Utilization of Prenatal Diagnosis For Cystic Fibrosis Over the Past Seven Years

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Utilization

of Prenatal

Diagnosis

For

Cystic

Fibrosis

Over

the

Past

Seven

Years

ilse Jedlicka-Kohler, PhD; Manfred G#{246}tZ,MD; and Irmgard Eichler, MD

ABSTRACT. Objective. First trimester prenatal

diag-nosis (PD) by DNA analysis for cystic fibrosis (CF) has

been available for parents of affected children since May

1986.

Methods. In a prospective study 37 couples with a single child affected by CF were investigated. Fathers and mothers were interviewed simultaneously, and their

attitudes towards further childbearing and potential

uti-lization of PD ascertained. Parental answers were treated as one. A 7-year follow-up allowed comparison between intended and actual behavior.

Results. At the time of the interview, 16 parents (43%) were determined to have further children. Nineteen parents

(51%) said they would certainly or probably utilize PD in case of pregnancy. Their predominant reason for favoring PD was

the strong desire to have a healthy child (47%). Among the 18 rejechis(49%)thefearofanunsolvableconffictincaseofan

affected fetus prevailed (39%). Twenty-four pregnancies

actu-ally occurred in 18 families. Utilization of PD was arranged in

five 21%) and finally performed in four (17%) cases.

Conclusion. Availability of PD does not substantially change the repmductive behavior of parents of children with

civ.

for this were multifactorial, with anticipated

dif-ficulty in deciding to continue or terminate pregnancy being

predominant Pediatrics 199494i13-16; behavioi cystic

fthm-sL

-

dia, psydwlogy.

ABBREVIATIONS. CF. cystic fibrosis; PD, prenatal diagnosis.

A large proportion of families with a child with

cystic fibrosis (CF) tend to stop having further chil-then to avoid the one-in-four risk of another affected

child.” In one study 20% of the investigated 50

mothers even indicated they would commit suicide rather than have another child with CF.3

In cystic fibrosis, the most frequent monogenic hereditary defect in Caucasians, the defective gene causes altered membrane function in a variety of

organs, ranging from the lungs to the sweat glands.

Although median survival age doubled from 14 to 28 years between 1969 and 1990k with a predicted

me-dian life expectancy for babies born today of up to 40

years5 the disease still remains incurable. Demanding

lifelong therapy, physical limitations, and ensuing

psychosocial restrictions contribute to progressively decreasing quality of life.

From the University Children’s Hospital, Vienna, Austria.

The results of this study were presented, in part, at the Sixth Annual North American Cystic Fibrosis Conference, Washington, DC, October 15-18,

1992.

Received for publication Jun 16, 1993; accepted Dec 15, 1993.

PEDIATRICh (IS5N 0031 4005). Copyright C 1994 by the American

Acad-amy of Pediatrics.

Given the severity of the disease, availability of first trimester prenatal diagnosis (PD) by DNA anal-ysis was considered to increase substantially the

re-productive options for couples with an affected

child. This assumption was supported by findings of studies before PD was generally available, exploring what parents might do in a hypothetical situation.’ Then, pronounced interest in this option was

re-vealed. Eighty-one to 94% of parents of children with

CF favored the development of fetal diagnosis”, and

85% had the intention to use PD should pregnancy

occur.6 The purpose of this prospective study, there-fore, was to explore the reproductive behavior of parents of children with CF who faced the actual availability of a preventive strategy. Our specific

aims were 1) to examine the effect of availabifity of

PD on family planning, 2) to identify attitudes to-wards PD, 3) to find out to what extent parents intended to have PD prior to a subsequent

preg-nancy,

and 4) to assess actual performance of PD in case of pregnancy.

Subjects

MATERIALS AND METHODS

Since mid-1986 the CF Center at the UniVersity Children’s Hospital in Vienna has been able to provide first trimester prenatal diagnosis by

DNA analysis. This center serves a third ofthe Austrian FpOpUIa6OTh StartinginMay l98#{243}weselected families who met the following cnteia:

1) The child with

c

born after January 1980 and had to be the

firstborn and still the only child atthe beginning of the study. This was

toavoid thepreviouslyreported finding thatthehigherthebirth rank of

thechild withO, thelessprobableasubsequentpregnancy.6 From May

1986 onwards all parents of newly diagnosed children enrolled in our

center were enlisted in our study. 2) No children from previous

mar-riage. 3) Biological parents were married or cohabiting. A stable

rela-tionship was considered a basic requirement for amassing future family planning. 4) Maternal age at the birth of the child with F had to be

below 30 years in order to avoid the bias of older gravidas. Subject

recruitment ended in April 1991 and follow-up was finished in Apiil

1993. This irttervalallowed even theparentsof theyoungestchild at least 2 years to consider a subsequent pregnancy.

Methods

Information about PD was performed twice by the

pediatri-dana (MG, IE). Parents whose child was born between May 1986

and April 1991 received this information in the context of

corn-munication of diagnosis and again within a month. To parents whose child was born between January 1980 and April 1986 PD was explained between May and September 1986 at a regular clinic visit and repeated at the consecutive appointment 1 to 3 months later.

