Cystic Fibrosis Newborn Screening: Impact on Reproductive Behavior and
Implications for Genetic Counseling
Elaine H. Mischler, MD*; Benjamin S. Wilfond, MD‡; Norman Fost, MD, MPH§; Anita Laxova, BS§; Catherine Reiser, MS§; Christine M. Sauer, MSi; Linda M. Makholm, MT§; Guanghong Shen, MS§;
Lynn Feenan, RN, MS§; Catherine McCarthy, RN, MSN*; and Philip M. Farrell, MD, PhD§
ABSTRACT. Objective. To evaluate the impact of newborn screening for cystic fibrosis (CF) on the repro-ductive knowledge and behavior of CF families and to determine if heterozygote detection with the immunore-active trypsinogen (IRT) method in conjunction with DNA analysis (IRT/DNA) influences knowledge and at-titudes about reproduction in false-positive families.
Methods. The Wisconsin CF Neonatal Screening Project investigated 650 340 infants from 1985 to 1994 in a comprehensive randomized controlled trial to study both benefits and risks of newborn screening and to deter-mine if early diagnosis would improve the prognosis of children with CF. Assessments of reproductive knowl-edge, attitudes, and behaviors of 135 families of children diagnosed as having CF in both the early treatment group and control groups were made 3 months after diagnosis using a questionnaire which was completed by 100 fam-ilies. The same questionnaire was administered 1 year later to evaluate retention of information. It was com-pleted by 71 families. A follow-up assessment tool was also administered in 1994 and responses obtained from 73 families. Knowledge, attitudes, and behavior among false-positive families were also assessed at the time of the sweat test in 206 families who experienced IRT screening and 109 families tested with the IRT/DNA method. Follow-up assessments were completed 1 year later in 106 IRT families and 63 IRT/DNA families.
Results. In families with a CF child, 95% initially understood that there was a 1 in 4 risk in subsequent pregnancies, and there was good retention of this infor-mation 1 year later. At the 1994 assessment, 52% of fam-ilies had not yet conceived more children, but 74% of these already had children. In the couples in whom CF was diagnosed in the first child, 70% (95% confidence interval5 54% to 85%) conceived more children. There were 43 subsequent pregnancies in 31 families. Prenatal diagnosis was used by 26% of the families (8/31) for 21% of the pregnancies (9/43). There were 3 pregnancies with CF detected, all of which were carried to term. In the false-positive groups,>95% of families initially under-stood that their child definitely did not have CF. There was no difference between false-positive IRT and IRT/ DNA groups, and the information was retained at 1 year. Follow-up assessment 1 year after negative sweat tests
revealed that 7% of the IRT and 10% of the IRT/DNA families still thought about the results often or con-stantly. When asked whether the experience of screening affected feelings about having more children, an affirma-tive response was obtained in 4% of IRT families but in 17% of IRT/DNA families. One year later, more than half of the false-positive IRT/DNA families did not under-stand that they were at increased risk of having a child with CF.
Conclusions. We conclude that CF neonatal screening does not have a significant impact on the reproductive behavior of most families and that prenatal diagnosis is not used by the majority of CF families. IRT/DNA testing experiences seem to affect attitudes about having more children, and some parents are confused about the im-plications of the results, even with genetic counseling. However, persistent concerns about the sweat test result are limited. Questions raised by this study confirm the need for more research regarding the process of genetic counseling and its impact on reproductive attitudes and behavior in the newborn screening setting. Pediatrics 1998;102:44 –52;cystic fibrosis, newborn screening, immu-noreactive trypsinogen, carrier detection, reproductive de-cision making, prenatal diagnosis, genetic counseling, health policy.
ABBREVIATIONS. CF, cystic fibrosis; IRT, immunoreactive trypsinogen; CFTR, cystic fibrosis transmembrane conductance regulator; CI, confidence interval.
