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• Caffeine and pregnancy: The need for calm reflection. Reply to Murphy et al.
  JACK JAMES
  Published on: 21 May 2021
• Caffeine and pregnancy: Advice to women. Reply to Castanyer
  JACK JAMES
  Published on: 21 May 2021
• Caffeine and pregnancy: Don’t shoot the messenger, please. Reply to Fernando
  JACK JAMES
  Published on: 21 May 2021
• Caffeine and Pregnancy: Bias? Is this a case of the pot calling the kettle black? Reply to O'Connor
  JACK JAMES
  Published on: 21 May 2021
• It remains unclear whether caffeine causes adverse pregnancy outcomes; but naive policy recommendations could cause harm.
  Clare Murphy, Tracey Brown, Heather Trickey, Julia Sanders, Rebecca Blaylock, Caitlin Dean, Marita Hennessy, Laura Schellas, Fiona Woollard, Gemma Sharp, Luisa Zuccolo, Marcus Munafò, Kathleen Cairns, Maria Booker, Peter Tennant, Jane Fisher, Ellie Lee, Erin Williams, Elizabeth Duff, Irene Petersen and Amber Marshall
  Published on: 21 May 2021
• Is this evidence enough to change our medical advice to coffee-consumer pregnant mothers?
  Maria Josep Gibert Castanyer
  Published on: 21 May 2021
• Bias in reporting
  Shavi Fernando
  Published on: 21 May 2021
• Insufficiently Robust Methodology and risk of bias
  Raymond F O'Connor
  Published on: 21 May 2021

• Published on: 21 May 2021

  Caffeine and pregnancy: The need for calm reflection. Reply to Murphy et al.

  • JACK JAMES, University Professor Reykjavík University

  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 conf...

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  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.

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  Conflict of Interest:
  None declared.

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• Published on: 21 May 2021

  Caffeine and pregnancy: Advice to women. Reply to Castanyer

  • JACK JAMES, University Professor Reykjavík University

  Dr Castanyer1 wonders about the soundness of the advice she gives her patients about the reputed safety of moderate caffeine consumption during pregnancy. Her concerns regarding current clinical practice warrant consideration. I agree that “aging or prior medical history may act as confounders of negative pregnancy outcomes”. As reported in the review,2 numerous potential confounders have been examined (and often re-examined many times), including “diverse demographic variables, behaviour patterns, and living environment . . . age at conception, health status, pregnancy history, use of oral contraceptives, alcohol and other substance use, exposure to pollutants, maternal body mass, physical activity, religion, education, and occupation . . . pregnancy symptoms . . . potential recall bias and maternal cigarette smoking” (p. 5).2 However, as also reported in the review, caffeine-related negative pregnancy outcomes have repeatedly proven “robust to threats from potential confounding”.

  In addition, Dr Castanyer suggests that any “change of medical recommendation” should await the outcome of randomised clinical trials. Again, that option is examined in the review, which includes a section headed, “Are Randomized Controlled Trials the Solution?” (pp. 5-6).2 However, as reported in the review, beyond the single trial conducted to date,3 it is doubtful whether mooted clinical trials will proceed due to ethical concerns over exposing pregnant women to caffeine, even at reput...

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  Dr Castanyer1 wonders about the soundness of the advice she gives her patients about the reputed safety of moderate caffeine consumption during pregnancy. Her concerns regarding current clinical practice warrant consideration. I agree that “aging or prior medical history may act as confounders of negative pregnancy outcomes”. As reported in the review,2 numerous potential confounders have been examined (and often re-examined many times), including “diverse demographic variables, behaviour patterns, and living environment . . . age at conception, health status, pregnancy history, use of oral contraceptives, alcohol and other substance use, exposure to pollutants, maternal body mass, physical activity, religion, education, and occupation . . . pregnancy symptoms . . . potential recall bias and maternal cigarette smoking” (p. 5).2 However, as also reported in the review, caffeine-related negative pregnancy outcomes have repeatedly proven “robust to threats from potential confounding”.

