Introduction

Preconception expanded carrier screening (ECS) aims to detect carrier couples of autosomal recessive (AR) disorders who face a 25% risk of having an affected child in each pregnancy, in order to facilitate informed reproductive decision making. Most of these couples are unaware of this risk, as carrier status does not affect one’s health, and in most cases the birth of an affected child is highly unexpected [1]. Carrier screening is preferably offered before a pregnancy, in order to increase the reproductive options for prospective parents [1, 2]. There are more than 1300 AR disorders, ranging from mild to severe, and it is estimated that up to 2 in 100 couples in the general population is a carrier couple of a severe AR disorder [1, 3, 4]. Targeted ECS panels for specific AR disorders have been successfully introduced for populations at high risk, such as individuals of Ashkenazi Jewish descent [5] and genetically isolated communities [6]. More recently, universal ECS panels have been made available to the general public, predominantly offered by commercial companies [7]. In the Netherlands, two academic medical centers, Amsterdam UMC and the University Medical Center Groningen, now offer universal preconception ECS to the general public who have no a priori risk for being a carrier couple based on ancestry and/or a consanguineous relationship. However, these panels are not reimbursed by health insurance companies [8, 9]. Typically, the disorders included in these two panels are severe disorders with a childhood onset resulting in significant intellectual and/or physical disability and/or a limited life expectancy due to lack of a sufficiently effective disease-modifying treatment, as is advised in the field of preconception carrier screening [1]. The majority of these disorders are inborn errors of metabolism (IEMs), such as mucopolysaccharidosis (MPS) type III, Tay–Sachs disease and Krabbe disease [8, 9]. The IEMs included in ECS panels generally have a progressive course. Previous studies in the USA, Sweden and the Netherlands have investigated the opinions of the general population toward universal preconception ECS and reported that between 30% and 34% of the respondents would consider to use preconception ECS [10,11,12]. The study by Ong et al., conducted in Australia, showed that genetic knowledge, i.e., baseline knowledge on genetics, is instrumental in influencing ECS participation [13]. Several other studies also underpinned that genetic knowledge and experiential knowledge, i.e., the objective and subjective knowledge gained from experience with the disease, influence and shape decision making on participating in genetic testing and understanding of carrier test results [14,15,16,17,18]. In a recent study by our group on the attitudes of the general Dutch population toward ECS [19], 31% of the respondents would consider ECS. However, familiarity with a genetic disease was not associated with intended ECS participation. This may be explained by the diverse spectrum of supposedly genetic diseases mentioned by the participants, including multifactorial disorders such as diabetes mellitus and eczema. Studies in patients with an AR or X-linked disorder and their families show that the majority is in favor of preconception population carrier screening for the specific disorder in their family: 75% of affected families with spinal muscular atrophy (SMA) [20], 81–86% of cystic fibrosis (CF) patients and their parents [21], 83% of caregivers of a child with fragile X syndrome [22], and 75% of hemophilia patients [23]. MPS III (Sanfilippo disease) is an example of a disorder generally included in ECS panels, as it is characterized by progressive neurodegeneration resulting in cognitive decline, behavioral problems, loss of motor functions and early demise [24]. Parenting a child with MPS III strongly impacts the well-being of parents, resulting in anxiety, depression and post-traumatic stress symptoms [25]. We hypothesized that genetic and experiential knowledge on the nature of a disorder generally included in universal preconception screening panels and its potential impact on the patient and the family leads to a more positive attitude toward ECS. We therefore assessed the attitudes of parents and relatives of MPS III patients toward preconception ECS and compared these outcomes to attitudes of people of reproductive age from the general Dutch population.

Methods

Participants and procedures

Parents of all MPS III patients known to the MPS III expert center of the Amsterdam UMC, location Academic Medical Center, were invited by letter to participate in this online questionnaire study. All mothers and fathers who agreed to participate were asked individually to invite their first and second degree relatives (parents, siblings, and/or healthy children ≥18 years of age) to participate as well and provided us with contact details after consent. Contact details were available to one researcher (SCMN) and were stored in a coded database. Participants received an e-mail with a personal link to the online questionnaire. The purpose of the study, and its anonymous data management were explained to all potential participants preceding the start of the questionnaire. Previously collected attitudes of people from the general Dutch population toward preconception ECS were used as comparator [19]. This group, here defined as ‘reference group’, comprises 781 participants in the reproductive age (18–45 years). A full explanation of data collection procedures of the reference group is presented in Nijmeijer et al. [19]. Ethical approval for this study and the previous study with the reference group was waived by the Medical Ethics Committee of the Amsterdam UMC, the Netherlands, as this is an anonymous questionnaire study.