N
ewborn screening for cystic fibrosis (CF) has been controversial primarily because of un-certainty regarding whether early diagnosis improves the long-term prognosis.1–3This issue is not yet conclusively resolved, although there is increas-ing evidence of pulmonary4and nutritional benefits.5 Some of the arguments for and against newborn screening are based on the psychosocial impact of the screening program.1The potential psychosocial ben-efits of CF newborn screening relate to eliminating delayed diagnoses which may cause anxiety associ-ated with caring for an ill child with an undiagnosed problem6 and providing genetic information that may influence a parent’s reproductive plans.7 Poten-tial adverse psychosocial effects to the family with a CF child focus on the impact of early diagnosis on the family’s ability to bond with a labeled child and on the child’s own developing self-image.8 Addi-tional psychosocial effects may occur in families with false-positive screening test results who may misun-derstand the meaning of the test, have persistent From the *Department of Pediatrics, Medical College of Wisconsin,Mil-waukee, Wisconsin; ‡Department of Pediatrics, University of Arizona, Tuc-son Arizona; §Department of Pediatrics, University of Wisconsin, MadiTuc-son, Wisconsin; and theiGenetics Center, Children’s Hospital of Wisconsin, Milwaukee Wisconsin.
Received for publication Sep 29, 1997; accepted Jan 26, 1998.
concerns about CF, experience discrimination by in-surance companies because of carrier status, or even alter reproductive decisions on the basis of this mis-understanding.9
To address the medical and psychosocial impact of CF newborn screening, a randomized controlled trial has been conducted in the State of Wisconsin with randomization of infants between 1985 and 1994.10 During the first 6 years, the screening was based on the analysis of immunoreactive trypsinogen (IRT) followed by confirmation with a sweat test.11 With the identification of the CF transmembrane conduc-tance regulator (CFTR) gene in 1989,12it became fea-sible to couple the IRT assay with subsequent anal-ysis for CFTR mutations to improve both the sensitivity and the positive predictive value of the screening program.11 During the last 3 years of the study, such a two-tiered approach (IRT/DNA) was utilized for routine detection of the major CFTR mu-tation, namely theDF508 allele. During this phase of the study, the positive predictive value of the IRT/ DNA test to detect CF was 15.2%, but in this same cohort, a single IRT screening protocol would have had a positive predictive value of 6.4%.13 Similar IRT/DNA approaches have also been used by groups in Australia.14 –16
In this report, we present observations on genetic counseling and reproductive decision-making asso-ciated with participation in the Wisconsin CF Neo-natal Screening Project. Regarding the parents of a child diagnosed as having CF, we describe the knowledge of CF genetics, decisions to have future children, and use of prenatal diagnosis. Although there have been studies about the impact of newborn screening on reproductive decision making in the United Kingdom,17 Netherlands,7 and Australia,15 this is the first analysis of reproductive behaviors from CF newborn screening programs in the United States.
A consequence of the introduction of the two-tiered strategy has been the identification of previ-ously unknown CF heterozygotes, including some infants tested and at least one of their parents. This knowledge can potentially cause psychologic stress and influence reproductive attitudes and behav-iors.17–19CF carrier testing has raised concerns about confusion, stigmatization, and discrimination, partic-ularly for children identified as carriers.18,19The cen-tral ethical issue regarding carrier detection in non-consenting participants is that they are exposed to possible risks with little or no likelihood of direct benefit. Regarding the parents of children with a false-positive IRT/DNA test (CF heterozygotes), we have studied their knowledge of CF genetics and their interest in further genetic testing of themselves and family members. We have also compared their postscreening attitudes with parents who had chil-dren with false-positive IRT tests. One particular issue addressed in this article is whether parents will understand that the chance that they are both carriers is reduced from 1 in 30 to 1 in 300 but not to 0,20even with additional genetic testing of both parents that detect 90% of mutations. Our results are important in considering whether the advantage of the IRT/DNA
approach in reducing the number of false-positive screening tests is offset by adverse psychologic ef-fects and by misunderstanding about the familial implications of their child’s carrier status.
METHODS
Wisconsin CF Neonatal Screening Program
The design of the Wisconsin CF Neonatal Screening Project is described in detail elsewhere.5,10,21It may be summarized as a
randomized trial of early diagnosis achieved through CF neonatal screening with comprehensive assessment of potential benefits and risks of the screening program. From April 15, 1985, through June 30, 1994, we tested Guthrie cards from 650 340 infants for CF markers in conjunction with the State Neonatal Screening Pro-gram using randomized assignment into an early diagnosis group and a standard diagnosis group. Infants in the early diagnosis group with abnormal screening results were contacted via their primary care provider within 4 to 8 weeks of life to obtain a sweat test at either the Madison or Milwaukee CF centers. Participants in the standard diagnosis group did not have results reported in the newborn period and were typically referred by their primary care provider to one of the CF centers because of either symptoms suggestive of CF or positive family history, or when their positive screening result was unblinded at 4 years of age. All parents were informed about the voluntary nature of CF screening with a pamphlet given to mothers in the hospital at the time of delivery. This study was approved by the University of Wisconsin Human Subjects Committee, the Milwaukee Children’s Hospital Human Rights Review Board, and the Medical College of Wisconsin Hu-man Research Review Committee.
