In his narrative review of the association between maternal caffeine consumption and pregnancy outcomes, Professor Jack E James claimed there was sufficient evidence of harmful causal effects to suggest that pregnant women or women contemplating pregnancy should 'avoid caffeine' (1). His opinions were widely reported by the media in line with a sensational press release that claimed there was "No safe level of caffeine consumption for pregnant women and would-be mothers". We do not however consider these claims to be appropriate or justified, due to a number of serious methodological limitations, statistical errors, and a concerning lack of objectivity. The author declared no conflicts of interest, yet has written extensively on the 'lethality' of caffeine (2). For this, and the following reasons, we believe the review and its recommendations should be interpreted with extreme caution.

1. Scientific conduct
a) The article is described as a ‘narrative review’, and thus by its nature, falls well short of the standards expected for a formal systematic scientific review of the literature. It is not clear how the author identified articles for inclusion, nor what criteria were used for exclusion, or what approach, if any, was used to critically appraise the studies identified or synthesise the information obtained. It is therefore difficult to have confidence that the articles presented offer an unbiased reflection of the literature and that equal scepticism was applied to the evaluation of each article identified. If the article was intended as a ‘review of reviews’ - which would have been merited by the number of systematic reviews and meta-analyses discovered - then we would have expected much more critical engagement with the limitations of each review and how these are addressed, if at all, by the different approaches used.

b) The author does not appear to demonstrate the level of self-scepticism required for an investigation of this nature. More space, for example, is devoted to discussing the potential mechanism through which caffeine may cause harm rather than considering the various ways in which such an association may be observed through non-direct means. The inductive scientific method dictates a sceptical approach to the generation of theory, with confidence gained from a theory’s resilience to alternative hypotheses. In order to provide evidence that caffeine causes adverse pregnancy outcomes, the article should therefore have focussed primarily on discounting all other possible explanations. Instead, the review primarily focuses on uncritically reporting those findings that appear to support the primary hypothesis; sometimes placing James in conflict with the original interpretation of the study being cited. For example, Gaskins et al’s 2018 is cited as showing an association between maternal caffeine consumption and miscarriage, yet Gaskins et al state that a “component other than caffeine could be driving the association” (3). Similarly, Greenwood et al 2014 (4) describe any potential effects observed as being ‘minimal’ or ‘modest’, yet this is dismissed without quantification by simply stating that ‘In reality...the cumulative population impact... are demonstrably neither 'modest' nor 'minimal'.

c) From previous reviews, such as Greenwood et al 2014, it seems clear that caffeine intake is associated with a higher risk of adverse pregnancy outcome. However, whether this reflects a causal effect is unresolved. In his discussion, James claims “likely causation is supported by a compelling body of evidence”, and speculates that industry may be involved in feeding doubts of this conclusion. Unfortunately, this claim grossly underestimates the challenge of making causal inference from observational data. James highlights ‘potential confounding or misclassification’ as threats to causal inference and identifies smoking as a prominent potential confounder. Since most studies make some effort to control for smoking, James states that “concerns about smoking as a source of confounding have been conclusively disconfirmed”. This however disregards the possibility of residual confounding, either due to a lack of accurate and detailed information, flawed adjustment strategies, or both. Studies that have used Mendelian Randomisation or negative control designs strongly suggest that smoking causes both caffeine consumption (5) and fetal outcomes (6-7). However, it has also been demonstrated that self-reported smoking does not adequately control for confounding (8-9). It therefore seems very likely that every study that either failed to adjust for maternal smoking, or used self-reported information - and every meta-analysis that included such studies - will be biased by residual confounding. Other confounders besides smoking are of course also likely to contribute to the observed association, and will similarly suffer from a risk of residual confounding if not properly measured or adjusted. In general, studies that have not used robust causal inference approaches, such as causal diagrams or Mendelian Randomisation, should not be considered to provide evidence of causal effects. This is not changed by the existence of a ‘dose response’ relationship, which by itself offers negligible proof that a relationship is directly causal (10).

