Objective The ALBINO Trial (NCT03162653) investigates effects of very early postnatal allopurinol on neurocognitive outcome following perinatal asphyxia where prenatal informed consent (IC) is impossible. Ethically and legally, waiver of consent and/or deferred consent (DC) is acceptable in such an emergency. Short oral/two-step consent (SOC, brief information and oral consent followed by IC) has recently been investigated.
Methods Mixed-methods analysis of parental opinions on DC versus SOC in the context of neonatal asphyxia in a survey at two German centres. Prospective parents (ProP), parents of healthy newborns (PNeo) and parents of asphyxiated infants (PAx) born between 2006 and 2016 were invited.
Results 108 of 422 parents participated (ProP:43; PNeo:35; PAx:30). Most parents trusted physicians, wanted preinterventional information and agreed that in emergencies interventions should begin immediately. Intergroup and intragroup variability existed for questions about DC and SOC. In the ALBINO Trial situation, 55% preferred SOC, and 26% reported DC without information might adversely affect their trust. Only 3% reported to potentially take legal action after DC. PAx were significantly more likely to support DC. PAx more frequently expressed positive emotions and appreciation for neonatal research. In open-ended questions, parents gave many constructive recommendations.
Conclusion In this survey, parents expressed diverse opinions on consent, but the majority preferred SOC over DC. Parents who had experienced emergency admission of their asphyxiated neonates were more trusting. Obtaining parental perspectives is essential when designing studies, while being cognisant that these groups of parents may not represent the opinion of all parents.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT’S IS ALREADY KNOWN ON THIS SUBJECT
Obtaining parental consent for investigations in emergencies (eg, perinatal asphyxia) is ethically complex and sometimes impossible.
Deferred/waiver of consent is a controversial topic where parental/stakeholders' perspectives are scarce.
WHAT THIS STUDY ADDS
Stakeholders can have diverse opinions. In the context of asphyxia, the majority of parents preferred short oral consent followed by informed consent over deferred consent.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Considering parental perspectives when designing studies including waiver/deferred consent is essential.
Two-(or multi-)stage consent with the opportunity to opt-out may be a good approach and following participants in those studies for their perspectives is recommended.
According to current legislation, guidelines on Good Clinical Practice and the Declaration of Helsinki1 ethically justified research in humans requires informed consent (IC).2 3 In paediatrics, parents/guardians provide consent for their children.4
In neonatal research, this may be considered in trials on delivery room management,5 where DC has been used before,6 but is deemed ethically and legally complex.7 The alternative, prenatal consent, was reported to negatively impact on validity and representativeness.8 9 Recently, short oral/two-step consent (SOC) has been described, where researchers seek oral opt-out assent for participation during time-critical periods, followed by later IC.10
The ALBINO Trial (NCT03162653) investigates the effects of early allopurinol versus placebo, administered ≤45 min after birth, on neurocognitive outcome following perinatal asphyxia,11 12 where prenatal and detailed IC before enrolment is not feasible because birth asphyxia is unpredictable and parents are burdened in such situations.13 Nevertheless, research in these situations is essential to improve outcomes.14
Designing the ALBINO Trial, investigators, ethicists and parent advocates discussed the consent methodology and sought guidance by surveying parental perspectives about DC and SOC in perinatal emergencies.
The anonymous semistandardised questionnaire was co-developed by clinicians and experts in parental perspectives and qualitative healthcare research. The original questionnaire was in German (online supplemental appendix 1, online). Data were collected from October 2016 to October 2017.
In the standardised section, parents were asked about their general trust in physicians/paediatricians, decisions about medical interventions for their child, decision-making during emergencies, and consent in the context of ALBINO and other pharmaceutical trials. Answers were given on a 4-point Likert-Scale (‘I fully agree’ to ‘I fully disagree’) or, alternatively, ‘I don’t know/cannot judge this’.
Additionally, open-ended questions inquired parental perspectives on their child’s participation in trials (eg, ALBINO), their reaction after DC and recommendations for the ALBINO team.
Subjects and recruitment
Three parent groups were invited:
Prospective parents (ProP) recruited during routine prenatal outpatient appointments.
