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Study 2: experimental test of placebo acceptability and framing effects in the context of antibiotic overprescribing | A nationally representative UK sample was recruited to increase the generalisability of our qualitative findings and experimentally test acceptability and efficacy ratings for different placebo treatments to substitute unnecessary antibiotic use in primary care. Additionally, we compared two framing contexts, while also testing for the potential role of demographic factors and individual difference variables. | PMC10510165 |
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Hypotheses | chronic illness, anxiety | CHRONIC ILLNESS | Our quantitative hypotheses were based on previous research findings and included the following:Qualitative hypothesis: Existing perceptions of placebos will vary with regard to the underlying level of knowledge and personal attitudes. However, a common theme will be a perceived need for deception to ensure placebo effectiveness.Framing hypothesis: Participant ratings for general treatment acceptability, personal treatment acceptability and expected treatment efficacy of different placebos will be affected by the terminology used. Participants in the sugar pill condition (vs. placebo condition) will rate placebo treatments as more acceptable, but less effective.Treatment type hypothesis: There will be significant differences in the acceptability and effectiveness ratings for different treatment options in the hypothetical patient scenarios. Open-label placebos will be rated more acceptable but less effective than blinded placebos. Any placebo treatment will be rated as less acceptable and less effective compared to antibiotic treatment. Acceptability and effectiveness ratings will be lowest for the “no treatment” scenario.Demographic hypothesis: Participants of a lower age (vs higher age), and participants, who have visited a doctor in the past 12 months (vs. not visited a doctor), taken antibiotics in the past 12 months (vs. not taken antibiotics), never taken a placebo (vs. previously taken a placebo) and who consider themselves to have a chronic illness or be immunocompromised (vs. healthy with normal immune systems) will rate placebo treatments as more acceptable and effective.Covariate hypothesis: High scores in health anxiety and health risk aversion and low scores in health risk literacy will be correlated with lower acceptance levels and lower effectiveness ratings of placebos. All three variables will explain a significant amount of variance in the ANCOVA analysis. | PMC10510165 |
Methods | PMC10510165 |
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Participants | Following an a priori power calculation with an estimated a power of 0.99 and an α error probability of 0.01 to detect a medium effect size | PMC10510165 |
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Design | chronic illness, anxiety | CHRONIC ILLNESS | We employed a 2 × 5 between-within subjects design and measured three dependent variables. This included (1) the general acceptability of a treatment offered in a hypothetical patient scenario (measured on a 5-point Likert scale ranging from “highly unacceptable” to “highly acceptable”), (2) the personal acceptability of a treatment offered in a hypothetical patient scenario (measured on 5-point Likert scale ranging from “very unhappy to receive this treatment” to “very happy to receive this treatment”), and (3) expected effectiveness of a treatment offered in a hypothetical patient scenario (measured on 5-point Likert scale ranging from “very ineffective” to “very effective”). Participants were randomly assigned to one of two between-subjects framing groups (“placebo” vs. “sugar pill”), which determined the wording of treatment options in the patient scenario they were shown. All participants completed five within-subjects treatment conditions in randomised order, including (1) blinded + pure placebo, (2) open-label + pure placebo, (3) open-label + impure placebo, (4) antibiotic treatment, and (5) no treatment. In the “sugar pill” framing group, the term “placebo” was consistently replaced with the term “sugar pill”.Additionally, we assessed three individual difference variables: (1) health anxiety (Likert rating ranging from 1 to 4, with low scores indicating low health anxiety), (2) health risk literacy (Likert rating ranging from 1 to 3, with low scores indicating low health risk literacy) and (3) health risk aversion (Likert rating ranging from 1 to 5, with low scores indication low risk-seeking). Finally, we tested the impact of several quasi-experimental between-subject variables including sex (female/male) and age (high/low) and four medical history variables: “doctor’s visits over the past year” (yes/no), “antibiotics used during the past year” (yes/no), “previous use of placebos” (yes/no) and “affected by chronic illness and/or an immunocompromised state” (yes/no). | PMC10510165 |
Materials and procedure | Study completion took approximately 10 min. The mean completion times were 13:34 min for Study 1 and 11:05 min for Study 2. Participants completed the study in their own time and could decide for themselves how much time to spend on each section. All materials can be accessed in Additional File | PMC10510165 |
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Data analysis | All data were rigorously vetted prior to the analyses. We excluded participants who met one or more of the following criteria: (1) identical responses to all three qualitative questions, (2) study completion in less than 5 min (which may indicate a lack of engagement with the study contents) or more than 60 min (which may indicate a high level of distraction during study completion), (3) suspected of “straightlining” (i.e. providing the same answers to all quantitative questions). Criteria for straightlining were set as having a standard deviation of ≤ 0.4 for the Likert ratings across all five treatment scenarios and/or a standard deviation of 0 for all Likert responses to the psychometric questionnaires. | PMC10510165 |
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Qualitative analyses | The free-text responses to the survey were examined using content analysis—a systematic method for uncovering patterns and themes within qualitative data [ | PMC10510165 |
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Quantitative analyses | anxiety | REGRESSION | Before conducting any ANCOVAs or ANOVAs, assumptions were tested for each DV by checking for significant outliers, producing QQ plots and running Shapiro–Wilk tests (to check normality assumptions), running Mauchly’s test of sphericity, conducting Levene’s tests for homogeneity of variance and running a Box’s M test to check for homogeneity of covariances. Additionally, we produced scatterplots to check for linear relationships between the covariates and each DV and ran tests for homogeneity of regression slopes. Most assumptions were met, but the results showed the existence of some outliers and violations of the normality and sphericity assumptions across almost all conditions of all DVs. Additionally, there were violations of the assumptions regarding linearity and homogeneity of regression slopes for covariates. Given our large sample size, we considered ANOVAs robust to normality violations. To account for violations of sphericity, we will report Greenhouse–Geisser adjusted values throughout. However, given the assumption violations pertaining to our covariates, we decided against conducting an ANCOVA. Instead, we transformed the continuous covariate scores for age, health anxiety (HAQ), health literacy (HLQ) & and health risk-taking (DOSPERT) into binary variables, in order to enter these as independent variables in additional ANOVA analyses. This was done by summing individual participant ratings for the respective questionnaire items. For the health literacy questionnaire, items 1 and 3 were reverse coded. Subsequently, the median score was determined and participants were re-coded as either high- or low-scoring depending on their score’s position relative to the median. Participants with a HAQ score of > 34 were coded as “high in health anxiety” (vs. low in health anxiety), participants with an HLQ score of > 25 were coded as “high in health literacy (vs. low in health literacy) and participants with a DOSPERT score of > 10 were coded as “high in health risk taking” (vs. low in health risk taking). Similarly, demographic variables were transformed into binary variables. Participants aged > 46 years were recoded as “high age” (vs. “low age). For analyses involving the variable “sex”, participants were excluded if they identified as “other” ( | PMC10510165 |
Results | PMC10510165 |
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Content analysis of qualitative answers | An overview of content codes and associated frequencies is provided in Additional File The participants identified positive psychological effects and the utility of placebos in monitoring medication efficacy as major advantages. In addition, respondents also highlighted the absence of side effects associated with placebos, as well as their potential to reduce the use of unnecessary medications, thus serving to reduce costs to both the patient and NHS.However, the potential for patient deception and the fact that placebos are fundamentally inactive were the primary disadvantages identified by respondents. Relatedly, the participants highlighted that the use of placebos could delay the administration of necessary active medications, resulting in the prolongation or exacerbation of illness. Some respondents also proposed that the use of placebos could erode trust in clinicians and healthcare providers. | PMC10510165 |