d) Although establishing a causal effect of caffeine on one or more adverse pregnancy outcomes would be scientifically valuable, the public health implications - and justification for any policy recommendations - would still depend on the size of any such effect. In this regard, James’ review again falls short of providing any insight beyond what can be found elsewhere. Greenwood et al 2014, for example, are clear that any true effect is likely to be minimal or modest, and therefore suggest that while upper limits of intake may be justified there is no reason to modify the existing message of moderation. No similar real-world nuance is present in James’ review, which also did not report or attempt to estimate absolute risks, which are far easier to interpret than risk ratios, particularly for rare outcomes such as childhood acute leukaemia (11).

2. The findings and recommendations do not account for the lived realities of women’s lives
a) Evidence from the WRISK Project (12) (forthcoming) shows that alarmist media headlines on pregnancy-related public health advice cause immense anxiety and guilt for pregnant women and mothers, particularly those who have experienced a pregnancy loss or poor outcome. The author’s claim that 280,000 of the approximately 1 million miscarriages that take place in the USA each year are attributable to maternal caffeine consumption is a shocking extrapolation which will undoubtedly cause many women extreme anxiety, and may lead them to blame themselves for what is likely to be an unavoidable pregnancy loss (13). This inaccurate extrapolation is extremely irresponsible and in direct contradiction of the principle to ‘do no harm’ in health research.

b) Policy recommendations and public health advice that arise from research must be thoughtfully considered and account for the complex circumstances in which people live their lives. It is not practical or desirable for all people planning a pregnancy, or who are pregnant, to completely avoid caffeine consumption. Many women value and use a precautionary approach when it comes to their pregnancies, but there is a growing body of evidence to suggest that public health advice to abstain completely from a wide range of substances leads to fatigue and anxiety. Some women may be less likely to follow advice as a result (14).

3. The press release accompanying the paper was sensationalist
a) The press release led with “No safe level of caffeine consumption for pregnant women and would-be mothers”, which is an overstatement of the findings.

b) The press release was not clear about the methods of the paper, which is essentially expert opinion rather than a systematic review of the existing research.

c) You will be aware of the media headlines that often result from new studies, particularly those relating to pregnancy. Existing and forthcoming evidence (15-16) suggests that journalists use information taken directly from journal or university press releases to write their articles and bylines, rather than sensationalising study results themselves. In order to prevent irresponsible or inaccurate reporting, press releases must be transparent about research methods, clearly state where evidence is weak, and contextualise the risk that is reported in the paper (e.g. by providing a comment on absolute risk). The pursuit for impact and media coverage must not trump our responsibility to provide evidence-based, transparent information to the public. Indeed, evidence suggests that aligning press releases with the evidence, being cautious about claims, and including caveats does not harm “news interest” (17).

ENDS.

1. James J E.Maternal caffeine consumption and pregnancy outcomes: a narrative review with implications for advice to mothers and mothers-to-be. BMJ Evidence-Based Medicine Published Online First: 25 August 2020. doi: 10.1136/bmjebm-2020-111432

2. James J E. Death By Caffeine: How Many Caffeine-Related Fatalities and Near-Misses Must There Be Before We Regulate? Journal of Caffeine Research. Dec 2012.149-152.http://doi.org/10.1089/jcr.2013.1226

3. Gaskins AJ, Rich-Edwards JW, Williams PL, Toth TL, Missmer SA, Chavarro JE. Pre-pregnancy caffeine and caffeinated beverage intake and risk of spontaneous abortion. Eur J Nutr. 2018;57(1):107-117. doi:10.1007/s00394-016-1301-2

4. Greenwood DC, Thatcher NJ, Ye J, et al. Caffeine intake during pregnancy and adverse birth outcomes: a systematic review and dose-response meta-analysis. Eur J Epidemiol. 2014;29(10):725-734. doi:10.1007/s10654-014-9944-x

5. Shipton, D. et al. Reliability of self-reported smoking status by pregnant women for estimating smoking prevalence: a retrospective, cross sectional study. BMJ 339, (2009).