  In addition, Dr Castanyer suggests that any “change of medical recommendation” should await the outcome of randomised clinical trials. Again, that option is examined in the review, which includes a section headed, “Are Randomized Controlled Trials the Solution?” (pp. 5-6).2 However, as reported in the review, beyond the single trial conducted to date,3 it is doubtful whether mooted clinical trials will proceed due to ethical concerns over exposing pregnant women to caffeine, even at reputedly “safe” levels.4 As the review explains, such concerns are ironic if not contradictory. Health authorities worldwide have promulgated the view that “moderate” caffeine consumption during pregnancy is safe. Were that view correct, there should be no ethical concerns. Nevertheless, though feasible, large-scale clinical trials to assess the consequences of maternal caffeine consumption appear unlikely. Accordingly, the principal evidence upon which we must rely is likely to continue to be that provided by observational studies, systematic review, meta-analysis, and (as with my review) narrative synthesis.

  References
  1. Castanyer MJG. Is this evidence enough to change our medical advice to coffee-consumer pregnant mothers? 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. Bech BH, Obel C, Henriksen TB, et al. Effect of reducing caffeine intake on birth weight and length of gestation: randomised controlled trial. BMJ 2007;334:409.
  4. Jahanfar S, Jaafar SH. Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcomes. Cochrane Database Syst Rev 2015:CD006965.

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  Conflict of Interest:
  None declared.

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• Published on: 21 May 2021

  Caffeine and pregnancy: Don’t shoot the messenger, please. Reply to Fernando

  • JACK JAMES, University Professor Reykjavík University

  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 contr...

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  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.

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  Conflict of Interest:
  None declared.

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• Published on: 21 May 2021

  Caffeine and Pregnancy: Bias? Is this a case of the pot calling the kettle black? Reply to O'Connor

  • JACK JAMES, University Professor Reykjavík University

  Dr O’Connor1 is concerned that I have published previous reviews, and in so doing may be biased. Indeed, I have published previous reviews, and my familiarity with the relevant literature has led me increasingly to question current relaxed attitudes towards caffeine consumption during pregnancy. The first review, published in 1985,2 reported that evidence available at that time tentatively supported the conclusion that caffeine may contribute to foetal growth restriction and low birth weight. That review highlighted methodological shortcomings in the then extant literature, and called for more research employing improved methods for measuring caffeine exposure and better controls against potential confounders.

  An updated review, in 1991,3 found that more and improved research had been published since the earlier review, and that the overall evidence of caffeine-related negative pregnancy outcomes had strengthened. With a subsequent update in 1997,4 it was concluded that the evidence against maternal caffeine consumption had become strong. The latest review5 reported that the balance of evidence, including findings from original observational studies and meta-analyses, supported the conclusion that consumption of caffeine during pregnancy increases the risk of several serious negative pregnancy outcomes. Perversely, Dr O’Connor appears to believe that familiarity with research implies bias. In fact, my conclusions evolved over time, and the direction of that evolutio...

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  Dr O’Connor1 is concerned that I have published previous reviews, and in so doing may be biased. Indeed, I have published previous reviews, and my familiarity with the relevant literature has led me increasingly to question current relaxed attitudes towards caffeine consumption during pregnancy. The first review, published in 1985,2 reported that evidence available at that time tentatively supported the conclusion that caffeine may contribute to foetal growth restriction and low birth weight. That review highlighted methodological shortcomings in the then extant literature, and called for more research employing improved methods for measuring caffeine exposure and better controls against potential confounders.

  An updated review, in 1991,3 found that more and improved research had been published since the earlier review, and that the overall evidence of caffeine-related negative pregnancy outcomes had strengthened. With a subsequent update in 1997,4 it was concluded that the evidence against maternal caffeine consumption had become strong. The latest review5 reported that the balance of evidence, including findings from original observational studies and meta-analyses, supported the conclusion that consumption of caffeine during pregnancy increases the risk of several serious negative pregnancy outcomes. Perversely, Dr O’Connor appears to believe that familiarity with research implies bias. In fact, my conclusions evolved over time, and the direction of that evolution was dictated by accumulating evidence of harm. Thus, the overall trajectory of my conclusions reflects the normal progression of scientific knowledge.

