports of birth defects [Romitti and Burns, in press].

Contract grant sponsor: The University of Iowa Center forHealth Effects of Environmental Contamination; Contract grantsponsor: U.S. National Institute of Dental Research; Contractgrant number: DE09170.

*Correspondence to: Dr. P.A. Romitti, Department of Pediat-rics, 408 Westlawn Bldg S, University of Iowa, Iowa City, Iowa52242. E-mail: paul-romitti@uiowa.edu

Received 13 December 1996; Accepted 9 May 1997

American Journal of Medical Genetics 72:422–429 (1997)

© 1997 Wiley-Liss, Inc.

Using these data, we examined the concordance be-tween interview responses of birth mothers and self-reports of birth defects provided by relatives. In addi-tion, we investigated the effects of selected family andbirth mother characteristics on the sensitivity andspecificity of interview responses.

METHODSIowa Case-Control Study of Orofacial Clefts

Birth mothers selected for the current investigationwere participants in the Iowa Case-Control Study ofOrofacial Clefts. The methods used in the Iowa Studyhave been presented elsewhere [Romitti et al., inpress]. Briefly, live births, stillbirths, and aborted fe-tuses diagnosed with an orofacial cleft during the years1987 to 1991 were identified through the Iowa BirthDefects Registry, an active, population-based surveil-lance system. Control children were randomly selectedfrom all Iowa live-born infants without a birth defectduring the same time period. Telephone interviews, in-cluding a comprehensive family history interview, wereconducted with parents of case and control children.

Family History Interview

The family history interview developed for the IowaStudy was divided into three parts. First, birth moth-ers were asked to provide a complete reproductive his-tory, including information on all live births, still-births, tubal and ectopic pregnancies, and spontaneousand elective terminations. Second, mothers were askedto provide full name, gender, year of birth, biologicalrelationship (half/full), and vital status for each of theirand the birth fathers’ first-degree (children, full sibs,and parents) and second-degree (half-sibs, nieces andnephews, and aunts and uncles) relatives. Lastly,mothers were asked to provide birth defect and cancerdiagnoses for each relative identified. The length of thefamily history interview averaged 45 minutes.

Birth Mothers

As mentioned, we previously conducted a pilot studyin which relatives of participants in the Iowa Studywere asked to provide self-reports of birth defects [Ro-mitti and Burns, in press]. To do this, a sample of caseand control mothers was sent a questionnaire andasked to provide permission (yes/no) and a current ad-dress for each living, adult relative listed in the familyhistory interview. The name and address of a next-of-kin (spouse) was requested for each deceased or men-tally impaired adult relative. Mothers were also askedto indicate the typical number of annual contacts—personal visits, telephone calls and written correspon-dence—with each living, adult relative. In addition,mothers were asked to provide information regardingparticipation in family genealogy activities.

Relatives

Birth defect reports were requested from adult rela-tives for whom a current address was provided by birthmothers. Sibs of birth parents were also asked to indi-cate defects diagnosed for each of their offspring underthe age of 18. Due to budgetary constraints, a mailed

questionnaire, rather than a telephone interview, wasused to collect birth defect reports. The questionnairecontained a subset of the birth defect items used in thefamily history interview. Items retained were thoughtto be the least ambiguous and most suitable for a self-administered format. Relative reports of omitted de-fects were compared to the appropriate item includedin the family history interview. For example, if a rela-tive reported a defect of the eye for the questionnaireitem ‘‘Other birth defect not listed,’’ that response wascompared to the respective interview response for theitem, ‘‘Unusual problems with the eyes other thanglasses or eye problems that come with age.’’

Data Analysis

Birth defect information obtained from all completebirth mother-relative pairs was analyzed. A completepair required that neither the mother’s nor the rela-tive’s response to an item could have been coded aseither unknown or missing. Also, only information forrelatives reported to have been born prior to or duringthe year that the birth mother completed the familyhistory interview were included in the analyses. Toevaluate agreement for presence (yes/no) of a birth de-fect, sensitivity, specificity, and positive predictivevalue were calculated using the relative’s report as thegold standard. Sensitivity was defined as the propor-tion of relatives who reported the presence of a birthdefect on the self-administered questionnaire and forwhom the mothers identified the presence but not nec-essarily the type of defect during the family historyinterview. Specificity was defined as the proportion ofrelatives who did not report the presence of a birthdefect on the self-administered questionnaire and forwhom the mothers did not identify the presence of abirth defect during the family history interview. Posi-tive predictive value was defined as the proportion ofrelatives who have a birth defect for whom the mothersidentified the presence of a defect during the familyhistory interview. To assess agreement by defect group,reports from birth mother-relative pairs that were con-cordant for the presence of a birth defect were com-pared. A pair was concordant if the mother’s responsewas coded to match the same defect group as the rela-tive’s response.