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Effects of framing and treatment conditions on dependent variables | Three 2 × 5 mixed ANOVAs were conducted to test for effects of the framing group (placebo vs. sugar pill) and the treatment condition (blinded + pure placebo vs. open-label + pure placebo vs. open-label + impure placebo vs. antibiotic treatment vs. no treatment) on general acceptability, personal acceptability and expected effectiveness of the treatment. Descriptive statistics for all groups and conditions are presented in Additional File Study 2 ratings for general acceptability, personal acceptability and predicted effectiveness across five treatment conditions. Box plot showing the rating scores for general acceptability, personal acceptability and predicted effectiveness across the five treatment conditions (blinded + pure placebo; open-label + pure placebo; open-label + impure placebo; antibiotic treatment; no treatment) and two framing groups (placebo frame; sugar pill frame)For general acceptability, there was a significant interaction effect, For personal acceptability, there was a significant interaction effect, For expected effectiveness, there was no significant interaction effect. The main effect of the framing group was again non-significant ( | PMC10510165 |
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Effects of demographic variables and medical history on dependent variables | Additional 2 × 5 mixed ANOVAs were conducted to test for effects of the binary variables pertaining to demographic information and medical history and the treatment conditions on general acceptability, personal acceptability and expected effectiveness of the treatment. Only significant results will be presented below. Full tables with means and standard deviations for all additional ANOVAs are included in Additional File | PMC10510165 |
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Age | Age showed significant interactions with treatment conditions across all three DVs. For general acceptability ( | PMC10510165 |
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Sex | Sex showed significant interactions with treatment conditions across all three DVs. For general acceptability ( | PMC10510165 |
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Antibiotics taken | Whether or not participants had taken antibiotics in the past 12 months had significant interaction effects with treatment conditions across all three DVs. Participants who had recently taken antibiotics, rated the antibiotics treatment option as more generally acceptable ( | PMC10510165 |
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Chronic illness and immunocompromised conditions | chronic illness | CHRONIC ILLNESS | An underlying chronic illness or immunocompromised condition was found to have significant main effects on general treatment acceptability ( | PMC10510165 |
Effects of individual differences on dependent variables. | Additional 2 × 5 mixed ANOVAs were conducted to test for effects of the binary variables pertaining to individual differences and the treatment conditions on general acceptability, personal acceptability and expected effectiveness of the treatment. Again, only significant results will be presented below. | PMC10510165 |
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Health anxiety | anxiety | Health anxiety produced significant interaction effects with the treatment condition for general acceptability ( | PMC10510165 |
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Health literacy | Health literacy was found to have a significant interaction effect with the treatment condition on general acceptability ( | PMC10510165 |
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Health risk-taking | Health-related risk-taking has a significant interaction effect with the treatment condition on personal acceptability ( | PMC10510165 |
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Brief discussion | respiratory infections, anxiety | RESPIRATORY INFECTIONS, CHRONIC ILLNESSES | Study 2 provides the first comprehensive evidence of the general acceptability of clinical placebo use by the UK general population. Our nationally representative online study confirmed beliefs in efficacy and general support for the use of open-label impure placebos to replace unnecessary antibiotic treatments for respiratory infections in primary care. Below follows a detailed discussion of our specific hypotheses.The content analysis of free text answers confirmed the qualitative hypothesis—the theme of deception featured highly in both the participants’ definitions of placebos, as well as in their identifications of disadvantages associated with placebo use. This was also echoed in the suggestion that a further disadvantage to placebo use would be the loss of trust in healthcare providers for potentially misleading patients.Our framing hypothesis was partially confirmed. The framing group produced significant interaction effects, but the effects differed from our predictions. General and personal acceptability of blinded pure placebos were higher in the placebo group compared to the sugar pill group. Even though effect sizes were small, these findings appear to suggest that describing placebos as “sugar pills” could decrease people’s acceptability for clinical placebo use, specifically with regard to blinded pure placebo types.Our treatment type hypothesis was partially confirmed. The treatment condition had significant effects on placebo attitudes in the hypothetical patient scenario, but the effects differed slightly from out predictions. Open-label impure placebos were rated highest in terms of general acceptability and predicted effectiveness, but scored slightly lower in terms of personal acceptability. Indeed, in terms of personal acceptability, participants showed a significant preference for antibiotic treatment. This suggests that even though the UK general public expressed general support for open-label placebo use, their attitudes differed if they imagined themselves to be the patients. These findings link in with patient attitudes in wider healthcare settings. For example, UK national surveys suggest that almost 90% of the population believe emergency care services are used inappropriately [Our demographic hypothesis was again partially confirmed. Most of the demographic and medical history variables investigated had significant effects on placebo attitudes. As predicted, younger participants had more favourable attitudes towards placebo treatments compared to older participants. This might be explained by a greater openness of younger people towards new or alternative treatment options. Additionally, interesting sex differences were found, with female participants being more dismissive of blinded pure placebos and having stronger faith in the efficacy of open-label pure placebos compared to males. This seems to suggest that women are more sensitive to deception, supporting previous findings that women are more averse to lying than men [Finally, our covariate hypothesis on the effects of health anxiety, health literacy and health-related risk-taking was partially confirmed. Health anxiety had significant effects on placebo attitudes. Higher anxiety levels resulted in higher acceptability of antibiotic use and lower acceptability of the no treatment option, which might be explained by higher levels of risk aversion leading to a preference of medicine treatments over placebo use. It is possible that anxious patients have stronger preferences for “real” medication and feel more apprehensive about less established treatment alternatives including placebos. Additionally, our findings suggested that patients with lower levels of health literacy may hold more favourable attitudes towards the use of antibiotics and blinded pure placebos. A potential reason for their antibiotic treatment preference could be lower awareness of the threat imposed by antimicrobial resistance. Their comparatively stronger acceptance of blinded pure placebos might be explained by lower levels of objection towards deception, but further qualitative investigations are needed to explore the reasons in detail.Overall, our findings suggest generally favourable attitudes towards open-label placebo use to replace antibiotic medication that lacks a clear indication. However, our findings of different preferences when making personal treatment choices (as opposed to expressing more general attitudes) need to be addressed. The personal preference for antibiotic treatment could present a challenge when trying to implement clinical placebo use in practice. Given that this personal preference is likely to be fuelled by higher levels of personal risk and loss aversion, strategies of patient safety-netting (e.g. regular reviews post-placebo prescription) might provide reassurance and result in a greater personal willingness to forgo unnecessary prescriptions of active medicines. In any case, the use of placebo treatments may need to take into account individual patient characteristics. Our results suggest that older individuals with chronic illnesses or high levels of health anxiety might be less open to placebo prescriptions and that patients with lower health literacy may have a stronger preference for real medicines and blinded pure placebos, thus making them less accepting of open-label placebos specifically. Additionally, the use of blinded pure placebos appears to be particularly unacceptable to female individuals. To gain a more thorough understanding of attitudinal predictors and influences, follow-up qualitative investigations could be fruitfully employed. | PMC10510165 |