Parents of healthy newborns (PNeo) recruited during inpatient maternity care.
Parents of neonates treated for perinatal asphyxia (PAx) in 2006–2016 (meeting ALBINO Trial inclusion criteria), invited by letter and reminded once.
ProP and PNeo received a brief verbal explanation before receiving the study documents.
Formal sample size calculation was not performed due to the exploratory and qualitative character of the study. The initial sample size was determined based on the prevalence of perinatal asphyxia in the preceding 10 years at Dresden and Tübingen, and an expected response rate of 30% in PAx.
Analyses of the standardised questions were descriptive using percentages, means and SDs. Couples were treated as independent observations. Likert-Scale results were dichotomised (positive vs negative). The neutral answer (‘I don’t know/cannot judge this’) was set to ‘missing’. Associations between answers (positive vs negative) and parent groups, gender, religious affiliation and education were evaluated exploratively by χ2 test for questions with (predefined) differences of >10%. χ2 tests were done with SPSS (Statistics V.25; IBM Corp.; Armonk, New York, USA). Significance level for alpha was <0.05 without adjustment for multiple comparisons.
Answers to open-ended questions were analysed using descriptive content analysis.15 16 Themes were developed simultaneously and independently by three investigators. After reaching consensus on codes/definitions, answers were coded independently by two investigators, resolving discrepancies with a third.
Parents signed a consent form before participation. The anonymity of respondents was preserved by having an evaluation-independent person open the return envelopes, file the consent forms and hand the sealed, anonymous questionnaires to the investigators.
There were 108 participants (ProP: 43/120; PNeo: 35/114; PAx: 30/188; figure 1); overall return rate was 25.6%; mean age was 34 years (SD 4.9); 63% were mothers; 57% were Christians, 41% non-religious or stated that religion had no influence on their decisions; 58% had a university degree.
The following section summarises the main results (all answers detailed in online supplemental appendix 1, online).
Trust in physicians
The majority (88%) trusted their own physicians to make the right decisions/recommendations. Only 27% would generally seek a second opinion. Parents with university degree tended to rely less on the opinion of their child’s physician than those without (76 vs 92%; p=0.028).
Medical interventions (in general)
The majority (95%) wanted to be informed before agreeing to a medical treatment for their child. Half insisted on information beforehand, even if this delay would reduce the intervention’s benefit (50%); Some (44%) favoured starting treatment immediately.
Almost all (97%) agreed that in emergencies treatment must begin immediately and no time should be wasted on information; most (84%) reported that, especially in emergencies, more research should be done in order to better prevent serious harm (3% disagreed).
DC in the context of perinatal asphyxia
The majority thought they would be able to cope better with a situation of perinatal asphyxia and administration of study medication without prior information/consent if they had already heard about this (eg, by community engagement; 78%).
When asked for their preferences in the ALBINO Trial context, 55% preferred SOC, while 43% preferred DC. PAx more frequently favoured DC over SOC (54% vs 30%; p=0.032) (table 1).
In the ALBINO scenario, 91% would wish the medication to be given even without their prior consent, provided its therapeutic effect had been proven in previous studies. Administration of study medication in an emergency was acceptable without consent for 80%, provided it was safe (minor side effects only).
If the study medication had been administered without prior information/consent, 26% responded that it might adversely affect trust in their paediatrician. Men (40% vs 18%; p=0.029) and non-religious parents (36% vs 18%, p=0.040) reported this more frequently. Twenty-three per cent would later suspect that new health problems of their child might have been caused by the study medication. 74% would not consider legal action against the study team, whereas 3% would and 6% would at least consider it (table 1).
Concerning DC, 57% of respondents thought that information about such a study with flyers or posters in the delivery area and/or information in the media would be sufficient. PAx more frequently agreed with this point (70% vs 52%; p=0.149).
An ‘emergency card’ indicating the intention to participate in a study for perinatal asphyxia (yes/no) was considered helpful by 83%, while only 41% would use such a card.