The effects of several family and birth mother char-acteristics on the sensitivity and specificity of inter-view responses were evaluated. Family characteristicsincluded number and gender of relatives as well as in-dex child birth order. Birth mother characteristics in-cluded age, education, marital status, number of con-tacts with relatives, and participation in family gene-alogy. The number of relatives and index child birthorder were determined from the family history inter-view; gender of relatives was collected by self-report.Data on birth mother characteristics were obtainedfrom interview responses with the exception of valuesfor contact with relatives and participation in familygenealogy, which were collected using the mailed ques-tionnaire. Independent effects of each variable on theconcordance of each birth mother-relative pair were ex-amined using stratified analyses and conducting uni-

Evaluation of Birth Defect Reports 423

variate and multiple logistic regression analyses usingSAS [SAS, 1989]. For stratified analyses, sensitivityand specificity were calculated. Case-control differencein sensitivity was computed by subtracting the sensi-tivity estimate for control mothers from that of casemothers. Sensitivity differences were analyzed using95% confidence intervals for differences in proportions[Fleiss, 1973]. A difference was considered to be statis-tically significant if the confidence interval did not con-tain zero. For logistic regression analyses, the depen-dent variable assessed was the mother’s interview re-sponse (concordant vs. discordant) for the presence of abirth defect. Multiple logistic analyses included use ofstepwise entry of independent variables into the model.The significance level for a variable to enter the modelwas 0.15, and the significance level for a variable toremain in the model was 0.10. An association was con-sidered statistically significant when the significancelevel was less than 0.05. The study was approved bythe University of Iowa Human Subjects Review Com-mittee. Each questionnaire mentioned is availableupon request from the authors.

RESULTS

Data collection for the investigation extended fromMarch 1993 through May 1994. There were 188 eligiblecase and 224 eligible control mothers who had com-pleted a family history interview for the Iowa Study.Forty-eight randomly selected mothers from eachgroup were contacted and 28 (58.3%) cases and 29(60.4%) controls participated. Participants and nonpar-ticipants differed little with regard to age, education,marital status, parity, and number of relatives. Like-wise, characteristics of participants were comparableto unselected Iowa Study participants, with the excep-tion that current participants were more likely to bemarried. The mean age for participants was 28.9 ± 3.5years for case mothers and 32.2 ± 4.3 years for controlmothers. Most case (64.3%) and control (72.4%) moth-ers reported having attended college. Each mother wasmarried to the birth father of the index child, and themean number of years married was 10.3 ± 3.1 years forcases and 11.5 ± 4.3 years for controls. The mean num-ber of pregnancies (cases 4 2.8 ± 1.3; controls 4 3.0 ±1.3) and number of relatives (cases 4 35.7 ± 6.3; con-trols 4 38.3 ± 7.1) reported were similar for bothgroups.

Birth mothers granted permission to contact 543(86.3%) case and 565 (89.5%) control relatives. Overall,526 (96.9%) case relatives and 552 (97.7%) control rela-tives were located, and of these, 345 (65.6%) cases and380 (68.8%) controls participated. In addition, reportsfor 130 case and 169 control nieces and nephews wereprovided by sibs of birth parents. As displayed in TableI, reports from maternal relatives were nearly equalbetween cases and controls (276 vs. 262), but less so forpaternal relatives (199 vs. 287). With the exception ofpaternal second-degree relatives, the distribution of re-ports by type (maternal or paternal) and degree of re-lationship (first- or second-degree) was similar betweencases and controls.