Study 3: experimental test of placebo acceptability across different contexts of primary care prescribing | depression, lower back pain, chronic back pain, pain | RESPIRATORY INFECTIONS | Study 3 aimed to extend the previous quantitative study by comparing placebo attitudes across a wider range of clinical scenarios. In addition to the initial scenario of respiratory infections, we included vignettes involving less severe depression and lower back pain, where participants had to rate the acceptability and expected effectiveness of different placebo types compared with active medical treatment in the form of antidepressants and prescription pain killers, respectively. The scenarios of less severe depression and chronic back pain were chosen because they are contexts of frequent overtreatment in primary care [ | PMC10510165 |
Hypotheses | infection, depression, back pain, pain | INFECTION | Our quantitative hypotheses were based on the findings from Study 1 and Study 2. The hypotheses reported and tested here deviate slightly from our pre-registration. We had planned to test, again, for the effects of demographic variables, medical history and individual differences variables on placebo attitudes. However, given the comprehensive analyses conducted as part of Study 2, we decided to exclusively focus on the comparison of different clinical scenarios and their effects on attitude ratings pertaining to different treatment options.Clinical scenario hypothesis: Participant ratings for general treatment acceptability, personal treatment acceptability and expected treatment efficacy of different placebos will be affected by the clinical scenario presented. Participants in the infection condition (vs. depression and back pain conditions) will rate placebo treatments as less personally acceptable. Participants in the depression condition (vs infection condition and back pain conditions) will rate placebo treatments as more acceptable and effective.Treatment type hypothesis: There will be significant differences in the acceptability and effectiveness ratings for different treatment options in the hypothetical patient scenarios. Open-label placebos (where participants are fully informed about their placebo treatment) will be rated more acceptable but less effective than blinded placebos. Impure placebos like lozenges/vitamin pills/heat spray, which are treatments with known pharmacological value for some of the symptoms, but without therapeutic effects for the underlying illness, will be rated as most acceptable and effective compared to all other placebo types. Any placebo treatment will be rated as less acceptable and less effective compared to the non-placebo (i.e. active medical) treatment. | PMC10510165 |
Methods | PMC10510165 |
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Participants | Following an a priori power calculation with an estimated a power of 0.99 and an α error probability of 0.01 to detect a medium effect size | PMC10510165 |
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Design | depression, lower back pain, pain | DISEASE, RESPIRATORY INFECTION | We employed a 3 × 5 between-within subjects design and measured the same three dependent variables as in Study 2. Participants were randomly assigned to one of three between-subjects groups, which differed in the disease context of the patient scenario. Group 1 were presented with the same scenario of a respiratory infection involving potential antibiotic treatment as in Study 2. Group 2 were presented with a scenario of less severe depression involving potential treatment with antidepressants. Group 3 were presented with a scenario of lower back pain involving potential treatment with prescription pain killers. Like in Study 2, all participants completed five within-subjects treatment conditions in randomised order, including (1) blinded + pure placebo, (2) open-label + pure placebo, (3) open-label + impure placebo, (4) medicine treatment, and (5) no treatment. | PMC10510165 |
Materials and procedure | depression, chronic back pain, infections | RESPIRATORY INFECTION, INFECTIONS | Materials and procedure were almost identical to Study 2. The main difference pertained to the use of clinical scenarios. Instead of a single focus on infections, we included three alternative patient scenarios describing either a respiratory infection, a case of less severe depression or a case of chronic back pain (see full materials in Additional File | PMC10510165 |
Data Analysis | The same quality screening criteria were applied as in Study 2. Variables were computed the same way as in Study 2. Again, assumptions of normality and sphericity were violated for our ANOVAs, which is why we will report Greenhouse–Geisser adjustments throughout. | PMC10510165 |
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Results | PMC10510165 |
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Effects of scenario group and treatment conditions on dependent variables | Three 3 × 5 mixed ANOVAs were conducted to test for effects of the scenario group (infection/antibiotics vs. depression/antidepressants vs. back pain/pain killers) and the treatment condition (blinded + pure placebo vs. open-label + pure placebo vs. open-label + impure placebo vs. antibiotic treatment vs. no treatment) on general acceptability, personal acceptability and expected effectiveness of the treatment. Descriptive statistics for all groups and conditions are presented in Additional File Study 3 ratings for general acceptability, personal acceptability and predicted effectiveness across five treatment conditions. Box plot showing the rating scores for general acceptability, personal acceptability and predicted effectiveness across the five treatment conditions (blinded + pure placebo; open-label + pure placebo; open-label + impure placebo; antibiotic treatment; no treatment) and three scenario groups (infection/antibiotics; depression/antidepressants; back pain/pain killers). White dots represent mean valuesFor general acceptability, there was a significant interaction effect (For personal acceptability, there was a significant interaction effect (For expected effectiveness, we found a significant interaction effect ( | PMC10510165 |
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Brief discussion | respiratory infections, respiratory infection, pain, infection, depression | RESPIRATORY INFECTIONS, INFECTION, RESPIRATORY INFECTION, HEAT | Study 3 extended our previous focus group study and online experiment through the comparison of different prescribing contexts and their respective effects on public attitudes around placebos. We replicated our previous findings on the acceptability of different placebo types for replacing unnecessary antibiotic treatments in the context of respiratory infections and showed that public acceptability of clinical placebo use differed for different clinical scenarios.Hence, our clinical scenario hypothesis on the effect of the prescribing context on placebo attitudes was confirmed. However, contrary to our predictions, participants demonstrated the most favourable placebo attitudes in the infection condition, followed by the depression condition and finally the back pain condition. Similar to the results from Study 2, there were notable differences between the general acceptability and the personal acceptability ratings for using antibiotics in our respiratory infection scenario. Again, participants showed a stronger preference for antibiotics when they were asked to indicate their personal willingness to receive each treatment, thus providing further evidence for differences in self and other decision-making.The comparatively lower acceptability and efficacy ratings for clinical placebo use to treat depression and back pain are more difficult to interpret. Based on our initial focus group study, we had indeed predicted lower ratings in the context of pain management, because participants had described beliefs that highly tangible symptoms of pain may not be effectively managed with placebos. However, with several participants from the focus groups suggesting mental health as the prescribing context most appropriate for placebo use, we had expected to find more positive attitude ratings in the depression scenario. One possibility for the unexpected findings is that the infection scenario stood out by highlighting societal consequences (i.e. antimicrobial resistance) as well as personal side effects of medicine overuse. Based on this explanation, more detailed patient information on both societal and personal consequences of overtreatment across different treatment contexts might help to further raise placebo acceptability.With regard to our second hypothesis, the Treatment type hypothesis, all our predictions were confirmed. Similar to the results from Study 2, open-label impure placebos received the highest acceptability ratings compared to the other types of placebos and the open-label pure placebo condition received the lowest ratings for expected effectiveness. Furthermore, as predicted, the active medical treatment was overall rated most favourable, even though the infection scenario differed from this pattern as described above. These findings suggest that any clinical treatment using blinded placebos should be avoided, but highlight the specific potential of using open-label impure placebo treatments such as anti-inflammatory lozenges, vitamin supplements or pain relief heat spray more strategically. Given previous survey findings on the existing practice involving the informal use of impure placebos [ | PMC10510165 |