  While claiming that the review lacks features characteristic of systematic review and meta-analysis, claims repeated by Fernando6 and Murphy et al.,7 O’Connor fails (as do those other authors) to acknowledge the continuing legitimacy of the “traditional” or narrative review. In particular, he fails to acknowledge that the literature examined in my review is substantially comprised of prior systematic reviews and meta-analyses. It is important to choose a review format that reflects the current state of knowledge. As such, my latest review is a response to current need for previous literature to be synthesised conceptually, which I judged could be best achieved by way of narrative review. Unfortunately, Dr O’Connor appears not to appreciate that in common with review practice in general, narrative review seeks to provide a comprehensive, critical, and objective analysis of current knowledge. It is wrong to assume that systematic review (so-called) and meta-analysis are necessarily superior to narrative review at all times and under all circumstances.

  References
  1. O’Connor RF. Insufficiently robust methodology and risk of bias. Evid Based Med 2020. Available: https://ebm.bmj.com/content/early/2020/09/01/bmjebm-2020-111432.responses.
  2. James JE, Paull I. Caffeine and human reproduction. Rev Environ Health 1985;5:151–67.
  3. James JE. Caffeine and health. London: Academic Press, 1991.
  4. James JE. Understanding caffeine: a biobehavioral analysis. Thousand Oaks, CA: Sage Publications, 1997.
  5. 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.
  6. James JE. Caffeine and pregnancy: Don’t shoot the messenger, please. Reply to Fernando. Evid Based Med 2020;25.
  7. James JE. Caffeine and pregnancy: The need for calm reflection. Reply to Murphy et al. Evid Based Med 2020;25.

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  Conflict of Interest:
  None declared.

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• Published on: 21 May 2021

  It remains unclear whether caffeine causes adverse pregnancy outcomes; but naive policy recommendations could cause harm.

  • Clare Murphy, Director of External Affairs and Principal Investigator British Pregnancy Advisory Service and The WRISK Project
  • Other Contributors:
    • Tracey Brown, Director
    • Heather Trickey, Research Fellow
    • Julia Sanders, Professor of Clinical Nursing and Midwifery
    • Rebecca Blaylock, Research and Engagement Lead
    • Caitlin Dean, Chairperson
    • Marita Hennessy, Postdoctoral Researcher
    • Laura Schellas, Doctoral Researcher
    • Fiona Woollard, Professor in Philosophy
    • Gemma Sharp, Senior Lecturer in Epidemiology
    • Luisa Zuccolo, Senior Lecturer in Epidemiology
    • Marcus Munafò, Professor of Biological Psychology
    • Kathleen Cairns, General Practitioner
    • Maria Booker, Programmes Director
    • Peter Tennant, University Academic Fellow in Health Data Science
    • Jane Fisher, Director
    • Ellie Lee, Director and Professor
    • Erin Williams, Senior Lecturer in Reproductive Anatomy and Physiology
    • Elizabeth Duff, Senior Policy Adviser
    • Irene Petersen, Professor of Epidemiology and Health Informatics
    • Amber Marshall, Founder

  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 an...

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  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

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  Conflict of Interest:
  None declared.

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• Published on: 21 May 2021

  Is this evidence enough to change our medical advice to coffee-consumer pregnant mothers?

