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. 2022 Aug 18;17(8):e0272585. doi: 10.1371/journal.pone.0272585

Parents’ views on accepting, declining, and expanding newborn bloodspot screening

Sylvia M van der Pal 1,*,#, Sophie Wins 1,#, Jasmijn E Klapwijk 2, Tessa van Dijk 2, Adriana Kater-Kuipers 2, Catharina P B van der Ploeg 1, Suze M P J Jans 1, Stephan Kemp 3, Rendelien K Verschoof-Puite 4, Lion J M van den Bosch 5, Lidewij Henneman 2
Editor: Elsayed Abdelkreem6
PMCID: PMC9387838  PMID: 35980961

Abstract

Introduction

The goal of newborn bloodspot screening (NBS) is the early detection of treatable disorders in newborns to offer early intervention. Worldwide, the number of conditions screened for is expanding, which might affect public acceptance. In the Netherlands, participation is high (>99%), but little is known about how parents perceive NBS. This study assessed parents’ views on accepting, declining and expanding NBS.

Methods

A total of 804 of 6051 (13%) invited parents who participated in NBS in the Netherlands during the last two weeks of December 2019, and 48 of 1162 (4%) invited parents who declined participation in NBS in 2019 and 2020, completed a questionnaire.

Results

The most important reason for parents to participate in NBS was to prevent health complaints, whereas the most important reason to decline NBS was parents’ viewpoint on life and the belief that the heel prick would be painful for the child. Compared to NBS participants, respondents who declined NBS were more actively religious, considered alternative medicine or lifestyle more important, were less inclined to vaccinate their child for infectious diseases, and reported more doubt about NBS participation (all differences p < .001). Informed choice was lower among respondents who declined NBS (44%) compared to participants in NBS (83%, p < .001), mostly due to insufficient knowledge. Of the NBS participants, 95% were positive about NBS expansion. Most NBS participants agreed to include conditions that could unintentionally reveal a diagnosis in the mother instead of the child (86%) or a condition that may not cause symptoms until later in the child’s life (84%).

Conclusion

Most participants made an informed decision to participate in NBS and are positive about screening for more conditions. Insights into parents’ views on (non-)participation and expansion of NBS can help to ensure that NBS suits the population needs while safeguarding ethical principles for screening.

Introduction

Newborn bloodspot screening (NBS) is considered one of the most successful public health programs, aiming at early detection of treatable disorders in newborns to offer early intervention [1]. Worldwide, due to technological developments, improved clinical understanding, and the availability of new treatments, the number of disorders eligible for NBS is continuously increasing [2, 3].

Studies have shown that the public is generally positive about NBS and its expansion [4–7]. In the Netherlands NBS participation is not mandatory and parents are asked if they agree to NBS [8]. NBS is nevertheless well accepted. In 2020, 99.4% of parents of newborns participated in newborn screening which, in that year, included 24 disorders [9]. Few studies have addressed parental reasons to decline NBS [10, 11]. More insight into the reasons for non-participation can lead to valuable knowledge that can be used, for example, to improve information for parents. It is important that parents make an informed decision to participate and maintaining a high acceptance and participation level is needed to achieve maximal health benefit.

Although expanded NBS can improve early diagnosis and treatment of more disorders to prevent irreversible health damage [12], it also raises questions, and is expected to increase the number of false positives and uncertain outcomes which may have far-reaching implications [13]. In the Netherlands, ethical issues challenge implementation of the addition of new disorders to the Dutch program as advised by the Dutch Health Council [14]. For example, the screening for organic cation/carnitine transporter 2 (OCTN2) deficiency in newborns may detect carnitine deficiency in asymptomatic mothers, which is beyond the goal of NBS and may have a medical and/or psychological impact on these women [15]. Furthermore, in 2015 the Dutch Health Council recommended screening only boys for X-linked adrenoleukodystrophy (ALD) [16]. With timely detection, ALD is treatable in boys, whereas symptoms in female carriers usually only develop later in life and are untreatable [17]. Studies show that most parents want to know whether their child has a certain condition, regardless of the availability of effective treatment [7, 18, 19]. However, it is unclear how screening under certain conditions, for example screening only boys, is perceived by parents.

Since societal acceptance of NBS is an important criterion for success, this study aimed to assess parents’ reasons for, and views on participating or not participating in Dutch NBS, whether they make an informed decision, and their views on expansion of NBS in the Netherlands.

Materials and methods

Design and ethics statement

A cross-sectional survey study was performed using questionnaires among participants and non-participants in the Dutch NBS program. The Medical Ethical Committee of the VU University Medical Center Amsterdam approved the study protocol (no. 2019–509). Before parents completed the (online) questionnaire, they were asked to tick a box (written consent) to confirm that they had read the information letter and that they gave their informed consent to participate in the study.

Setting

In the Netherlands, NBS is organized and coordinated by the Dutch National Institute for Public Health and the Environment (RIVM). Standardized information on NBS, including a leaflet, is provided during pregnancy by an obstetric healthcare provider, and issued before the screening is done, a few days after birth, at home by a youth health care worker, maternity nurse or midwife. When the baby is admitted to the hospital during the first week after birth, the blood spot is collected by a hospital health care worker. If the NBS result is good parents will get a letter from RIVM within five weeks, as from March 1st, 2020 (before that time, no result was given). If an abnormality is detected, the general practitioner will inform parents about the results.

Study population

During the last two weeks of December 2019, all parents whose child had been offered NBS five weeks earlier (n = 6,051), received a letter from the RIVM inviting them to participate in a survey study. The invitation could only be sent by the RIVM due to of privacy reasons, and therefore no reminders could be sent. A period of five weeks was chosen because almost all parents will know their child’s test result by then. In addition, all parents who declined participation in NBS in the whole of 2019 (n = 515) received an invitation to complete the same online questionnaire at the beginning of 2020, and all parents who declined participation in NBS in 2020 received an invitation at the beginning of 2021 (n = 647). When parents indicated that they did not participate in NBS, questions that were not relevant were automatically skipped. The questionnaire was available in Dutch and English and could be filled in online or could be sent to them on paper by post upon request. As the number of non-participants in 2019 who filled out the questionnaire was very low, all NBS non-participants in 2020 were sent a paper questionnaire, in addition to the online link, to lower the threshold for completing the questionnaire.

Questionnaire and procedure

The questionnaire was developed based on interviews with stakeholders [14], a previous questionnaire study about Dutch parents’ attitudes towards NBS [20, 21], and literature [19, 22]. The questionnaire was pre-tested among five parents. Readability of the questionnaire was evaluated by Pharos, the Dutch Centre of Expertise on Health Disparities. The questionnaire assessed reasons for participating and not participating, informed decision to participate or not, views on current NBS, views on expanding NBS, and background characteristics. NBS non-participants were not asked about their views on expanding NBS and views on current NBS to keep the questionnaire as short as possible and encourage completion. A copy of the entire questionnaire can be found in S1 Appendix. The different themes in the questionnaire are described below.

Reasons to participate or not in NBS

Respondents were first asked if they participated in NBS. Respondents were then asked to rate the importance of eight reasons to participate or not in NBS on a 5-point scale ranging from not at all important (1) to very important (5), and an open question was added to check for additional reasons. For parents who did not participate in NBS in 2020, the additional reason ‘because of COVID’ was added.

Informed decision to participate or not in NBS

Informed decision was assessed based on the Multidimensional Measure of Informed Choice (MMIC) [23], and a previous study [20, 21], combining knowledge, attitude, and participation in NBS. Knowledge was measured using six items (see S1 Table) with three answer options (true, not true, don’t know). Five items with a five-point semantic differential scale were used to measure the respondents’ attitude towards NBS (bad–good; useless–useful; not reassuring–reassuring; scary–not scary; annoying–pleasant) (see S2 Table). The attitude items were scored from 1 to 5, where a score of 1 means a negative attitude and a score of 5 a positive attitude.

Knowledge was defined as sufficient when four or more items were answered correctly (≥ 4 of 6 items). The five attitude items (scale 1 to 5) were combined into a mean and recoded into an attitude score ranging from 2 (all 5 items very negative; (1/5)*10 = 2) to 10 (all 5 items very positive; (5/5)*10 = 10) score. The attitude of respondents was defined as positive when their attitude score was 6 or more (≥ 6 out of 10) and a negative attitude was defined by an attitude score less than six (< 6 out of 10).

A well-informed decision was defined based on the MMIC [23]. Parents who made a well-informed decision to participate in NBS were defined as having sufficient knowledge (≥ 4 items correctly answered) and a positive attitude (attitude score ≥ 6) towards NBS. Parents who made a well-informed decision not to participate in NBS were defined as having sufficient knowledge (≥ 4 items correctly answered) and a negative attitude (attitude score < 6) towards NBS.

In addition to informed choice, three statements were added to assess whether parents made an undisputed choice whether or not to participate in NBS (see S3 Table).

Views on current NBS

Views on current NBS consisted of five statements of parents’ experiences with the heel prick screening process and the information that was provided on a 5-point Likert scale. Moreover, three questions assessed respondents’ perceived reliability of the test, regret, and whether they would participate again on a 5-point answering scale.