General discussion | respiratory infections, infection, chronic illness, anxiety | RESPIRATORY INFECTIONS, INFECTION, CHRONIC ILLNESS, DISEASE | Our three-part, mixed methods study provides the first comprehensive evidence for the public acceptability of clinical placebos. It thereby indicates support for a novel, behavioural approach to reduce overtreatment in primary care. Our qualitative and quantitative results both highlight particular potential for the use of open-label impure placebos, which are treatments with known pharmacological value for some of the patients’ symptoms, but without therapeutic effects for the underlying illness. This is aligned with previous research, which suggested patient support for and curiosity about open-label placebos [Our results demonstrated interesting differences in self- and other decision-making. When presented with a decision scenario on respiratory infections involving the potential inappropriate use of antibiotics, participants generally opposed the use of antibiotics. Yet, they still indicated a personal preference for receiving antibiotics if they were the ones suffering from the infection. This suggests heightened levels of loss aversion when making choices for oneself as found in previous experimental research [Additionally, Study 2 suggests that individual levels of placebo acceptability and beliefs around effectiveness may vary depending on a person’s demographic background, previous medical history and individual differences in health anxiety and health literacy. Older people, individuals suffering from chronic illness or those showing higher levels of health anxiety, may be less amenable to placebo use. Individuals with lower health literacy may be less accepting of open-label placebos, supporting previous research which found that health literacy predicted people’s responses to health messages [Finally, our results suggest an important role of language when communicating information about placebos. Specific terms such as “impure” or “sugar pills” may carry negative connotations suggestive of contamination or child-like properties respectively, which could shape public attitudes around placebos and should therefore be avoided. These findings are aligned with previous results on the effects of language framing, including work highlighting the importance of disease names and related medical terminology [ | PMC10510165 |
Implications for clinical practice and policy | infections | INFECTIONS | Our findings have important implications for clinical practice, because they suggest an acceptable behavioural approach towards reducing overtreatment in UK primary care. It appears that replacing unnecessary medication with open-label impure placebos could be supported by the general UK population—particularly in the context of antibiotic prescribing. Hence, our research has confirmed a key pre-requisite to conducting follow-up trials for testing the actual effectiveness of this behavioural strategy for reducing medicine overuse. Our findings could provide a starting point for informing whether placebos should feature more prominently in treatment guidelines, such as relating to infections. Whilse providing support for placebo use in clinical practice, our research raised several points that need to be considered when trialling placebo use practice. | PMC10510165 |
Importance of shared decision-making | Our findings point to the likely importance of shared decision-making approaches when trialling clinical placebo use. A key theme emerging from our focus groups was the prerequisite of a trusting doctor-patient relationship, which is unlikely to emerge without building a rapport during a process of shared decision-making [ | PMC10510165 |
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Communication about placebos | When communicating about placebos, language is likely to play an important role. Both Studies 1 and 2 demonstrated public sensitivity to terminology. Our focus groups highlighted negative public associations with the term “impure”, which may affect acceptability of impure placebos. Instead, it may be favourable to describe these as “a type of placebos”, as done in Studies 2 and 3. Additionally, Study 2 suggested that using the term “sugar pill” instead of “placebo” may decrease public acceptability under certain circumstances. Additional research could help to identify further framing effects and the influences of other types of terminology that might shape public attitudes. | PMC10510165 |
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Provision of decision aids | infection | INFECTION, AIDS | To support the process of shared decision-making, the use of decision aids is likely going to be crucial. Both our PPI engagement activities and our focus group research highlighted the potential barrier of short appointment times for explaining the rationale behind placebo use and the scientific evidence around its effectiveness. Similarly, decision aids could provide additional background information about both personal side effects and societal consequences associated with medicine overuse in order to promote placebo acceptability. This suggestion is based on findings by Study 3, which found more favourable placebo attitudes in the infection scenario; the only scenario also highlighting societal harms of overtreatment (i.e. antimicrobial resistance). | PMC10510165 |
Practical considerations | When designing trials of clinical placebo use, several practical considerations will need to be accounted for. This includes specific contexts for placebo use, the mitigation of adverse consequences and administrative challenges. | PMC10510165 |
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Contexts of clinical placebo use | depression, infections, chronic pain, anxiety | CHRONIC PAIN, INFECTIONS | Our initial focus group results demonstrated that participants were most supportive of placebo use for non-serious illnesses and in the context of mental health treatments (e.g. anxiety and depression). Study 3 confirmed that placebo use for less severe depression was rated more acceptable and effective than for chronic pain conditions, but attitudes were most favourable in the scenario involving inappropriate placebo use for infections. Future research will need to pay attention to the particular prescribing context and consider placebo use against the background of previous attempts to de-license ineffective or unnecessary treatments [ | PMC10510165 |
Mitigation of adverse consequences | INFECTIONS TOE | Our focus groups raised a number of potential adverse consequences of clinical placebo use. These might include patients considering themselves treated through placebos and consequently taking less precaution about spreading their infections to others or failing to seek further help if symptoms worsen. An additional concern is that placebo prescribing for conditions not necessitating any medical treatment might result in an increase of health-seeking behaviours, potentially increasing patient demand for doctors’ appointments. All these consequences could undermine the overall practical utility of clinical placebo use and need to be monitored carefully in any clinical trials. | PMC10510165 |
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Administrative challenges | A final practical consideration is administrative challenges including the question about prescription charges for placebos. Our focus groups appeared divided on this point and future trials may need to collect further, context-specific data on public attitudes towards prescription charges. | PMC10510165 |
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Study limitations | When interpreting our research findings, a number of theoretical and practical study limitations need to be considered. | PMC10510165 |
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Defining placebos | pain | Previous research has highlighted the difficulties of defining what constitutes a placebo. Especially the category of “impure placebos” is not without contention, because of ambiguous terminology and inconsistent use in the past literature [The present study used a broad definition of impure placebos and adopted a pragmatic approach, in which all active medical treatments (antibiotics, antidepressants and pain killers) were conceptualised as such without consideration of their actual appropriateness. However, it is possible for public acceptability to differ depending on the specific placebo definitions applied. | PMC10510165 |
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Use of hypothetical patient vignettes | A more practical research limitation pertained to the use of hypothetical patient scenarios across all three studies reported in this article. We asked participants to consider a fictitious patient case rather than assessing decisionmaking in real-life medical contexts. This methodological approach has many advantages such as overcoming difficulties of accessing high-quality clinical data and reaching large numbers of participants [ | PMC10510165 |