  • Maria Josep Gibert Castanyer, Gynaecologist Public and private practice

  In my daily practice that is limited, I've been allowing my patients to drink two cups of coffee a day, although they tend to be restrictive when applying my advice. Most of them are healthy women in their 30s. Whenever they've had a bad result, it has been attributed to other causes. When reading your impeccable research work, I've missed some comment on the clinical relevance of certain outcomes as a minor change in birth weight; moreover, aging or prior medical history may act as confounders of negative pregnancy outcomes. I appreciate your effort very much, but I consider the change of medical recommendations requires a more in-depth assessment, by means of one or more randomized clinical trials. Let's bear in mind than in my home country, Spain, temperatures in summer may be unbearable if you are an active working mother-to-be. And, definitely, our medical role is to give evidence-based solutions and avoid changing our pieces of advice every couple of years.

  Conflict of Interest:
  None declared.

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• Published on: 21 May 2021

  Bias in reporting

  • Shavi Fernando, Obstetrician and Gynaecologist, Senior Lecturer, PhD The Ritchie Centre, Monash University, Department of Obstetrics and Gynaecology, Melbourne Australia

  ‘There is no safe level of caffeine intake in pregnancy’. That is the conclusion of this ‘narrative review’ of caffeine safety in pregnancy (BMJ Evidence Based Medicine, Open Access) which a patient brought to my attention very recently after hearing about it on the mainstream media. I felt that it requires clarification to avoid concern amongst the general public and those unable to analyse and critically appraise the literature.

  The single author concluded that, after finding 48 studies (37 observational studies and 11 meta-analyses), caffeine intake in pregnancy significantly increases the risk of miscarriage, stillbirth, low birth weight, childhood leukaemia and childhood overweight/obesity. The author then goes on to recommend that all worldwide guidelines (including American, UK and Australian) stating the safety of caffeine in doses<200mg/day (approximately 2 cups of coffee) should be revised to say ‘there is no safe level of caffeine in pregnancy’.

  However, there is no need to panic, which appears to be the response of the mainstream media and patients from the general population. Very soon after publication, this paper was picked up by several news outlets including CNN, The Guardian and also on a number of social media streams. Women were being told not to drink coffee in pregnancy the same way they were being told not to drink alochol.

  This paper is far from as conclusive as it tries to make the reader believe, but serves as a good exampl...

  Show More

  ‘There is no safe level of caffeine intake in pregnancy’. That is the conclusion of this ‘narrative review’ of caffeine safety in pregnancy (BMJ Evidence Based Medicine, Open Access) which a patient brought to my attention very recently after hearing about it on the mainstream media. I felt that it requires clarification to avoid concern amongst the general public and those unable to analyse and critically appraise the literature.

  The single author concluded that, after finding 48 studies (37 observational studies and 11 meta-analyses), caffeine intake in pregnancy significantly increases the risk of miscarriage, stillbirth, low birth weight, childhood leukaemia and childhood overweight/obesity. The author then goes on to recommend that all worldwide guidelines (including American, UK and Australian) stating the safety of caffeine in doses<200mg/day (approximately 2 cups of coffee) should be revised to say ‘there is no safe level of caffeine in pregnancy’.

  However, there is no need to panic, which appears to be the response of the mainstream media and patients from the general population. Very soon after publication, this paper was picked up by several news outlets including CNN, The Guardian and also on a number of social media streams. Women were being told not to drink coffee in pregnancy the same way they were being told not to drink alochol.

  This paper is far from as conclusive as it tries to make the reader believe, but serves as a good example of how language can be used to persuade when evidence does not.

  This ‘study’ is not a properly conducted systematic review or metanalysis and to publish it as an ''evidence synthesis'' is dangerous, as it implies a level of rigor which is not demonstrated. Literature from only PubMed and Google Scholar were searched. The search was not systematically or transparently documented and there was no reference to the PRISMA guidelines. This is important as it means that a significant number of studies will have been missed in the search, introducing significant reporting bias (studies with results showing caffeine is safe in pregnancy may not have been included).