Views on expanding NBS

Views on expanding NBS consisted of descriptions of seven conditions (e.g. a condition which will give your child symptoms only later in life) about which parents who had participated in NBS were asked if it would be a very bad, bad, neutral, good or very good idea to add these conditions to NBS. In addition, a scenario for including ALD in the NBS program (“ALD scenario”), describing the difference in disease manifestations between males and females, was added (see S1 Appendix; question B.3). Parents were asked whether they thought it was a good idea to test for this condition in NBS, and if so, whether either only boys or both boys and girls should be tested, and why (open text field).

Background characteristics

The background characteristics consisted of questions about whether mother, father or both completed the questionnaire, age, marital status, and educational level of the respondent, parents’ country of birth, whether or not parents had other children, the sex of the newborn, the result of the NBS (only for NBS participants), whether parents regard alternative medicine or lifestyle (e.g. anthroposophy, homeopathy or natural medicine) as important, whether parents were actively religious and whether parents were planning to have their newborn vaccinated.

Statistical analyses

The frequencies or means and standard deviations were calculated using descriptive analyses.

Five-point scales were reduced to three categories (e.g. (completely) disagree/neutral/(completely) agree) to avoid empty or small cells. Differences between the respondents who participated in NBS and those who declined NBS were tested with Chi square tests, or Chi square tests for trend for ordinal categories such as single items on a 5-point scale. Non-parametric Mann-Whitney U tests were done to compare respondents who participated in NBS and those who declined NBS, and also to compare low-/middle- and high- educated parents that participated in NBS, on their attitudes (recoded into a score ranging from 2 (all negative attitudes) to 10 (all positive attitudes)) and knowledge (also recoded into a score ranging from 0 (none correct) to 10 (all correct))/. The comparison based on education, was only done within the group of NBS participants because the numbers of low-educated parents were small (n = 15) in the smaller group of parents that did not participate in NBS (n = 48). Answers to open questions were coded and categorized by one person (MvE) and were discussed with a second person (SW) until agreement was reached. All analyses were performed using SPSS version 25 for Windows (IBM Statistics for Windows, IBM, NY, USA).

Results

Respondents’ characteristics

In total, 804 of 6,051 (13%) invited parents who participated in NBS completed the questionnaire. Among parents who declined NBS in 2019 and 2020, the questionnaire was completed by 3% (16/515) and 5% (32/647) respectively, meaning that 48 parents who declined participation in NBS were included in the analyses. The characteristics of parents who completed the questionnaire are shown in Table 1. Respondents who declined NBS were more often fathers (19% vs. 8%, p = .03), more often had more than one child (66% vs. 45%, p = .005), were more often actively religious than participants (57% vs. 23%, p < .001), considered alternative medicine/lifestyle as more important more often (67% vs. 21%, p < .001), and were less often inclined to vaccinate their child for infectious diseases (15% vs 96%, p < .001), compared to respondents who participated in NBS. Respondents were higher educated and more often born in the Netherlands, compared to the general Dutch population (2019).

Table 1. Characteristics of respondents who participated in NBS participants or declined NBS, compared to the general Dutch population.

Respondents who participated in NBS
n = 804a 		Respondents who declined NBS
n = 48b 		Dutch population 2019c
Questionnaire completed by n (%)
 Mother 657 (82) 34 (71) *
 Father/partner 62 (8) 9 (19)
 Both 85 (11) 5 (10)
Age of respondent, mean (SD) 32.2 (4.5) 32.1 (4.8) 31.5
Marital status, n (%)
 Married/registered partnership 504 (63) 35 (73) (58)
 Living together 275 (34) 10 (21)
 Single 23 (3) 3 (6)
Educational level of respondentd, n (%)
 Low/middle 202 (25) 15 (33) (46)
 High 602 (75) 31 (67) (54)
Country of birth mothere, n (%)
 Netherlands 739 (92) 41 (87) (67)
 Western 40 (5) 2 (4) (11)
 Non-Western 25 (3) 4 (9) (22)
Having other children (yes), n (%) 360 (45) 31 (66) *
Sex newbornf, n (%)
 Male 413 (53) 23 (48) (51)
 Female 373 (48) 25 (52) (49)
NBS (self-reported) result, n (%)
 Normal 776 (97) n.a.
 Inconclusive/abnormalg 27 (3) n.a.
 Unknown 1 (0.1)
Religion, n (%)
 Not (actively) religious 617 (77) 19 (43) *
 (Scarcely) actively religious 187 (23) 25 (57)
Alternative medicine/lifestyle is important, n (%)
 Yesh 166 (21) 31 (67) *
 No 629 (79) 15 (33)
Vaccinations, n (%)
 All vaccinations 775 (96) 7 (15) *
 Not all vaccinations 17 (2) 8 (17)
 No vaccinations 7 (1) 27 (57)
 Vaccinations postponed till later/undecided 5 (1) 5 (11)
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n.a. = not applicable.

The percentage does not always add up to 100% due to rounding.

*. p-value < .05 of difference between respondents participated in NBS and respondents who declined NBS.

aThe n slightly differed for some of the characteristics due to missing values (n = 795 to 802).

bThe n slightly differed for some of the characteristics due to missing values (n = 44 to 47).

cDutch population in 2019; for age, marital status, migration background and sex of newborn within all newborns or mothers of newborns in 2019; for educational level within women aged 25–35 years in 2019 (Statline Statistics Netherlands) [24]. Not all data were available, therefore some cells remain empty.

dLow education level = Elementary school, lower level of secondary school, and lower vocational training. Middle education level = higher level of secondary school and intermediate vocational training. High education level = High vocational training and university.

eCountry of birth of mother was categorized as Dutch, Other Western or Non-Western by the following algorithm: Dutch if the mother was born in the Netherlands; Other Western if the mother was born in Europe (excluding Turkey), North America, Oceania, Indonesia or Japan; and Non-Western if the mother was born in Africa, Latin America, Asia (excluding Indonesia and Japan) or Turkey.

fSex could not be specified for 17 twins and 1 triplet.

gInconclusive result (n = 13), abnormal result (n = 12), carrier (n = 1), waiting for an extra heel prick test (n = 1).

hRespondents indicated that one or more of the following was important to them: anthroposophy, homeopathy, natural medicine.

Reasons to participate in NBS or decline NBS

Table 2 shows that the most important reasons to participate in NBS screening was that disease symptoms in the child can be prevented and because respondents were confident that the results of the heel prick test are reliable. The most important reasons for respondents not to participate were due to their view of life, because they think that the heel prick test is painful for the child, and how their data and their child’s data are handled. Among the 32 parents who declined NBS in 2020 (COVID-19 pandemic), two (6%) respondents reported that the COVID-19 virus was an important or very important reason to decline NBS. The open question where respondents described their reasoning in their own words did not reveal any additional reasons.

Table 2. Reasons to participate in NBS or decline NBS.

“You did or did not participate in the heel prick test. Indicate how important the following reasons were for you in making a decision about participation” Respondents who participated in NBS “You did or did not participate in the heel prick test. Indicate how important the following reasons were for you in making a decision about participation” Respondents who declined NBS
Most important reasons first: n = 804
Mean (SD)		 Most important reasons first: n = 48
Mean (SD)
Because I can prevent my child from getting health complaints from a disorder 4.62 (0.65) Because of my view of life (e.g. anthroposophical or naturopathic) 3.66 (1.24)
Because I am confident that the results of the heel prick test are reliable 4.16 (0.74) Because I think the heel prick test is painful for my child 3.40 (1.44)
Because the heel prick test reassures me 4.06 (0.82) How my data and my child’s data are handled 3.38 (1.41)
How my data and my child’s data are handled 2.85 (1.17) Because I can prevent my child from getting health complaints from a disorder 2.74 (1.26)
Because the government arranges and pays for the heel prick test 2.83 (1.20) Because I am confident that the results of the heel prick test are reliable 2.64 (1.13)
Because I think the heel prick test is painful for my child 2.13 (0.91) Because the government arranges and pays for the heel prick test 2.57 (1.12)
Because of my view of life (e.g. anthroposophical or naturopathic) 1.65 (0.98) Because of my faith or religion 2.54 (1.61)
Because of my faith or religion 1.36 (0.74) Because the heel prick test reassures me 1.93 (1.02)
Because of Corona virusb n.a. Because of Corona virusb 1.74 (1.06)
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n.a. = not applicable.

a 1 = not at all important—5 = very important. Maximum of 2 missing values per reason.

b Only assessed among non-participants in 2020.

Informed decision to participate or not in NBS

Table 3 shows that 83% of respondents that participated in NBS made an informed decision to participate, based on 86% of respondents that showed sufficient knowledge and 97% that had a positive attitude towards NBS. Of the respondents that declined participation in NBS, 44% made an informed choice with sufficient knowledge (62%) and a negative attitude (71%). The difference in the percentage that made an informed decision to participate in NBS between respondents who participated in NBS (83%) and those who declined NBS (44%) was statistically significant (p < .001). S1 and S2 Tables show respondents’ answers per knowledge item and per attitude item, respectively, and show significant differences in knowledge-score (7.72 versus 5.87, p < .001) and attitude-score (8.33 vs 5.16, p < .001) between respondents who participated in NBS and those who declined NBS. S3 Table shows that respondents who participated in NBS made a more undisputed choice to participate (p < .001), while NBS non-participants indicated having more doubt (p < .001). S4 Table shows that of all respondents who participated in NBS, respondents with a high educational level had more knowledge about NBS (difference of 0.75, p<0.001) and a more positive attitude towards NBS (difference of 0.46, p<0.001), compared to respondents with a low/middle educational level.