Two laboratory methods were used for newborn screening tests. From the beginning of the study through June 30, 1991, the parents of infants with IRT levels.180 ng/mL (99.8th percentile) were contacted to obtain a sweat test.22A total of 220 862 infants
were randomized to the early treatment group. There were 369 with an elevated IRT, of whom 46 were diagnosed with CF. There were 10 additional CF patients identified who had false-negative IRT tests but were diagnosed when a sweat test was performed because of meconium ileus, other disease signs/symptoms, or a positive family history. Beginning on July 1, 1991, the IRT/DNA approach was used with a threshold level of 110 ng/mL (99th percentile). Guthrie cards with elevated IRT levels were then analyzed for theDF508 mutation.11The parents of infants with at
least one mutant allele present were contacted through their pri-mary care physician and were asked to obtain a sweat test. Fam-ilies were informed that the screening test was positive and only given the diagnosis of CF after confirmation with the sweat test. During the IRT/DNA phase, there were 104 308 children random-ized to the early treatment group; 132 had a positive screen and 21 were diagnosed with CF. One child with a negative screening test was identified because of meconium ileus.13
Genetic Counseling
The 135 families identified as having a child with CF in both the early treatment and standard treatment groups had information about the genetics of CF presented by a nurse practitioner at the time of diagnosis and during follow-up visits. They were also offered the option of referral to genetics counselors for informa-tion about prenatal diagnosis and implicainforma-tions for extended fam-ily members.
Beginning in July 1991, false-positive IRT/DNA families were provided in-depth counseling regarding the implications of their child’s heterozygosity by a certified genetic counselor, in the ma-jority of cases, or by a master’s-level nurse. If the sweat test was negative, an hour was devoted to discussing the genetic implica-tions for the child and extended relatives, and an information pamphlet developed for this study was provided. It was explained that at least one parent was a carrier, and possibly both. Further genetic counseling and genetic testing for parents was offered at no charge. A follow-up phone contact was made by the genetic counselor within a few days to answer additional questions and again to offer further counseling and carrier testing.
recessive inheritance; 2) gene mutations and DNA analysis; 3) benefits of genetic testing (reproductive and lifestyle options); 4) limitations of testing (negative results reduce but do not eliminate the risk of being a carrier); 5) psychosocial implications (change in self-image, misattributed paternity, and insurance discrimina-tion); and 6) implications for other family members. An additional pamphlet about CF carrier testing developed by the National Society of Genetic Counselors was provided at that time. Most of the parents who consented to carrier testing and further counsel-ing had blood drawn at the end of the session (56 of the 58 or 97%). In all 56 cases, one parent was identified as a carrier, and the test results were provided by telephone, and a follow-up letter was sent. The implications of that result were explained, and assistance for extended family members was offered, including additional testing of theDF508-negative parent.
Assessments of Knowledge, Attitudes, and Behaviors Families of CF Patients
A questionnaire that assessed knowledge about the disease, knowledge about CF genetics, attitudes about CF, and attitudes about reproductive decisions was sent to the 135 families 3 months after the sweat test.9It was completed by 100 families (74%). The
same questionnaire was administered 1 year later, and responses were received from 71 families. In June 1994, a final questionnaire was sent to 100 families still being followed that assessed past reproductive behaviors, including the number of subsequent pregnancies, use of prenatal diagnosis, and outcomes. There were 73 responses received. Data were compared with Fisher’s exact test.