Contemplating the ‘ALBINO situation’, 48% would consent to continued participation following detailed information in a DC scenario; 4% would not consent and 2% would have refused participation before birth if they had had the chance, for example, by community engagement; 46% were uncertain (table 1).
Pharmaceutical studies (in general)
Almost all (94%) agreed to participate in pharmaceutical trials, if there was a good chance for benefit and a low risk for harm.
Some (40%) would prefer a safe treatment with a proven small therapeutic effect over an experimental treatment with a potentially greater therapeutic effect.
When parents were asked which factors would impact on their decision to give consent in a study, 87 answers in the following main themes emerged: information and transparency of study (24%); side effects of study medication (23%); benefits of study (22%); risk-benefit ratio (16%); condition of the child (15%); relationship with the study team (14%); personal views regarding the necessity for study participation (14%); safety of/experience with the drug (11%); burden of the study intervention (9%); time needed to participate (8%) and reputation/commitment of the study team (7%).
Parents often invoked multiple themes. Examples of parental responses (each from a different participant) included:
‘If there were the (smallest) possibility of a “cure” or improvement, I would take part. The side effects shouldn't be too bad either.’ (ProP-mother)
‘[…] Do I have the feeling that I know exactly what is being done, what is being observed, what the goals are?’ (ProP-mother)
‘Are the doctors concerned with the well-being of my child or just with participating in the study? […]’ (PNeo-mother)
‘Follow-up examinations: time required, travel routes? […] child-friendly setting? […]’ (PNeo-mother)
Many of the 84 answers to the question on how parents would react after DC in an emergency trial were emotional: 19% reported only positive emotions (gratitude, satisfaction, relief, trust, etc), 26% only negative (anger, irritation, mistrust, frustration, sadness, etc), while about half answered without expressing emotions (table 2). Some parents also answered in a positive and negative manner, for example:
‘Fear and hope, anger or gratitude depending on success of the drug’ (ProP-father)
‘Worry about whether it might harm the child. Reassurance because everything has been done that is possible according to current research’ (ProP-father)
PAx more frequently reported positive feelings (28% vs 15%).
Fifty-six parents made recommendations for the ALBINO investigators, generally on ‘information’ and ‘communication’. Many encouraged researchers to continue with the ALBINO Trial:
‘I think flyers are great! Also, to inform parents in advance about the consequences of a lack of oxygen. […] because the public is not sufficiently informed and educated about rare conditions or disabilities. Always talk plainly, it can be difficult at first, but it is the best solution. […]’ (ProP-mother)
‘Information brochures with the essential facts for expectant parents, as well as an emergency card on the maternity booklet are definitely helpful to avoid misunderstandings/conflicts […].’ (ProP-father)
‘Humanity comes first, followed by honesty, openness, respect and professional competence. Don't make us feel like a lab animal! Child-friendliness must be a prerequisite.’ (PAx-mother)
To our knowledge, this is the first investigation on parental perspectives on consent for a trial in the context of neonatal asphyxia in a high-income country, and the only one asking a variety of parents with different pregnancy and birth experiences.
Previous poststudy surveys or hypothetical research studies indicated that parents may initially be upset by a study intervention started without their prior consent or short verbal information,17 18 although this can often be mitigated by further explanations.17 Parents wanted to be involved and asked for consent (even in an emergency),19 and they were more willing to accept DC in an emergency.18 We confirmed these findings in our survey. In contrast, after the randomised controlled PREMOD Trial, a low risk comparison between two standard-of-care interventions (cord-milking vs delayed cord-clamping), parents reported to be generally satisfied with the use of DC.20 However, in this online survey, several parents reported that physicians spoke about the study before delivery, and only half the respondents explicitly recalled that they had been informed after their baby’s inclusion. Another successful DC example might be the ‘milking in non-vigorous’ trial.21
Seeking parental perspectives for an investigation about neonatal asphyxia raises the question which parents should be asked. ProPs (whose unborn child is at risk of asphyxia), parents of newborns (at the time when detailed IC would be obtained in the ALBINO Trial), parents of children who met ALBINO inclusion criteria in the past (both bereaved and non-bereaved parents)? When involving stakeholders, researchers generally seek the information of parents of living children who met inclusion criteria, generally those engaged in support groups. Such stakeholders may be more positive towards research. However, when consent is obtained in a suddenly evolving emergency (like perinatal asphyxia), parents are in a different frame of mind and acutely anxious whether their child will survive. This distinguishes them from parents of premature infants, who frequently have some time to prepare for the upcoming situation. Perhaps the best way to obtain stakeholders’ opinions is to ask a variety of stakeholders.