Table 3. Informed decision to participate in NBS or decline NBS.

Knowledge & Attitude Respondents who participated in NBS
n = 801a 		Respondents who declined NBS
n = 45a
n (%) n (%)
Sufficient knowledge & positive attitude 667 (83)b 8 (18)
Sufficient knowledge & negative attitude 20 (3) 20 (44)b
Insufficient knowledge & positive attitude 106 (13) 5 (11)
Insufficient knowledge & negative attitude 8 (1) 12 (27)
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aThree participants and three non-participants completed 3 or less of the 5 attitude questions and were excluded from analyses.

bInformed decision (for NBS participants: sufficient knowledge & positive attitude, for NBS non-participants: sufficient knowledge & negative attitude).

Parents’ views on current NBS

Table 4 shows that 92% of respondents who participated in NBS did not feel pressured by the person who carried out the heel prick. The majority (74%) reported to have received sufficient information about the heel prick test to make a decision about whether or not to participate. Overall, 47% reported that they were well informed about NBS during pregnancy. Most respondents (92%) trust that the government will inform them adequately about the screening results. Most respondents think that the heel prick is reliable (97%), and four respondents (0.5%) reported regretting NBS participation; one parent’s child was diagnosed with a condition after NBS, one parent was already in doubt about participating in NBS and did not get satisfactory answers to their questions about NBS, and the other two parents left no remarks on the questionnaire. Almost all respondents (99.6%) would participate again in the case of a future pregnancy.

Table 4. Parents’ views on current Dutch newborn bloodspot screening.

Participants n = 804 (Completely) disagree Neutral (Completely) agree
Mean (SD) n (%) n (%) n (%)
Do you agree with the following statements?a
 • The person who carried out the heel prick test did not put me under any pressure 4.35 (0.80) 27 (3) 39 (5) 738 (92)
 • The person who carried out the heel prick test, was very professional 4.30 (0.73) 21 (3) 47 (6) 736 (92)
 • The person who carried out the heel prick test, gave adequate information 4.05 (0.85) 50 (6) 85 (11) 669 (83)
 • I was well informed about the heel prick test during pregnancy 3.11 (1.22) 273 (34) 157 (20) 374 (47)
 • I received sufficient information about the heel prick test so that I could make a well-founded decision about whether or not to participate 3.89 (1.05) 87 (11) 124 (15) 593 (74)
 • I trust that the government will inform me adequately about the heel prick test 4.34 (0.74) 21 (3) 40 (5) 743 (92)
Not reliable Neutral Reliable
How reliable do you think the heel prick is?b 4.49 (0.57) 2 (0.2) 22 (3) 780 (97)
A lot of regret Neutral No regret
Do you regret participating in the heel prick?c 4.95 (0.31) 4 (0.5) 0 (0) 800 (99.5)
Definitely not Neutral Definitely
If you are ever pregnant again, would you participate in the heel prick?d 4.95 (0.27) 2 (0.3) 1 (0.1) 801 (99.6)
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a(1 = completely disagree– 5 = completely agree).

b(1 = not reliable– 5 = reliable).

c(1 = a lot of regret– 5 = no regret).

d(1 = definitely not– 5 = definitely).

Parents’ views on expanding Dutch NBS

Most NBS participants (95%) thought it was a good idea to add new conditions to the NBS screening, whereas 4% did not know whether it was a good idea. Only two respondents thought it was a bad idea. Table 5 shows the degree of acceptance of specific conditions about which parents were asked if they thought it was a good idea to add these conditions to the heel prick test. For each condition, the majority of respondents thought it was a good or a very good idea, varying from 59% to 86% agreement. On average, the respondents scored the highest on: ‘a condition in which the result could indicate that the child is not sick but that the mother is sick’ (mean: 4.05; SD: 0.72) and the lowest on: ‘a condition for which there is no treatment or no medication’ (mean: 3.56; SD: 0.98). A minority (5%) believed it was a bad or very bad idea to include disorders for which the child’s DNA needs to be tested.

Table 5. Degree of acceptance of adding a specific condition to the heel prick test.

A condition: Mean (SD) (Very) bad idea
n (%)		 Neutral
n (%)		 (Very) good idea
n (%)
for which the result could indicate that the child is not sick but that the mother is sick. 4.05 (0.72) 34 (4) 75 (9) 695 (86)
which will give your child symptoms only later in life. 4.01 (0.70) 30 (4) 102 (13) 672 (84)
for which some of your child’s DNA (the genetic material) needs to be tested. 3.94 (0.76) 39 (5) 125 (15) 640 (80)
for which treatment can cause serious side effects for your child. 3.80 (0.81) 48 (6) 204 (25) 552 (69)
with which your child can lead a normal life, such as going to school, participate in sports etc., even without treatment. 3.75 (0.97) 107 (13) 128 (16) 569 (71)
for which it is uncertain whether your child will get any complaints. 3.58 (0.90) 104 (13) 223 (28) 477 (59)
for which there is no treatment or no medication. 3.56 (0.98) 121 (15) 193 (24) 490 (61)
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With regard to the “adrenoleukodystrophy (ALD) scenario” (see S1 Appendix, question B.3), only 8 out of 804 respondents (1%) did not think it was a good idea to add a condition to NBS with great differences in disease manifestation and treatability between males and females. Of the 796 respondents that thought it was a good idea to add ALD, a majority of respondents (665/796, 84%) thought it is a good idea to test for this disorder in both boys and girls. Respondents’ main reason was “the opportunity to know what to expect” (192/665, 29%), and “because the information is important for both sexes” (105/665, 16%). Only 131/796 respondents (16%) would test only boys because “boys have treatment options and girls do not have treatment options” (80/131, 61%), “consequences for boys are greater” (27/131, 21%), “girls can experience unnecessary stress or worries” (24/131, 18%).

Discussion

Overall, NBS participants in this study carried out in the Netherlands were very positive about the current NBS program, while those who declined NBS felt differently, and the large majority of NBS participants was also positive about expanding the number of disorders screened for. The proportion of respondents making an informed decision to participate in NBS was lower for NBS non-participants compared to NBS participants, mostly due to a lack of knowledge among NBS non-participants.

Reasons to participate or not in NBS

The reason respondents reported as most important for participating in NBS was to prevent disease symptoms in their child, in line with the aim of screening [2], as well as with findings from other studies assessing parents’ views [25, 26]. For example, one interview study in Australia found that the majority of women with newborns thought screening was useful if it prevents a disease (85%) or reduces severity of a disease (87%) [25]. In an interview study with parents in the UK, the ability to act on screening results was also noted as important, with earlier knowledge on potential conditions in a child allowing for treatment strategies [26].

For parents that declined NBS, the highest rated reasons for declining NBS concerned their view of life, and because they thought that the heel prick test would be painful for their child. Parents who declined NBS were more often in doubt concerning whether to participate or not, compared to NBS participants. In the literature, studies including parents that declined NBS are scarce [27]. A Canadian qualitative study showed that decisions among three declining parents were shaped by their previous experiences with blood collection [11]. In that same interview study, healthcare professionals reflected on why parents reported to them that they did not wish to participate in NBS. Reasons included: to avoid pain for the baby, previous experiences with healthcare, perceiving the test as unnecessary, religious reasons, and not trusting the government with their child’s DNA [11]. Our study suggests that how the parents’ data and the child’s data are handled might play a role in parents’ decision to decline NBS.

Our results showed that parents who declined NBS were more actively religious and more often indicated that alternative medicine/lifestyle is important to them when compared to participating parents. Moreover, more than half of the parents that declined NBS indicated that they were not planning to vaccinate their child for childhood infectious diseases. Declining both the NBS and the vaccination program might therefore also be representative decisions for a way of life. One parent in our study stated that their main reason for declining NBS was ‘we live in trust and not in fear’ in the open-ended section of the question. Among the parents who declined NBS in 2020, when the COVID-19 pandemic might have caused additional concerns for parents, very few parents (n = 2; 6%) reported that the COVID-19 virus was an important reason to decline NBS.

Informed participation for current NBS

In the Netherlands, NBS is voluntary, however participation rates are nevertheless very high: above 99% [9]. In the Netherlands, parents are asked for verbal consent before the heel prick is carried out. According to the informed consent procedure [8], the screener should check beforehand whether the parent has both received the information leaflet on NBS screening and read it. If this is not the case, the screener should explain the main points of the screening to the parents. In some other countries, although informed (verbal) consent is likewise required for participation (e.g. United Kingdom) [28], a sense of routinization has been described in which parents did not feel they made an active choice or did not remember giving consent [11]. In the Netherlands, information leaflets on NBS screening are handed out on several occasions, including during pregnancy. However, leaflets are easily overlooked by parents [20, 21]. Given such circumstances of information provision, it has been questioned whether participants perceive participating in NBS as an actual choice [29]. Nevertheless, we have shown that most respondents believe that they were informed well enough to be able to decide to participate, although only 47% of participants said they were well-informed during pregnancy. Previous calls for information provision during pregnancy have been made, as this may allow parents to better absorb and understand the NBS process and the possible implications [13].