6. Bjørngaard, J. H. et al. Heavier smoking increases coffee consumption: findings from a Mendelian randomization analysis. International Journal of Epidemiology 46, 1958–1967 (2017).

7. Tyrrell, J. et al. Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5–CHRNA3–CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight. Hum Mol Genet 21, 5344–5358 (2012).

8. England, L. et al. Misclassification of maternal smoking status and its effects on an epidemiologic study of pregnancy outcomes. Nicotine & Tobacco Res. 9, 1005–1013 (2007).

9. Munafò, M. R. et al. Association Between Genetic Variants on Chromosome 15q25 Locus and Objective Measures of Tobacco Exposure. J Natl Cancer Inst 104, 740–748 (2012).

10. Rothman KJ, Greenland S. Hill’s Criteria for Causality. Encyclopedia of Biostatistics. [Online] John Wiley & Sons, Ltd; 2005. Available from: doi:10.1002/0470011815.b2a03072

11. How to communicate benefits, risks and uncertainties. Patient Information Forum. Revised August 2019 www.pifonline.org.uk

12. www.wrisk.org/research-and-engagement/

13. Pollock D, Ziaian T, Pearson E, Cooper M, Warland J. Understanding stillbirth stigma: A scoping literature review. Women and Birth. 2020;33(3):207-218.

14. Grant A, Morgan M, Gallagher D, Mannay D. Smoking during pregnancy, stigma and secrets: Visual methods exploration in the UK. Women and Birth. 2020;33(1):70-76. doi.org/10.1016/j.wombi.2018.11.012

15. Bratton L, Adams RC, Challenger A et al. The association between exaggeration in health-related science news and academic press releases: a replication study [version 2; peer review: 2 approved]. Wellcome Open Res 2019, 4:148 (https://doi.org/10.12688/wellcomeopenres.15486.2)

16. Sumner P, Vivian-Griffiths S, Boivin J, et al. Exaggerations and Caveats in Press Releases and Health-Related Science News. PLoS One. 2016;11(12):e0168217. Published 2016 Dec 15. doi:10.1371/journal.pone.0168217

17. Adams RC, Challenger A, Bratton L, et al. Claims of causality in health news: a randomised trial. BMC Med. 2019;17(1):91. Published 2019 May 16. doi:10.1186/s12916-019-1324-7

Dr Fernando’s1 concerns about potential confounding from alcohol consumption and smoking do not warrant comment here as they are addressed in my review2 and summarised in my letter of reply to Murphy et al.3 A separate concern, shared by O’Connor4 and Murphy et al.,3 reveals Dr Fernando’s misguided presumption that narrative review is not “proper”. More specifically, while claiming that “a significant number of studies will have been missed” by my review, he cites no actual examples of publications he believes should have been included.

Additionally, along with O'Connor4 and Murphy et al.,3 Dr Fernando believes that prior publication renders authors biased when writing again on the same or similar topic. Pursuing the point, he injects an impugning embellishment regarding his claimed “insight into the motives of the author”. He refers to two books “about the dangers of caffeine”, a description that misrepresents the contents of those books and is a thinly veiled attempt at disparagement. The books are titled Caffeine and Health (1991)5 and Understanding Caffeine: A Biobehavioral Analysis (1997),6 respectively. Neither book is “about the dangers of caffeine”. On the contrary, both books seek to provide a comprehensive evidence-based biopsychosocial account of the most widely-consumed psychoactive substance in history, including reputed harms and benefits.

Dr Fernando finds it “interesting” that my review contains a description of just “one randomised controlled trial”, ignoring the fact that to date only one such trial has been published. A previous review,7 which employed meta-analysis (Dr Fernando’s apparent favoured method), found the trial in question to be of limited value, and the reasons are reported in my review. Despite that, Dr Fernando asserts that my review somehow pre-emptively “discredited” that study. The claim is untrue, not least because the misattributed term, “discredited”, appears nowhere in my review. However, in the manner he himself suggests, the false claim raises questions about what his “motives” might be. Were Dr Fernando genuinely committed to meaningful discussion, direct engagement with the substance of the “message” (i.e., the scientific challenges of the topic before us) rather than irrelevant barbed comment aimed at the “messenger”, might have proved more constructive.