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Attitude measurement | A final limitation is the use of Likert-type rating scales to measure attitudes around general acceptability, personal acceptability and predicted effectiveness of different treatment types. Attitudes are inherently difficult to quantify and opinions lack absolute values. While the use of Likert-type scales is common practice in attitude research and is typically associated with high internal consistency [ | PMC10510165 |
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Conclusions | Clinical placebo use could be a publicly acceptable approach for combatting overprescribing in primary care. Acceptability appears to be highest for the use of open-label impure placebos for cases where overtreatment is likely to result in both personal side effects and negative consequences for wider society (e.g. antibiotic overprescribing), although personal risk concerns, individual differences and co-variates will need to be considered. Clinical research is necessary to test practicalities (e.g. around doctor-patient communication and trust) and develop guidelines around clinical placebo use across a range of specific prescribing contexts. | PMC10510165 |
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Acknowledgements | Sarah Tonkin-Crine | WRIGHT | The authors gratefully acknowledge comments by Dr Haroon Ahmed, Dr Miroslav Sirota, Dr Sarah Tonkin-Crine and Prof David Wright, which informed the research design and interpretation of findings. | PMC10510165 |
Authors’ contributions | EMK: conceptualisation, data collection, data analysis, writing—original draft, writing—review and editing. TE: data analysis, writing—original draft, writing—review and editing. EY: conceptualisation, data collection. SS: conceptualisation, writing—review and editing. ST: conceptualisation, writing—review and editing. | PMC10510165 |
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Funding | This research was funded by an internal grant at the University of Leicester from the Wellcome Trust Institutional Strategic Support Fund (204801/Z/16/Z). | PMC10510165 |
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Availability of data and materials | OSF | The quantitative datasets generated during the current studies, study materials and study preregistration forms are available in the Open Science Framework (OSF) with the identifier | PMC10510165 |
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Declarations | PMC10510165 |
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Ethics approval and consent to participate | All studies received ethical approval from the Institutional Review Board of the University of Leicester (reference numbers for Studies 1, 2 and 3 respectively: 37530-emk12-ls:psychology&visionsciences; 37978-eieo1-ls:psychology&visionsciences; 39206-emk12-ls:psychology&visionsciences). Participants gave informed consent to participate. The studies did not involve any deception of participants. | PMC10510165 |
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Consent for publication | Consent for publication was obtained from all participants across the three studies reported in the manuscript. This included consent to publish anonymised quotations from qualitative research. | PMC10510165 |
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Competing interests | The authors declare that they have no competing interests. | PMC10510165 |
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References | PMC10510165 |
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Objective | miscarriages | MISCARRIAGES, MISCARRIAGE, COMPLICATIONS | The complications associated with miscarriages have surfaced as a major concern in maintaining women’s physical and mental health. The present study evaluated the efficacy of three medication regimes for the complete expulsion of retained intrauterine tissues in patients who underwent a miscarriage. | PMC10557307 |
Methods | coagulative blood disorders | DISEASES, MISCARRIAGE | In this randomized clinical trial, 90 patients participated with their gestational age below 12 weeks, each having undergone a recent miscarriage. After being screened for underlying diseases and coagulative blood disorders, they were randomly allocated into three groups. For the first group, labeled as the control group, misoprostol was administered alone. In contrast, the combination of misoprostol plus methylergometrine and misoprostol plus oxytocin was prescribed for the second and third groups, respectively. Further, the data obtained were analyzed by descriptive and inferential statistics using Stata software version 14. | PMC10557307 |
Results | abortion, bleeding, RPOC, pain | BLEEDING | The mean age of participants and gestational age were 29.76 ± 5.53 years and 8.23 ± 2.29 weeks, respectively. There was no significant difference between the three treatment groups regarding the amount of bleeding after the abortion(P = 0.627). Regarding pain severity, the group that received Misoprostol plus Methylergometrine had less pain intensity than the other two groups(p = 0.004). The mean rate of RPOC expulsion was in the Misoprostol plus Oxytocin (9.68 ± 10.36) group, Misoprostol plus Methylergometrine (11.73 ± 12.86), and Misoprostol groups (19.07 ± 14.31)(p = 0.013). The success rate in outpatient medical abortion in the misoprostol plus oxytocin and misoprostol plus methylergonovine group was 93.33%, but in patients treated by misoprostol alone was 83.33%. | PMC10557307 |
Conclusion | pain | The effectiveness of the drugs in the two drug groups combined with oxytocin and methylergometrine is higher than the misoprostol group alone. An outpatient approach was deemed more satisfactory against surgical maneuvers and hospitalizations by patients since family support influenced their pain coping mechanism. | PMC10557307 |
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Trial registration | The trial was registered in the Iranian registry of clinical trials on 04/10/2019. ( | PMC10557307 |
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Keywords | PMC10557307 |
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Introduction | bleeding, death, infertility, infection, RPOC, abortion, intrauterine tissue retention, muscle contractions | BLEEDING, POSTPARTUM HEMORRHAGE, COAGULATION DISORDERS, INTRAUTERINE ADHESION, RETAINED PRODUCTS OF CONCEPTION, INFECTION, MISCARRIAGE, COMPLICATIONS | Globally, the complications succeeding a spontaneous or unsafe abortion have been recognized as an impediment to women’s general well-being [The prevalent long-term complications of intrauterine tissue retention include infertility, bleeding, intrauterine adhesion, coagulation disorders, infection, and death, which are in a linear relationship with age advancement [Some studies have been carried out to ascertain the expulsion rate of persistent placental or trophoblastic tissue, to compare oxytocin efficacy on uterine smooth muscle contractions, and also to relate the prophylactic effects of methylergometrine on postpartum hemorrhage [This study aimed to investigate the efficacy and safety of misoprostol for treating retained products of conception (RPOC) following a miscarriage, with the added importance of avoiding hospitalization during the COVID-19 pandemic. To evaluate the efficacy and side effects of each medication regime, a comparison was drawn between the administration of misoprostol with the combined use of misoprostol plus oxytocin and misoprostol plus methylergometrine for complete expulsion of retained intrauterine tissues in patients who underwent a miscarriage. The outcome evaluated whether outpatient treatment could be substituted with a surgical approach as a safe maneuver. | PMC10557307 |
Main text | PMC10557307 |
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Methods and materials | PMC10557307 |
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Study design | bleeding, miscarriage, spotting, pain | ADVERSE EVENTS, BLEEDING, MISCARRIAGE, SECONDARY | This clinical trial was performed on 90 patients referred to the gynecology and obstetrics clinic affiliated with Jahrom University of Medical Sciences with miscarriage and a gestational age below 12 weeks from March to July 2020.The sample size was calculated according to Paris et al. [After taking a comprehensive history from each patient, the data obtained was registered in the relevant code sheets. After being matched in gestational age, the next step involved randomly allocating patients into three distinctive groups. To reduce outcome assessment bias in this study, the radiologist examined the images without prior knowledge of the patient’s status, thus ensuring impartial evaluation. Subsequently, the patients were checked for success rates of pregnancy tissue expulsion as the primary outcome and bleeding, pain, and spotting as a secondary outcome. The protocol of this study was approved by the ethical committee of Jahrom University of Medical Sciences issued with code No.: IR.JUMS.REC.1396.143 was further registered in the Iranian registry of clinical trials with code ID IRCT20200122046221N1. It is worth mentioning that all patients recruited in this study have provided their written informed consent to the researchers, and all probable adverse events and benefits of the research were explained to them. | PMC10557307 |