Our results indicate that the majority (83%) of the NBS participants made an informed decision, which is comparable to results of a similar study in 2008 (84%) carried out after the expansion of NBS screening from three to seventeen disorders [20, 21]. These results suggest that even with a greater number of conditions included in NBS, the proportion of parents making an informed decision to accept NBS remained the same. The current study found a lower percentage (44%) of informed choice in parents that declined NBS, mostly due to insufficient knowledge about NBS. For example, only 56% of declining parents were aware that conditions tested for with NBS can have serious consequences if untreated (S1 Table). This could indicate room for improvement in the information provision, by explaining or highlighting these consequences. A literature review showed that the main acceptability component identified for newborn screening and other screening interventions related to parental knowledge and understanding [27]. It remains to be seen whether improved information, or other factors such as timing of information provision, will increase knowledge and thus the willingness to participate among the parents who declined. On the one hand, our results indicate that parents mostly decline because of their beliefs, namely their way of life, religion or beliefs about pain. On the other hand, parents who did decline NBS also indicated having more doubt and a less undisputed choice not to participate.

Parents’ views on expanding Dutch NBS

Our results suggest that NBS participants are generally positive towards the expansion of NBS. Even for conditions for which there is no treatment or medication available or a condition in which it is uncertain whether the child will develop complaints, more than half of the participants thought inclusion of these disorders in the NBS program would be a good idea. This is also supported by earlier research [6, 18, 19]. For example, a Canadian survey study showed that only 38% of parents believed that NBS should only be available for health conditions for which treatment or even supportive treatment is available [6]. Ataxia Telangiectasia (AT) is a specific example of an untreatable condition which occurs as an incidental finding in NBS when screening for severe combined immunodeficiency (SCID). A Dutch survey study found that the most important arguments given by the majority of parents that supported early detection of AT were to prevent a long period of uncertainty between first symptoms and diagnosis (often referred to as a “diagnostic odyssey”) and immediate optimal guidance when first symptoms occur [30].

In the United States, the public is generally positive about NBS expansion [5], despite a persistent lack of knowledge about NBS [31]. Our interview study among NBS stakeholders including healthcare professionals, NBS policy makers, researchers, laboratory specialists, and parents in the Netherlands showed that they had a positive attitude toward NBS expansion provided that it is aimed at detecting treatable disorders and achieving health gain [14]. Stakeholders with a “targeted-scope perspective” thought that the focus should be on achieving health gain for the newborn, while other stakeholders expressed broader aims and beneficiaries of NBS, for example also taking reproductive choices for family members into account [14]. Among health professionals, the topic of benefits to family members has been controversial. For example, United States research on healthcare practitioners views on Pompe disease showed that opinions on the use of reproductive benefit as a justification for NBS were markedly divided [32].

In 2021 a pilot study was carried out in four provinces in the Netherlands in which only boys were screened for ALD [33]. For this disorder, the Dutch Health Council advised screening only boys, because only boys are at risk of developing adrenal insufficiency or cerebral ALD for which treatment is available, whereas symptoms in girls usually only develop in adulthood and are untreatable [34]. In our earlier Dutch interview study, we showed that most parents did not seem to perceive the screening of subgroups as problematic in itself [14]. However, the current study showed that most parents that participated in NBS believed that both boys and girls should be tested for a disorder such as ALD, as is the case in the United States [35]. Our findings also showed that these parents support screening for a condition that may not cause symptoms until later in a child’s life.

Our study showed that 86% of NBS participants would support the addition of a disorder where NBS reveals that the mother has a certain condition as opposed to the newborn (such as OCTN2 deficiency). Most NBS participants did not object to including conditions in NBS for which DNA needs to be tested. Although many obstacles still need to be addressed before Next Generation Sequencing (NGS) can be implemented in practice, it is likely that NGS will be increasingly applied in NBS [36]. A recent UK public dialogue showed support for the potential use of whole genome sequencing in NBS provided that appropriate resources and safeguards are in place [37]. Additionally, 60 of 66 (91%) US parents indicated they definitely wanted genomic sequencing in general for their newborn if presented with this option [38].

Strengths and limitations

A significant strength of this study pertains to the inclusion of parents who declined NBS. Due to the high uptake of NBS in general, non-participants are low in numbers. Parents that declined NBS also tend to decline participating in studies on NBS, while including non-participants’ views and attitudes can be valuable [26].

This study also has some limitations. Due to privacy and data protection issues, only the RIVM could invite the participants to complete the questionnaire. This also meant that no reminders could be sent. Due to the low numbers of NBS non-participants, analytical tests between NBS participants and non-participants were not possible. It is possible that respondents were more positive or more negative based on their experiences than parents in general (potential selection bias). Furthermore, the majority of NBS-participating parents were highly educated and of Dutch origin, which may have led to an overestimation of the proportion of parents making an informed decision. Additional subgroup analyses within NBS participants showed that higher educated parents have more knowledge and are more positive about NBS (S4 Table). More research is needed among parents with lower education levels and of non-Dutch origin. Also, different NBS test results (i.e. negative, inconclusive, abnormal) could influence views and attitudes toward the NBS screening. However, in this study only few parents with abnormal and inconclusive test results responded; subgroup analyses for these groups were therefore not possible. More insight into their perceptions is needed—also regarding NBS expansion—as screening for more disorders will result in more abnormal results, including false positives. Finally, parents might not oversee all ethical, social, and financial implications of NBS expansion. Qualitative research methodologies such as in-depth interviews and focus groups give more room for explanation and are more suitable to further explore motivations behind parents’ responses in detail [14, 39].

Conclusions

In conclusion, most NBS participants made an informed decision to participate in NBS and are positive about screening for more conditions. With new conditions on the horizon and fast-developing screening technologies, insights into parents’ views on expansion of NBS can help to ensure a program that suits the population needs while safeguarding the ethical principles for screening. In addition to participants’ experiences and choices, this study also attempted to provide insight into non-participant attitudes and reasons for declining. These insights may be especially relevant when considering expansion of NBS in order to maintain a high uptake rate (and thus benefit from the health gains of NBS) and provide parents with the information and support they need to make an informed decision that is in line with their values.

Supporting information

S1 Appendix. Questionnaire used in this study.

(DOCX)

Click here for additional data file. (586.9KB, docx)
S1 Table. Number of respondents (participants and non-participants in NBS) who correctly answered the knowledge questions.

(DOCX)

Click here for additional data file. (41.9KB, docx)
S2 Table. Attitude towards NBS screening by participation.

(DOCX)

Click here for additional data file. (45.1KB, docx)
S3 Table. Undisputed choice to participate or not in NBS.

(DOCX)

Click here for additional data file. (44.3KB, docx)
S4 Table. NBS knowledge and attitude of low-/middle- versus high-educated parents that participated in NBS.

(DOCX)

Click here for additional data file. (44.7KB, docx)

Acknowledgments

We would like to thank all parents for completing the questionnaire. The National Institute for Public Health and the Environment (RIVM) is acknowledged for sending the invitational letters to the parents, especially Ellen Elsinghorst and Roger Venema. Merel van Eick is thanked for coding the open-ended questions. We thank all project advisors of the PANDA study for their input.

Data Availability

The data underlying the results are available from the secretary of department of Child Health, TNO (contact via childhealthsecretary@tno.nl) for researchers who meet the criteria for access to confidential data.

Funding Statement

This questionnaire study received funding from the Netherlands Organisation for Health Research and Development (ZonMw grant no. 543002006). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors received no other specific funding for this work.

