(7) ALINA RODRIGUES 73-86 Upsala J Med Sci 111 (1): 73–86, 2006 Parents’ Perspectives on Research Involving Children Alina Rodriguez, Ph.D1.1Torsten Tuvemo, M.D., Ph.D2, Mats G. Hansson, Th.D3. 1Dept. of Psychology, Uppsala University, 2Dept. of Women’s and Children's Health, Uppsala University, 3Centre for Bioethics at Karolinska Institutet and Uppsala University ABSTRACT Children's participation in research is essential for the development of safe and age- appropriate treatments. However, children's participation is limited. The aim of this study was to determine (1) mothers' and fathers' views on which agencies/persons should evaluate the level of acceptable risk for children and (2) parents' willingness to allow children to participate in research. Medical factors, sociodemographics, and research attitudes were related to willingness. The study used a cross-sectional and lon- gitudinal design with 863 expectant parents (435 women; 428 men) consecutively recruited at gestational week 19 during routine ultrasound examination at 2 hospitals in Uppsala County, Sweden. 123 women at gestational week 34 were followed-up. Parental ratings of agencies/persons' degree of involvement in risk-evaluation for child research participants and parents' willingness to allow children to participate in research were the main outcome measures. Most parents believed that more pediatric research was needed. Attitudes played a major role in willingness, indicating a potential for information that could modify will- ingness. Over 80% of mothers and fathers rated the attending physician as needing to be "fully involved" in risk evaluation for research participants. Parents’ views contra- dict current trends in research ethics which place evaluation of risk in the hands of regional agencies. Instead, the majority of parents would like the decision to be indi- vidually based on the attending physicians advise. We conclude that children's participation in research could be improved by actively incorporating the attending physician and by educating the public so that research atti- tudes can be based on accurate information. 73 Received 17 October 2005 Accepted 27 October 2005 INTRODUCTION Medical research is the cornerstone for developing safe and effective treatments. The price for the patient is the risk incurred while serving as a research participant. Systematic exclusion of children in research unjustly denies them access to benefits of research participation, i.e. evidence-based medicine. Only a subgroup of children receives treatments approved for pediatric use (1-3). Prevalence of adverse drug reac- tions to off-label medication are high (4), because doses are estimated by body weight (5-7) under the assumption that children are small adults. However, pediatric pharma- chology shows that children react differently than adults to medicines (8-10) and pain management (11). Policy statements urging the inclusion of children in research have been published around the globe by major research groups and professional bodies (12). However, there are a number of barriers to research participation, which result in smaller sample sizes and reduced statistical power (13). The international trend is to allocate the decision-making process regarding both research and clinical ethics to external institutional review boards (scientists plus com- munity members) (14,15). However, the parental perspective is lacking. Knowledge about parents’ attitudes and willingness to allow children to participate in research can help us guide information to parents. If research is acceptable to parents, then we can expect that childrens' participation will be more likely. Individual differences among parents may be important determinants of willingness. For example, socially disadvantaged parents have been more likely to volunteer their children in some studies (16,17), but not in others (18,19). Parents with less education have been found to be more negative to research than college educated parents (20). Despite some recognition that parents’ attitudes are relevant for their willingness to enroll their child in research, there is a paucity of prospective data adequately address- ing this issue in large representative samples. Studies addressing parental attitudes are limited by small sample sizes (21,22), often reliance on responses from one parent or do not provide information separately for mothers and fathers (23), and lack in general- izability because refusal and attrition rates are unknown (20,24,25). Parental attitudes gathered retrospectively may be unduly biased by the outcome of the research project. It is likely that if parents’ were happy with the outcome, their attitudes about research will be more positive or more negative if they are unhappy. Generalizability is also limited when only parents' of a sick child are studied. Parents' of sick children may be amidst a medical crisis. Thus, their attitudes may not generalize to parents of healthy children, e.g. whose participation is necessary in screening studies. Preterm birth on most occasions is unexpected and linked to medical emergencies. Thus, it is especially important to learn expectant