Several patterns were observed for birth defect re-

sponses recorded by relatives. Reports for approxi-mately 391 (82.3%) case and 466 (84.9%) control rela-tives were completed as instructed; that is, a response(yes/no) was provided for each item listed in the ques-tionnaire. An alternative pattern noted for 50 (10.5%)case and 42 (7.7%) control relatives was inclusion of aresponse only for birth defects that were present; thus,a missing response was assumed to indicate absence ofa defect and was coded as ‘‘no.’’ Lastly, 34 (7.2%) caseand 41 (7.5%) control relatives failed to provide a re-sponse for each item and were excluded from analyses.Each birth defect reported by mothers and relativeswas reviewed by a board-certified clinical geneticist(JCM) and classified as: definite; possible, but moreinformation needed; or excluded (i.e., not a birth de-fect). Of the 51 defects mentioned by case mothers, 19(37.3%) were classified as definite, 4 (7.8%) as possible,and 28 (54.9%) were excluded. Of the 33 defects men-tioned by control mothers, 19 (57.6%) were classified asdefinite, 2 (6.1%) as possible, and 12 (36.4%) were ex-cluded. Among relatives, the corresponding totals were31 (47.0%), 10 (15.1%), and 25 (37.9%) for case rela-tives, and 37 (45.7%), 17 (21.0%), and 27 (33.3%) forcontrol relatives.

Concordance Between Mother and RelativeReports of Birth Defects

Telephone interview responses obtained from birthmothers were compared with questionnaire reports re-ceived from relatives. For the presence of a birth defect,the sensitivity of interview responses was 31% for casemothers and 9% for control mothers, and the differencewas statistically significant (Table II). The specificity ofinterview responses was 98% for cases and 97% forcontrols. Using a prevalence of 6% for all reportablebirth defects in Iowa during the study period, positive

TABLE I. Number and Type of Relative Reports

Relatives Cases Controls Total

Maternal 276 262 538All first-degree 92 91 183

Sisters 28 37 65Brothers 25 17 42Mothers 21 20 41Fathers 18 17 35

All second-degree 184 171 355Half-sisters 1 1 2Half-brothers — 2 2Nieces 42 33 75Nephews 37 42 79Aunts 64 50 114Uncles 40 43 83

Paternal 199 287 486All first-degree 82 97 179

Sisters 28 35 63Brothers 20 27 47Mothers 20 18 38Fathers 14 17 31

All second-degree 117 190 307Half-sisters — — —Half-brothers — — —Nieces 24 44 68Nephews 27 50 77Aunts 33 59 92Uncles 33 37 70

424 Romitti et al.

predictive values were estimated to be 50% for casemothers and 16% for control mothers. Excluding de-fects coded as possible resulted in small increases inoverall case (36%) and control (13%) sensitivity esti-mates and a slight increase in control specificity (98%).Likewise, positive predictive values were higher forcase (53%) and control (29%) mothers (data not shown).As a result, both definite and possible reports wereincluded in subsequent calculations in order to pre-serve the most conservative estimates.

Examination of sensitivity by type of relationshipfound that estimates for maternal relatives were lowerthan those for paternal relatives for both cases andcontrols (Table II). With the exception of control ma-ternal relatives, sensitivity tended to decrease with in-creasing degree of relationship. Positive predictive val-ues for maternal relatives were also lower for maternalcompared to paternal relatives; however, estimates forsecond-degree relatives were consistently higher thanthose for first-degree relatives.

Case relatives recorded 29 birth defects (18 definite)and control relatives 47 birth defects (30 definite) thatwere not mentioned by mothers during the family his-tory interview (Table III). Fourteen of the case reportsand 26 of the control reports were from maternal rela-tives. Defects listed for nieces and nephews comprisedapproximately one-half of the case (7/16) and control(20/34) reports for second-degree relatives. For cases,five of the 16 ear, face, and neck defects along with eachof the gastrointestinal and genital system defects re-ported were for nieces and nephews. The type and pro-portion of each defect group recorded for control niecesand nephews were: central nervous system defects (1/2); ear, face and neck defects (14/28); genital systemdefects (3/5); musculoskeletal defects (1/2); and urinarysystem defects (1/1).