Families With False-positive Tests
After having the sweat test results explained, parents were given a questionnaire to assess their understanding of the results.9
During the IRT phase, questionnaires were given to 268 families and 206 responses were completed (77%). When the IRT/DNA strategy was implemented in 1991, the questionnaire was modi-fied to include questions about understanding the implications of carrier status. Of 111 families in this group, questionnaires were completed by 109 families (98%). A follow-up questionnaire was sent 1 year after the sweat test. This included an assessment of long-term understanding about the sweat test result and whether screening had changed their feeling about having children. During the IRT phase, 106 follow-up questionnaires were completed (51%), including 101 who also completed the first questionnaire. After 1991, there was an additional assessment of understanding of carrier status, and also questions about reasons why families decided to pursue or decline further genetic testing. There were 63 follow-up questionnaires completed (58%), including 59 who com-pleted the first questionnaire. The educational level of the respon-dents and nonresponrespon-dents are described in Table 1. Data were compared with Fisher’s exact test.
RESULTS Families With CF Children
The comprehension of genetics information in families with a child diagnosed with CF and the retention of knowledge for.1 year are summarized in Table 2. The data indicate that nearly all families retained the information that both parents are carri-ers and that there is a 1 in 4 chance to have a child with CF with each pregnancy. The risk of CF in subsequent pregnancies was also assessed as a mul-tiple-choice question: “If you have another child, what is the chance that he/she will have cystic fibro-sis?” The choices were: a) 1:100; b) 1:10; c) 1:4; or d) 1:2. This question was answered correctly by 90% at 3 months and by 97% 1 year later. Only 1 family demonstrated persistent misunderstanding of the risks of having another child with CF. The assess-ment of this knowledge is necessary to interpret decisions to have more children as it is possible that decisions to have more children would be related to inaccurate understanding of the risk. Another factor that could influence decisions is the birth order of the child with CF. The relationship between decisions to have more children and number of children already in the family after a diagnosis of CF is shown in Table 3. Although 52% (n5 38) of the families did not conceive more children after the diagnosis of CF at the time of follow-up, 74% (28/38) of these had already had at least one child.
At the completion of the study, 14% (10/73; 95% CI56% to 22%) had only one child. In the 33 couples in whom CF was diagnosed in the first child, 23 (70%; 95% CI 5 54% to 85%) conceived more chil-dren. In the 10 couples in which there have been no more conceptions, 5 families report that their deci-sion was based on the diagnosis of CF. Among the 23 who did conceive more children, only 5 (22%; 95% CI55% to 39%) utilized prenatal diagnosis.
In the 35 families in which there were additional pregnancies reported, there were 31 with the same two parents who had the child with CF. There were 43 subsequent pregnancies in these families, and the use of prenatal diagnosis in these pregnancies is shown in Table 4. In the first subsequent pregnancy,
TABLE 1. Education Levels of Responders and Nonresponders to Questionnaires of False-positive Families
Sample N #8th Grade/
Some High School %
Graduated From High School %
Some College or Vocational School %
Graduated From College/Postgraduate
Training %
Unknown %
IRT*
Total 268 20 32 20 14 15
Responders to questionnaire at sweat test 206 20 34 22 18 5
Nonresponders to questionnaire at sweat test 62 21 23 11 0 45
Responders to questionnaire 1 year after sweat test
106 10 34 27 23 6
Nonresponders to questionnaire 1 year after sweat test
104 29 34 19 13 6
IRT/DNA*
Total 111 12 32 26 28 2
Responders to questionnaire 1 year after sweat test
63 6 30 30 30 3
Nonresponders to questionnaire 1 year after sweat test
48 19 35 21 25 0
26% (8/31) used prenatal diagnosis. In 12 additional pregnancies, there was only one additional instance of prenatal diagnosis. Of the 9 pregnancies (21%) in which prenatal diagnosis was performed, there were 3 fetuses with CF, all of whom were carried to term. To clarify whether the use of prenatal diagnosis was limited by lack of knowledge about its availability, this was evaluated at the 3-month questionnaire; the results revealed that 84% (26/31) were aware that prenatal diagnosis could be done for CF.
Families With False-positive Screening Tests Understanding of Sweat Test Results
An accurate understanding of the sweat test re-sults is fundamental to the minimization of ad-verse effects. Parents were asked to select among multiple- choice options to determine if they be-lieved that their child “definitely does not have CF.” In the IRT group, 95% (190/199) answered correctly at the time of the sweat test and 92% (97/105) answered correctly 1 year later. In the IRT/DNA group, 100% (109) and 97% (61/63) an-swered correctly at the time of the sweat test and at 1 year, respectively. There were no significant dif-ferences between groups or throughout time. The carrier information could have confused parents in the IRT/DNA group, but this did not occur. We also asked the families how often they thought about the sweat test results, as a measure of the impact of the testing process on their lives (Fig 1). One year later, only 7% of the IRT parents and 10% of the IRT/DNA parents thought about the results once a week or more. There is no difference be-tween these groups, but this observation raises
concerns about the long-term impact of false-positive results in a minority of families.