Sociodemographic characteristics

The sociodemographic characteristics age, gender, educational level, religious beliefs, marital status, if the participant was considering a (future) pregnancy or currently pregnant (partner of self) were collected from the three groups (parents, relatives, and the reference group). Two questions were asked to investigate the familiarity with carrier screening: (1) ‘Have you ever heard of a carrier test before this questionnaire?’ and (2) ‘Have you ever taken a carrier test?’ followed by an open text field to allow to substantiate their answer.

Educational text

Prior to the start of the questionnaire, a brief educational text including information on (1) the principle of AR inheritance; (2) the fact that an ECS test is available in the Amsterdam UMC and includes 50 severe AR childhood disorders; and (3) the clinical features of MPS III as an example of the types of disorders included in the test (Supplementary material A). This educational text was identical to the one used for the reference group [19].

Genetic knowledge test

After reading the educational text, a brief genetic knowledge test (on AR inheritance and ECS) consisting of seven items on a three-point scale were used to verify if the educational text was correctly understood (incorrect, correct and I do not know) (Supplementary material B).

Perceived MPS III severity

Perceived severity of MPS III was evaluated with two questions on a five-point Likert scale: ‘I believe that MPS III is a severe disease’ and ‘I believe that the life expectancy of MPS III patients is very bad (severe patients often die before reaching adulthood)’ (Supplementary material B).

Questions from these two domains were also asked in our previous study but the results were not included in the publication on attitudes of the general Dutch population toward ECS [19]. In the current study, these data are used to assess whether relatives of MPS III patients have more genetic knowledge and perceive MPS III as more severe (experiential knowledge) than the reference group.

ECS questionnaire

The current study (Supplementary material C) uses the ECS questionnaire which was also used in Nijmeijer et al. [19]. The questionnaire was developed in consensus by members of the research team (including experts in pediatric metabolic diseases, psychology, genetics and health sciences) based on items from existing questionnaires used for assessing attitudes toward ECS among the Ashkenazi Jewish population [26] and toward carrier screening for CF [27]. The questionnaire includes the following six domains: I. Intention to participate in ECS. II. Level of agreement on feelings toward ECS (e.g., ‘I find it positive that all couples considering a (future) pregnancy can take the carrier test for 50 severe hereditary disorders’). III. Perceived benefits of (A) and barriers against ECS (B), and freedom-of-choice statements (C). IV. Most important reasons in favor of ECS and against ECS. V. Perceived social influences when considering ECS. VI. Perceived personal consequences of ECS; considerations regarding test results of ECS, perceived consequences as a carrier (couple), and perceived reproductive choices as a carrier couple. Domain I consisted of a multiple-choice question. Answers from domain II were measured using a semantic five-point differential scale with seven adjective word pairs: negative–positive, undesirable–desirable, frightening–nonfrightening, unwise–wise, non-reassuring–reassuring, unethical–ethical, and logical–illogical. The level of agreement on the domains III, V, and VI was given on a five-point Likert scale (1 = totally disagree/unimportant to 5 = totally agree/important). The answers from domain IV were measured by choosing a maximum of two arguments out of a list of arguments.

Statistical analyses

The Statistical Package for Social Sciences (SPSS) version 25.0 for Windows was used for all statistical analyses (SPSS, Inc., Chicago, IL, USA). First, items from the test on genetic knowledge were converted to binary items (0 = incorrect/I do not know, 1 = correct) in order to calculate a total sum score ranging from 0 to 7. Second, items on five-point scales were converted to binary items (0 = (totally) disagree/do not disagree and do not agree/(very) low/not low, not high, 1 = (totally) agree/(very)high). Third, the outcomes on the word pairs (domain II) were summarized into three answer categories: 1 = (totally) disagree, 2 = do not disagree/do not agree to 3 = (totally) agree. Answers on the genetic knowledge test and the perceived severity of MPS III (experiential knowledge) were compared between parents and relatives of MPS III patients, and the reference group.

