Attitudes towards prenatal diagnosis and carrier screening for cystic fibrosis among the parents of patients in a paediatric cystic fibrosis clinic.

The parents of all children attending the Royal Brompton National Heart and Lung Hospital cystic fibrosis paediatric clinic were asked to complete an anonymous postal questionnaire addressing attitudes towards prenatal diagnosis and population carrier screening for cystic fibrosis (CF); 65% (170/261) of parents responded. Of the respondents, 92% would support the introduction of a population screening test to detect carriers of CF and 19% felt such a test should be mandatory. A total of 64% of CF parents felt they would choose not to have any further children in the knowledge that they were both carriers, 74% would choose to have a prenatal test if they became pregnant, 44% would consider terminating an affected pregnancy, 33% would not, and 23% were unsure. Overall, 72% of respondents indicated they would choose to avoid having a further child with CF either by not having further children or by terminating an affected pregnancy.     

'It is not in my world': an exploration of attitudes and influences associated with cystic fibrosis carrier screening

Carrier screening for cystic fibrosis has been recommended for pregnant women and their partners, individuals and couples prior to conception, and for people with a family history. Many pilot programmes offering cystic fibrosis carrier screening, most commonly in the prenatal setting, have shown that uptake and acceptability are high. This article explores perspectives of the Victorian community regarding carrier screening for cystic fibrosis prior to offering screening. In particular whether or not such carrier screening should be offered, the best time for offering carrier screening, the information required for making a decision about carrier screening, and how this information can best be provided. A qualitative approach was taken to enable exploration of the views of stakeholders. Four focus groups and 32 interviews were conducted with a total of 68 participants. Participants were in agreement that cystic fibrosis carrier screening should be made available to everyone. However, potential consumers viewed cystic fibrosis carrier screening as 'not in my world' and were unlikely to request such screening unless it was offered by a health professional, or they had a family history. The best time for carrier screening was seen to be an individual preference and an information brochure was perceived to be useful when considering carrier screening. Lack of knowledge around the irrelevance of family history is a barrier to cystic fibrosis carrier screening. This study highlights the importance of community consultation, with stakeholders, prior to implementation of carrier screening programmes.     

What do young people think about screening for cystic fibrosis?

We investigated the knowledge of cystic fibrosis and the views about neonatal and carrier screening in 216 school students aged 14 to 16 years. This work was completed before the published identification of the cystic fibrosis gene in September 1989. Although initial knowledge of cystic fibrosis was low (only 17% of the students knew that the disease affected the lungs), there was good recall of basic information about cystic fibrosis and of recessive inheritance after a brief lecture. A total of 86% considered that carrier detection should be offered routinely and 88% felt that an offer of prenatal diagnosis for cystic fibrosis should be made if both prospective parents were known to be carriers. We believe that pilot studies of cystic fibrosis carrier screening in schools should be undertaken.     

Personal experiences of cystic fibrosis (CF) carrier couples prospectively identified in CF families

This qualitative study explores the experiences of cystic fibrosis (CF) carrier couples, prospectively identified in CF families, and the impact of the resulting genetic risk on reproductive behavior. Of the 12 couples identified until 1997, seven couples participated in semistructured interviews and two couples filled in a questionnaire, two to eight years after receipt of the test-results. After receiving the results, most couples reported that they were shocked, because they did not expect to both be carriers. More anxiety was expressed by those who were pregnant (n = 4) at the time of testing. There were reported difficulties in disclosing the results to family members, and the reactions of family members were not always supportive. After testing, some couples had problems with reproductive decision-making. All viable pregnancies (17 in 8 couples) were monitored by prenatal diagnosis; all affected pregnancies were terminated (6 in 4 couples). Couples who have live-born children after testing may subsequently have concerns during infancy about the correctness of the results of prenatal diagnosis and how to inform their children. Most couples did not regret the testing and, in general, the counseling was experienced positively, although some dissatisfaction was reported with regard to the psychological support received during pregnancy. Couples supported the idea of carrier screening in the general population, although various concerns were expressed. The results indicate a preference for testing before pregnancy. These findings may be useful in investigating possible dilemmas caused by the introduction of population carrier screening. Observations reported here might also apply to other recessively inherited disorders.     