References
1. Fernando S. Bias in reporting. Evid Based Med 2020. Available: https://ebm.bmj.com/content/early/2020/09/01/bmjebm-2020-111432.responses.
2. James JE. Maternal caffeine consumption and pregnancy outcomes: A narrative review with implications for advice to mothers and mothers-to-be. Evid Based Med 2020;25. Available: doi.org/10.1136/bmjebm-2020-111432.
3. James JE. Caffeine and pregnancy: The need for calm reflection. Reply to Murphy et al. Evid Based Med 2020;25.
4. James JE. Caffeine and Pregnancy: Bias? Is the pot calling the kettle black? Reply to O'Connor. Evid Based Med 2020;25.
5. James JE. Caffeine and health. London: Academic Press, 1991.
6. James JE. Understanding caffeine: a biobehavioral analysis. Thousand Oaks, CA: Sage Publications, 1997.
7. Jahanfar S, Jaafar SH. Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcomes. Cochrane Database Syst Rev 2015:CD006965.

The Murphy et al. letter1 is notable for its ad hominem claims, the first of which comes in their introductory remarks. Noting that my review2 reports no conflicts of interest, they make the exaggerated claim that I have “written extensively on the ‘lethality’ of caffeine”. That claim cites one published article, titled “Death by Caffeine”,3 which summarises reports of death by poisoning involving documented cases from coronial and other official public inquiries. As reported in that article, official records in several countries report multiple confirmed cases of death by poisoning due to caffeine. Although relatively rare, such cases have been (and continue to be) reported worldwide. Predicated on the mere fact that I have previously reported findings from official inquiries into caffeine-related harm, the claim by Murphy et al. of “conflict” is perverse. By implication, their reasoning would mean that the reporting of harm from any source (which includes much of the content of medical journals) renders authors (i.e., most medical researchers) evermore vulnerable to bias warranting formal disclosure of conflict of interest in all future reports on the same or related topic. Of course, no such custom or practice exists.

Notably, the assertion of conflict in this instance indicates poor understanding of the matter, a lamentable situation considering the professional identities of Murphy and her 20 co-authors. Conflict of interest arises when a primary interest conflicts with a secondary interest.4,5 Examples of healthcare primary interests include researcher interest in producing generalisable knowledge, educator interest in sharing impartial knowledge, and healthcare personnel interest in delivering effective care. The quintessential example of secondary interest requiring disclosure is potential financial gain. However, disclosure is also required in such circumstances as affiliation with a stakeholder where such association could serve a secondary interest even when direct financial reward is not involved. We have no such affiliations, and our studies of caffeine, including caffeine and pregnancy,6 do not generate income.

Echoing sentiments held by O’Connor7 and Fernando,8 Murphy et al. claim that because my article2 is a narrative review, it falls “short of the standards”. In reality, it is common knowledge that all methods of scientific review possess particular advantages and disadvantages. In common with all scientific enterprise (including theoretical and empirical endeavours), each instance of scientific review should be assessed on its merits. The fact that much of the published literature examined in my review is in the form of systematic reviews and meta-analyses contributed to the choice of narrative review in this instance. Given the inconsistency between persistent claims of safety, on one hand, and extensive reports from prior quantitative syntheses of significant caffeine-related negative pregnancy outcomes on the other, there was need for the quantitative literature to be synthesised conceptually by way of “traditional” or narrative review. The claim by Murphy et al. of inherent superior objectivity for one or other review approach over legitimate alternatives reveals poor understanding of review practice and tradition.

Murphy et al. also claim that the articles examined in my review may not be “an unbiased reflection of the literature”. However, the review is transparent with respect to source material, and anyone concerned about selection bias is free to identify additional material. Murphy et al.’s belief that such material exists, despite no attempt by them to identify it, could itself be suggestive of bias. A litany of complaints then follows, wherein Murphy et al. express views contrary to those argued in the review. In particular, while it is (in their words) “clear that caffeine intake is associated with a higher risk of adverse pregnancy outcome”, Murphy et al. nevertheless seem unwilling to consider the implications of that reality. Oddly, they engage in ad hominem generalisations about confounding/misclassification and evidence of causation, when much of the review addresses those very issues in detail.