parents' views, because they may suddenly need to deliberate over enrolling their preterm baby in research. In order to increase generalizability of our results, we solicited expectant parents because they are involved in repeated contacts with medical professionals and have heightened aware- ness of health risks, but are not involved in a medical crisis. A subgroup of these par- ents will have to decide in the impending months whether to enroll their infant in research. We solicited both nulliparous and multiparous participants so that the results 74 could be generalized to both parents expecting their first child and to those already having children. The objectives were to study mothers' and fathers' (1) views on which agencies/per- sons should evaluate the level of acceptable risk to children in research and (2) willing- ness to allow children to participate in research. We investigate in a large representa- tive sample whether willingness to allow children to be research participants would vary depending on research attitudes, sociodemographic variables, parental age, med- ical factors (current medical risk status and previous experience with medical care), and current perceived risk. METHODS Participants A total of 863 expectant parents (435 women and 428 men) were consecutively recruited at 19 weeks of gestation (M=19.00, SD=2.37) in conjunction with routine ultrasound examination at the 2 hospitals in Uppsala County, Sweden during July 2001 to March 2002. The university hospital serves a population of 300 000 local residents and a region of 1.3 million for referred cases and a smaller hospital was located in a neighboring city. All deliveries were scheduled at the university hospi- tal. Prenatal health care including ultrasound examination is free of charge in Swe- den and is used by nearly 100% of the population (26), thus there are no differences among women attending the hospitals in terms of socioeconomic status. Of the 551 couples that were approached 79% of the pregnant women and 78% of their part- ners agreed to participate. Less than 1% (0.60%) attended specialized prenatal care due to high-risk status. Because the frequency of women experiencing a high-risk pregnancy was low at midpregnancy, we administered a second questionnaire to a subset of the sample. Follow-up participants were consecutively chosen from pool of those indicating interest in further participation (79%). We invited 140 women by mail to participate and 123 completed the follow-up questionnaire (88%). All ques- tionnaires were completed by the participants in their home and returned to the researchers in self-addressed stamped envelope. The inclusion criterion was the ability to understand written Swedish. The sam- ple consisted mostly of Swedes while 4% of the women and 5% of the men were of non-Scandinavian origin. All aspects of this study received ethical approval. Measures Participants rated to what extent agencies/persons should evaluate the level of acceptable risk to children in research. The list consisted of: pharmaceutical indus- tries, ethics committees (including researchers and community members), institu- tional review boards (IRB) including only researchers, elected hospital administra- tors, elected national government representatives, The National Board of Health and 75 Welfare, researchers involved in the particular study, attending physician, both par- ents, mother, father, child, and "other," which the participant specified. Involvement by each person or agency was rated on a 4-point scale ranging from should not be involved to fully involved. Attitudes concerning research participation consisted of 11 items rated on a 5- point scale developed in part on previous research (23,27) (items listed in Table 3). Willingness to allow children to participate in research was tapped by 9 items (listed in Table 4) based in part on conditions associated with randomized trials (28-30). Two items (bottom of Table 4) were rated on a 5-point scale which allowed for uncertainty whereas the rest of the items were answered on a 4-point scale (ranging from very unwilling to very willing) to reflect the real life situation in which parents have to take a stance. We also asked whether approval of both parents was deemed necessary before a child could participate in research. Questionnaires were tested in a pilot sample of expectant parents and proved easy to understand and useful. Psy- chometric properties were excellent in the research sample including internal con- sistency for willingness to participate in research, Cronbach a ≥ .75. Sociodemographic characteristics among parents included age, educational attainment, income, and subjective social status. The MacArthur Scale of Subjective Social Status with an easy pictorial format (10-rung "social ladder") taps partici- pants’ perceived social standing by placing an "X" on the rung which they feel they stand in comparison to others in terms of education, income, and profession. Sub- jective social status has been found to be associated to health outcomes more strongly than objective socioeconomic measures (31). We assessed whether partici- pants had previous experience with medical care for a