Descriptive analyses were used to report on sociodemographic characteristics and the answers on the questionnaire. To compare sociodemographic characteristics and attitudes of the three groups (parents, relatives of MPS III patients, and the reference group), Chi-Square Tests were used for categorical variables and Independent Sample T-tests and Mann–Whitney U tests for continuous variables. Multivariate logistic regression analyses were performed to investigate whether being a parent or a relative of a MPS III patient, age, gender, educational level, marital status, religion, and considering a (future) pregnancy were associated with outcomes on the following questions: ‘Intention to participate in ECS’ (domain I), ‘I find it ethically acceptable that all couples considering a (future) pregnancy can take the carrier test’ (domain II), ‘ECS can prevent suffering for future parents’ (domain III), ‘as a carrier couple, I would consider in vitro fertilization (IVF) with embryo selection’ (domain VI) and, ‘as a carrier couple, I would consider in prenatal diagnostics’ (domain VI). Standardized regression coefficients (β) of 0.1 are considered small, 0.3 as medium and 0.5 as large. For predictor variables that are binary coded, 0.2 can be considered small, 0.5 as medium and 0.8 as large [28]. p values < 0.05 were considered statistically significant.

Results

Participants

Parents of 57 MPS III patients were invited to participate in this study of which parents of 9 patients declined participation or could not be reached. In total, 58 out of 68 parents (85%) of 46 MPS III patients participated; 48 out of 57 (84%) parents of living MPS III patients and 10 out of 11 (91%) parents of deceased MPS III patients. Some families consisted of more than one MPS III patient or of a single parent household. As parents were asked to invite their relatives at their discretion, no response rate could be calculated. In total, 101 relatives participated.

Sociodemographic characteristics

Parents and relatives were significantly older, more often female, more often in a relationship, and considered less often a (future) pregnancy compared with the reference group. A lower proportion of respondents in the reference group had a low educational level compared with parents and relatives of MPS III patients. The frequency of having religious beliefs was similar in the different groups (Table 1).

Table 1 Sociodemographic characteristics.
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Genetic knowledge test

Parents and relatives of MPS III patients scored significantly higher on the total sum score of the genetic knowledge test (range 0–7) compared with the reference group (respectively median 7 (range 3–7, n = 58) and 6 (range 2–7, n = 101) vs. median 5 (range 0–7, n = 781)) (p < 0.001).

Perceived severity of MPS III

Parents and relatives of MPS III patients more often agreed with the statement that MPS III is a severe disease (respectively 85% and 95%) compared with the reference group (72%, p < 0.001) and more often agreed that MPS III patients have a very bad life expectancy (respectively 86% and 94%) compared with the reference group (75%, p < 0.001).

ECS questionnaire

Intention to participate in ECS

Parents and relatives of MPS III patients were more likely to (probably or certainly) take a (similar) preconception ECS test (respectively 84.3% and 62.5%) compared with the reference group (people in the reproductive age from the Dutch general population) (31%, p < 0.001). Twelve percent of the parents and 21% of the relatives reported that they had previously taken a similar preconception carrier test compared with 1% of the reference group (p < 0.001).

II. Level of agreement on feelings toward ECS in general and on personally considering ECS

The level of agreement of parents of MPS III patients and the reference group on feelings toward ECS in general (Fig. 1a) and when personally considering ECS (Fig. 1b) differed significantly between the two groups, in favor of ECS for the parents, on all word pairs. Level of agreement of relatives are not shown to keep the manuscript concise, but were in line with those of parents of MPS III patients.