Attitudes About Newborn Screening and Having Children To address concerns about long-term impact, we asked false-positive families whether the “experi-ence with screening changed your feelings about having more children.” More participants in the IRT/DNA group, 17% (10/58), compared with the IRT group, 4% (4/106), believe that screening did have an influence and, therefore, might alter atti-tudes about subsequent pregnancies (P,.01). This difference must be interpreted in the context of the variations in communication with IRT/DNA fam-ilies who received extensive genetic counseling,
TABLE 2. Knowledge About Genetics of CF in Families With a Child With CF Which of the Statements About
CF Are True?
3 Months After Sweat Test (N5100) 1 Year Later (N571)
% Yes % No % Unsure % Yes % No % Unsure
If a couple has a child with CF, both of them must have the gene for it.
99 1 0 99 1 0
If you have had one child with CF, the chance of your next child having it is 1 in 4.
95 2 3 96 4 0
TABLE 3. Effect of Birth Order of Child With CF on Reproductive Planning/Outcome Subsequent
Pregnancies
First-born N(%)
Second-born N(%)
Third-born N(%)
Fourth-born N(%)
Total N(%)
None 10 (30) 22 (71) 6 (86) 0 38 (52)
One 14 (42) 6 (19) 0 2 (100) 22 (30)
Two 6 (18) 2 (6) 1 (14) 0 9 (12)
Three 3 (9) 0 0 0 3 (4)
Four 0 1 (3) 0 0 1 (1)
Total 33 31 7 2 73
TABLE 4. Use of Prenatal Diagnosis by CF Families for Subsequent Pregnancies
No Prenatal Diagnosis Outcome Prenatal Diagnosis Outcome Total
No CF CF Other* No CF CF
First subsequent pregnancy 14 8 1 6 2 31
Second subsequent pregnancy 4 4 1 0 1 10
Third subsequent pregnancy 2 0 0 0 0 2
Total 20 12 2 6 3 43
* Includes two miscarriages.
compared with the IRT group. When parents were asked a year later, there was no significant differ-ence in attitudes about the desirability of CF neo-natal screening. Specifically, 92% (98/106) and 90% (57/63) of the IRT and IRT/DNA groups, respec-tively, thought that newborn screening for CF should be done.
Knowledge of Carrier Information About the Child With a False-positive IRT/DNA Test
One of the concerns about the IRT/DNA approach is whether information about the child’s carrier sta-tus is retained or is misinterpreted. In Table 5, pa-rental knowledge about the meaning of the child’s carrier status is described. After a year, the vast majority of families retained this information and understood that their child should discuss his/her carrier status with a health care professional when planning to have children. However, a few families did not understand the meaning of being a carrier and seem to believe that their child could develop CF.
Knowledge, Attitudes, and Behavior About Parental Genetic Testing
Of those in the IRT/DNA group who completed the 1-year follow-up questionnaire, both parents were tested in 58% (36/62) of families, as well as 3 additional mothers. Of those mothers who chose to be tested, 71% (28/39) had at least some college education, in contrast to 43% (10/23) of those who chose not to be tested (P 5 .019). The factors that influenced parents’ decisions about genetic testing are described in Fig 2. The most important factor associated with further testing was the desire to ob-tain more accurate information about recurrence risks for future pregnancies. Although time and travel to the CF center was associated with a decision not to be tested, for both groups this was not an important consideration in their decision. Both groups attached some importance to the consultation and testing being provided free of charge.
Because one of the reasons that people were inter-ested in parental genetic testing was to obtain more accurate information about reproductive risk, we asked about the meaning of a negative test. The parents were provided both written and verbal in-formation that there was still a small chance that they were a carrier, even with a negative test, because of the CFTR mutations other than DF508. However, 47% (18/38) with negative tests falsely answered, “I am definitely not a carrier of cystic fibrosis” rather than “There is still a small chance that I am a carrier.”