serious condition. Perceived risk status was assessed by two items (5-point scale) measuring anticipated need of medical care for the newborn. Medical risk was defined as ultrasound examinations showing deviations from normality and receiving information from medical profes- sionals concerning elevated medical risk. Additionally, at week 34, absence from work due to disability was included. Statistical analyses Descriptive statistics are presented for the two outcomes: agencies/persons who should evaluate the risk in research and willingness to allow children to participate in research. Changes over time in women’s opinions and differences between part- ners were evaluated with paired t-tests. Associations between predictors and out- comes were analyzed using correlations and multiple regression analyses. RESULTS Participant characteristics are shown in Table 1. Family structure consisted of two bio- logical parents for the overwhelming majority. Participants were of mainly middle 76 77 class. Approximately half of the women were multiparous. Only 1% of the fetuses were considered to be at high risk for medical complications at mid-pregnancy, but was significantly higher during late pregnancy. Parents' on average perceived their fetuses as having only slight risk of needing medical care at delivery. Table 2 presents the percentages of parents' endorsements of agencies/persons they believe should evaluate the level of risk for children in research. The majority of par- ticipants would like the attending physician to evaluate whether the amount of risk is acceptable or not. 'Both parents' and 'mother' were also ranked highly. Less than 10% of participants rated "other," and in most cases parents did not specify. Table 1 Participant characteristics in means (standard deviation) or percentages where applicable men women (gestational week 19) women (gestational week 34) total sample % cohabitating 98.6% unplanned pregnancy 9% 9% parity 49% nulliparous Age, yrs 31.9 (5.3) 29.5 (4.6) yrs post-secondary education 2.6 (2.9) 2.3 (2.4) Income per month 2556 € (939) 1998 € (585) perceived social status1 6.3 (1.4) 5.8 (1.3) previous experience w medical care 27% 30% perceived risk status2 2.2 (0.5) 2.3 (0.6) 2.3 (0.6) elevated medical risk to fetus 1% 16.5% elevated medical risk to mother 17% 19.7% number of disability days 25 (44) 1 possible range 1-10, where 10 equals highest social status 2 1 = no risk, 2 = slight risk, 3 = some risks, 4 = rather large risk, 5 = very high risk of medical complications at birth for the newborn. Frequencies in % agency/ person Mothers Fathers Uninvolved or Slightly Involved Very or Fully involved Uninvolved or Slightly Involved Very or Fully involved Pharmaceutical Industries 89 11 92 8 IRB (researchers + community mem.) 35 65 36 64 IRB (researchers only) 46 54 46 54 Elected Hospital Administrators 95 5 93 7 Government Representatives 93 7 92 7 National Board of Health & Welfare 57 43 66 34 Researchers involved in the project 42 58 47 53 Attending Physician 2 98 3 97 Both Parents 11 89 12 88 Mothers 12 88 13 87 Fathers 37 63 33 67 Children 12 88 22 78 Frequencies of endorsements in percent for attitude items* Table 1. Participant characteristics in means (standard deviation) or percentages where applicable Table 2. Frequencies of parent's endorsements of agencies/persons should evaluate the level of risk children may be exposed to in research Table 3 shows the frequency of endorsements for each attitude collapsed into three cat- egories. Men and women were very similar in their attitudes. Women did not change 78 Table 3 Frequencies of parent's attititude endorsements Disagree Slightly Agree Agree Doctors opinions of treatments differ Mothers Gestational week 19 8 39 53 Mothers Gestational week 34 9 38 53 Fathers 10 37 53 More research is needed in pediatrics Mothers Gestational week 19 2 16 82 Mothers Gestational week 34 3 14 83 Fathers 5 17 78 Not all side-effects are known Mothers Gestational week 19 16 33 51 Mothers Gestational week 34 3 13 84 Fathers 21 33 46 Most treatments have been scientifically tested Mothers Gestational week 19 9 24 67 Mothers Gestational week 34 18 28 54 Fathers 11 17 72 Only scientifically tested treatments should be given Mothers Gestational week 19 7 16 77 Mothers Gestational week 34 3 9 89 Fathers 7 18 75 It is acceptable to give adult treatments to neonates Mothers Gestational week 19 49 33 18 Mothers Gestational week 34 26 38 36 Fathers 51 32 17 Research participation increases the chances of successful treatment Mothers Gestational week 19 26 37 37 Mothers Gestational week 34 22 39 39 Fathers 28 35 37 Research participation decreases quality of care Mothers Gestational week 19 91 7 2 Mothers Gestational week 34 50 40 10 Fathers 89 9 2 Research participants receive better care Mothers Gestational week 19 22 38 40 Mothers Gestational week 34 19 46 35 Fathers 21 33 46 Research participation is a given at a Univ. Hosp Mothers Gestational week 19 40 30 30 Mothers Gestational week 34 46 32 22 Fathers 47 31 22 All research is approved by an ethics committee Mothers Gestational week 19 9 24 67 Mothers Gestational week 34 3 12 85 Fathers 12 20 68 *Participants rated the