Birth mother responses for 12 case (9 definite) and16 control (14 definite) birth defects were not verifiedby relative reports (Table IV). Seven of the 12 defectsmentioned by case mothers were for maternal rela-tives, with six of the reports being for first-degree rela-tives. Each of the five defects identified for paternalrelatives were also for first-degree relatives. For con-trols, 13 of the 16 defects mentioned were for maternal

TABLE III. Number and Type of Birth Defects* Reported byRelatives Only

Relative/defect group Na

Cases 29Maternal first-degree 6

Cardiovascular defects 1Ear, face, and neck defects 2Limb defects 1Musculoskeletal defects 2

Maternal second-degree 8Cardiovascular defects 1Central nervous system defects 1Ear, face, and neck defects 4Eye defects 1Other 1

Paternal first-degree 7Central nervous system defects 1Ear, face, and neck defects 5Other 1

Paternal second-degree 8Cardiovascular defects 1Ear, face, and neck defects 5Gastrointestinal defects 1Genital system defects 1

Controls 47Maternal first-degree 7

Ear, face, and neck defects 6Eye defects 1

Maternal second-degree 19Cardiovascular system defects 3Ear, face, and neck defects 12Genital system defects 3Musculoskeletal defects 1

Paternal first-degree 6Cardiovascular defects 1Central nervous system defects 1Ear, face, and neck defects 2Eye defects 1Other 1

Paternal second-degree 15Cardiovascular defects 1Central nervous system defects 1Ear, face, and neck defects 8Genital system defects 2Limb defects 1Musculoskeletal defects 1Urinary system defects 1

*Includes birth defects categorized as definite or possible.aNumber of birth defects reported.

TABLE II. Sensitivity, Specificity, Positive Predictive Value and Case-Control Difference in Sensitivity for Interview Responses ofBirth Mothers for Presence of a Birth Defect*

Casesa Controlsa

Relatives N

M(+)

M(+)

M(−)

M(−)

Sens Spec PPV N

M(+)

M(+)

M(−)

M(−)

Sens Spec PPV

Case-controldifference insensitivity(95% CI)

R(+)

R(−)

R(+)

R(−)

R(+)

R(−)

R(+)

R(−)

All 441 11 10 25 395 0.31 0.98 0.50 508 4 13 43 448 0.09 0.97 0.16 0.22 (0.05, 0.39)Maternal 253 4 6 12 231 0.25 0.97 0.35 241 1 12 23 205 0.04 0.94 0.04 0.21 (−0.02, 0.44)

First-degree 84 2 5 4 73 0.33 0.94 0.26 84 0 4 7 73 0.00 0.95 0.00 0.33 (−0.05, 0.71)Second-degree 169 2 1 8 158 0.20 0.99 0.56 157 1 8 16 132 0.06 0.94 0.06 0.14 (−0.13, 0.41)

Paternal 188 7 4 13 164 0.35 0.98 0.53 267 3 1 20 243 0.13 0.99 0.45 0.22 (−0.03, 0.47)First-degree 77 4 4 6 63 0.40 0.94 0.30 89 1 1 6 81 0.14 0.99 0.47 0.26 (−0.14, 0.66)Second-degree 111 3 0 7 101 0.30 1.00 1.00 178 2 0 14 162 0.13 1.00 1.00 0.17 (−0.16, 0.50)

*Includes a birth defect classified as definite or possible.aM (+) 4 birth mother reported a birth defect for a relative; M (−) 4 birth mother did not report a birth defect for a relative; R (+) 4 relative reporteda birth defect; R (−) 4 relative did not report a birth defect; Sensitivity 4 M(+)/R(+)/[M(+)/R(+) + M(−)/R(+)]; Specificity 4 M(−)/R(−)/[M(+)/R(−) +M(−)/R(−)]; PPV 4 Prevalence × Sensitivity/[Prevalence × Sensitivity] + [(1-Prevalence) × (1-Specificity)]; CI 4 confidence interval.

Evaluation of Birth Defect Reports 425

relatives, with twice as many for second-degree (n 4 9)as for first-degree (n 4 4) relatives. Both case and con-trol mothers reported additional ear, face, and neckdefects. Case mothers also tended to overreport eye de-fects, whereas control mothers were more likely tooverreport urinary system defects.