Under the heading “recommendations” and “lived” experience, Murphy et al. draw attention to concerns about the potential for information such as that reported in the review to cause distress, especially among women who have experienced a negative pregnancy outcome. This is a dilemma of real concern demanding calm and sensitive attention. Murphy et al.’s proselytising does not treat that dilemma with the calmness and sensitively it deserves, nor is the complex multifaceted nature of the dilemma given due consideration. While it is undeniably important that anxiety and guilt be avoided where possible, it is equally important not to withhold inconvenient information, especially information that could assist women in avoiding preventable harm. Thus, it is obviously appropriate to address anxiety or guilt women may feel on receipt of potentially disturbing new information. Likewise, it is important that appropriate support be given in the event of anger and anxiety being triggered when women learn of the failure by relevant authorities to give due prominence to long-held suspicions about caffeine-related harm.

Unfortunately, the contribution of moderate caffeine consumption to negative pregnancy outcomes does not leave an indelible footprint in its wake. Thus, for those who have experienced a negative pregnancy outcome, it is important to stress that caffeine could be but one of a plethora of potential contributing factors. There is simply no basis for making a specific assessment about the possible contribution of caffeine at the level of the individual case. It is equally important, however, to understand that whereas caffeine-related increased risk of harm is small at the level of each individual, that small increased risk when aggregated across populations is demonstrably not trivial,9 as evidenced by the many articles examined in our review.2 Geoffrey Rose, the eminent British epidemiologist, expressed the relevant principle well when he stated, “A population-wide preventive measure [in this instance, avoidance of caffeine during pregnancy] may offer a disappointingly trivial benefit to individuals, but yet its cumulative benefit for the population as a whole can be unexpectedly large” (pp. 102).10

Sadly, Murphy et al. falsely state that the review contains a “claim that 280,000 of the approximately 1 million miscarriages that take place in the USA each year are attributable to maternal caffeine consumption”. The claim appears to be a deliberate misreading of a table in an earlier version of the review. The earlier version (which I decided to amend) included a table (Table 3) predicated on a series of assumptions that included a hypothetical scenario about possible implications were all pregnant women to consume the recommended “safe” level of 200 mg caffeine per day (which the review posited as a purely theoretical, and unlikely, occurrence). However, it was apparent from early reader comment that speculation based on a hypothetical scenario, overtly intended merely to illustrate a point of principle, was potentially confusing and risked diverting some reader attention away from key evidence-based conclusions in the review. Accordingly, I deleted the content describing hypotheticals from the final version. Murphy et al.’s attempt to discredit the review by misreporting material that had been formally withdrawn seems to vindicate the decision to omit that content. However, it is important to note that inclusion or omission of the aforementioned theoretical argument has no bearing whatever on the conclusions, which remain entirely unaltered in both the earlier and amended (i.e., current) version of the manuscript.

Expressing a novel objection, Murphy et al. suggest that the conclusions of the review are “irresponsible” because women are incapable of avoiding caffeine. In that context, it is important to note that caffeine is a psychoactive substance and that repeated exposure leads to physical dependence.11,12 At the same time, it is equally important to understand that the addictive potential of caffeine is less than that of classic drugs of abuse (e.g., alcohol, amphetamines, cocaine, opioids). Indeed, relevant empirical research shows that simple and effective strategies are available to enable those who desire to reduce or eliminate caffeine consuming habits to succeed in so doing.13-15 The terms “avoid” and “eliminate” in this context refer to caffeine beverages (coffee, tea, so-called “energy” drinks, etc.) which account for almost all of the caffeine that is regularly consumed.