References

  • 1.AAP Newborn Screening Task Force EGVI. Serving the family from birth to the medical home: newborn screening: a blueprint for the future—A call for a national agenda on state newborn screening programs. Pediatrics. 2000;106(Supplement 2):389–422. doi: 10.1542/peds.106.S2.389 [DOI] [PubMed] [Google Scholar]
  • 2.Cornel MC, Rigter T, Jansen ME, Henneman L. Neonatal and carrier screening for rare diseases: how innovation challenges screening criteria worldwide. J Community Genet. 2021;12(2):257–65. doi: 10.1007/s12687-020-00488-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Furnier SM, Durkin MS, Baker MW. Translating molecular technologies into routine newborn screening practice. Int J Neonatal. 2020;6(4):80. doi: 10.3390/ijns6040080 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Mak CM, Lam CW, Law CY, Siu WK, Kwong LLT, Chan KL, et al. Parental attitudes on expanded newborn screening in Hong Kong. Public Health. 2012;126(11):954–9. doi: 10.1016/j.puhe.2012.08.002 [DOI] [PubMed] [Google Scholar]
  • 5.DeLuca JM. Public attitudes toward expanded newborn screening. J Pediatr Nurs. 2018;38:e19–e23. doi: 10.1016/j.pedn.2017.10.002 [DOI] [PubMed] [Google Scholar]
  • 6.Etchegary H, Dicks E, Hodgkinson K, Pullman D, Green J, Parfey P. Public attitudes about genetic testing in the newborn period. Journal of Obstetric, Gynecologic & Neonatal Nursing. 2012;41(2):191–200. doi: 10.1111/j.1552-6909.2012.01341.x [DOI] [PubMed] [Google Scholar]
  • 7.Plass AMC, van El CG, Pieters T, Cornel MC. Neonatal screening for treatable and untreatable disorders: prospective parents’ opinions. Pediatrics. 2010;125(1):e99–e106. doi: 10.1542/peds.2009-0269 [DOI] [PubMed] [Google Scholar]
  • 8.National Institute for Public Health and the Environment (RIVM) [Internet]. RIVM; 2021 [updated 22 November 2021; cited 2021]. Informed consent procedure. https://draaiboekhielprikscreening.rivm.nl/uitvoering-hielprik/informed-consent.
  • 9.Wins S, Verkerk PH, van der Ploeg CPB. De neonatale hielprikscreening monitor 2020. Leiden, The Netherlands: TNO, 2021 Dec. Report No.: TNO 2021 R11693. Dutch.
  • 10.Newson A. Should parental refusals of newborn screening be respected? Camb Q Healthc Ethics. 2006;15(2):135–46. doi: 10.1017/s0963180106060166 [DOI] [PubMed] [Google Scholar]
  • 11.Etchegary H, Nicholls SG, Tessier L, Simmonds C, Potter BK, Brehaut JC, et al. Consent for newborn screening: parents’ and health-care professionals’ experiences of consent in practice. Eur J Hum Genet. 2016;24(11):1530–4. doi: 10.1038/ejhg.2016.55 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Waisbren SE, Albers S, Amato S, Ampola M, Brewster TG, Demmer L, et al. Effect of expanded newborn screening for biochemical genetic disorders on child outcomes and parental stress. JAMA. 2003;290(19):2564–72. doi: 10.1001/jama.290.19.2564 [DOI] [PubMed] [Google Scholar]
  • 13.White AL, Boardman F, McNiven A, Locock L, Hinton L. Absorbing it all: A meta-ethnography of parents’ unfolding experiences of newborn screening. Soc Sci Med. 2021;287:114367. doi: 10.1016/j.socscimed.2021.114367 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.van Dijk T, Kater A, Jansen M, Dondorp WJ, Blom M, Kemp S, et al. Expanding neonatal bloodspot screening: a multi-stakeholder perspective. Front Pediatr. 2021;9(1078). doi: 10.3389/fped.2021.706394 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.El-Hattab AW, Li F, Shen J, Powell BR, Bawle EV, Adams DJ, et al. Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects. Genet Med. 2010;12(1):19–24. doi: 10.1097/GIM.0b013e3181c5e6f7 [DOI] [PubMed] [Google Scholar]
  • 16.Health Council of the Netherlands. Neonatal screening: new recommendations. The Hague: Health Council of the Netherlands: 2015 April. Report No.: 2015/08E.
  • 17.Engelen M, Barbier M, Dijkstra IME, Schür R, de Bie RMA, Verhamme C, et al. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Brain. 2014;137(3):693–706. doi: 10.1093/brain/awt361 [DOI] [PubMed] [Google Scholar]
  • 18.Hasegawa LE, Fergus KA, Ojeda N, Au SM. Parental attitudes toward ethical and social issues surrounding the expansion of newborn screening using new technologies. Public Health Genomics. 2011;14(4–5):298–306. doi: 10.1159/000314644 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Tarini BA, Simon N-J, Payne K, Gebremariam A, Rose A, Prosser LA. An assessment of public preferences for newborn screening using best-worst scaling. J Pediatr. 2018;201:62–8. e1. doi: 10.1016/j.jpeds.2018.05.035 [DOI] [PubMed] [Google Scholar]
  • 20.van der Pal S, Detmar S. Evaluatie hielprik voorlichting 2008. Leiden, The Netherlands: TNO, 2008 Oct. Report No.: KvL/P&Z 2008.105. Dutch.
  • 21.van der Pal S, Otten W, Detmar S. Evaluatie van de voorlichting aan ouders over de hielprik. TSG. 2010; 88(8):[449–53 pp.]. https://repository.tno.nl//islandora/object/uuid:17adef8f-bacd-4c5a-bf90-edc2201575c1. Dutch. [Google Scholar]
  • 22.Hayeems RZ, Miller FA, Bombard Y, Avard D, Carroll J, Wilson B, et al. Expectations and values about expanded newborn screening: a public engagement study. Health Expect. 2015;18(3):419–29. doi: 10.1111/hex.12047 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Marteau TM, Dormandy E, Michie S. A measure of informed choice. Health Expect. 2001;4(2):99–108. doi: 10.1046/j.1369-6513.2001.00140.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Statline Statistics Netherlands [Internet]. CBS; 2019 [updated 13 October 2021; cited 2019]. Population; key figures. https://opendata.cbs.nl/#/CBS/en/dataset/37296eng/table?ts=1640540040972.
  • 25.Quinlivan JA, Suriadi C. Attitudes of new mothers towards genetics and newborn screening. J Psychosom Obstet Gynaecol. 2006;27(1):67–72. doi: 10.1080/01674820500420652 [DOI] [PubMed] [Google Scholar]
  • 26.Nicholls SG, Southern KW. Parental decision-making and acceptance of newborn bloodspot screening: an exploratory study. PLoS One. 2013;8(11):e79441. doi: 10.1371/journal.pone.0079441 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Carlton J, Griffiths HJ, Horwood AM, Mazzone PP, Walker R, Simonsz HJ. Acceptability of childhood screening: a systematic narrative review. Public Health. 2021;193:126–38. doi: 10.1016/j.puhe.2021.02.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Public Health England [Internet]. UK Government; 2018 [updated 3 August 2018; cited 2020]. Guidance: 2. Screening pathway. https://www.gov.uk/government/publications/health-professional-handbook-newborn-blood-spot-screening/2-screening-pathway#informed-choice.
  • 29.Parsons EP, King JT, Israel JA, Bradley DM. Mothers’ accounts of screening newborn babies in Wales (UK). Midwifery. 2007;23(1):59–65. doi: 10.1016/j.midw.2006.05.008 [DOI] [PubMed] [Google Scholar]
  • 30.Schoenaker MHD, Blom M, de Vries MC, Weemaes CMR, van der Burg M, Willemsen MAAP. Early diagnosis of ataxia telangiectasia in the neonatal phase: a parents’ perspective. Eur J Pediatr. 2020;179(2):251–6. doi: 10.1007/s00431-019-03479-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Botkin JR, Rothwell E. Whole genome sequencing and newborn screening. Curr Genet Med Rep. 2016;4(1):1–6. doi: 10.1007/s40142-016-0084-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Davids L, Sun Y, Moore RH, Lisi E, Wittenauer A, Wilcox WR, et al. Health care practitioners’ experience-based opinions on providing care after a positive newborn screen for Pompe disease. Mol Genet Metab. 2021;134(1–2):20–8. doi: 10.1016/j.ymgme.2021.09.001 [DOI] [PubMed] [Google Scholar]
  • 33.Barendsen RW, Dijkstra IME, Visser WF, Alders M, Bliek J, Boelen A, et al. Adrenoleukodystrophy newborn screening in the netherlands (SCAN Study): The X-factor. Front Cell Dev Biol. 2020;8(499). doi: 10.3389/fcell.2020.00499 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy–neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016;12(10):606–15. doi: 10.1038/nrendo.2016.90 [DOI] [PubMed] [Google Scholar]
  • 35.Vogel BH, Bradley SE, Adams DJ, D’Aco K, Erbe RW, Fong C, et al. Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines. Mol Genet Metab. 2015;114(4):599–603. doi: 10.1016/j.ymgme.2015.02.002 [DOI] [PubMed] [Google Scholar]
  • 36.Remec ZI, Trebusak Podkrajsek K, Repic Lampret B, Kovac J, Groselj U, Tesovnik T, et al. Next-generation sequencing in newborn screening: a review of current state. Front Genet. 2021;12(710). doi: 10.3389/fgene.2021.662254 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Hopkins van Mil, Hopkins H, Kinsella S, Evans G. Implications of whole genome sequencing for newborn screening. London, UK: UK National Screening Commitee, 2021 July.
  • 38.Moultrie RR, Paquin R, Rini C, Roche MI, Berg JS, Powell CM, et al. Parental views on newborn next generation sequencing: implications for decision support. Matern Child Health J. 2020;24:856–64. doi: 10.1007/s10995-020-02953-z [DOI] [PubMed] [Google Scholar]
  • 39.Detmar S, Hosli E, Dijkstra N, Nijsingh N, Rijnders M, Verweij M. Information and informed consent for neonatal screening: opinions and preferences of parents. Birth. 2007;34(3):238–44. doi: 10.1111/j.1523-536X.2007.00176.x [DOI] [PubMed] [Google Scholar]

Decision Letter 0

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18 Apr 2022

PONE-D-22-02051Parents’ views about newborn bloodspot screening  (non-)participation and expansionPLOS ONE

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Reviewer #1: Thank you for the opportunity to review this paper about parents’ attitudes to newborn screening (NBS) in the Netherlands. Manuscript presents a survey distributed to parents, which accepted or declined participation in NBS to analyse if they made an informed decision about participation and to collect their views on current NBS and its possible expansion. The results are based on a sample of 804 NBS participants and 48 NBS non-participants and might give an important feedback to Dutch NBS programme. However, some changes are needed to clearly present the research conducted and its results.