extent of their agreement with each attitude statement as follows: 1=do not agree; 2=practically do not agree; 3=slightly agree, 4=mostly agree, 5=completely agree Table 3. Frequencies of parent's attititude endorsements 79 Table 4 Frequencies of parent's willingness to allow children to be research participants Willingness to… Mothers Gestational week 19 Mothers Gestational week 34 Fathers 1. Allow my child to participate in research that may benefit my child's health. unwilling 16 12 18 willing 84 88 82 2. Allow my child to participate in research that may benefit other children's health, but not necessarily my own child's health. unwilling 45 39 45 willing 55 61 55 3. Try a new and untested treatment, which lacks information on side-effects, when routine treatments do not have the desired effect. unwilling 49 52 52 willing 51 48 48 4. Accept participation in research during pregnancy concerning care of newborns. unwilling 76 47 69 willing 24 53 31 5. Allow healthy children to participate in clinical research, which can involve small risks for themselves, but which may benefit other children's health. unwilling 60 60 57 willing 40 40 43 6. Allow sick children to participate in clinical research, which can involve small risks for themselves, but which may benefit for other children's health. unwilling 43 44 37 willing 57 56 63 7. Allow sick children to participate in clinical research, which can involve small risks for themselves, but may benefit for their own health. unwilling 15 15 13 willing 85 85 87 Willingness to receive… Unwilling Unsure Willing 8. Information about ongoing research concerning treatment alternatives. Mothers Gestational week 19 3 10 87 Mothers Gestational week 34 1 9 90 Fathers 6 17 77 9. An invitation to participate in a research project that is relevant for my child's treatment. Mothers Gestational week 19 6 16 78 Mothers Gestational week 34 4 16 80 Fathers 7 25 68 Table 4. Frequencies of parent's willingness to allow children to be research participants over time, with the exception of an increased proportion at gestational week 34 who ‘slightly agreed’ with the statement that research participation decreases the quality of care. The majority of parents held strong attitudes concerning the need for more pedi- atric research and the use of only scientifically approved treatments in pediatrics. Willingness to allow children to participate in research was normally distributed for both men and women. Parity was non significant (t 416 =-.21, ns), thus results are not presented separately by parity. Table 4 shows that parents are overwhelmingly willing to receive information and an invitation to clinical research on behalf of their child. Results of paired t-tests showed that women were clearly more willing to receive information (t417=3.62, p<.001) and an invitation to clinical research for their children than their part- 80 Table 5 Results of stepwise multiple regression analyses for factors predicting willingnes allow own child to participate in research F p< R2 total Men Only scientifically tested treatments should be given 15.93 .0001 .07 Research participation is a given at a Univ. Hosp 10.49 .001 .11 Research participation decreases quality of care 6.23 .01 .13 Education 5.46 .02 .15 Women (week 19) Research participation is a given at a Univ. Hosp 31.29 .0001 .10 Research participation decreases quality of care 24.18 .0001 .17 Education 14.42 .001 .21 Only scientifically tested treatments should be given 7.25 .001 .23 Subjective social status 6.37 .01 .25 Research participation increases the chances of successful treatment 5.94 .01 .27 All research is approved by an ethics committee 4.17 .04 .28 More research is needed in pediatrics 3.61 .05 .29 Women (week 34) Research participation is a given at a Univ. Hosp 32.24 .0001 .40 Only scientifically tested treatments should be given 6.35 .02 .46 Risk of complications for newborn 4.86 .03 .48 Total number of days on disability 4.78 .03 .57 Education 4.55 .04 .66 Presently on disability 4.05 .05 .70 Table 5. Results of stepwise multiple regression analyses for factors predicting willingness to allow own child to participate in research ners (t 414 =3.05, p<.01). As delivery approached, women tended to become even more positive, but the differences were not statistically significant. Table 4 indicates parents were more willing to allow their own children than children in general to participate in research. More than half the parents were willing to volunteer their own child to a research project for the benefit of other children. During mid-preg- nancy few parents were willing to enroll their infant in a research project. However, a shift in opinion occurred by gestational week 34 when women were more willing to enroll their expectant infants in research (t 120 =3.35, p<.001). To evaluate which factors predicted willingness, we ran stepwise multiple regression analyses. The predictors were attitude questions, socioeconomic indicators, parental age, previous experience with medical care, medical risk indicators, and perceived risk. We predicted willingness to allow their own child to participate in research (items 1-4 and 8- 9 on Table 4). The top of