Evidence synthesis: Maternal and child health BMJ EBM: first published as 10.1136/bmjebm-2020-111432 on 25 August 2020. Downloaded from Maternal caffeine consumption and pregnancy outcomes: a narrative review with implications for advice to mothers and mothers- to- be Jack E. James 10.1136/bmjebm-2020-111432 Abstract Summary box Objectives Caffeine is a habit- forming substance consumed daily by the majority of pregnant ► Additional material is What is already known about this women. Accordingly, it is important that women published online only. To subject? view please visit the journal receive sound evidence- based advice about ► Pharmacological actions of caffeine online (http:// dx. doi. org/ potential caffeine- related harm. This narrative suggest potential threats to fetal 10.1136/ bmjebm- 2020- review examines evidence of association between development from maternal caffeine 111432). maternal caffeine consumption and negative consumption. pregnancy outcomes, and assesses whether current In recent decades, many observational health advice concerning maternal caffeine ► studies of maternal caffeine consumption is soundly based. Correspondence to: consumption have reported potential Methods Database searches using terms linking Professor Jack E. James, increased risk for diverse negative caffeine and caffeinated beverages to pregnancy Psychology, Reykjavik pregnancy outcomes. University, 101 Reykjavik, outcomes identified 1261 English language peer- ► However, current policy advice Iceland; jack@ ru. is reviewed articles. Screening yielded a total of 48 assumes that 'moderate' caffeine original observational studies and meta-analyses consumption during pregnancy is of maternal caffeine consumption published in the safe. past two decades. The articles reported results for one or more of six major categories of negative What are the new findings? pregnancy outcomes: miscarriage, stillbirth, low ► Substantial majority findings from birth weight and/or small for gestational age, observational studies and meta- preterm birth, childhood acute leukaemia, and analyses indicate that maternal childhood overweight and obesity. caffeine consumption is reliably Results Of 42 separate sets of findings reported in associated with miscarriage, stillbirth, 37 observational studies, 32 indicated significantly low birth weight and/or small for increased caffeine- related risk and 10 suggested gestational age, childhood acute http://ebm.bmj.com/ no or inconclusive associations. Caffeine- related leukaemia and childhood overweight increased risk was reported with moderate to high and obesity, but not preterm birth. levels of consistency for all pregnancy outcomes ► Overall findings are robust to threats except preterm birth. Of 11 studies reporting 17 from potential confounding and meta- analyses, there was unanimity among 14 misclassification. analyses in finding maternal caffeine consumption ► Findings frequently include significant to be associated with increased risk for the four dose–response associations on September 27, 2021 by guest. Protected copyright. outcome categories of miscarriage, stillbirth, suggestive of causation, and studies low birth weight and/or small for gestational frequently report no threshold age, and childhood acute leukaemia. The three of consumption below which remaining meta- analyses were also unanimous associations are absent. in reporting absence of a reliable association How might it impact on clinical practice between maternal caffeine consumption and in the foreseeable future? preterm birth. No meta-analyses were identified Current evidence does not support © Author(s) (or their for childhood overweight and obesity, although ► assumptions about safe levels of employer(s)) 2020. Re- use four of five original observational studies reported maternal caffeine consumption. permitted under CC significant associations linking maternal caffeine The cumulative scientific evidence BY- NC. No commercial consumption to that outcome category. ► supports advice to pregnant women re- use. See rights and Conclusions The substantial majority finding and women contemplating pregnancy permissions. Published from observational studies and meta-analyses is to avoid caffeine. by BMJ. that maternal caffeine consumption is reliably To cite: James JE. BMJ associated with major negative pregnancy Evidence- Based Medicine outcomes. Reported findings were robust to threats Epub ahead of print: from potential confounding and misclassification. causation, and