The psychologist (I J-K) conducted a structured interview with

both parents present 4 to 8 weeks following the second

commu-nication of information on PD. Parents were interviewed during a

regular dinic visit at the hospital. Each session lasted 60 to 90

minutes. In part 1 of the interview, parents’ baseline knowledge of

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14 PRENATAL DIAGNOSIS FOR CYSTIC FIBROSIS to ensure that the information given by the pediatricians had been

retained. In case of false answers, correct information was pro-vided. In part 2 of the interview a number of standardized

ques-tions were asked. Items focused on: assessment of initially

planned family size before and reproductive plans after the birth of the CF child; attitudes towards prenatal diagnosis; assessment of the potential utilization of PD. Parents’ responses represent

their shared views. Part 3 of the interview gave parents the

op-portunity to verbalize concerns and to pose questions.

Data collection included review of medical records for

infor-mation on age at diagnosis, age at counseling, and health status of the child. Severity of disease was calculated by the pediatricians

according to the Shwachman score? from case history, pulmonary

physical findings, and cough, growth, and nutrition. As chest

radiographs are taken routinely only once a year, not all children had recent documentation of this item. Therefore, chest

radio-graphs were not considered, thus rendering the maximum

Shwachman score available at 75.

Statistics

Questionnaire data were entered into a Statistical Package for the Social Sciences.8

Differences between firstborn children with CF whose mothers

had a subsequent pregnancy and children remaining without sibs,

in relation to age and health status, were examined using t tests and Mann-Whitney U tests depending on the distribution of the

variable under consideration. Differences between intended and

performed utilization of PD were assessed by means of the McNemar’s test for paired groups.

P values of <.05 or less were accepted as significant.

RESULTS

The psychologist interviewed 37 sets of parents; 35 were married and two cohabiting. At diagnosis, cM!-dren’s median age was 1 month (range, 0 to 40 months), and, at the time their parents were first counseled about PD, it was 3 months (range, 0 to 63

months). A mean Shwachman score of 63 (range, 46

to 72) at the time of counseling about PD reflects good health in most of the children (maximum score without chest radiograph, 75). Eleven children were

born before May 1986 and 26 thereafter. Mean fol-low-up was 5.1 years (range, 24 months to 7 years).

At the time of the interview 16 (43%) couples were determined to have two or more children whereas 21 (57%) decided against further offspring. Compared to their intentions before the child with CF was born a number of parents changed their plans.

Attitudes Towards Prenatal Diagnosis

Parents were asked if they intended to use PD

should pregnancy occur. Fifty-one percent thought that they would certainly or probably use it, while 49% answered that they would certainly or probably not use it. Parents were requested to state their rea-sons for favoring or rejecting PD in their own words. Reasons were manyfo!d as shown in Tables 1 and 2 with many parents

giving

two answers.

TABLE 1. Reasons for Favoring Prenatal Diagnosis (n = 19)

n %

9

Desire to have a healthy child 47

Unbearable psychological distress caused by two 6 32 children with CF

Inabifity to master the demanding and time consuming 6 32

management of two affected children

Wish for a surviving child 2 11

Early emotional adjustment/relief 1 5

To perform selective termination I 5

TABLE 2. Reasons for Rejecting Prenatal Diagn osis (n = 18)

n %

Fear of an unsolvable conflict in case of an 7 39

affected fetus

implicit downgrading of the child with CF 6 33

Moral constraints 4 22

Religious beliefs 3 17

Good health in the child with CF 3 17

Frightening anticipation of repeated I 6 pregnancies and terminations

Fetus treated as a “guinea-pig” I 6

Increased risk of fetal mortality I 6

Normal intellectual development rules out PD I 6

Hope that, due to the I in 4 risk, the I 6

subsequent child will be healthy

The predominant reason for favoring PD (Table 1)

was the strong desire for a healthy child (47%). The

desire to have a surviving child, as expressed by two couples, differs in its meaning from the wish for a healthy child as it implicitly predicts the death of the child with CF. The anticipation of an unbearable emotional burden caused by two children with CF (32%) was as pronounced as the fear of insufficient capacity to care for the children. It is noteworthy, that only one couple definitely stated the intention to use PD as a means to terminate the pregnancy in case of an affected fetus.