Fig. 1: Level of agreement on feelings toward ECS in general and on personally considering ECS.
figure 1

a Level of agreement on feelings toward ECS in general. Questionnaire domain II. The figure illustrates the level of agreement of the reference group (R; n = 781) and parents of MPS III patients (P; n = 58) on seven feelings in response to the question: ‘That all couples considering a (future) pregnancy can take the carrier test for 50 severe hereditary disorders, I find’ The red bars represent the percentage of participants who (totally) agreed with the words on the left side of the figure. The gray bars represent the percentage of participants with a neutral opinion toward the word pairs. The green bars represent the percentage of participants who (totally) agreed with the words on the right side of the figure. *p < 0.05, **p < 0.001 by using Chi-Square Tests. b Level of agreement on feelings when personally considering ECS. Questionnaire domain II. The figure illustrates the level of agreement of the reference group (R; n = 781) and parents of MPS III patients (P; n = 58) on seven feelings in response to the question: ‘That I personally can take the carrier test for 50 severe hereditary disorders, I find’. The red bars represent the percentage of participants who (totally) agreed with the words on the left side of the figure. The gray bars represent the percentage of participants with a neutral opinion toward the word pairs. The green bars represent the percentage of participants who (totally) agreed with the words on the right side of the figure. *p < 0.05, **p < 0.001 by using Chi-Square Tests (Color figure online).

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III. Perceived benefits of and barriers against ECS, and freedom-of-choice statements

Parents and relatives of MPS III patients more often agreed with the statement that the use of ECS can avoid suffering for the entire family (respectively 88% and 86%) compared with the reference group (68%, p < 0.001) (Table 2a). In addition, parents and relatives less often agreed that ECS can lead to anxiety (respectively 19% and 21%) compared with the reference group (39%, p < 0.001) (Table 2b). Furthermore, the majority (66%, 65 and 55% of parents, relatives and the reference group respectively) agreed that the carrier test should be offered to every couple that wants to have children but parents and relatives more often agreed that every couple that wants to have children must take the carrier test (35% and 39%) compared with the reference group (22%, p < 0.001) (Table 2c).

Table 2 Statements regarding perceived benefits of and barriers against ECS and freedom-of-choice statements.
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IV. Most important reasons in favor of ECS and against ECS

Out of eleven suggested reasons, the most frequently selected reason in favor of ECS for parents (50%) and the reference group (47.2%) was that they ‘want to spare a child from a life with a severe hereditary disorder’. Relatives most frequently selected as reason in favor of ECS ‘the presence of a hereditary disease in their family’ (58.4%) (Table 3a). Out of thirteen suggested reasons, the most frequently selected reason against ECS for parents and the reference group was that ‘nobody in the family has one of these disorders’ (37.9% and 47.6%, respectively). Relatives most frequently selected ‘other’ reasons against ECS (open text response) (42.6%) (e.g., ‘I have no desire to have any (more) children’ or ‘I would want to take the test’) (Table 3b).

Table 3 Reasons in favor of and against ECS.
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V. Perceived social influences when considering ECS

Compared with the reference group, parents and relatives of MPS III patients less often stated that the opinion from their surroundings (partner, parents, family, and friends) is important when considering ECS. Parents, relatives, and the reference group equally stated that the opinion of the religious community was important (Table 4a).

Table 4 Statements regarding perceived personal consequences of ECS.
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VI. Perceived personal consequences of ECS

Considerations regarding test results (Table 4b) and perceived consequences as a carrier (couple) (Table 4c) all differed significantly between parents, relatives and the reference group. Parents and relatives of MPS III patients more often agreed with statements regarding perceived reproductive choices (Table 4d).

Multivariate logistic regression analyses

The results of the regression analyses are presented in Table 5. Being a parent or relative of a MPS III patient was the strongest variable associated with intended ECS participation. Parents and relatives were also more likely to believe that offering ECS is ethically acceptable, to believe that ECS prevents suffering for future parents, as a carrier couple to consider IVF with embryo selection and prenatal diagnostics. Age was the only variable not associated with any of the outcome variables.

Table 5 Multivariate logistic regression (n = 940).
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Discussion

The objective of this study was to investigate the attitudes of parents and relatives of patients with the severe, progressive and ultimately fatal AR disorder MPS III, toward universal preconception ECS and to compare this to the Dutch general population. We hypothesized that MPS III parents and relatives are more in favor of preconception ECS due to their genetic and experiential knowledge. This study indeed showed that parents (84%) and relatives (63%) are significantly more likely to participate in ECS than the participants from the general population (31%). Being a parent or relative of a MPS III patient turned out to be the strongest variable in the regression analyses for intended ECS participation, even when controlled for sociodemographic factors.