Title

I would suggest to the authors to either substitute the term (non-)participation with participation or rephrase the title completely.

Introduction

I miss the information about Dutch NBS programme. It would be useful for reader to learn how, when and by whom are parents informed about NBS, if the information is standardised, if there is an informed consent in place, when the sampling is performed, how many disorders are included in the current Dutch NBS, how are parents informed about result, etc. All these elements are also important for parents’ views about NBS. Some of this information is in the Discussion paragraph on Informed participation but reader should learn these facts earlier.

The aims of the study are not well described. I would expect to find their overview in the last paragraph of the introduction section. I have learned only in methods section that survey focused also on informed decision about participation in NBS.

Materials and Methods

Results

Table 1 – Can authors specify what they mean by low/middle and high education?

Table 1 - I guess the information about general Dutch population is not available and that’s why some of the boxes stay empty. Short explanation should be provided even it would be very interesting to know these numbers for comparison.

The presentation of the results in Tables 1, 2, 3, 4, 5 and S1 should be unified. The numbers in columns are sometimes presented with percentages and sometimes the percentage sign is only in the table header and in Table 1 it is also in a different column.

Can you specify better how the questions for non-participants were phrased? I revealed from the heading of the first column in Table 2 that the item in survey sounded like “I decided not to participate because I can prevent my child from getting health complaints from a disorder”. I have the same problem with next two items in Table 2.

On Page 14 in the paragraph on Parents’ views on current NBS survey revealed that few respondents had regretted NBS participation. Did they state why?

Discussion

On page 19 in the first paragraph authors say there finding is in line with other studies but they are not cited.

On the lines 310-311: “Our study suggests that how the data and … are handled…” Can you specify which data?

On page 22 in the second paragraph, can you specify the term stakeholders? Does it mean parents, healthcare professionals, healthcare providers or some other groups involved?

Conclusions

Can you explain the term “Dutch ethical principles for screening”? In my opinion ethical principles for screening are universal at least in Western countries. Does it mean ethical principles recommended by Dutch Health Council or other governance body?

General issue:

A stringent proof read would help to correct typos, grammatical errors, complex and unclear sentences, and non-standard use of parentheses. The last sentence in the conclusions is an example of most of these, but they are throughout the paper.

Reviewer #2: This is an excellent article overall and I particularly appreciate the efforts to recruit and gain insight into reasons for non-participation in NBS!

The introduction and discussion would be enhanced by inclusion of more recent articles in the literature; for example, those which have explored perspectives of parents with children who were diagnosed at NBS for conditions with late-onset subtypes and the ethical quandaries in detection of these at birth (see suggestions below).

Also, analytical statistics need to be performed for study results involving comparisons between groups, in order for them to be accepted as not obtained due to chance (significant). I know that your sample size is low for the non-participating group, but such analysis can be done using certain statistical techniques and vastly increases the conclusions you can draw from your data. Otherwise, there are certain statements / conclusions you just can’t scientifically make. As a result, not all of the conclusions made in this manuscript are supported by the data (yet).

Please see attachment for specific feedback throughout the manuscript.

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2022 Aug 18;17(8):e0272585. doi: 10.1371/journal.pone.0272585.r002

Author response to Decision Letter 0

16 Jun 2022

[see also the uploaded document with our "response to the reviewers]"

Dear Editor,

We would like to thank the reviewers for providing valuable feedback on our manuscript “Parents’ views on declining newborn bloodspot screening, participation and expansion”. We were glad that the reviewers commented favorably on our paper and have edited our manuscript according to their comments. Below you will find our point-by-point reply to their comments. Changes in the revised manuscript are visible with ‘track changes’.

We look forward to hearing your decision.

On behalf of the authors,

Dr. Sylvia van der Pal

Editor comments:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

� Answer: Format checked next to PLOS ONE requirements and minor changes made (see track changes). Supporting information, titles and file names were adjusted to style requirements (e.g. S1 Table) and upload supporting information as separate files.

2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed).

Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).

� Answer: Under the header “Study population” (p. 6) we had described the consent procedure in the following way: “Before parents completed the (online) questionnaire they were asked to tick a box to confirm that they had read the information letter and that they gave their informed consent to participate in the study.” We have moved this to the Design and ethics statement section (p. 5). To further specify the type of consent we added “(written consent)” to the sentence.

3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found.

� Answer: The Data Availability statement has been amended to “The data underlying the results are available from the secretary of department of Child Health, TNO (contact via childhealthsecretary@tno.nl) for researchers who meet the criteria for access to confidential data”

Reviewers’ Comments:

Reviewer #1: Thank you for the opportunity to review this paper about parents’ attitudes to newborn screening (NBS) in the Netherlands. Manuscript presents a survey distributed to parents, which accepted or declined participation in NBS to analyse if they made an informed decision about participation and to collect their views on current NBS and its possible expansion. The results are based on a sample of 804 NBS participants and 48 NBS non-participants and might give an important feedback to Dutch NBS programme. However, some changes are needed to clearly present the research conducted and its results.

Title

I would suggest to the authors to either substitute the term (non-)participation with participation or rephrase the title completely.

� Answer: The title was changed to: “Parents’ views on accepting, declining, and

expanding newborn bloodspot screening.”

Introduction

I miss the information about Dutch NBS programme. It would be useful for reader to learn how, when and by whom are parents informed about NBS, if the information is standardised, if there is an informed consent in place, when the sampling is performed, how many disorders are included in the current Dutch NBS, how are parents informed about result, etc. All these elements are also important for parents’ views about NBS. Some of this information is in the Discussion paragraph on Informed participation but reader should learn these facts earlier.

� Answer: In the introduction, we added information about the Dutch context. This can be found in the following sentences: “In the Netherlands NBS participation is not mandatory and parents are asked if they agree to NBS [8]. NBS is nevertheless well accepted. In 2020, 99.4% of parents of newborns participated in newborn screening which, in that year, included 24 disorders [9].”

Additionally, we added context to the Method section, under the new header “Setting”: “In the Netherlands, NBS is organized and coordinated by the Dutch National Institute for Public Health and the Environment (RIVM). Standardized information on NBS, including a leaflet, is provided during pregnancy by an obstetric healthcare provider, and issued before the screening is done, a few days after birth, at home by a youth health care worker, maternity nurse or midwife. When the baby is admitted to the hospital during the first week after birth, the blood spot is collected by a hospital health care worker. If the NBS result is good, parents will get a letter from RIVM within five weeks, as from March 1st, 2020 (before that time, no result was given). If an abnormality is detected, the general practitioner will inform parents about the results.”

The aims of the study are not well described. I would expect to find their overview in the last paragraph of the introduction section. I have learned only in methods section that survey focused also on informed decision about participation in NBS.

� Answer: The aims of the study were changed to: “this study aimed to assess parents’ reasons for, and views on participating or not participating in Dutch NBS, whether they make an informed decision, and their views on expansion of NBS in the Netherlands.”

Materials and Methods

Results

Table 1 – Can authors specify what they mean by low/middle and high education?

� Answer: Added as a footnote below Table 1: “dLow education level = Elementary school, lower level of secondary school, and lower vocational training. Middle education level = higher level of secondary school and intermediate vocational training. High education level = High vocational training and university.”

Table 1 - I guess the information about general Dutch population is not available and that’s why some of the boxes stay empty. Short explanation should be provided even it would be very interesting to know these numbers for comparison.

� Answer: We agree that more information would be interesting, however this is not available for this group. An explanation on the empty boxes was added as a footnote below Table 1, footnote c: “Not all data were available, therefore these cells remain empty.”

The presentation of the results in Tables 1, 2, 3, 4, 5 and S1 should be unified. The numbers in columns are sometimes presented with percentages and sometimes the percentage sign is only in the table header and in Table 1 it is also in a different column.

� Answer: For all Tables we removed the percentage signs after the numbers in each relevant cell. In Table 1 the percentage sign is in the rows, because age is included which uses means and SD’s.

Can you specify better how the questions for non-participants were phrased? I revealed from the heading of the first column in Table 2 that the item in survey sounded like “I decided not to participate because I can prevent my child from getting health complaints from a disorder”. I have the same problem with next two items in Table 2.

� Answer: Changed the heading of the first column in Table 2 to “You did or did not participate in the heel prick test. Indicate how important the following reasons were for you in making a decision about participation in the heel prick test”, which is how the question was formulated in the questionnaire.

On Page 14 in the paragraph on Parents’ views on current NBS survey revealed that few respondents had regretted NBS participation. Did they state why?

� Answer: We did not ask for reasons for regret in the question but we did check whether the four parents that indicated regret had left any remarks on the questionnaire. Two parents did not leave any remarks. One parent, who had ‘a bit regret’, indicated having been in doubt about participation but that they participated because they saw no disadvantages. This parent requested further information about the heritability of the NBS diseases but did not get a satisfactory answer. One other parent did not leave a remark but indicated that NBS showed that their child was diagnosed with one of the diseases. We have now specified this in the manuscript.