Table 5 shows that the same attitudes accounted men’s and women’s willingness to allow their child to participate in research, although their impor- tance differed by gender: (1) only scientifically tested treatments should be given, (2) research participation is a given at a university hospital, and (3) research participation decreases the quality of care (negatively related). Education also contributed to willing- 81 Table 6 Results of stepwise multiple regression analyses for factors predicting willingness to allow children in general to participate in researc F p< R2 total Men Not all side-effects are known 26.35 .0001 .10 Research participation is a given at a Univ. Hosp 19.83 .0001 .17 Only scientifically tested treatments should be given 4.09 .04 .19 Research participation decreases quality of care 4.41 .04 .21 Women (week 19) Only scientifically tested treatments should be given 12.76 .001 .04 Research participation is a given at a Univ. Hosp 11.58 .001 .08 Subjective social status 5.12 .02 .10 Not all side-effects are known 4.88 .03 .11 Women (week 34) only receive approved treatments 6.20 .01 .06 Table 6. Results of stepwise multiple regression analyses for factors predicting willingness to allow children in general to participate in research ness. More educated parents were more positive to research participation. The bottom of Table 5 shows the longitudinal prediction for women who participated in the follow-up. A large portion of variance was explained for this group (70%). The attitude that research participation decreases the quality of care was no longer important, instead, variables per- taining to medical risks or complications during pregnancy explained willingness. Table 6 shows results of multiple regression analyses for willingness to allow children in gen- eral to participate in research. The same variables were entered into the equation, but few were significant and a much smaller portion of variance could be explained. Approval by both parents to allow a child to participate in research was deemed nec- essary by 98.0% of men, 98.8% of women at week 19, and 99.1% of women at week 34. DISCUSSION Among studies evaluating ethical issues in pediatrics, this is the largest prospective inves- tigation of both parents' perspectives. The overwhelming majority of parents (women and men alike) would like the attending physician to evaluate the acceptable level of risk, which indicates that parents trust the doctor's expert advise (even more so than their own judgment). Both men and women judge mothers alone as highly as both parents together in evaluating level of acceptable risk. Results were not specific to parity, i.e. whether par- ticipants were first-time parents or already had children. Ethicists and policy makers contend that there is a real risk that ethics will lose its criti- cal function if too much power is placed in the hands of the doctor (32). Our study indi- cates the contrary; procedures for ethical decision-making in clinical research involving children should be developed that are more sensitive to the importance of the trust rela- tionships between doctors and parents. From a parental perspective, clinical research ethics should primarily be a concern for the attending physician and the parents, who are able to consider the unique individual circumstances, instead of far-removed public agen- cies (e.g. government officials). When it comes to their own child and in real life situa- tions parents seem to be in favour of a context-sensitive model of ethics where the dis- tance between the actual case and its ethical deliberation is kept to a minimum (33). Including the attending physician makes sense as pediatric expertise is often lacking in IRBs and as there are presently no criteria for judging whether the risks of research are reasonable (12). Differences in parents' willingness to allow children to participate in research were explained largely by attitudes and to a lesser extent by level of education, rather than socioeconomic status or perceived medical risk. The attitude that participation is a given when attending a university hospital was particularly relevant for both men and women. This is a rather general attitude that is not specific to pediatrics or the expected outcome of research. The number of women who had high-risk pregnancies increased by week 34. Indicators of medical risk at this point also predicted willingness, so that the higher the medical risk, the greater the willingness to allow one's child to participate in research. 