Caffeine at considerably lower concentrations is also contained in decaffeinated coffee and tea, hot chocolate, chocolate bars, chocolate confectionaries, and chocolate cake. Combined, those sources account for a trivial proportion of the total caffeine consumed worldwide, and are not the targets of the avoidance advice contained in our review. It is unclear why Murphy et al. prejudge pregnant women as incapable of avoiding caffeine. A more constructive approach would be to promulgate evidence-based findings and invite women to decide for themselves whether to expose their unborn child to a psychoactive drug, albeit one that is currently widely used, or to have, as far as is possible, a drug-free pregnancy.

To repeat key points from the review:2 chronic chemical exposure during pregnancy is always cause for concern; there is undisputed high biological plausibility of harm from caffeine consumed during pregnancy; there is consistent evidence of harm from diverse animal experiments, human observational studies, systematic reviews, and meta-analyses; findings are robust to threats form confounding and misclassification; caffeine has no nutritional benefit for either mother or baby; and persons wishing to reduce or eliminate dietary caffeine can do so successfully when shown how. Those and other realities provide compelling grounds for questioning the soundness of current advice about the reputed safety of “moderate” caffeine consumption during pregnancy.

Finally, while there is no reason to question good intentions, the emotional tone of the Murphy et al. letter and their fervent belief in the correctness of their views (despite current realities as summarised in the preceding paragraph), bear the hallmarks of a common cognitive bias, well-known to social psychology as self-serving bias. Extensive experimentation shows that human decision making is subject to an unintentional and unconscious self-serving bias, wherein reason and judgment are skewed in favour of outcomes in which the individual has a prior stake.16 It is reasonable to assume that most, if not all, of Murphy and her 20 co-authors are habitual caffeine consumers, sharing common features with other consumers, including physical dependence and desire to continue to consume. The self-serving bias therein is likely to encourage resistance to information that challenges habit. Absent of sound argument to reject the challenge, strong emotion and fervent belief typically come to the fore. Such reactions are understandable but regrettable. The public’s stake in women’s health is of a magnitude that calls for calm reflection and preparedness for sober engagement with the evidence concerning caffeine-related negative pregnancy outcomes.

References
1. Murphy C, Brown T, Trickey, H, et al. It remains unclear whether caffeine causes adverse pregnancy outcomes; but naive policy recommendations could cause harm. Evid Based Med 2020. Available: https://ebm.bmj.com/content/early/2020/09/01/bmjebm-2020-111432.responses.
2. James E. Maternal caffeine consumption and pregnancy outcomes: A narrative review with implications for advice to mothers and mothers-to-be. Evid Based Med 2020;25. Available: doi.org/10.1136/bmjebm-2020-111432.
3. James JE. Death by caffeine: How many caffeine-related fatalities and near–misses must there be before we regulate? J Caffeine Res 2012;2:149-152.
4. Relman AS. Dealing with conflicts of interest. N Engl J Med 1984;310:1182-3.
5. James JE. Disclosing conflict of interest does not mitigate healthcare bias and harm: It is time to sever industry ties. Eur J Clin Invest 2020;50, doi.org/10.1111/eci.13344.
6. James JE, Paull I. Caffeine and human reproduction. Rev Environ Health 1985;5:151–67.
7. James JE. Caffeine and Pregnancy: Bias? Is the pot calling the kettle black? Reply to O'Connor. Evid Based Med 2020;25.
8. James JE. Caffeine and pregnancy: Don’t shoot the messenger, please. Reply to Fernando. Evid Based Med 2020;25.
9. James JE. The health of populations. London: Elsevier-Academic Press, 2016
10. Rose G. The strategy of preventive medicine. Oxford, UK: Oxford University Press, 1992.
11. Griffiths RR, Juliano LM, Chausmer AL. Caffeine: pharmacology and clinical effects. In: Graham AW, Schultz TK, Mayo- Smith MF, Ries RK, Wilford BB (eds) Principles of addiction medicine, 3rd edn. (pp 134–193). Chevy Chase, MD: American Society of Addiction Medicine, 2003.
12. James JE, Rogers PJ. Effects of caffeine on performance and mood: Withdrawal reversal is the most plausible explanation. Psychopharmacol 2005;182:1-8.
13. Foxx RM, and Rubinoff, A. Behavioral treatment of caffeinism: reducing excessive coffee drinking. J App Behav.Anal. 1979;12:344-55.
14. James JE, Stirling K P, Hampton BAM. Caffeine fading: behavioral treatment of caffeine abuse. Behav Ther 1979;16:15-27.
15. James JE, Paull I, Cameron-Traub E, et al. Biochemical validation of self-reported caffeine consumption during caffeine fading. J Behav Med 1988;11:15-30.
16. Dana J, Loewenstein, G. A social science perspective on gifts to physicians from industry. JAMA 2003; 290:252–5.