Interestingly, ethical considerations (22%) and re-ligious beliefs (17%) were not predominant among rejectors of PD (Table 2). Parents’ major concerns were the anticipated difficulty in deciding to con-tinue or terminate the pregnancy when facing an affected fetus (39%). They preferred to avoid the anxiety of having to think about the implications of an affected fetus by avoiding the possibffity of PD entirely. Thirty-three percent of parents valued their relationship to the living child with CF and felt that the use of PD would lead to a disdain and disrespect for the firstborn.

Reproductive Behavior

Over the 7-year observation period, 24

pregnan-cies occurred in 18 families (49%). Nine out of these

18 couples had not changed their reproductive plans

after the CF diagnosis and decided for subsequent

children despite the disease in their firstborn child,

four couples reduced the number of planned

cM!-dren from three to two. Four families who had

de-cided against further offspring due to CF changed their mind. One family who initially had wanted only one child faced an unexpected pregnancy.

Age at diagnosis, age at first communication of PD and Shwachman score at the time of counseling did not differ statistically significantly between the

first-born children with CF whose mothers had a

subse-quent pregnancy and those who had not. This result suggests that age and health status of the child were not predictive of the occurrence of pregnancy.

Utilization of Prenatal Diagnosis

Among the 18 couples who had subsequent preg-nancies (Table 3), 11 (61 %) intended utilization of PD at the time of the interview. When pregnancy was

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TABLE

sequent

3.

Decision-Pregnancy

making Process in 18 Parents With

Sub-Family PD Intended

When Interviewed

PD Arranged

When Pregnant

Outcome of Pregnancy

I (3) No No (3) Spontaneous abortion (2)

Went to term (1)

2 (3) Yes No (3) Went to term (1)

Spontaneous abortion (2) 3 (2) No No (2) Went to term (2)

4 (2) Yes No (2) Elective termination (2)

5 (1) No No Went to term

6 (1) No No Went to term

7 (1) No No Went to term

8 (1) Yes No Went to term

9 (1) Yes No Went to term

10 (1) Yes Yes Went to term

11 (1) Yes No Went to term

12 (1) No No Went to term

13 (1) No No Elective termination

15 (1) Yes Yes* Spontaneous abortion

17 (1) Yes No Went to term

18(1) Yes Yes In progress

Number of pregnancies given in parentheses. *Spontaneous abortion preceded PD.

detected, statistically significantly less couples (n = 5) chose this option (:

P

< .05).

In four families two and three pregnancies,

respec-tively, occurred. For analysis of utilization of PD

each pregnancy was considered a separate event, taking into account that every pregnancy offers and

requires an individual decision-making process. PD

was arranged in five (21%) and eventually

per-formed in four (17%) cases, because one mother

ex-perienced a spontaneous abortion on the very day choriomc villus biopsy was to be performed.

All seven parents who initially had rejected PD remained unchanged. They decided in altogether 10 pregnancies against PD. Those 11 couples who had planned to use PD were less uniform, as only five stuck to their intention, whereas six eventually

re-fused testing in nine cases. This result demonstrates

that as testing became a reality the majority of par-ents in favor of PD changed their minds and made a new decision It is noteworthy that in six cases (29%) pregnancy was reported too late for PD by DNA analysis, ie, beyond 16-week gestation. This finding

suggests that some parents thus avoided a difficult

choice and an emotional dilemma.

Outcome of Pregnancies

Overall outcome of 24 pregnancies revealed six healthy children. In one case, although the family had met the selection criteria, it turned out that the father of the second child was different from the father of the firstborn. Nine children born are af-fected by CF. Five spontaneous abortions occurred,

three after a definite decision against PD had been

made. There were two spontaneous abortions in one family both at 6-week gestation, where the potential utilization of PD remained unclear but rejection of

this option had been apparent in the preceding preg-nancy that went to term. Three pregnancies resulted in elective termination after rejection of PD, two due

to the fear of an affected child and one because of

heart malformation diagnosed by ultrasound.

DISCUSSION

The objectives of this study were to ascertain parents’

views on prenatal diagnosis and to examine the actual utilization by following the families for up to 7 years. To

our knowledge this is the first study that has avoided the

previously described effect of birth rank order on further

childbearing by

solely

induding families with a single

child with F. Furthermore, because counseling was

un-dertaken outside the context of reproduction, intentions

unbiased by the need for urgent decision-making could

be investigated.