The parents’ understanding about their carrier status was also assessed by three “yes/no/unsure” ques-tions (Fig 3). Although all but 1 family understood that one parent was a carrier, confusion persisted that there was no chance that they both could be carriers and were not at risk of having a child with CF. Those individuals with a greater education level were not more likely to have correct responses. Genetic testing and further genetic counseling did not improve their understanding. Paradoxically, we found that people who had DNA testing for carrier status and more counseling had significantly more incorrect responses (Fig 3).
Communication of Results to Other Family Members
One of the implications of the IRT/DNA results is that not only is one parent a carrier, but other first-degree relatives may be carriers as well. Eighteen other family members were pregnant at the time the newborn was identified as a carrier. Eighty-eight percent (53/60) of participating parents informed other family members they may also be carriers.
DISCUSSION
Impact of Newborn Screening on Reproductive Behavior in CF Families
Although the reproductive and psychosocial is-sues will not determine national policy recommen-dations for CF newborn screening, our study has provided useful data on otherwise speculative con-cerns about potential benefits and harms of screen-ing. The families who responded to the survey seemed to have retained information about the like-lihood of having a subsequent child with CF. Knowl-edge of recurrence risk is a necessary condition for determining any impact of the diagnosis of CF on family planning issues. Five of the 10 families in the study with only one child stated that CF influenced their reproductive decisions. Throughout the re-maining years of the study, 70% of couples whose first born was diagnosed with CF had more children. This is a greater proportion than the results of Evers-Kiebooms et al23 who reported that 35% (20/56) of Belgian families whose first born has CF proceeded to have more children; their study was completed in 1987 and the difference may be related to greater availability of prenatal diagnosis, changing attitudes about the prognosis for children with CF, or cultural differences.
A 1984 survey of 346 CF families in California revealed that 78% felt that prenatal diagnosis would be important for reproductive decision making.24
TABLE 5. Knowledge About Genetics of CF in Families With Carrier Infants
Percent Correct Responses
At Time of Sweat Test (N5109)
1 Year After Sweat Test (N563)
Our child is a carrier of the CF gene 100 95
Being a CF carrier may cause illness 94 94
Our child may develop CF when he/she is older 100 97
Our child should seek a health care provider when he/she is planning to have children to learn more about the personal implications of being a carrier
This is also consistent with the study of 70 CF fam-ilies in New England, where 77% had or were con-sidering prenatal diagnosis.25 In a prospective study26of 37 families with a first-born child with CF, however, only 51% indicated an interest in using prenatal diagnosis for subsequent pregnancies; among the members of this cohort who became preg-nant, only 22% (4/18) used it. This is identical with the 22% (5/23) observed in our study. The small proportion of parents who took advantage of prena-tal diagnosis in both studies suggest that subsequent conceptions and pregnancies are not predicated on the availability of prenatal diagnosis.
If the use of prenatal diagnosis is a surrogate marker for the value of genetic information obtained via newborn screening, then this is a benefit only for a minority of individuals. Additionally, all the af-fected pregnancies were carried to term. One of the limitations of our data, however, is that there was no assessment of the families’ perception of raising a child with CF. The limited use of prenatal diagnosis by the majority of CF families could reflect both our counseling methods and the attitudes shaped by the experience of raising a young child with CF who has few symptoms,5coupled with information about the improving prognosis for CF. Additionally, the psy-chologic implications of prenatal diagnosis and pos-sibly being faced with a decision about abortion have unique complexities for families with a child who has CF.26
Our observations provide a benchmark to com-pare decisions about reproductive behavior with population carrier screening programs. In three such studies in the United States involving.11 685 wom-en,27–2913 at-risk couples were identified, of which 12
had prenatal diagnosis. There were 2 fetuses with CF, and 1 of these was terminated. The apparent greater interest in prenatal diagnosis among couples without a CF child may be related to the information they receive about the disease or who provides the information.30 In our CF neonatal screening project, information about the disease was provided by CF center staff, and the families had the opportunity to observe their first child with CF and to talk with other parents of children with CF. In the general population studies, the information was provided by clinicians not directly involved in CF care. Possibly, parents in the general population carrier screening programs would make different decisions if they were provided with information by CF clinicians and/or interacted with children who have CF. Which level of interest in prenatal diagnosis repre-sents a more authentic view of the perceived value of children with CF to their families is a broader nor-mative question than can be addressed in this article. Although this is the largest study of reproductive behavior after CF neonatal screening, it is still diffi-cult to reach definitive conclusions about the overall benefit/risk relationship of this component of the screening system.2 Newborn screening for CF does not seem to have a significant impact on reproduc-tive attitudes and behavior of parents. The majority of parents with CF children understood the genetic implications for future children. Most families whose first-born child has CF continue to have children, and only a few used prenatal diagnosis. Individual variation typically occurs in reproductive decision-making, and the relationship between knowledge, attitudes, and behavior of parents is complex. Nev-ertheless, this genetic risk information seems
able to some families and should still be considered a limited secondary benefit in national policy deci-sions about CF newborn screening.