Agreement by birth defect group was examined forbirth mother-relative pairs concordant for the presenceof a defect. Each defect reported by a mother or a rela-tive was regarded as an independent event. For the 11case mother-relative pairs, complete concordance wasfound for all but one of the 12 defects reported by rela-tives. A paternal sibling indicated that he had a bifiduvula, but the case mother failed to mention the defect.For the four control mother-relative pairs, two of sevendefects reported by relatives were identified as discor-dant. A maternal sibling reported her son had Downsyndrome, an undescended testicle and unspecifiedheart and ear, face, and neck defects; the controlmother reported that the nephew was mentally re-tarded and had a small hole in his heart.

Characteristics Affecting Sensitivity andSpecificity

The independent effects of selected family and birthmother characteristics on the sensitivity and specificityof interview responses were analyzed using stratifiedanalyses (Table V). Sensitivity was slightly higher forcase mothers with less than 40 relatives than for thosewith 40 or more relatives, whereas the opposite patternwas observed for control mothers. For cases and con-trols, sensitivity estimates were marginally higher forfemale compared to male relatives. Results for indexchild birth order were similar between the two groups;

TABLE IV. Number and Type of Birth Defects* Reported byBirth Mothers Only

Relative/defect group Na

Cases 12Maternal first-degree 6

Ear, face, and neck defects 4Eye defects 1Gastrointestinal defects 1

Maternal second-degree 1Eye defects 1

Paternal first-degree 5Cardiovascular defects 1Ear, face, and neck defects 1Eye defects 1Limb defects 1Other 1

Paternal second-degree 0Controls 16

Maternal first-degree 4Cardiovascular system defects 1Ear, face, and neck defects 2Urinary system defects 1

Maternal second-degree 9Ear, face, and neck defects 4Gastrointestinal defects 1Limb defects 1Urinary system defects 2Other 1

Paternal first-degree 2Ear, face, and neck defects 1Urinary system defects 1

Paternal second-degree 1Limb defects 1

*Includes birth defects categorized as definite or possible.aNumber of birth defects reported.

TABLE V. Sensitivity, Specificity and Case-Control Difference in Sensitivity by Selected Family and Birth Mother Characteristicsfor Interview Responses of Birth Mothers for Presence of a Birth Defect* in Relatives

Casesa Controlsa

N

M(+)

M(+)

M(−)

M(−)

Sens Spec N

M(+)

M(+)

M(−)

M(−)

Sens Spec

Case-controldifference insensitivity(95% CI)

R(+)

R(−)

R(+)

R(−)

R(+)

R(−)

R(+)

R(−)

FamilyNumber of relatives

Less than 40 236 6 7 13 210 0.32 0.97 248 1 7 18 222 0.05 0.97 0.27 (0.04, 0.50)40 or more 205 5 3 12 185 0.29 0.98 260 3 6 25 226 0.11 0.97 0.18 (−0.06, 0.42)

Gender of relativeFemale 242 6 4 13 219 0.32 0.98 279 2 9 19 249 0.10 0.97 0.22 (−0.03, 0.47)Male 199 5 6 12 176 0.29 0.97 229 2 4 24 199 0.08 0.98 0.21 (−0.03, 0.45)

Index child birth orderFirst 100 5 4 4 87 0.56 0.96 149 2 1 14 132 0.13 0.99 0.43 (0.07, 0.79)Second or more 341 6 6 21 308 0.22 0.98 359 2 12 29 316 0.06 0.96 0.16 (−0.02, 0.34)

Birth motherAge

Under 30 years 274 7 6 17 244 0.29 0.98 157 2 0 12 143 0.14 1.00 0.15 (−0.11, 0.41)30 years or older 167 4 4 8 151 0.33 0.97 351 2 13 31 305 0.06 0.96 0.27 (−0.01, 0.55)

EducationHigh school degree or less 176 5 2 12 157 0.29 0.99 151 3 5 14 129 0.18 0.96 0.11 (−0.17, 0.39)Some college or higher 265 6 8 13 238 0.32 0.97 357 1 8 29 319 0.03 0.98 0.29 (0.07, 0.51)

Participation in family genealogyb

Yes 196 8 7 10 171 0.44 0.96 170 2 2 13 153 0.13 0.99 0.31 (0.02, 0.60)No 219 3 3 14 199 0.18 0.99 322 1 11 29 281 0.03 0.96 0.15 (−0.04, 0.34)

