108 e-Letters

  • Caffeine and pregnancy: Advice to women. Reply to Castanyer

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

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

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

    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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  • Correcting the record: all studies of smokers with COVID-19 show a protective effect

    Usman et al (1) write that only one of the 18 studies of COVID-19 patients they included in their review of the Smoker's Paradox reported that "the prevalence of smokers resembles that of the general population."

    But this study--by Richardson et al in New York City (2)--actually only reported the prevalence of "never smokers" at 84.4%. It did not distinguish between current and former smokers among the remaining 15.6%, however, so Usman et al should have marked this combined result with an asterisk in their Table 1. Far from resembling the general population, the 15.6% combined rate is less than half the 34% expected in USA, where approximately 14% are current and 20% former smokers. With this correction, all 18 studies support the Smoker’s Paradox, which belies the authors’ conclusion that a “protective effect should NOT be inferred” [emphasis added].

    The protective effect is clearly real and further supported by the largest study of COVID-19 to date (n=7,162) with data on smoking status (3), which Usman et al did not include in their review. Current smokers in this CDC study comprised just 1.3% of all the COVID-19 patients seeking care from US hospitals in 50 states and Washington DC, 1.2% of those treated as outpatients, and 1.1% of those treated in intensive care units.

    Usman et al also did not mention the compound most likely responsible for the protective effects of smoking against respiratory infections, which...

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  • SARS-CoV-2 mimicry of an epithelial sodium ion channel (ENaC) linked to increased risk of severe COVID-19 symptoms in cigarette smokers

    Dear Editor,
    Recent literature suggested increased risk of severe COVID-19 in smokers which also got affirmation from World Health Organization (WHO) [1, 2]. However, original peer reviewed research which explained pathophysiological basis of the enhanced COVID-19 severity in smokers is currently scarce. Increased expression of SARS-CoV-2 cell entry receptor ACE2 in respiratory tract and lung tissue of smokers unraveled from analysis of gene expression data was used to predict higher chances of SARS-CoV-2 infection but that failed to explain enhanced COVID-19 severity [3]. Few authors have suggested that increased risk of severe complications and higher mortality rate in infected smokers may be due to host-specific factors like weakening of respiratory health and immunity caused by chronic smoking [4]. However, none of the virus-related factors which can be responsible for the COVID-19 severity in smokers has been reported until date. Based on the recent research updates on SARS-CoV-2 specific virulence in host cells, we propose a plausible mechanism which associates smoking with increased severity of COVID-19.
    Apart from a cell surface entry receptor, coronaviruses require furin (a host protease) mediated cleavage of their spike (S) protein for successful invasion of the host cell. SARS-CoV-2, a member of the genus betacoronaviruses, has evolved a unique furin protease S1/S2 cleavage site, which is absent in other family members, including SARS-CoV-1 [5]. Rec...

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  • Letter to the editor in response to “Analysis of reports of unintended pregnancies associated with the combined use of non-enzyme-inducing antibiotics and hormonal contraceptives”

    First available online on August 18, 2020 in BMJ Evidence-Based Medicine, Aronson and Ferner (1) concluded that women using hormonal contraceptives cannot rely on their contraceptive method if they take a short course of non-enzyme inducing antibiotics based on Yellow Card reports to the UK’s Medicines and Healthcare products Regulatory Agency.
    We believe that there are fundamental scientific issues and limitations with this study not adequately addressed by the authors. First, Yellow Card reports require provider reporting of an unintended pregnancy, which the authors acknowledge are subject to reporting bias. As the authors also acknowledge, many healthcare providers suspect there are drug-drug interactions between hormonal contraception and all antibiotics, despite the lack of definitive evidence (1). Therefore, there already exists a bias among providers that they would suspect and report an unintended pregnancy attributed to a drug-drug interaction among women taking antibiotics. The medications in each group are also not equivalent and bias the sample. For example, in the antibiotic group, metronidazole and nitrofurantoin are more commonly used in younger reproductive-aged and sexually active women (2,3), the population at highest risk of unintended pregnancies (4). In comparison, the control group includes such medications as propranolol and theophylline, which are used for treatment of cardiac and respiratory conditions more common among older women (5,6), wi...

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

    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.

  • Bias in reporting

    ‘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...

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  • Insufficiently Robust Methodology and risk of bias

    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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