Implications of CF Carrier Detection
The identification of infant CF heterozygotes in the IRT/DNA approach has several implications. Our data suggest that families from both the IRT and IRT/DNA screening programs understood that their child with a positive screening and negative sweat test did not have CF. A minority of families continue to think about the sweat test results. More families in the IRT/DNA group believed that screening has af-fected their feelings about having children. This must be interpreted cautiously, however, because we did not ask more precisely how it affected their decision. Further research is needed to understand how atti-tudes may be affected by the newborn screening experience and its actual impact on behavior. If it were the case that people choose to have fewer chil-dren because of misunderstanding, this would be an important consideration in developing policy.
Although most families understood the implica-tions for their child of being a carrier for CF, some were confused. These results are consistent with an assessment of 114 pregnant heterozygotes, in which mean knowledge scores on a six-item instrument increased from 51% to 82% after in-person genetic counseling.28 In our study, genetic counseling was done face to face by either a genetic counselor or, in a minority of cases, by a CF physician or a master’s-level nurse practitioner with extensive CF experience and knowledge. Clayton et al31 demonstrated that written and/or video information effectively con-veyed the meaning of negative results in an adult population screening study. This was understood by 96% of college-educated participants but only 68% of those with less than a high school education. It is not known how effective such alternative methods of providing genetic information will be in newborn screening.
Among those parents who received follow-up in-teractive genetic counseling and further genetic
test-ing to determine their carrier status, 69% did not understand that their risk of having a child with CF was still greater than the general population. This is particularly troubling because the expressed reason for those who requested further genetic testing was to obtain more accurate risk information. However, our results are similar to adult general-population carrier screening studies in which this was misun-derstood by 40% of 30 carriers32and 56% of 26 car-riers.33 Lippman-Hand and Fraser34 have observed that many families translate reduced risk to no risk in their processing of information. This may explain the paradoxical finding that mothers who had testing were less likely to understand that they were still at risk. They had a relatively reduced risk compared with those who did not have testing. Relative risk perception is a difficult concept for people who nor-mally do not think about probabilities; this poses problems not only for genetic counseling but even for developing valid methodologies to assess under-standing.
Our findings demonstrate that the genetic infor-mation presented to false-positive families is prone to misunderstanding. This suggests that the interac-tive approach to providing genetic information and counseling needs to be given careful consideration in the context of newborn screening programs. The anx-iety at the time of the sweat test may be an obstacle to understanding this information. For those who had subsequent testing, providing test results by telephone and a follow-up letter might also have contributed to the misunderstanding. It is also pos-sible that there was greater initial understanding but that this was not retained throughout time. More research is needed to understand why many parents do not understand that they are still at risk and whether there are alternative genetic counseling ap-proaches that are more effective in conveying this information. In the interim, we would recommend that those considering implementation of IRT/DNA programs utilize face-to-face counseling with trained personnel, such as genetic counselors or nurse spe-cialists, to convey genetic information to such
lies with interactive communication at the time of the sweat test.
Although more than half the families in this study pursued additional testing and counseling, they indicated that their decision was influenced by these services being provided free of charge. There may be less interest for follow-up counseling when it is not covered financially as part of the program. If follow-up testing is not provided gratis, a greater emphasis should be placed on the development and evaluation of effective materials and methods to be used at the time of the sweat test or immediately thereafter. It also suggests that policy makers should consider providing fol-low-up counseling and testing to false-positive families as an integral part of the subsidized pro-gram and in an attempt to minimize adverse events in this population.