Preimplantation genetic diagnosis for Huntington's disease with exclusion testing

Huntington's disease is an autosomal dominant, late-onset disorder, for which the gene and the causative mutation have been known since 1993. Some at-risk patients choose for presymptomatic testing and can make reproductive choices accordingly. Others however, prefer not to know their carrier status, but may still wish to prevent the birth of a carrier child. For these patients, exclusion testing after prenatal sampling has been an option for many years. A disadvantage of this test is that unaffected pregnancies may be terminated if the parent at risk (50%) has not inherited the grandparental Huntington gene, leading to serious moral and ethical objections. As an alternative, preimplantation genetic diagnosis (PGD) on embryos obtained in vitro may be proposed, after which only embryos free of risk are replaced. Embryos can then be selected, either by the amplification of the CAG repeat in the embryos without communicating results to the patients (ie non-disclosure testing), which brings its own practical and moral problems, or exclusion testing. We describe here the first PGD cycles for exclusion testing for Huntington's disease in five couples. Three couples have had at least one PGD cycle so far. One pregnancy ensued and a healthy female baby was delivered.     

Prenatal cystic fibrosis screening in a low-risk population undergoing chorionic villus sampling for fetal karyotyping

Screening for cystic fibrosis (CF) has been offered to pregnant women seeking chorionic villus sampling (CVS) for prenatal chromosomal abnormality investigation. The mutation panel has increased over the years to include 8 mutations and can detect 65% of abnormal CF genes in the Italian population. Testing was offered to a total of 2214 consecutive pregnant women; 45 of them declined screening (take up rate: 98%). In 1055 of the 2169 pregnancies screened, the test was at first done on the fetus, while in the remaining cases both parents were investigated. Among parents 46 carriers were identified (2.1%), in 41 of whom the mutation was delta F508. In two couples both parents were heterozygous, and in one the fetus was affected and the pregnancy was terminated. Although CF testing offered to pregnant women undergoing invasive investigation such as CVS may not be the model for a mass screening, its very high effectiveness can represent an advantageous component of more comprehensive strategies.     

Reproductive decision making of aunts and uncles of a child with cystic fibrosis: genetic risk perception and attitudes toward carrier identification and prenatal diagnosis.

This paper evaluates the perceived genetic risk, the perceived burden, the impact on reproductive decision making, and the attitudes of aunts and uncles of a child with cystic fibrosis toward carrier identification, prenatal diagnosis, and pregnancy termination. A mailed questionnaire was sent to the aunts and uncles of 32 CF children (1) who attended the Paediatric Department of the University Hospital and (2) whose parents agreed to give the names and addresses of their sibs. The results for the 109 respondents aged less than 40 years are discussed. About one-fourth of them was aware of the "approximate" level of the risk to be a carrier of the CF gene and/or of the risk of having a CF child themselves. Nevertheless the subjective evaluation of the genetic risk has played a part in the reproductive decision-making process of at least 39% of the respondents. About three-fourths would (probably) make use of heterozygote detection and would (probably) ask for prenatal diagnosis should they become pregnant. It is striking that less than half of the group would interrupt the pregnancy should the fetus be affected. The intention to use prenatal diagnosis was significantly correlated with age and educational level while the acceptance of pregnancy interruption was significantly correlated with perceived burden, respondents' age, and health situation of the proband.     

Prenatal genetic testing for cystic fibrosis: a systematic review of clinical effectiveness and an ethics review

PurposeWe aimed to assess the clinical value of prenatal testing for cystic fibrosis (CF) and whether ethical considerations would affect endpoint selection.MethodsTo determine effectiveness, we conducted a systematic literature review whose protocol outlined search strategies across eight databases, study inclusion criteria, and prespecified literature screening, data extraction, and synthesis processes. We conducted a scoping search on ethical considerations.ResultsThe genetic test showed good diagnostic performance. A change in clinical management was observed: termination of pregnancy (TOP) occurred in most cases where two pathogenic variants were identified in a fetus of carrier parents (158/167; 94.6%). The TOP rate was lower in pregnancies where CF was diagnosed after fetal echogenic bowel detection (~65%). TOP and caring for a child with CF were both associated with poor short-term parental psychological outcomes. Ethical analyses indicated that informed decisions should have been the main endpoint, rather than CF-affected births prevented.ConclusionCF testing leads to fewer CF-affected births. It is difficult to assess whether this means the test is valuable, since patients may not value TOP primarily in terms of maternal or fetal health outcomes, psychological or otherwise. The value of testing should arguably be measured in terms of improving patient autonomy rather than health.     