As hypothesized, relatives of MPS III patients scored significantly better on the genetic knowledge test compared with the participants from the general population and might explain the more positive attitudes toward ECS of relatives, as was previously described by Ong et al. [13].

Relatives of MPS III patients more often believed that MPS III is a severe disease compared with the reference group. This is not surprising as MPS III is a ultra-rare disorder [24, 29] and participants from the general population therefore likely had no (experiential) knowledge on this disease. The experiential knowledge of the relatives on the type of diseases generally included in ECS panels also might explains their overall positive attitudes toward ECS. A Belgian study investigating attitudes toward ECS of adult patients with CF and their parents, showed that 59% of the patients and 53% of the parents would want to get tested before a pregnancy for conditions other than CF [21]. This seems lower than the results of our study, suggesting that the perceived severity of the diseases included in ECS impacts on its uptake as patients with CF have a significant longer life expectancy than MPS III patients and do not have progressive cognitive decline.

The primary goal of offering ECS is not reaching the highest uptake but to increase reproductive autonomy among prospective parents [1]. Although increasing autonomy is generally regarded as positive, there have been some concerns [30]. The existence of ECS panels may lead to the feeling that it is a moral duty to participate or a moral obligation to avoid an affected child [2]. Moreover, concerns have been raised that human dignity, reflecting tolerance of the disabled, may be challenged as ECS programs could change the view on human value [31]. Parents and relatives in this study were nevertheless overall positive about ECS. Surprisingly, the absence of AR disorders in the family was the most frequently selected reason against ECS by parents of MPS III patients, as was also shown for the general population [19], and mentioned as reason not to participate in CF carrier screening in Australia by pregnant women and their partners, and couples prior to conception [32]. This shows that even parents and relatives of patients with a very severe AR disorder appear to estimate their chances of being a carrier as low when there is no medical history in the family. This emphasizes the importance of comprehensive genetic counseling. ECS providers should not assume that people with experiential knowledge because of a known AR genetic condition in the family will extend this knowledge about carrier status to their understanding of the risk of being a carrier for other genetic conditions. Moreover, as previously suggested, awareness of ECS and knowledge about genetic diseases in the general population should be increased to ensure successful implementation [16].

This study has some limitations. First, this study included parents and relatives of MPS III patients and research showed that parenting a MPS III child has great impact on the well-being of parents [25, 33, 34]. The impact of some of the other disorders included in ECS panels may be less severe which may have resulted in an overestimation of the potential uptake of ECS by affected families by our study. Second, as recruitment of relatives was done by parents of MPS III patients, we were not informed about reasons for declining participation (e.g., ethical or religious beliefs) or the number of relatives that were invited to participate. Therefore, the attitudes of our participants may not fully reflect the attitudes of all families of MPS III patients. Third, sociodemographics differed between relatives of MPS III patients and participants from the general population. These characteristics, however, were included in the logistic regression analyses and the effect of being a relative is the strongest variable associated with intended ECS participation. Although parents and relatives were significantly older than the reference group, age was not associated with any of the outcome variables. We verified this by analyzing intended ECS participation separate in the age group 35–45, which was significantly higher among parents (85%) and relatives (80%) compared with the reference group.

In conclusion, this study demonstrates a higher positive attitude of persons with genetic and experiential knowledge of a severe and yet untreatable AR disorder toward universal preconception ECS compared with participants of the Dutch general population. The fact that the most mentioned reason against participating in ECS was the absence of AR disorders in the family, suggest that people estimate their chances of being a carrier as low when there is no medical history in the family, even despite the fact that participants were informed that everyone is carrier for one or several AR disorders. As informed decision making is based on genetic knowledge in addition to personal values [35], we emphasize the importance of appropriate information and counseling in order to enable informed reproductive decision making about ECS. This is not only important for the general population, but also for families with experiential and genetic knowledge to avoid misconceptions on this complex matter.