In our case, participants agreed about some issues: almost all parents, when placing themselves in the ALBINO scenario, wished medication of proven efficacy to be given, even without their prior consent, and they were also in favour of research. However, when asked about DC and SOC, parents within and between groups were far from unanimous, for example, a large proportion favoured SOC over DC. However, parents of children having experienced perinatal asphyxia were different: Although their response rate was lower (presumably because of the method of contact), they preferred DC more often, were more often positive about emergency research and expressed more positive feelings and gratitude. Possibly, their experience resulted in a different understanding of the need for such research procedures and the limitations to judicious decision making in acute emergencies, whereas the purely hypothetical idea of a DC situation led to more emotional rejection/distrust.22
This survey has several limitations. The generalisability of the findings is limited by the low response rate, even if comparable to other surveys.20 23 Additionally, predominantly well-educated parents participated with little diversity concerning religious background, which limits our findings to this group of parents. Possibly, German parents may also have a different ethical approach to DC than others. In other contexts, where parental decisions about participation are guided by unreserved trust in physicians, parental perspectives about the most appropriate consent procedure may differ.24 Additional challenges for SOC have also been identified in low-income settings.25
Questionnaire studies have inherent biases, which we tried to reduce by asking different groups of parents. Because of their variety of perspectives and demographic factors, the results may represent the range of perspectives of parents in our centres. We even asked parents of children who had died of neonatal asphyxia, as their opinions were deemed to be particularly valuable, hoping that the chance for benefit from their potential participation, in the memory of their child, would exceed the risk of harm.26 Another limitation is that we did not ask what information parents needed for their decision to participate in an emergency study, for example, legislation and ethics committees insist on detailed information about data protection, whereas this may not be important to parents.
Supported by these results, the ALBINO investigators asked national ethics committees to choose between DC and SOC.11 DC was approved in Austria, Belgium, Estonia, Finland and Norway, whereas SOC was approved in Germany, Italy, the Netherlands, Portugal, Spain and Switzerland. In Poland, the leading ethics committee insisted on written IC from both parents before enrolment. Ethics committees considered the validity of parental consent in an emergency situation, burden to parents and legal requirements (eg, the European clinical trial regulation 536/2014 had not yet entered into force2). During the ongoing ALBINO Trial, parental satisfaction with the SOC/DC process will be evaluated.
The vast majority of parents wanted to be informed about study participation in an emergency such as perinatal asphyxia. SOC may improve parental satisfaction and safeguard their autonomy (parents can opt-out if they have concerns after receiving at least the most relevant information), while enabling emergency studies that are representative and valid. SOC could be complemented by prior study-related information such as provided in the delivery room. Parents’ perspectives on these issues are essential for future research and should be sought in trials using DC or SOC. Additionally, future trials may compare these consent approaches by randomly allocating the consent process prior to a randomised-controlled trial.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Patient consent for publication
This study involves human participants and was approved by the ethics committees at Tuebingen University Hospital (reference: 461/2016BO2) and TU Dresden (reference: EK444102016). Participants gave informed consent to participate in the study before taking part.