Discussion

On page 19 in the first paragraph authors say there finding is in line with other studies but they are not cited.

� Answer: This statement refers to the two interview studies that are summarized thereafter. The references are now shown after this sentence.

On the lines 310-311: “Our study suggests that how the data and … are handled…” Can you specify which data?

� Answer: This sentenced referred also to parents’ data, therefore we included this in the sentence: “Our study suggests that how the parents’ data and the child’s data are handled might play a role in parents’ decision to decline NBS. This was a general question about (privacy of) data. We are unable to specify further, because this was not specified in the questionnaire.

On page 22 in the second paragraph, can you specify the term stakeholders? Does it mean parents, healthcare professionals, healthcare providers or some other groups involved?

� Answer: We changed the sentence to “Our interview study among NBS stakeholders including healthcare professionals, NBS policy makers, researchers, laboratory specialists and parents in the Netherlands showed that…”

Conclusions

Can you explain the term “Dutch ethical principles for screening”? In my opinion ethical principles for screening are universal at least in Western countries. Does it mean ethical principles recommended by Dutch Health Council or other governance body?

� Answer: We agree with the reviewer and removed the word “Dutch”.

General issue:

A stringent proof read would help to correct typos, grammatical errors, complex and unclear sentences, and non-standard use of parentheses. The last sentence in the conclusions is an example of most of these, but they are throughout the paper.

� Answer: We followed the reviewers advice and asked a professional translator to proofread the manuscript and correct mistakes. These corrections can be seen via ‘track changes’ throughout the manuscript.

Reviewer #2

Overall

This is an excellent article overall and I particularly appreciate the efforts to recruit and gain insight into reasons for non-participation in NBS!

The introduction and discussion would be enhanced by inclusion of more recent articles in the literature; for example, those which have explored perspectives of parents with children who were diagnosed at NBS for conditions with late-onset subtypes and the ethical quandaries in detection of these at birth (see suggestions below).

Also, analytical statistics need to be performed for study results involving comparisons between groups, in order for them to be accepted as not obtained due to chance (significant). I know that your sample size is low for the non-participating group, but such analysis can be done using certain statistical techniques and vastly increases the conclusions you can draw from your data. Otherwise, there are certain statements / conclusions you just can’t scientifically make.

Abstract

Please reword the 1st sentence is the results subsection of the abstract to make clear that these are the most important reasons reported by the parents in the study.

� Answer: We amended the sentence to “The most important reason for parents to participate in NBS was to prevent health complaints”.

You cannot make the comparisons between groups in the 2nd and 3rd sentences of the abstract results without having analytical statistics to back up your claim.

� Answer: We have now added the according p-values to the abstract.

In the final section of the abstract results, please reword to say that “Most parents in the NBS-participating group agreed……”

� Answer: We replaced “parents” with “NBS participants”

In the abstract conclusions section, please reword to say that “Most parents in the NBS-participating group made an informed decision……” Might include a sentence about the non-participating group’s informed decisions not to participate as well, since this is new data and relevant to your results.

� Answer: Added “NBS” to participants.

Introduction

The van Dijk article citation is excellent, but a lot of the other literature cited on parental perspectives on NBS in the Introduction is dated. Recent articles have been published exploring the perspective of parents whose children’s conditions were actually detected via NBS (e.g. Pruniski et al 2018’s Newborn screening for Pompe disease: Impact on families)(White et al 2021’s Absorbing it all – a meta-ethnography of parents’ unfolding experiences of NBS)(Kariyawasam et al 2021’s We needed this)(etc.). In addition, a few recent articles have asked adults with genetic conditions whether they would have wanted to know their condition at birth via NBS (e.g. Lisi et al’s 2016 & 2021 articles). Please update your literature review to include some of these.

� Answer: Thank you for pointing us to these papers. We have included the review paper of White et al. in the manuscript introduction and discussion, as was suggested by the reviewer. However, besides this review paper, these are all papers about the (psychological) impact on parents and families of a specific abnormal NBS result such as for Pompe disease (Pruniski 2018) or for SMA (Kariyawasam 2021), or on the perspectives of health professionals (Lisi 2016) or of adult patients on NBS inclusion of specific diseases (Lysosomal storage diseases), while our study assesses the general views of a general group of parents on NBS, with very few parents having an abnormal results. In our next study that is currently being done, we focus on psychological well-being after abnormal results and we will include these articles.

Methods

Page 5, lines 95-99 - Are the #’s of parents who declined participating in NBS in 2019 and 2020 from the entire year or just the five-weeks-earlier period the parents who consented to NBS were taken from? It’s not clear from the wording in the text – please clarify.

� Answer: We added the words “the whole of” to reflect that these parents were from the entire year. The sentence now reads: “In addition, all parents who declined participation in NBS in the whole of 2019 (n = 515) received an invitation to complete the same online questionnaire at the beginning of 2020, …”

Page 6, line 111 – Please clarify whether the 5 parents the questionnaire was tested on had allowed their children to have NBS or declined it, whether their children had positive NBS results or whether all had received negative NBS results, whether or not the 5 parents also participated in the study, etc.

� Answer: We don’t know. The questionnaire was piloted among parents. This was done to see whether the questionnaire was clear. We did not specifically ask or look at their answers and did not incorporate their answers in the data as the questionnaire was in its test phase.

Page 7, lines 148-151 – Tables S1, S2, and S3 allow the reader to see the questions asked of the participant. It would be nice to see the Views on current NBS questions as well. Consider adding a copy of the entire survey in an Appendix for reader reference.

� Answer: We added the survey in an Appendix as suggested by the reviewer. In the Method section, under the header Questionnaire and procedure (p.7) we refer to the appendix in the following way: “A copy of the entire questionnaire can be found in S1 Appendix.” The numbering for the other supplemental materials has been adjusted according to order of appearance (e.g. S1 Table is now S2 Table). The ALD scenario formerly described as S4 appendix has been removed, as this is incorporated in S1 Appendix (question B.3).

Page 8, line 153 – Please include which 7 conditions participants were asked to evaluate for expanded NBS, if these questions were about specific genetic conditions. If they are about more general scenarios (as Table 5 suggests), please make that clear. In general, the questions asked seem to be spread out over a large # of tables. Again, consider consolidating them all by placing a copy of the entire survey in an Appendix for ease of reader reference.

� Answer: We added an example to illustrate: “Views on expanding NBS consisted of descriptions of seven conditions (e.g. a condition which will give your child symptoms only later in life) for which parents who had participated in NBS were asked if it would be a very bad, bad, neutral, good or very good idea to add these conditions to NBS.” We also added the survey in an Appendix (S1 Appendix) as suggested by the reviewer in the previous comment.

Results

Please clarify the %’s in the “Statistics” column in Table 1. As stated now (%s), I do not know how to interpret them. Are they simply meant to reflect the % of each row out of the total possible? If so, why do we not see them for every row? If they are meant to represent something else, what else? A p-value to determine whether there were any pre-existing significant differences between groups would lend greater credibility to your results.

� Answer: We have now replaced the %’s in the last column with (..), as this is indeed the way it is displayed in the other columns. We have now also clarified that this last column represents the values within the Dutch population to put the values in the previous column’s in perspective. As this is mainly for perspective we did not include statistical analyses. We did include statistical analyses to compare the other two columns with respondents who did and did not participate in NBS. It is however questionable whether differences are caused by actual differences between the two groups or a difference in response-bias in the two groups.

Also in Table 1, please define how you categorized someone as having “low/middle” levels of education versus “high” education.

� Answer: Added as a footnote below Table 1: “dLow education level = Elementary school, lower level of secondary school, and lower vocational training. Middle education level = higher level of secondary school and intermediate vocational training. High education level = High vocational training and university.”

Table 2: Please include p-value or similar analytical statistic to allow reader to determine whether difference between columns is significant or not.

� Answer: We believe that these means cannot be compared as the reasoning for those who participated in NBS and those who declined cannot be compared. To make this more clear we have now redesigned the table with displaying the most important reason for each group at the top.

Page 13, lines 236-237 – You cannot conclude that respondents who participated in NBS made a more undisputed choice to participate or that NBS non-participants indicated more doubt without some form of analytical analysis to show that the difference in score was not due to chance. Please do analysis, as was done in Table S5 (also, please define the terms “low-middle educated” and “high-educated in Table S5).

� Answer: We have performed Chi square tests for ordinal trend on the variables displayed in S4 Table and added this to the table and added a sentence in the text under Informed Decision: “S4 Table shows that respondents who participated in NBS made a more undisputed choice to participate (p<.001), while NBS non-participants indicated having more doubt (p<.001)”. We also added a footnote beneath Table S5: “dLow education level = Elementary school, lower level of secondary school, and lower vocational training. Middle education level = higher level of secondary school and intermediate vocational training. High education level = High vocational training and university.”

Discussion

Page 18, lines 287-289 - The beginning of the discussion states that overall respondents were very positive about the current NBS program, as well as expanded screening. However, this is confounded by the vastly different sample sizes between those who opted in for NBS vs those that opted out. You can reword this to say that those participants who opted into NBS were very positive about the current NBS system, while those who opted out felt differently (but you have to do analytical statistics to show the differences between groups were not obtained by chance).