The inadvertent identification of neonatal CF car-riers raises the question of the adequacy of prenatal education and informed consent for newborn screen-ing.35 With further advances in genetic information and technology, it will become feasible to screen for a greater number of diseases in which the benefits are less compelling than is the case with phenylke-tonuria and hypothyroidism.2 Furthermore, the fa-milial implications of carrier detection are complex and unpredictable, as found in our study. Informed consent for newborn screening in the prenatal setting may increase parental understanding, and consent may allow the few parents concerned about neonatal carrier detection to decline. A 1994 report on assess-ing genetic risks from the Institute of Medicine an-ticipated this trend and recommended that educa-tion and consent for newborn screening be strengthened as newborn screening programs ex-pand to DNA-based tests.36
Routine clinical testing for autosomal recessive traits in infants is not recommended because hetero-zygote carrier infants are not likely to benefit from such information and there are a range of potential psychosocial harms.37 In the IRT/DNA approach, it is a foreseen but unintended consequence for carrier infants to be identified to offer the possibility of benefit to those diagnosed with CF. Policy decisions about CF newborn screening will be determined not only on the basis of the data from this and additional studies, but also on the basis of normative assess-ments of whether the benefits outweigh the potential harms.38 Additional challenges are posed when the benefits accrue to one subgroup and the harms occur in others, but this is true of all newborn screening programs.2
It is essential, in our judgment, that centers doing the definitive sweat testing have counselors available to explain the genetic implications for the newborn’s family, parents and siblings, extended family mem-bers, and ultimately the newborns themselves when they reach an age at which information is relevant to them. As more states embark on implementation of CF neonatal screening programs, it will be important to develop standard methods for informing parents and other family members about the genetic impli-cations of newborn screening. In addition, more
re-search is needed on the process of genetic counseling methods and its impact on knowledge and behav-iors. This should be pursued as an integral compo-nent of CF neonatal screening programs as recom-mended by the Centers for Disease Control and Prevention.39
ACKNOWLEDGMENTS
This research was supported by Grant A001 5– 01 from the Cystic Fibrosis Foundation and Grants DK 34108 and RR03186 from the National Institutes of Health. Benjamin S. Wilfond, MD, was supported by Grant R29 HS08570 from the Agency for Health Care Policy and Research. We thank Rebecca Koscik for her in-valuable support of the data management aspects of this study and all the investigators of the Wisconsin Cystic Fibrosis Neonatal Screening Study Group, especially the CF center directors who collaborated in this project: Drs W. Theodore Bruns, Christopher Green, Michael Rock, and Mark Splaingard.
The Wisconsin Cystic Fibrosis Neonatal Screening Group in-cludes Miriam Block, RN; Lisa A. Davis, RD; Philip M. Farrell, MD, PhD; Lynn Feenan, RN, MS; Christopher Green, MD; Rebecca E. Koscik, MS; Michael R. Kosorok, PhD; Anita Laxova, BS; Mari Palta, PhD; Michael J. Rock, MD; Guanghong Shen, MS; Audrey Tluczek, RN, MS; L. J. Wei, PhD; Benjamin S. Wilfond, MD; and Lan Zeng, MS, at the University of Wisconsin-Madison Medical School, Madison, Wisconsin; David J. Hassemer, MS; Gary Hoff-man, and Ronald H. Laessig, PhD, at the Wisconsin State Labora-tory of Hygiene, Madison, Wisconsin; and W. Theodore Bruns, MD; Holly Colby, RN; Mary Ellen Freeman, RN; William Gershan, MD; Catherine McCarthy, RN; Elaine H. Mischler, MD; Mark Splaingard, MD; and Lee Rusakow, MD, at the Medical College of Wisconsin, Milwaukee, Wisconsin.
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DOI: 10.1542/peds.102.1.44
1998;102;44
Pediatrics
Catherine McCarthy and Philip M. Farrell
Reiser, Christine M. Sauer, Linda M. Makholm, Guanghong Shen, Lynn Feenan,
Elaine H. Mischler, Benjamin S. Wilfond, Norman Fost, Anita Laxova, Catherine
Implications for Genetic Counseling
Cystic Fibrosis Newborn Screening: Impact on Reproductive Behavior and
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DOI: 10.1542/peds.102.1.44
1998;102;44
Pediatrics
Catherine McCarthy and Philip M. Farrell
Reiser, Christine M. Sauer, Linda M. Makholm, Guanghong Shen, Lynn Feenan,
Elaine H. Mischler, Benjamin S. Wilfond, Norman Fost, Anita Laxova, Catherine
Implications for Genetic Counseling
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