To the Editor,

We read with great interest the recent publication by Prager et al in BMJ Evidence-Based Medicine (1) and commend the authors on their important work. The authors characterize blinding practices in point-of-care ultrasound (POCUS) diagnostic accuracy clinical research. The authors evaluated whether the interpreter was blinded to patient clinical information in articles published in Emergency Medicine, Anesthesia, and Critical Care journals from January 2016 to 2020. Among 97 studies, the authors found that the POCUS interpreter was blinded to clinical information in 38.1% of studies, not blinded in 35.1%, and that the blinding practice was not reported in 26.8%. They additionally report that the same person obtained and interpreted images in 74.2% of studies, was different in 14.4%, and was not reported in 11.3%. These results demonstrate significant variability in POCUS research, leading the authors to conclude that to ensure generalizability of future research, the same person should perform and interpret the POCUS scan and not be blinded to clinical information.

The authors are firm in their recommendation and its perceived benefit. We believe, however, that it is short-sighted to uniformly recommend a study design in this rapidly evolving field. The authors (and importantly, future researchers) should carefully weigh the advantages and disadvantages of differing study designs. Both blinding and not blinding to clinical information allow comprehensive evaluation of POCUS for educational uses, quality improvement, and accurate integration into clinical care. The translational science research spectrum provides a framework, from proof of concept to population level outcomes research (2), among which POCUS research undoubtedly falls. Bias, validity, reliability, reproducibility, and the research question are all important considerations researchers need to consider in developing their study design (3, 4).

We disagree with the author’s assertion that research biases are an intrinsic limitation to POCUS research methodology. Importantly, these biases should not be disregarded by unifying research methodology. As an example, researchers evaluating unstudied POCUS techniques will require a different study design than research evaluating a well-established technique, due to differing research questions; even if the final research outcome is the same.

While Prager et al have highlighted differences in study design and limitations to the performance of meta-analyzes because of significant heterogeneity, we would highly encourage prospective researchers to carefully determine the purpose of their project and to design studies to best answer their question while maximizing scientific rigor. We agree with the author’s that applicability of POCUS research to a generalized clinical setting is optimized by tailoring the study design to real-world application but this is not the sole purpose of ultrasound research which also includes education, monitoring, and quality improvement. Each researcher needs to consider his or her study purpose, and design a study to meet that purpose.

References:
1. Prager R, Wu K, Bachar R, et al. Blinding practices during acute point-of-care ultrasound research: the BLIND-US meta-research study. BMJ Evid Based Med. 2020 Nov 11: bmjebm-2020-111577. doi: 10.1136/bmjebm-2020-111577. Epub ahead of print. PMID: 33177166.
2. Westfall JM, Mold J, Fagnan L. Practice-Based Research— “Blue Highways” on the NIH Roadmap. JAMA. 2007; 297(4): 403–406. doi:10.1001/jama.297.4.403.
3. Stone JC, Glass K, Clark J, et al. A unified framework for bias assessment in clinical research. Int J Evid Based Healthc. 2019 Jun;17(2):106-120. doi: 10.1097/XEB.0000000000000165. PMID: 31094882.
4. Simundić AM. Bias in research. Biochem Med (Zagreb). 2013; 23(1):12-5. doi: 10.11613/bm.2013.003. PMID: 23457761; PMCID: PMC3900086.