� Answer: We now did statistical tests and on the knowledge-score and attitude-score differences between NBS participants and those who declined NBS and added this to S2 and S3 tables and added a sentence about this in the Results under Informed Decision; “S2 and S3 Tables show respondents’ answers per knowledge item and per attitude item, respectively, and shows a difference in knowledge-score (7.72 versus 5.87, p<.001) and attitude-score (8.33 vs 5.16, p<.001) between respondents who participated in NBS and those who declined NBS.” Furthermore, we amended this first sentence in the discussion to: “Overall, NBS participants in this study carried out in the Netherlands were very positive about the current NBS program, while those who declined NBS felt differently, and the large majority of NBS participants was also positive about expanding the number of disorders screened for.”

Page 18, lines 289-291 – Likewise, in order to make the statement here regarding the proportion of those making an informed decision being lower in one group than the other, a p-value or other analytical statistic is needed to prove that the results were not obtained by chance. The only part of this statement that has been statistically analyzed is the education part (Table S5).

� Answer: We now statistically tested whether the difference in informed decision (yes/no) between respondents that participated in NBS and those who declined NBS with a chi square test and this was highly significant (p<.001). We included this in the Results under Informed Decision: “The difference in the percentage that made an informed decision to participate in NBS between respondents who participated in NBS (83%) and those who declined NBS (44%) was statistically significant (p<.001).”

Page 19, line 294 – Would recommend rewording this sentence to “The reason respondents reported as most important to participate in NBS was…..,” so as to make clear it is the respondents’ opinion, not the authors. This is well done at the beginning of the 2nd paragraph on this page, so maybe copy that wording for the 1st paragraph as well.

� Answer: Amended to “The reason respondents reported as most important for participating in NBS was to prevent disease symptoms in their child, in line with the aim of screening [2], …”

Page 19, lines 303-304 – Cannot say that “Non-participating parents were more actively religious…..compared to participating parents” without a p-value to prove this.

� Answer: We now performed statistical tests and included this in Table 1.

Page 19, lines 312-314 - Cannot say that “Non-participating parents were more often in doubt….compared to NBS participants” without a p-value to prove this.

� Answer: We now performed statistical tests and included this in S4 table.

Page 20, line 339 – It looks as though you have only included the group that made the informed decision to participate in this % (83%). Wouldn’t it be more accurate to include those who made the informed decision NOT to participate in this # as well? Either that or change the wording of the sentence to make clear that you are only referring to the NBS-participating group, not the entire group of participants.

� Answer: We changed participating parents to NBS participants to clarify that here we only refer to the group that participated; “Our results indicate that the majority (83%) of the NBS participants made an informed decision, …”.

We did include those who made an informed decision not to participate. This is shown in the results section and discussion: “The current study found a lower percentage (44%) of informed choice in parents that declined NBS.”

Page 21, line 344 – You need a p-value to be able to scientifically declare this a difference between groups.

� Answer: We have now done a statistical test to compare the %’s of informed decision between respondents who participated in NBS and those who declined NBS and added a sentence about this in the Results under Informed Decision: “The difference in the percentage that made an informed decision to participate in NBS between respondents who participated in NBS (83%) and those who declined NBS (44%) was statistically significant (p<.001).”

Page 21, line 355 - You need a p-value to be able to scientifically declare this a difference between groups.

� Answer: We have now done statistical tests to look at this difference and added this to the S4 table.

Page 21-23, section on “Parents’ views on expanding Dutch NBS” – This section does a much better job of incorporating some newer article citations – love it A few others which are relevant and add a different perspective include O’Connor et al’s 2018 Psychosocial impact on mothers receiving expanded NBS results, as well as some of the research on NBS for lysosomal storage diseases mentioned earlier in this review.

� Answer: Although we fully agree with the reviewers that some newer citations would be helpful; there are not many recent papers on parents’ views on expanded NBS, moreover, the citations that are suggested by the reviewer, though very interesting, are mainly about the psychological impact of receiving an abnormal result. We therefore believe that these are not completely helpful in discussing our findings that focus more on the views of parents with a normal result. In our next study that is currently being done, we focus on psychological well-being after abnormal results and we will include these articles.

Page 22, lines 376-379 – Not sure who you are including as stakeholders in this section, but you may find it interesting to compare with the results in Davids et al 2021 article asking about the use of NBS for reproductive choices for family members regarding Pompe disease (Health care practitioners’ experienced-based opinions on providing care after a positive NBS for Pompe)

Answer: Thank you for pointing us to the paper of Davids et al. We included this paper in the discussion. “Among health professionals, the topic of benefits to family members has been controversial. For example, United States research on healthcare practitioners views on Pompe disease showed that opinions on the use of reproductive benefit as a justification for NBS were markedly divided.”

Moreover, we have added which stakeholders were included in the interview study as also suggested by Reviewer #1. “Our interview study among NBS stakeholders including healthcare professionals, NBS policy makers, researchers, laboratory specialists, and parents in the Netherlands showed that they had a positive attitude toward NBS”.

Page 22, lines 390-393 – Please clarify the wording of these sentences to make clear that the percentages you report only pertain to the NBS-participating-parents, not the entire group of respondents.

� Answer: Amended by adding “that participated in NBS” to specify which parents, and replaced “parents” by “NBS participants” in the following sentences describing our study results.

Page 24, Conclusions section - Please clarify the wording of the first sentence to make clear that the conclusions you report only pertain to the NBS-participating-parents, not the entire group of respondents. Any other conclusion is confounded by the vast difference is sample size between groups.

� Answer: Changed “parents” to “NBS participants”

Supplementary Tables & Figures

Table S1: Please include p-value or similar analytical statistic to allow reader to determine whether difference between columns is significant or not. You might also consider adding a column to show how many participants checked “I don’t know” as opposed to answering incorrectly, since both choices were given to participants.

� Answer: We have added the mean Knowledge-score to the S2 table and statistically tested the significance of the difference between respondents who participated in NBS and those who declined NBS. We added a sentence about this in the results under Informed Decision: “S2 and S3 Tables show respondents’ answers per knowledge item and per attitude item, respectively, and show significant differences in knowledge-score (7.72 versus 5.87, p<.001) and attitude-score (8.33 vs 5.16, p<.001) between respondents who participated in NBS and those who declined NBS.” We however feel that emphasizing on the %’s that gave a correct answer provides the reader with a clear overview and therefore decided not to add the participants that answered ‘I don’t know’.

Table S2: Please include p-value or similar analytical statistic to allow reader to determine whether difference between columns is significant or not.

� Answer: We have added the mean Attitude-score to the S3 table and statistically tested the significance of the difference between respondents who participated in NBS and those who declined NBS. We added a sentence about this in the results under Informed Decision: “S2 and S3 Tables show respondents’ answers per knowledge item and per attitude item, respectively, and show significant differences in knowledge-score (7.72 versus 5.87, p<.001) and attitude-score (8.33 vs 5.16, p<.001) between respondents who participated in NBS and those who declined NBS.”

Table S3: Please include p-value or similar analytical statistic to allow reader to determine whether difference between columns is significant or not.

� Answer: We now performed statistical tests and added this to the S4 table. We have also added a sentence in the Results under Informed Decision: “S4 Table shows that respondents who participated in NBS made a more undisputed choice to participate (p<.001), while NBS non-participants indicated having more doubt (p<.001).”

Attachment

Submitted filename: ResponseToReviewers_PLOSONE_16june2022.docx

Click here for additional data file. (54.4KB, docx)

Decision Letter 1

Elsayed Abdelkreem

22 Jul 2022

Parents’ views on accepting, declining, and expanding newborn bloodspot screening

PONE-D-22-02051R1

Dear Dr. van der Pal,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Elsayed Abdelkreem, MD, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: All comments have been addressed

**********

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**********

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Reviewer #1: Yes

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Acceptance letter

Elsayed Abdelkreem

9 Aug 2022

PONE-D-22-02051R1

Parents’ views on accepting, declining, and expanding newborn bloodspot screening

Dear Dr. van der Pal:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

Dr. Elsayed Abdelkreem

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Appendix. Questionnaire used in this study.

    (DOCX)

    Click here for additional data file. (586.9KB, docx)
    S1 Table. Number of respondents (participants and non-participants in NBS) who correctly answered the knowledge questions.

    (DOCX)

    Click here for additional data file. (41.9KB, docx)
    S2 Table. Attitude towards NBS screening by participation.

    (DOCX)

    Click here for additional data file. (45.1KB, docx)
    S3 Table. Undisputed choice to participate or not in NBS.

    (DOCX)

    Click here for additional data file. (44.3KB, docx)
    S4 Table. NBS knowledge and attitude of low-/middle- versus high-educated parents that participated in NBS.

    (DOCX)

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    Data Availability Statement

    The data underlying the results are available from the secretary of department of Child Health, TNO (contact via childhealthsecretary@tno.nl) for researchers who meet the criteria for access to confidential data.

    Articles from PLoS ONE are provided here courtesy of PLOS

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