*Includes a birth defect classified as definite or possible.aM (+) 4 birth mother reported a birth defect for a relative; M (−) 4 birth mother did not report a birth defect for a relative; R (+) 4 relative reporteda birth defect; R (−) 4 relative did not report a birth defect; Sensitivity 4 M(+)/R(+)/[M(+)/R(+) + M(−)/R(+)]; Specificity 4 M(−)/R(−)/[M(+)/R(−) +M(−)/R(−)]; CI 4 confidence interval.bExcludes case (n 4 26) and control (n 4 16) relatives of birth mothers who omitted a response to this item.

426 Romitti et al.

sensitivity was greater if the index child was first inthe birth order compared to second or more.

Sensitivity estimates for case mothers also increasedwith increasing age and education, whereas the oppo-site trend was found for control mothers. For bothgroups, sensitivity was higher for mothers who partici-pate in family genealogy compared to those who do notparticipate in family genealogy. The impact of maritalstatus of birth mothers was not examined, since eachmother was married at the time of interview. For eachcharacteristic evaluated, case mother sensitivity washigher than control mother sensitivity and the differ-ences were statistically significant when relativesnumbered less than 40, when the study child was firstin the birth order, when the birth mother had attendedcollege, as well as when mothers participated in familygenealogy. Specificity estimates were high for all char-acteristics.

Logistic regression analyses were conducted to ascer-tain which family and birth mother characteristicswere independently associated with family history in-terview responses. The dependent variable in theanalyses was the birth mother response (concordant vs.discordant) for the presence of a birth defect in rela-tives, with the event of interest being a concordant re-sponse. Independent variables for the logistic regres-sion analyses included each of the variables discussedin the stratified analyses as well as the total contactscore between mothers and relatives. This score wascalculated by first assigning a value (0–5) to each re-spective interval of contact (none or less than one peryear, one to three per year, one per month, two to threeper month and one or more per week) and then bysumming the scores for each type of contact (personalvisits, telephone calls, and written correspondence).Univariate logistic analyses identified participation infamily genealogy (P < 0.02) and case status (P < 0.02) tobe independently associated with concordant birthmother responses. An association was suggested if theindex child was first in the birth order (P < 0.06) andthe mother was less than 30 years of age (P < 0.09).Each independent variable was also allowed to enterthe prediction model in a stepwise multiple logisticanalysis. Results confirmed that both participation infamily genealogy (P < 0.05) and case status (P < 0.02)were statistically significant predictors of concordance.

DISCUSSION

We evaluated the quality of birth defect informationcollected using a family history interview. Responses ofbirth mothers were compared with self-reports fromrelatives. The sensitivity of interview responses forpresence of a defect was only 31% for cases and just 9%for controls. For both groups, sensitivity for maternalrelatives tended to be lower than that for paternal rela-tives, and estimates also tended to decrease as the de-gree of relationship increased.

Overall, birth mothers failed to mention 29 defectsreported by case relatives and 47 reported by controlrelatives. Ear, face, and neck defects were most fre-quently underreported. We attribute this in part to thedesign of the family history interview. Since the Iowa

Study was an investigation of orofacial clefts, the in-terview included items for several ear, face, and neckabnormalities, such as those for ‘‘definite’’ structuralanomalies (e.g., cleft palate) and those for ‘‘possible’’associated conditions (e.g., missing teeth that nevercame in). In contrast, several other defects not reportedby mothers were less severe conditions generally notassociated with orofacial clefts (e.g., undescended tes-ticle). Another factor that may have attributed to theunderreporting of birth mothers was the desire to usesimilar questionnaire items for mothers and relatives;thus, affirmative responses to items such as ‘‘born witha heart defect’’ were categorized as a birth defect. Be-cause of this, individuals with certain but unspecifiedconditions (e.g., heart murmur) may have been mis-classified. Furthermore, approximately one-half of thedefects not mentioned by mothers were for nieces andnephews. Since we did not request date of diagnosis,some defects (e.g., cardiovascular system) reported fornieces and nephews could have been identified duringthe interval between the Iowa Study interview and thecurrent investigation; thus, sensitivity of birth motherresponses for these relatives may have been underes-timated.