Participants | vaginal bleeding, pelvic infection, seizure, asthma, glaucoma, RPOC, sepsis, hypersensitivity | VAGINAL BLEEDING, PELVIC INFECTION, HEPATIC DISORDERS, ASTHMA, INCOMPLETE ABORTION, GLAUCOMA, THROMBOEMBOLISM, SEPSIS, HYPERTENSION, HYPERSENSITIVITY | The eligibility criteria assigned for the patients to enter the study were as follows: gestational period below 12 weeks as confirmed by sonography & Last Menstrual Period (LMP); spontaneous and/or incomplete abortion diagnosed by sonography; and vaginal bleeding history in the current pregnancy that encouraged patients to pursue outpatient treatment to expel RPOC. However, the exclusion criteria that disqualified the patients for the study were the following: hypersensitivity to misoprostol or certain prostaglandins; drug limitations for taking prostaglandins in patients with asthma, glaucoma and hypertension, hepatic disorders, seizure history, history and/or presence of thromboembolism; smoking habits; Intrauterine device (IUD); Hb < 10 mg/dl; temperature > 38º C and finally, pelvic infection or sepsis that caused patient’s discontentment for outpatient treatment. Moreover, an unstable hemodynamic status was considered among the exclusion criteria. | PMC10557307 |
Randomization and blindness | BLIND | Random allocation was done using Random Allocation Software as a random division with the nine-way random block method by an epidemiologist who was not involved in the study. Using the lottery, the letters A, B, and C will be considered symbols of one of the three intervention groups. In the next step, each of the nine codes was placed in a sealed envelope that could not be read from the envelope. At the patients’ visit, one of the envelopes was randomly selected, and the patients were assigned to one of the study arms in the order of the letters mentioned.In this study, it was impossible to blind the participants or researchers to the treatment group assignments, as each group received a different medication regimen, and participants were aware of the treatment they were receiving. Additionally, this study involved outpatient treatment, and participants had to go to the nearest clinic to receive injections, reducing the likelihood of blinding. | PMC10557307 |
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Intervention | ADVERSE EVENTS, COMPLICATIONS | A thorough and organized history was obtained from the patients who met the criteria to participate in the study. Additionally, they received a particular informed consent form to acquaint them with the research objectives and were categorized into three groups regarding gestational age. The first group of patients was designated to be the control group. It was given misoprostol 200 mg (Misoglandin, Samisaz Co, Mashhad, Iran) every 6 h sublingually and three suppositories through the posterior vaginal fornix per night [The second and third groups followed different medication regimes as their treatment. In the second group, misoprostol 200 mg was prescribed in the form of sublingual tablet intake every 6 h and three suppositories through the posterior vaginal fornix combined with intramuscular methylergometrine 0.2 mg (Minoo Co, Tehran, Iran) thrice a day. These groups were also advised to refer to the closest clinic to take the injection cautiously [On the other hand, the third group was prescribed misoprostol 200 mg sublingually every 6 h and three suppositories through the posterior vaginal fornix every night. Also, this group was simultaneously administered oxytocin (Vetocin, Aburaihan Pharma Co., Tehran, Iran), 30 units in the morning and 30 units intramuscularly in the afternoon. It was advised to refer to the nearest healthcare center for these injections [Likewise, in those patients with negative Rh, an intramuscular Rhogam 300 mg injection was prescribed to prevent iso-immunization [Participants in all three study arms received education on potential side effects to ensure the safe use of oxytocin and other regimes in the outpatient setting. They were instructed to report any adverse events promptly to the gynecology and obstetrics clinic affiliated with Jahrom University of Medical Sciences. The clinic was well-equipped to handle potential complications, and participants were fully monitored throughout the study. These safety measures were implemented to minimize the risks associated with outpatient use of oxytocin. | PMC10557307 |
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Data Collection | intrauterine death, bleeding, RPOC, pain | BLEEDING, DISEASES | A demographic questionnaire used to gather information about age, sex, weight, blood pressure, existing underlying diseases, and the gestational age of the patients was given to the patients to fill in. Also, sonographic studies were employed to confirm intrauterine death.After a 3-day outpatient intervention, the patients were asked to refer to the gynecology and obstetrics clinic affiliated with Jahrom University of Medical Sciences for further follow-up. In this follow-up session, data such as spotting in pregnancy, pain, bleeding, and finally, successful expulsion of RPOC were asked and recorded carefully in relevant code sheets. For the assessment of the pain severity in the patients, the Visual Analogue Scale system (VAS), a 10 cm scaled ruler, was used to show the degree of the pain in these patients, such that 0 and 10 were its two extremes representing no pain and worst pain, respectively. Data during follow-up were recorded in a blinded fashion and using forms prepared in advance. Furthermore, a 1–3 score denoted relative pain, 4–6 moderate pain, and 7–10 severe pain overall [ | PMC10557307 |
Statistical analysis | Data analysis was done using Stata software version 14. At first, the Kolmogorov-Smirnov test was used to check the normality of the data. The descriptive statistics section reported the results as mean, standard deviation, frequency, and percentage. The analytical statistics section used one-way ANOVA, Chi-square, and independent-sample t-test. Furthermore, the Significance level for all tests was less than 0.05. | PMC10557307 |
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Results | PMC10557307 |
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Population characteristics | In this study, among the 110 eligible patients, 90 patients were evaluated and randomly allocated into three distinctive groups, each consisting of 30 participants. The first, second, and third groups received a dose of misoprostol, misoprostol plus methylergometrine, and misoprostol plus oxytocin, respectively, and were thus named accordingly(Fig.
The CONSORT flow chart of the randomized trial regarding administered drugs in abortionThe mean age of all the patients and the mean gestational age attained 29.76 ± 5.53 and 8.23 ± 2.29, respectively. The weight, height, age, and blood pressure variables in the intervention and control groups were not significantly different (p > 0.05, Table
Comparison of demographic variables in three groups under study before intervention*One-way ANOVA, significance level < 0.05 | PMC10557307 |
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Comparison of therapeutic effects | bleeding, PCOS, pain, RPOC, abortion | BLEEDING, STILL, DRUG SIDE EFFECTS, RETAINED PRODUCTS OF CONCEPTION, POLYCYSTIC OVARY SYNDROME, RETAINED PRODUCTS OF CONCEPTION | There was no significant difference between the three treatment groups regarding the amount of bleeding after the abortion(P = 0.627). Still, in the Misoprostol + Methylergometrine group, 80% of the patients were in the mild bleeding group. In contrast, in the two groups of Misoprostol + Oxytocin and Misoprostol alone, this amount was 63.33% and 53.33%, respectively(Table In terms of pain severity, there was a statistically significant difference between the three groups(p = 0.004). The group receiving Misoprostol + Methylergometrine had less pain intensity than the other two groups (Table In addition, no statistically significant difference was observed between the three groups regarding spotting after abortion (P = 0.894) (Table
Abortion indications in three groups under study
*VAS: Visual Analogue Scale, * Chi-square test, significance level < 0.05
Minimum, maximum, and median of pain severity based on VAS scores in three groups under studyAssessing the rate of RPOC expulsion, no significant difference was seen before the intake of different medications(P = 0.434). However, a statistical difference was detected after patients’ exposure to these medications(P = 0.013). The mean rate of RPOC expulsion was in the Misoprostol + Oxytocin(9.68 ± 10.36) group, Misoprostol + Methylergometrine (11.73 ± 12.86), and Misoprostol groups (19.07 ± 14.31). As can be seen, the effectiveness of the drugs in the two drug groups combined with oxytocin and methylergometrine is higher compared to the misoprostol group alone (Table Finally, the outcomes demonstrated an 83.33% success rate in outpatient medical abortion patients treated with misoprostol alone. In contrast, those groups treated with misoprostol plus oxytocin and misoprostol plus methylergonovine illustrated a success rate of 93.33%. In addition, the results showed no statistically significant difference in drug side effects in the treatment groups under study (P = 0.329) (Table
Comparison of retained products of conception (RPOC) and state of ovary before and after medical therapy in three groups under studyRPOC: Retained products of conception, PCOS: Polycystic ovary syndrome, *One-way ANOVA, * * independent t-test,* * * Chi-square test NA: Not applicable, significance level < 0.05 | PMC10557307 |