Reconsidering reproductive benefit through newborn screening: a systematic review of guidelines on preconception,prenatal and newborn screening

The expansion of newborn screening (NBS) has been accompanied by debate about what benefits should be achieved and the role of parental discretion in their pursuit. The opportunity to inform parents of reproductive risks is among the most valued additional benefits gained through NBS, and assumes prominence where the primary goal of identifying a treatable condition is not assured. We reviewed 53 unique guidelines addressing prenatal, preconception and newborn screening to examine: (1) how generating reproductive risk information is construed as a benefit of screening; and (2) what conditions support the realization of this benefit. Most preconception and prenatal guidelines – where generating reproductive risk information is described as a primary benefit – required that individuals be given a ‘cascade of choices'', ensuring that each step in the decision-making process was well informed, from deciding to pursue information about reproductive risks to deciding how to manage them. With the exception of three guidelines, NBS policy infrequently attended to the potential for reproductive benefits; further, most guidelines that acknowledged such benefits construed voluntarism narrowly, without attention to the choices attendant on receiving reproductive risk information. This review suggests that prenatal and preconception guidance identifies a coherent framework to support the pursuit of reproductive benefits through population screening programmes. Interestingly, attention to reproductive benefits is increasing among NBS guidance, yet reflection on how such benefits ought to be pursued remains limited. Traditional norms for NBS may require reconsideration where the remit of screening exceeds the primary goal of clinical benefits for infants.     

Ethical and social aspects of risk predictions

This paper reviews past, present and future social and ethical considerations of screening carriers of autosomal disorders and other heterozygotes. A body of ethical and social guidance has evolved in the 1970's and 1980's for screening. The values of voluntaristic participation and informed consent are high. The goal of programs should be to provide couples, families, and individuals with knowledge respecting their reproductive choices. The dangers are coercive strategies, stigmatization, and careless communication of risk information. It is assumed that the number of autosomal carrier states that are screenable will undoubtedly increase as will states of heterozygosity that cause susceptibility to common diseases. Before the end of the century, something approaching a "biopsy of the human genome" will be a practical reality. To balance the potential for harmful psychological and social effects of so much new genetic knowledge, new efforts must be made to find treatments for progeny affected by recessive disorders. Maternal and paternal screening, prenatal diagnosis and treatment will be increasingly linked in the future. This paper will report on a case of fetal therapy for congenital adrenal hyperplasia as a paradigm for the future. The argument will be made that society ought to put a higher priority on prenatal care and prevention of disorders of prematurity than genetic disorders with a low frequency, lest genetic screening be distorted by unfounded concern about eugenics.     

Informing on prenatal screening for Down syndrome prior to conception. An empirical and ethical perspective

In most Western countries, information on prenatal screening for Down syndrome is provided in the first-trimester of pregnancy. The purpose of this study was to examine whether this information should additionally be provided before pregnancy to improve the informed decision-making process. In an empirical study, we obtained data from pregnant women with respect to their preferences regarding information on prenatal screening preconceptionally. Questionnaire data (n?=?510) showed that 55.7% of responding women considered participating in prenatal screening for Down syndrome before pregnancy. 28.0% of women possessed information on prenatal screening preconceptionally. 84.6% preferred not to receive information preconceptionally in retrospect. In an ethical analysis, we elaborated on these preferences by weighing pros and cons. We considered two arguments against the provision of information on prenatal screening preconceptionally: women's preference to receive information in a step-by-step manner, and the risk of providing a directive message. We identified three reasons supporting its provision preconceptionally: the likelihood of making an informed decision could, firstly, be increased by "unchaining" the initial information from possible subsequent decisions, and, secondly, by providing women sufficient time to deliberate. Thirdly, the probability of equal access to prenatal screening may increase. To conclude with, we propose to incorporate an information offer on prenatal screening for Down syndrome in preconception care consultations. By offering information, instead of providing information, prospective parents are enabled to either accept or decline the information, which respects both their right to know and their right not-to-know.     

Parents' experiences of universal screening for haemoglobin disorders: implications for practice in a new genetics era.