  The paper looks at both observational studies and meta-analyses and it is not clear whether non-independence has been accounted for – that is, some of the individual studies may have been included in the reported metanalyses. This would result in duplication of the data and an overestimation of the effect size. Because the review was not systematic, there is no detailed analysis of confounding factors (ie. Women who drank alcohol or smoked as well as drank coffee during their pregnancy which could also effect the outcomes). The variation between the studies have not been reported or investigated (therefore, cannot be compared or summed). This ‘heterogeneity’ has not been identified or reported. There is no consideration of publication bias (when only studies with positive results tend to get published), and even more importantly, no analysis of bias in each individual study (which is mandatory for any meta-analysis).

  The author appears to try to make conclusions based on the ‘number of studies that found an effect’ instead of the ‘number of participants that were effected’. It also doesn't account for the quality or lack of quality of each study. Even if a lot of studies find an effect, if they are not well designed then the effect may not exist.

  This paper seems to be written without any balance, making one concerned about the agenda of the author. The author states that the safety of caffeine may be supported by caffeine corporations (coffee and soft drink manufacturers). Indeed, a quick ‘Google’ search of the author’s name shows that he has written two books about the dangers of caffeine. While this does not mean that this report can be discounted, it does give some insight into the motives of the author.

  Interestingly, one randomised controlled trial which found no effect of caffeine in pregnancy is briefly mentioned in the discussion of the study, but quickly ‘discredited’.

  In short, this ''narrative review'' has probably gained far more media attention than was initially intended, however, the overarching and far-reaching consequences of this are significant when the evidence behind its recommendations is non-systematic and biased. Publication of such work should be discouraged, as the impact on the general population cannot be underestimated.

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  Conflict of Interest:
  None declared.

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• Published on: 21 May 2021

  Insufficiently Robust Methodology and risk of bias

  • Raymond F O'Connor, General Practitioner; Senior Research Fellow University of Limerick Medical School

  Editor,
  I welcome this publication with it's focus on a potentially important cause of adverse pregnancy outcomes.
  This study has several methodological faults that need to be declared and addressed.
  The study's single author has written extensively on this topic over the last 29 years. He cites several of his own publications in the paper, As far as I can judge, they are all critical of caffeine in pregnancy. Surely this puts him at risk of bias.
  The best way to address such bias is to conduct a systematic review with precise methodology. Also, at least one other author should be involved in assessing suitability of the papers, and minimising bias.
  Only English language papers are studied.
  Only PubMed and Google Scholar are searched. No reference is made to other important databases such as CDSR, Medline, EMBASE and CINAHL.. There does not appear to have been any pre-specified eligibility criteria in assessing whether or not studies should be included in the review e.g. community based populations or pre defined study methods.
  There is no attempt made to assess the quality of the studies used in writing the paper.
  The search strategy appears vague.
  The results in table 1 give odds ratio but there is no quantification of this. What we need is absolute risk with numbers needed to harm. If this figure cannot be calculated then we should be told and given the reasons why.

  These limitations need to be ackno...

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  Editor,
  I welcome this publication with it's focus on a potentially important cause of adverse pregnancy outcomes.
  This study has several methodological faults that need to be declared and addressed.
  The study's single author has written extensively on this topic over the last 29 years. He cites several of his own publications in the paper, As far as I can judge, they are all critical of caffeine in pregnancy. Surely this puts him at risk of bias.
  The best way to address such bias is to conduct a systematic review with precise methodology. Also, at least one other author should be involved in assessing suitability of the papers, and minimising bias.
  Only English language papers are studied.
  Only PubMed and Google Scholar are searched. No reference is made to other important databases such as CDSR, Medline, EMBASE and CINAHL.. There does not appear to have been any pre-specified eligibility criteria in assessing whether or not studies should be included in the review e.g. community based populations or pre defined study methods.
  There is no attempt made to assess the quality of the studies used in writing the paper.
  The search strategy appears vague.
  The results in table 1 give odds ratio but there is no quantification of this. What we need is absolute risk with numbers needed to harm. If this figure cannot be calculated then we should be told and given the reasons why.

  These limitations need to be acknowledged. For such an important topic potentially affecting so many vulnerable women, a more precise review and assessment of current evidence is warranted.

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  Conflict of Interest:
  None declared.

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