Discussion | bleeding, fetus abortion, pain, RPOC, abortion, RPOC expulsion | BLEEDING, POSTPARTUM HEMORRHAGE, UTERINE CERVIX, CONTRACTION, UTERUS, FETAL DEATH, INCOMPLETE ABORTION, COMPLICATIONS | The result of this study confirms an improved efficacy of the medical therapy of misoprostol, either combined with oxytocin or with methylergonovine, in successful expulsion of the RPOC. Although treatment by misoprostol alone (83.3%) has not resulted in remarkable statistical significance, greater therapeutic efficacy was reported in the groups (93.33%) treated by a combination of misoprostol plus oxytocin or misoprostol plus methylergonovine. Moreover, by designating the degree of persistent residual tissues in the patients, it was concluded that those treated with misoprostol plus oxytocin had the best outcome compared to the other groups. Likewise, all the patients treated with other medications showed a sufficient successful rate of RPOC expulsion.Kaviani et al. concluded that ‘the efficacy of methylergonovine in the successful expulsion of retained pregnancy tissues in patients with incomplete abortion showed 94.6%’ [Misoprostol is a prostaglandin E1 analog, a uterotonic pharmacological agent that functions either by contracting the uterine smooth muscles or by dilating the uterine cervix [Although the mean age of all the patients in this study was 29.76 ± 5.53 with no statistical significance in the three different groups, the age-related physiological factors could alter the outcomes. Niroumanesh et al. concluded that older multiparous patients with several previous pregnancies had more tendencies for surgical and curettage approaches than the other patients [Another conclusive point about the patient’s mean age is that younger patients experiencing abortion need to be educated thoroughly about contraceptives and preventive methods, unlike the other age groups. However, this perspective might appear irrelevant to the current study’s aim.Abnormal weight in mothers has a crucial impact on fertility and sanitizations during a healthy pregnancy; that is why determining factors like Body mass index (BMI) like weight and height can play a substantial role in abortion physiology. All the patients were examined for weight and blood pressure, but no statistical significance in these variables was noted that might have altered the outcomes. These findings were compatible with a study conducted by Ghasemi et al. [After the prescription of drugs in the different groups, bleeding, pain, and spots, considered pregnancy tissue expulsion-associated complications, were carefully evaluated. A persistent postpartum hemorrhage after fetus abortion signifies small fragments of trophoblast and decidua still retained in the uterus after fetal death or RPOC expulsion [A study was conducted by Whitehouse et al. to compare the efficacy of medical management for bleeding prevention after surgical abortion in over 336 patients with a history of recent abortion. Their study discovered that 72% of the patients used contraceptive drugs to prevent bleeding and 83% preferred vasopressin over other medications. Likewise, they declared that these patients were willing to intake methylergonovine during the second trimester to control severe bleeding and then preferred misoprostol [Methylergonovine and oxytocin are stimulators of uterine contraction that act directly on uterine smooth muscle and peripheral vasculature, especially uterine vessels, and thus reduce bleeding [Similarly, regarding spotting manifestation after abortion and medication intake, the analysis proved no significant difference between different study groups. This fact confirms the results obtained from the degree of bleeding reported by the participants.Considering medication intake and postpartum pain followed by fetal abortion, our study has discovered that the combination of misoprostol plus methylergonovine showed the best efficacy in pain management. A varied number of guidelines published for pain management by various medical associations have recommended only a normal dosage of common analgesics [Although they strongly recommend controlling, monitoring, and measuring the pain [A study by Kemppainen et al. [ | PMC10557307 |
Limitations | bleeding | BLEEDING | Our study had several limitations. First, Short-term follow-up and small sample size were among the barriers that limited the present study. Second, in this study, to evaluate bleeding, only the severity of bleeding was considered, and the volume of bleeding and the average number of days during which there is bleeding was not assessed. | PMC10557307 |
Acknowledgements | The authors are grateful to all the participants in this study. Also, We would like to express our sincere gratitude to the Clinical Research Development Unit of Peymanieh Hospital, affiliated with Jahrom University of Medical Sciences, for providing suitable environmental facilities and research requirements. | PMC10557307 |
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Authors’ contributions | HT | AR and ZZ considered and planned the study. AR and VR were responsible for the literature search and screening. ZZ and HT were responsible for data collection. VR participated in the statistical analysis. AR, HT, and ZZ contributed to data interpretation. AR and ZZ drafted the manuscript, and VR critically revised the manuscript. All authors read the final manuscript and approved it for publication, [AR] had full access to all of the data in this study and take complete responsibility for the integrity of the data and the accuracy of the data analysis. | PMC10557307 |
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Funding | This study was done with the financial support of Jahrom University of Medical Sciences. The funding agency had no role in the study design, collection, analysis, and interpretation of data and manuscript writing. | PMC10557307 |
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Data Availability | The datasets generated and analyzed during the current research are not publicly available as individual privacy could be compromised, but are available from the corresponding author on reasonable request. | PMC10557307 |
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Declarations | PMC10557307 |
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Ethics approval | Written informed consent was obtained from the patients in our study. The purpose of this research was completely explained to the patient, and assured that the researcher would keep their information confidential. The protocol of this study was approved by the ethical committee of Jahrom University of Medical Sciences issued with code No.: IR.JUMS.REC.1396.143 was further registered in the Iranian registry of clinical trials with code ID IRCT20200122046221N1. Furthermore in this study, we adhered to CONSORT guidelines (We confirm that all methods were carried out in accordance with relevant guidelines and regulations. | PMC10557307 |
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Consent for publication | Not applicable. | PMC10557307 |
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Competing interests | The authors declare that they have no competing interests. | PMC10557307 |
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Abbreviations | RPOC | World Health Organization, RPOC:retained products of conceptionLast Menstrual PeriodIntrauterine device, VAS:Visual Analogue Scale system | PMC10557307 |
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References | PMC10557307 |
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Abbreviations: | Long-chain PUFA (LC-PUFA) are transferred from the mother to the fetus during pregnancy to meet the fetal needs for development; maternal LC-PUFA supply is crucial since the synthesis of LC-PUFA by the fetus and placenta is very lowPrevious evidence has indicated that consumption of fish oil which is rich in Interestingly, preliminary evidence shows that probiotics may affect serum fatty acid (sFA) levels: the administration of Less is known about the combination of fish oil and probiotics. In our previous study in pregnant women, the combination of fish oil and probiotics increased serum DHA and We hypothesise that probiotics and fish oil jointly modify blood | PMC10751948 |
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Materials and methods | PMC10751948 |
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Study design and participants | LATE PREGNANCY, SECONDARY | This single centre double-blind, placebo-controlled randomised trial
Flow diagram of the study.For this secondary analysis of the main trial, blood samples were obtained at two study visits, early and late pregnancy (mean 13·8 ( | PMC10751948 |
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Clinical parameters | EARLY PREGNANCY | Weight was obtained from welfare women clinic records and was self-reported. Height was measured with a wall stadiometer at the first visit. Pre-pregnancy BMI (kg/mGDM was diagnosed at 24–28 gestational weeks on the basis of a 2 h 75 g oral glucose tolerance test if one or more values were: 0 h ≥ 5·3, 1 h ≥ 10·0 and 2 h ≥ 8·6 mmol/lBlood pressure was measured with an Omron M5-1 (IntelliThree-day food diaries were obtained in early pregnancy. The daily intakes of energy and energy-yielding nutrients and fibre were calculated by using computerised software (AivoDiet 2.0.2.3, Aivo) utilising the Finnish Food Composition Database FineliQuestionnaires were collected to obtain information about education and smoking, and the participants were interviewed about their fish oil supplement usage before participation. | PMC10751948 |