The pre-ALBINO study group and the ALBINO consortium are indebted to all parents and future parents who contributed to this survey. The ALBINO consortium involved in this project consists of the coordinating investigators as well as the beneficiaries and national coordinators. Coordinating investigators are Axel R Franz (University Hospital Tuebingen, Germany) and Mario Rüdiger (University Hospital CG Carus, Dresden, Germany). The beneficiaries and national coordinators are Axel R Franz and Christian F Poets (Tuebingen, Germany), Mario Rüdiger (Dresden, Germany), Manon Benders and Frank van Bel (Utrecht, the Netherlands), Karel Allegaert and Gunnar Naulaers (Leuven, Belgium), Dirk Bassler (Zurich, Switzerland), Katrin Klebermass-Schrehof (Vienna, Austria), Maximo Vento (Valencia, Spain), Hercilia Guimaraes (Porto, Portugal), Tom Stiris (Oslo, Norway), Isabella Mauro (Udine, Italy), Marjo Metsäranta (Helsinki, Finland), Sampsa Vanhatalo (Helsinki, Finland), Jan Mazela (Poznan, Poland), Tuuli Metsvaht (Tartu, Estonia) and Roselinda van der Vlugt-Meijer (ACE Pharmaceuticals, Zeewolde, the Netherlands).
Correction notice The licence for this article has been updated to Open Access.
Collaborators ALBINO-consortium: The ALBINO-consortium involved in this project consists of the coordinating investigators as well as the beneficiaries and national coordinators. Coordinating investigators are Axel R Franz (University Hospital Tuebingen, Germany) and Mario Rüdiger (University Hospital CG Carus, Dresden, Germany). The beneficiaries and national coordinators are Axel R Franz and Christian F Poets (Tuebingen, Germany), Mario Rüdiger (Dresden, Germany), Manon Benders and Frank van Bel (Utrecht, the Netherlands), Karel Allegaert and Gunnar Naulaers (Leuven, Belgium), Dirk Bassler (Zurich, Switzerland), Katrin Klebermass-Schrehof (Vienna, Austria), Maximo Vento (Valencia, Spain), Hercilia Guimaraes (Porto, Portugal), Tom Stiris (Oslo, Norway), Isabella Mauro (Udine, Italy), Marjo Metsäranta (Helsinki, Finland), Sampsa Vanhatalo (Helsinki, Finland), Jan Mazela (Poznan, Poland), Tuuli Metsvaht (Tartu, Estonia) and Roselinda van der Vlugt-Meijer (ACE Pharmaceuticals, Zeewolde, the Netherlands).
Contributors CAM conceptualised the study, designed the survey, recruited parents on the maternity ward in Tübingen and drafted the first version of the manuscript (including translation of the survey and the answers). CAM approved the final version of the manuscript and agreed to be accountable for all aspects of the work. CR contributed to the design of the survey, recruited parents on the maternity ward in Tübingen and coordinated the data collection in the obstetric practices and in Dresden. CR revised the manuscript, making important contributions, approved the final version of the manuscript and agreed to be accountable for all aspects of the work. MR coordinated data collection in Dresden. MR and CFP supervised the project as heads of the neonatal departments involved and critically reviewed the manuscript for important intellectual content and translations. Both authors revised the manuscript, making important contributions, approved the final version of the manuscript and agreed to be accountable for all aspects of the work. HS and MM assisted in the design of the survey from a perspective of healthcare research and critically reviewed the manuscript. Both authors made important contributions and approved the final version of the manuscript. AJ encouraged this study by critically commenting on ‘deferred consent’ for ALBINO as member of the ALBINO Ethics Advisory Board. AJ revised the manuscript critically for important intellectual content and with regard to the English language as a native speaker. AJ agreed to the final version of the article and agreed to be accountable for all aspects of the work. GM made important contributions as member of the ALBINO ethics advisory board. GM revised the manuscript critically for important intellectual content, agreed to the final version of the article and agreed to be accountable for all aspects of the work. H-JE made important contributions as member of the ALBINO ethics advisory board. H-JE revised the manuscript critically for important intellectual content, agreed to the final version of the article and agreed to be accountable for all aspects of the work. ARF conceptualised the study and designed the survey and was coordinator of the project. ARF was responsible for concept and design and supervised assessment of the data. ARF revised the manuscript, making important contributions, approved the final version of the manuscript and the translations and agreed to be accountable for all aspects of the work. ARF and CAM are guarantors.
Funding This study has been partially funded within the ALBINO project under the Horizon 2020 Framework Program of the European Union, call H2020-PHC-2015-two-stage, grant 667224.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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