82 These factors together explained 70% of the variance. It may be that the benefits of research may be perceived as greater for the individual as medical risk increases. Willingness to allow children in general was more difficult to predict. Only a small portion of the variance could be explained, but attitudes were again significant. These results suggest that parents are willing to take a stance regarding their own children, but are more hesitant when it comes to others. Future research should therefore address par- ents' views about their own children. Nearly 78% of men and 82% of women in our sample agree with the statement that more research in pediatrics is needed and over 80% are willing to allow their child to become research participants. However, approximately 50% of parents are unwilling to try a new treatment and only a small minority realizes that most treatments have not been studied in pediatric populations. Our results show an inconsistency in parental attitudes to pediatric research and their knowledge about the conditions of pediatric treatment. Participation in research may increase if accurate information about medical treatment for children is provided. We found that parents hold altruistic attitudes, which is in line with other research findings (34-37) Thus, scientists need not view pediatric research to be “in crisis” due to dwindling participation (38), instead, pediatric researchers should handle parents’ trust in medical professionals with care and take the opportunity to educate the public. Previous research has shown that parents have poor understanding of the ele- ments of informed consent even after volunteering their children as research participants, which clearly opposes the intent of the Declaration of Helsinki (39). Our research points to the opportunity of educating parents about research practices while awaiting the birth of their child as we found that parents are willing to receive such information. The con- text of receiving prenatal care, with repeated contacts with healthcare professionals with whom patients have build a relationship based on trust, makes for an ideal situation. A potential limitation of the study design is that we did not obtain a behavioural mea- sure of willingness, i.e. we do not know to what extent willingness translates into behav- iour. Naturally, the specifics of each research project will be decisive for parents' permis- sion to be granted. However, our focus on willingness provides important information regarding how open parents are to research projects in general. Previous research shows that those initially positive to research are likely to enroll their children (36). Parents were not necessarily willing to enroll their child already during mid-pregnancy, but they were willing to learn about research. Our finding is particularly important because preterm birth is difficult to predict especially for nulliparous women, information received during pregnancy may help alleviate their distress at the time of preterm delivery. The finding that attitudes, rather than socioeconomic status or perceived risk, played a major role in willingness is encouraging. Modifying parents' attitudes through informa- tion at prenatal health care clinics and via media, for example, may serve as a catalyst for greater involvement in research. In conclusion, a partnership between parents and researchers is needed to design stud- ies that will be acceptable for parents. This study showed that parents´ views contradict current medical trends which place evaluation of risk in the hands of regional agencies (11), instead, most parents would like this decision to be individually based on the attend- 83 ing physician’s advise. In other words, parents would like to have individualized deci- sions for children rather than a formula that could be applied to many. Thus, future recommendations should include not only regional overseeing agencies which are important for multi center studies, but also include the provision for local members such as the attending physician and parents to evaluate risk for children. However, this does not mean that parents are willing to relinquish their right to consent to the attending physician, as nearly all participants reported that consent from both parents is necessary. A clear majority of parents in this study felt that more pediatric research was needed and were willing to allow their child to participate. Greater participation by children could be achieved through attitudes based on accurate information on the conditions of pediatric treatment and based on responsible research practices, which would ultimately lead to safer medications in pediatrics. ACKNOWLEDGEMENTS This work was funded by The Foundation for Health Care Sciences and Allergy Research grant nr. E2001 046 and an endowment from Barnens hus. This research has been carried out within the framework of The Research Program Ethics in Bio- medicine at Uppsala University. Gustaf Arrhenius, Uwe Ewald and Leif Olsen have contributed to valuable discussions. REFERENCES 1. Collier J, (1999) Paediatric prescribing: using unlicensed drugs and medicines outside their licensed indi- cations. Br J Clin Pharmacol 48:5-8. 2. Rudolf MC, Lyth N, Bundle A, Rowland G, Kelly A, Bosson S, et al. (1999) A search for the evidence supporting community paediatric practice. Arch Dis Child 80:257-61. 3. 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Snowdon, C, Garcia, JO, Elbourne D (1997) Making sense of randomisation; Responses of parents of critically ill babies to random allocation of treatment in a clinical trial, Soc.Sci.Med. 45:1337-55 85 Corresponding author: Alina Rodriguez, Ph.D. Department of Psychology Uppsala University Box 1225, SE-751 42 Uppsala, Sweden fax: +46 18 471 2123, tel.: +46 18 471 7980 Alina.Rodriguez@psyk.uu.se 86