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Dietary intervention | LATE PREGNANCY | Women consumed two fish oil capsules and one probiotic capsule (or matched placebos) daily from early pregnancy/first study visit until 6 months postpartum; herein, we include data from the intervention from early until late pregnancy. The fish oil capsules (Incromega E1070, Croda Europe Ltd) contained 2·4 g of | PMC10751948 |
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Fatty acid analyses | BLOOD | Blood samples were obtained from the antecubital vein of the mother in the morning after at least 9 h fasting and were then separated into aliquots and frozen in −80°C. The fatty acid composition of four serum lipid fractions (PC, CE, TAG and NEFA) was determined by GC (Agilent Technologies). Samples were batch-analysed between 21 October 2018 and 15 February 2019. The methodology of these analyses is described in more detail in Fisk | PMC10751948 |
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Low-grade inflammation | Serum hsCRP was analysed using an automated colorimetric immunoassay on a Dade Behring Dimension RXL autoanalyzer (Siemens Healthcare) in a certified laboratory (TYKSLAB, the Hospital District of Southwest Finland). The lower limit of detection was 0·1 mg/l. The data are expressed as mg/l. A high-throughput proton NMR spectroscopy metabolomics platform (Nightingale) was used to quantify GlycA | PMC10751948 |
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Statistics | LATE PREGNANCY, EARLY PREGNANCY | Natural log-transformation was performed for fatty acid variables with skewness > 1. Z-scores were calculated for all fatty acid variables. The effect of the intervention on the fatty acids was determined in late pregnancy: one-way ANOVA followed by Tukey’s post hoc test or Welch ANOVA followed by Tamhane’s T2 post hoc test. To control the baseline fatty acid data, the fatty acids, which differed between the intervention groups at late pregnancy, were evaluated with one-way ANOVA or Welch ANOVA at baseline, and thus no differences were detected. The fatty acid variables, which differed between the intervention groups at late pregnancy, were adjusted with their early pregnancy values in general linear model. To control the possible effect of smoking, the analyses, which showed difference in the fatty acids in late pregnancy between the intervention groups, were adjusted for smoking before pregnancy (yes/no). Further, those fatty acids, which were influenced by the smoking status, were further studied with independent-samples | PMC10751948 |
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Results | PMC10751948 |
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Baseline characteristics of the pregnant women | Obese | OBESE, GESTATIONAL DIABETES MELLITUS | Clinical characteristics and diet intake of the women are presented in
The baseline characteristics and dietary intake of all pregnant women and according to the intervention groups(Mean values and standard deviations; inter-quartile ranges; numbers and percentages)GDM, gestational diabetes mellitus.The statistical significance is denoted with One-way ANOVA.Kruskal–Wallis.Welch ANOVA.
Obese is defined as BMI ≥ 30 kg/mFisher’s exact test. | PMC10751948 |
Change in | pregnancy-induced | The pregnancy-induced changes in With respect to | PMC10751948 |
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Impact of the dietary intervention with fish oil and/or probiotics on serum fatty acid composition in the four lipid fractions | LATE PREGNANCY | The dietary intervention had an impact on the total
(Mean values and standard deviations)The following variables were natural log-transformed: 18:3One-way ANOVA followed by Tukey’s post hoc test.Welch ANOVA followed by Tamhane’s T’2 post hoc test.Significantly different from probiotics Significantly different from placebo
(Mean values and standard deviations)The following variables were natural log-transformed: 18:3One-way ANOVA followed by Tukey’s post hoc test.Significantly different from probiotics Significantly different from probiotics Significantly different from placebo Significantly different from placebo
(Mean values and standard deviations)The following variables were natural log-transformed: 18:3One-way ANOVA followed by Tukey’s post hoc test.Welch ANOVA followed by Tamhane’s T’2 post hoc test.Significantly different from probiotics Significantly different from placebo
(Mean values and standard deviations)The following variables were natural log-transformed: 18:3One-way ANOVA followed by Tukey’s post hoc test.Welch ANOVA followed by Tamhane’s T’2 post hoc test.Significantly different from probiotics Significantly different from placebo Significantly different from placebo Significantly different from placebo The dietary intervention had an impact on the total The The results for other fatty acids (i.e. SFA as well as MUFA) are shown in online Supplementary Tables The raw % values of all fatty acids according to the intervention groups are presented in online Supplementary Tables Furthermore, the effect of the intervention on the change from early to late pregnancy of the fatty acids, which differed statistically significantly between the intervention groups in late pregnancy, was investigated (PC, NEFA, CE and TAG in online Supplementary Tables The effect of the intervention on | PMC10751948 |
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The | EARLY PREGNANCY | Out of all forty-eight
(a) The heatmap describing the Pearson correlation coefficients between early pregnancy serum hsCRP and GlycA and In early pregnancy, positive correlations with GlycA were observed for ALA (18:3In late pregnancy, GlycA correlated positively with eicosatetraenoic acid (ETA, 20:4 | PMC10751948 |
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The | GDM | GDM, REGRESSION | Regarding the association between the
(a)–(d) The association of Out of all The fatty acids related to the onset of GDM in the univariate logistic regression analyses ( | PMC10751948 |
Discussion | hypertriacylglycerolaemia, inflammation, GDM | GDM, INFLAMMATION | We demonstrate that fish oil and the combination of fish oil and probiotics had an impact on the sFA profile in pregnant women with overweight and obesity whilst against our expectations probiotics did not when the four intervention groups were compared. However, when women receiving probiotics were compared against women not receiving probiotics, EPA in serum NEFA was lower in those who received probiotics as compared with those who did not. Low-grade inflammation was related to serum Interestingly, the impact of the intervention on some Less is known about the effects of probiotics on circulating fatty acid levels. In a study with non-pregnant adults with hypertriacylglycerolaemia, We demonstrated that sFA are related to risk for GDM: a higher level of One mechanism that may link fatty acids and GDM risk is inflammation-mediated alterations in insulin metabolism. The production of pro-inflammatory eicosanoids via increased levels of precursor AA, which was associated with higher odds for GDM in our study, can increase the levels of some other inflammatory factors, for example, some cytokines, as reviewed by CalderWe found that correlations between hsCRP and Plasma or serum contains fatty acids in multiple chemical forms (TAG, CE, PL and NEFA). Here, we report the fatty acid composition of each of these pools. TAG are carried mainly in chylomicrons (of gut origin in the fed state) and VLDL (of hepatic origin in the fasting state) and are a transport pool of fatty acids being delivered to peripheral tissues. CE are mainly carried in VLDL remnants (ultimately LDL) and are a transport pool of fatty acids being delivered to peripheral tissues and to the liver. PL are found in the monolayer that coats all lipoproteins ensuring their solubility in the aqueous bloodstream; the main PL in human plasma and serum is PC. The fatty acid composition of circulating PL, including PC, is related to the fatty acid composition of many cell types. In the fasting state, NEFA are mainly fatty acids released from adipose tissue lipolysis and so their composition represents that of adipose tissue TAG. Thus, the fatty acids in different plasma lipid pools align with different metabolic or functional roles. It is well described that the fatty acid composition of each of these pools is modified by an increased intake of EPA and DHAWe report fatty acids in each pool as both weight percentage and absolute concentration. Weight % describes the concentration of each fatty acid relative to all fatty acids in the pool. It is the most common way of reporting fatty acid composition dataOne strength of our study is its randomised placebo-controlled design, which is the gold standard design for studies evaluating the impact of dietary interventions on any clinical or laboratory measure. Another strength is the high number of participants who gave a blood sample after at least 9 h over night fasting for the analysis of the fatty acids. Even though the power calculations were done based on the reduction of incidence of GDM and fasting glucose levels | PMC10751948 |
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