Our data show that specificity of interview responseswas high for all relatives. This occurred in part becauseof the low prevalence of birth defects (i.e., large numberof unaffected individuals) which resulted in less vari-ability among estimates. Nonetheless, 10 case and 13control relatives were incorrectly reported by mothersas having a defect. Although these relatives may havedeclined to disclose a diagnosis, this seems unlikelygiven the number of reported defects mentioned previ-ously that were not identified by mothers. In addition,some relatives included detailed letters regarding theirconditions or drew family tree diagrams.

Consistent with sensitivity estimates, positive pre-dictive values tended to be higher for cases compared tocontrols and for paternal rather than maternal rela-tives. In contrast to these estimates, positive predictivevalues tended to increase with increasing degree of re-lationship. This trend occurred in part because esti-mates for second-degree relatives were based on, forthe most part, more than twice the number of first-degree relatives; thus, positive predictive values forfirst-degree relatives may have been less stable andsubject to greater variability.

Two previous evaluations of family history reports ofbirth defects [Axelsson and Rylander, 1984; Rasmus-sen et al., 1990] compared maternal reports of defectsin offspring with birth defect registry records. From asample of 745 mothers with information recorded inthe Swedish Register of Congenital Malformations, Ax-elsson and Rylander [1984] found that maternal ques-tionnaire reports failed to identify 10 of the 38 childrenrecorded in the registry as having a malformation, andmothers listed 24 malformations which were not listedin the registry. Although sensitivity and specificity val-ues were not reported, estimates computed using datapresented by the authors would be 74% and 97%, re-spectively. In a similar comparison between motherswho participated in the Atlanta Births Defects Case-Control Study and registry records from the Metropoli-

Evaluation of Birth Defect Reports 427

tan Atlanta Congenital Defects Program Registry, Ras-mussen et al. [1990] found that 3,024 of 4,929 casemothers reported their child had a major birth defect(defined by the authors as any defect that affects mor-bidity, mortality, and/or health prospects of affectedinfants) resulting in an overall sensitivity of 61%.Sixty-seven of 3,029 control mothers gave responsesindicating their child had a major birth defect resultingin an overall specificity of 98%. Positive predictivevalue was estimated to be 47%.

In the current investigation, agreement by type ofbirth defect was evaluated for birth mother-relativepairs concordant for the presence of a defect. The lownumber of reports limited assessment to groups ofanomalies rather than individual malformations. Gen-erally, if a mother correctly identified a relative whorecorded a birth defect, agreement was also found forthe defect group. Defects omitted by mothers were ei-ther subtle and less phenotypically evident (ear, face,and neck defects) or surgically repaired early in life(undescended testicle). This finding is in agreementwith Rasmussen et al. [1990], who found that motherswere more likely to underreport ear, face, and neckdefects (excluding orofacial clefts) and also genital sys-tem defects in their offspring.

The sensitivity of interview responses for case moth-ers appeared to be affected by several family and birthmother characteristics; less variation in sensitivity es-timates was found for control mothers. Sensitivity washigher if the case child was first in the birth ordercompared to second or more. Estimates for case moth-ers were also greater for those who were less than 30years of age and for those who participated in familygenealogy. It is intuitive that the case mothers wereyounger in age for the birth of their first child thantheir second child, and so forth; therefore, it seems rea-sonable to conclude that a mother whose first-born isdiagnosed with a birth defect may be more motivated toexplore the occurrence of birth defects among herchild’s relatives. One possible method of explorationmay be through participation in family genealogy. Ras-mussen et al. [1990] also determined that several birthmother characteristics were independently associatedwith the sensitivity of interview responses. Among thefactors identified were age (25 years), education (col-lege), and race (white).

Central to the conclusions drawn from this investi-gation is the use of self-reports from relatives as thegold standard. To our knowledge, the accuracy of self-reports of birth defects has not been evaluated. Theestablishment of most state birth defect registries, in-cluding Iowa’s, has occurred within the past 15 years;thus, validation of birth defect reports for adult rela-tives would entail requests for medical record informa-tion. The cost and labor required to request such infor-mation precluded our ability to verify all but five birthdefects, each of which were reported for nieces andnephews of the birth mothers [Romitti, 1994]. Three ofthe five defects recorded for these children were veri-fied by Iowa Birth Defect Registry information.