The major finding that only a minority of those

parents who undertook pregnancy agreed to PD

(21 %) questions the predictive value of

investiga-tions

dealing with hypothetical reproductive deci-sions (ie, in the absence of availabffity of test), at least for CF. Meanwhile, three studies from the United States, though not really comparable with regard to

study design and sample selection, reported uptake

rates of 13% and 29%, respectively, thus also reflect-ing low rates of utilization of antenatal diagnosis by mothers of children with CF.9” These low uptake rates suggest that the intention to use PD was more pronounced when 1) PD was not available or 2) the study subjects were not facing an at-risk pregnancy that personally concerned them. In other chronic diseases such as sickle cell disease,’2 thalassaemia major,’3 Down’s syndrome or neural tube defect,’4 and spina bifida’5 utilization of PD was generally

much higher. The demand for PD can be influenced

by factors such as the type of the diagnostic

proce-dure, the type of fetal abnormality, the physical and psychological characteristics of the disease, the amount and intensity of treatment required, and the predicted prognosis. We assume that in CF these factors influenced parents’ subjective appraisal of disease severity thus partly explaining differences in demand for PD compared to other diagnoses.

In our study, attitudes towards PD were many-fold. About half of parents did not regard PD as a beneficial option. Instead, the anticipation of an in-evitable conifict between the fear of an affected child and the fear of possibly not being prepared to termi-nate the pregnancy predominated; feelings of guilt towards the child with CF and a number of personal

reasons and concerns mirror the tremendous distress

caused by what was considered to be an urgently awaited reproductive option. We assume that the element of choice partly explains parents’ reluctance to face a decision about continuing or terminating the pregnancy. In contrast to their first pregnancy, by undergoing PD, the responsibility for the birth of an affected child is no more a result of fate or coinci-dence. It is the parents who must decide whether the child is to live or not to live. Obviously, parents are placed in an unusually difficult position. They only have the choice between two undesirable goals where either decision brings with it emotional costs.

Psychologists call this situation an

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16 PRENATAL DIAGNOSIS FOR CYSTIC FIBROSIS alternatives. The latter was preferred among parents declining PD.

Actual utilization of PD in our sample was lower

than intended. Although we only observed a shift

from intending to use PD towards rejecting it, an

inverse shift also might occur. We suggest that

ge-netic counseling and information about PD should

be provided to all parents no matter what their initial

reaction. When parents underwent the psychological

interview, most were not yet familiar with the dis-ease but preoccupied with the threatening facts such as incurabifity and diminished life expectancy. Due

to the dramatic progress in the therapy of CF, many

children pass through their early years without

sig-nificant health problems, not distinguishable from their peers in terms of cognitive and psychosocial development. It is in these early years that parents make a decision about further offspring. We

assume

that parents’ growing experiences with the near normal

and pleasing development of their child, coupled with the potential for even better prognosis due to the

ex-pected advances in pharmacologic and gene therapy

partly

accounts for the lower than

intended

use

of PD.

We speculate that this also might be a reason why a

number of parents who initially did not want any more

children eventually decided in favor of further

off-spring. In addition, we observed that quite a number of

parents reported different opinions on subsequent

cM!-dren, sometimes varying a few times within a month.

These shifts usually were related to changing health conditions of their child, learning other pafients

histo-lies, hospital admission, and the ongoing experience

with CF. We condude from these observations and the

above mentioned results that parents’ decisions to

re-frain from further children alter over time. Therefore,

irreversible procedures such as sterilization should not

be recommended.

In contrast to other researchers we have not

ad-dressed the issue of abortion. For reasons of the

extreme hypothetical nature of the question and the

anticipated emotional inability to predict such a

de-cision years ahead parents were not asked about

their personal willingness to abort a fetus with CF.

Since the four fetal diagnoses performed predicted

healthy children no termination of pregnancy had to be considered. Still, the topic deserves attention. As in hypothezised and actual utilization of PD,

predic-tion of termination similarly shows discrepant

re-suits. In a study by Botkin et al., 29% of pregnant

women with no family history of CF would abort for

CF.’6 Among parents of a child with CF 20% and

52%, respectively, would terminate an affected

preg-nancy.’7”8 contrast, the range of actually

per-formed terminations after positive PD for CF was 64

to 100%.19_21

Due to the young age of the children and their

parents, among families where no subsequent

preg-nancy had occurred till the end of the study, future pregnancies may be expected, thus possibly shifting

our results. We therefore reassessed those parents’

attitudes towards further children and PD in March

1993. Seven couples stated they definitely would not have another child. Eight of the remaining 12 couples

rejected and four favored PD. With respect to the

observed shift from parents initially in favor of PD to rejecting it when pregnancy occurred, we therefore speculate that the reported utilization rate of PD will not drastically change in the near future.

ACKNOWLEDGMENTS

We thank Wolfgang Dorda, MD, MSc, for his statistical advice and Andrea Kofinger, MTA, for her help in data processing.

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1994;94;13

Pediatrics

Ilse Jedlicka-Köhler, Manfred Götz and Irmgard Eichler