BACKGROUND: England is the only country in the world that currently has universal population screening for haemoglobin disorders through linked antenatal and newborn screening. Little is known about the acceptability of such screening. AIM: To explore parents' experiences of, and attitudes towards, new universal genetic screening for haemoglobin disorders. DESIGN OF STUDY: Narrative interview study. SETTING: Primary and community care settings across England. METHOD: Narrative interviews were undertaken with a maximum variation sample of 39 people who had experienced gene-carrier identification through antenatal and newborn screening for sickle cell, thalassaemia, and other haemoglobin variants within the previous 2 years. RESULTS: Most parents were unaware screening had occurred or had given it little consideration and so were surprised or shocked by results. However, they were glad to learn of their carrier status, reproductive genetic risk, or their newborn's carrier status. Participants emphasised that antenatal screening should happen as early as possible. Many would rather have known their carrier status before pregnancy or before entering a relationship. Although most were satisfied with the information they received, significant misunderstandings remained. There were culturally diverse attitudes towards prenatal diagnosis and termination. These procedures were acceptable to some parents with strong religious beliefs, including Christians and Muslims. CONCLUSION: Parents support screening for haemoglobin disorders but need to be better informed and better prepared for results and what they mean. Sensitivity to patient diversity in attitudes and choices is also required. Universal screening for genetic reproductive risk will increasingly involve generalists, particularly in primary care, presenting opportunities for screening before or earlier in pregnancy, which is likely to be welcomed by patients.     

ACMG position statement on prenatal/preconception expanded carrier screening

For years, clinicians have offered gene-by-gene carrier screening to patients and couples considering future pregnancy or those with an ongoing pregnancy early in gestation. Examples include ethnic-specific screening offered to Ashkenazi Jewish patients and panethnic screening for cystic fibrosis and spinal muscular atrophy. Next-generation sequencing methods now available permit screening for many more disorders with high fidelity, quick turnaround time, and lower costs. However, instituting these technologies carries with it perils that must be addressed. The basis for the selection of disorders on expanded carrier screening panels should be disclosed. The information provided about disorders with mild phenotypes, variable expression, low penetrance, and/or characterized by an adult onset should be complete and transparent, allowing patients to opt out of receiving these test results. Patients also must be made aware of the concept of residual risk following negative test results. Laboratories have a duty to participate in and facilitate this information transfer.Genet Med 2013:15(6):482–483     

An evaluation of PGD in clinical genetic services through 3 years application for prevention of beta-thalassaemia major and sickle cell thalassaemia

PGD represents an alternative within prenatal diagnosis services, which avoids terminating affected on-going pregnancies. In Greece, prevention programmes for haemoglobinopathies, including the option of prenatal diagnosis, are well established. Following optimization of a single-cell genotyping strategy (designed to be applicable for the majority of beta-thalassaemia major or sickle thalassaemia genotype interactions) along with close collaboration with an IVF unit, we integrated the option of PGD for at-risk couples with a problematic reproductive history. A total of 59 couples requesting PGD were counselled, of whom 41 initiated 63 PGD cycles. Following standard assisted reproduction treatment for oocyte retrieval, 20 cycles were cancelled (too few oocytes and/or poor quality embryos), but in 43 cycles single blastomeres were biopsied from 3 day embryos and genotyped (total 302). Diagnosis was achieved for 236 embryos, and 100 of 125 unaffected embryos were transferred. Sixteen pregnancies were established, although six were lost within the first trimester. Ten pregnancies underwent second trimester prenatal diagnosis, with nine pregnancies (13 babies: six singletons, two twins and one triplet) confirmed unaffected, although one singleton was a PGD misdiagnosis and terminated. The triplet pregnancy was selectively reduced to twins, and nine pregnancies went to term, with 12 healthy babies born. This report highlights advantages, limitations and approaches towards improvement when incorporating PGD within genetic services for a common recessive disease.     

Three-month follow-up of Western and non-Western participants in a study on preconceptional ancestry-based carrier couple screening for cystic fibrosis and hemoglobinopathies in the Netherlands

ObjectiveTo study psychological outcomes, knowledge, recall and understanding of test-results, satisfaction, and reproductive intentions among 97 Western and 46 non-Western participants in a unique preconceptional carrier screening study for both cystic fibrosis and hemoglobinopathies in a multiethnic population the Netherlands, in which a couple's eligibility for cystic fibrosis and/or hemoglobinopathies testing was based on both partners' ancestry.MethodsQuestionnaires before and after pretest consultation, and 1 week and 3 months after receiving test-results. Three cystic fibrosis and seven hemoglobinopathy carriers were identified, but no carrier couples.ResultsOverall, anxiety levels were low, knowledge improved after pretest consultation but decreased after 3 months. Ninety-four percent remembered their test-results. Western compared with non-Western participants had higher knowledge-scores and better understanding of test-results. None of the carriers felt less healthy, six felt relieved, and one felt disappointed. Four carriers were unaware of the residual risk of having an affected child. Participants intended to draw reproductive decisions from test-results, were satisfied, did not regret participation, and did not report major feelings of discrimination or stigmatization.ConclusionsSimilar to previous studies, no major adverse psychological effects were demonstrated among the Western and non-Western participants in this study, and they would draw reproductive decisions on test-results. No arguments for rejecting a combined offer of preconceptional ancestry-based cystic fibrosis and hemoglobinopathies carrier screening were found. An extensive implementation study should be carried out, in which understanding of test-results needs further attention, to investigate whether or not this type of screening should be implemented on a large scale in the Netherlands.     