A potential limitation of our conclusions is the mod-est number of families who participated. Characteris-tics of birth mother participants, however, were com-

parable to those of all Iowa Study participants. Fur-ther, case and control mothers provided permission tocontact a similar proportion of relatives. Among therelatives contacted, participation rates differed littlebetween cases and controls. Moreover, the frequency ofbirth defects reported by case (31/441 or 7.0%) and con-trol (37/508 or 7.3%) relatives was only slightly higherthan the rate (6.0%) in Iowa for all reportable defects(unpublished data).

The number of relatives contacted made the use oftelephone interviews cost-prohibitive. Compared totelephone interviews, use of mailed questionnairespresents an increased potential for missing or incom-plete responses; however, in the current investigation93% of case and control relatives responded to birthdefect items. A related issue is the potential for inap-propriate responses, although we found that the over-all proportion of birth defect reports excluded for rela-tives was similar to those excluded for control mothers.Previous studies have shown that mailed question-naires can yield valid responses to sensitive questionsregarding health histories [Pless and Miller, 1979; Si-emiatycki, 1979; Zielhuis, 1992]. In particular, Cole etal. [1978] designed a mailed family history question-naire to replace interview collection of pedigree infor-mation for patients attending a medical genetics clinic.The authors found that the questionnaire offered sev-eral advantages over in-clinic interviews, including pa-tient consultation with other relatives, increased pa-tient awareness regarding reasons for the clinic visit,reduced clinic time, and increased standardization ofdata collection.

For each family and birth mother characteristicevaluated in the current investigation, case mothersensitivity was higher than control mother sensitivity.These findings may be an indication of recall bias. As aresult of having a child with a birth defect, case moth-ers may have examined the birth defect histories ofrelatives more intensely and more thoroughly thancontrol mothers. This conclusion is consistent with aprevious report which found that case mothers weremore personally motivated to participate in studies ofbirth defects than were control mothers [Schaffer andShaw, 1992].

The effect of birth mother participation in family ge-nealogy should be interpreted cautiously. Participationwas established by response (yes/no) to a single ques-tionnaire item; thus, it is uncertain whether a mothermay have acquired birth defect information from suchactivities. Future studies need to consider a more de-tailed assessment of this variable. Additional question-naire items should be included to document the type ofinformation a birth mother acquires through her par-ticipation in family genealogy.

In conclusion, we evaluated the concordance betweenfamily history interview responses provided by birthmothers with questionnaire reports obtained from rela-tives. Agreement was evaluated for both the presenceand group of birth defect reported. Our results suggestthat interview responses provided by birth mothersshould be viewed with caution. Mothers were found tounderreport the presence of birth defects in relatives.Case status and participation in family genealogy were

428 Romitti et al.

found to be associated with mothers correctly identify-ing relatives with a defect; however, these findings arefor Iowa families for whom the index child had an oro-facial cleft, and may not be indicative of families ofchildren in other states or of families with childrendiagnosed with other defects. Attention should also begiven to the type of birth defect items used. To retainconsistency, relatives in the current investigation wereadministered a subset of identically worded items usedfor birth mothers in the Iowa Study interview. The typeof item appeared to influence reports—less specificitems (e.g., born with an eye defect) tended to encour-age the recording of defects (e.g., far-sighted) that wereneither classified as definite nor possible birth defects.As well, use of these items resulted in reports of un-specified defects (e.g., limb defects) in excess of ex-pected prevalence rates. It is recommended that familyhistory questionnaires for investigations of birth de-fects contain only specific, closed-ended items relevantto the defect under study. Consistent with the conclu-sions of Cole et al. [1978], the use of a mailed question-naire rather than an interview would provide mothersthe opportunity to consult with relatives regarding theoccurrence of such conditions and may improve thequality of the data collected. To this end, we have de-veloped a self-administered family history question-naire for orofacial clefts and are currently using theinstrument to survey birth mothers of case and controlchildren [Romitti et al., in preparation].

ACKNOWLEDGMENTS

We thank the individuals who participated in thisstudy. We are also grateful to James Hanson, CharlesLynch, Ronald Munger, Helmut Schrott, and JamesTorner for their helpful comments.

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