Place of preimplantation diagnosis in genetic practice

Preimplantation genetic diagnosis (PGD) is currently one of the practical options available for couples at-risk to avoid the birth of children with genetic and chromosomal disorders. Despite its novelty, PGD has already become an alternative to traditional prenatal diagnosis, allowing establishing only unaffected pregnancies avoiding the risk for pregnancy termination. Indications for PGD have currently expanded beyond those practices in prenatal diagnosis, such as late-onset diseases with genetic predisposition, and preimplantation HLA typing with the purpose of establishing potential donor progeny for stem cell treatment of siblings, which makes PGD also an important compliment to prenatal diagnosis. The fact that more than 1,000 apparently healthy unaffected children have been born after PGD suggests its accuracy, reliability, and safety. PGD is presently an excellent option for carriers of balanced translocations, and appears to be of special value for avoiding age-related aneuploidies in patients of advanced reproductive age. The accumulated experience of thousands of PGD cycles for poor prognosis in vitro fertilization (IVF) patients provides strong evidence of the improvement of clinical outcome, particularly obvious from the reproductive history of patients. This makes of practical relevance to inform couples at-risk about availability of PGD option, so they make their own choice in avoiding the birth of affected offspring and having healthy children of their own.     

Strategies and outcomes of PGD of familial adenomatous polyposis

Owing to adult onset of hereditary cancer, prenatal diagnosis (PND) raises numerous ethical issues on the acceptability to terminate an affected pregnancy (TOP). PND for these disorders is often considered as unacceptable by couples as well as geneticists and legal or ethical authorities, but preimplantation genetic diagnosis (PGD), even if subject to controversy, seems to be a more acceptable option. Therefore, many couples, who do not want to transmit their cancer to their children, consider PGD as their only reproductive option. This article describes our experience of PGD for familial adenomatous polyposis (FAP). Twelve couples were referred between 2000 and 2005. We developed PGD tests to detect the mutation alone, but we rapidly set up multiplex PCR combining mutation detection and indirect diagnosis. Finally, we set up duplex and triplex indirect diagnoses to be able to offer a PGD, whatever mutation was involved in familial cases. PGD strategies were based on (i) a new double allele-specific PCR approach (D-ARMS) allowing the detection of the wild-type and mutated allele; (ii) PCR fragments sizing and (iii) restriction length polymorphisms. For the 12 referrals, we developed eight tests, and 11 cycles have been performed for four couples, resulting in eight embryo transfers and five pregnancies, with the birth of one healthy boy and two ongoing pregnancies. We are now able to propose PGD to most couples at risk of transmitting FAP to their offspring, whether the mutation is familial or occurred de novo.     

Clinical utility of expanded carrier screening: results-guided actionability and outcomes

PurposeExpanded carrier screening (ECS) informs couples of their risk of having offspring affected by certain genetic conditions. Limited data exists assessing the actions and reproductive outcomes of at-risk couples (ARCs). We describe the impact of ECS on planned and actual pregnancy management in the largest sample of ARCs studied to date.MethodsCouples who elected ECS and were found to be at high risk of having a pregnancy affected by at least one of 176 genetic conditions were invited to complete a survey about their actions and pregnancy management.ResultsThree hundred ninety-one ARCs completed the survey. Among those screened before becoming pregnant, 77% planned or pursued actions to avoid having affected offspring. Among those screened during pregnancy, 37% elected prenatal diagnostic testing (PNDx) for that pregnancy. In subsequent pregnancies that occurred in both the preconception and prenatal screening groups, PNDx was pursued in 29%. The decision to decline PNDx was most frequently based on the fear of procedure-related miscarriage, as well as the belief that termination would not be pursued in the event of a positive diagnosis.ConclusionECS results impacted couples' reproductive decision-making and led to altered pregnancy management that effectively eliminates the risk of having affected offspring.