frequent reports of no threshold [please include Day Month Among both observational studies and meta- of consumption below which associations were Year]. doi:10.1136/ analyses, there were frequent reports of significant absent. Consequently, current evidence does not bmjebm-2020-111432 dose–response associations suggestive of support health advice that assumes 'moderate' BMJ Evidence- Based Medicine Month 2020 | volume 0 | number 0 | 1 Evidence synthesis: Maternal and child health BMJ EBM: first published as 10.1136/bmjebm-2020-111432 on 25 August 2020. Downloaded from caffeine consumption during pregnancy is safe. On the contrary, Consequently, caffeine half-life increases from the usual adult rate the cumulative scientific evidence supports pregnant women and of about 5 hours in the first trimester to about 18 hours by the 38th women contemplating pregnancy being advised to avoid caffeine. week of pregnancy.26 27 The symptoms of nausea and vomiting that frequently accompany pregnancy-related changes in hormonal milieu and associated reduced rate of caffeine clearance help to explain the observation that women often spontaneously Introduction reduce their intake of caffeine when pregnant.24 Reduced intake There are almost no age, gender, geographical or cultural barriers means that plasma caffeine concentrations tend to be maintained to the consumption of caffeine, making it the most widely at levels comparable to the pre-pregnant state instead of reaching consumed psychoactive substance in history.1 Consumers include the appreciably higher levels that would occur if intake remained pregnant women,2 3 82% of whom have been reported to consume unchanged. 4 5 caffeine daily in the USA and 91% in France. That caffeine is Once ingested, caffeine is readily distributed throughout the commonly consumed during pregnancy has been confirmed by body, with peak plasma concentrations occurring within about reports of pharmacologically active concentrations of caffeine in 40–60 min.28 Thereafter, caffeine exerts a variety of pharmacolog- 6 7 the blood of a majority of newborn infants in France and the ical actions at diverse sites, both centrally and peripherally. These 8 UK. actions are due mostly to competitive blockade of the neuro- In 1980, the United States Food and Drug Administration (FDA) modulator adenosine, with A and A receptors appearing to be 1 2A responded to findings of caffeine- induced teratogenic effects in the primary targets.29 Effects include maintenance of transmitter rodents by issuing a warning advising pregnant women to restrict release in the CNS (anti-somnolent effect), constriction of cerebral 9 or abstain from the drug. However, current advice from relevant and coronary blood vessels, renal diuresis, respiratory bronchodi- 10 authorities, including the FDA, is generally more relaxed. For lation and gastrointestinal acid secretion.30–32 A and A recep- 1 2A example, the American College of Obstetricians and Gynecolo- tors also interact in functionally important ways with dopamine 11 gists (ACOG) advises that pregnant women may safely consume receptors,33 34 and caffeine stimulates secretion of the catechol- up to 200 mg caffeine (the approximate equivalent of two cups amine stress hormones of epinephrine and norepinephrine.35 In of moderate- strength coffee) per day, and the same advice is turn, elevated catecholamine levels have the potential to increase contained in the (currently under review) Dietary Guidelines for placental vasoconstriction and increase fetal heart rate36 leading 12 Americans (DGAC). to impaired fetal oxygenation.37 Similarly, the European Food Safety Authority (EFSA) states Furthermore, habitual caffeine consumption leads to phys- that maternal consumption of caffeine up to 200 mg per day does ical dependence, indicated by behavioural, physiological and 13 “not give rise to safety concerns for the fetus” (p. 75), and the subjective withdrawal effects (caffeine withdrawal syndrome) 14 UK National Health Service (NHS) advises pregnant women to in response to even brief abstinence.38 Sleepiness, lethargy and 'limit' daily intake to 200 mg. Notwithstanding the current broad headache are common symptoms,39 40 which may occur following consensus among health authorities, a recent study found that cessation of habitual intake of as little as 100 mg (1 cup of coffee) more than 40% of pregnant women in Finland reported consuming per day and less.41 42 With reference to standard criteria, princi- more than the widely promulgated recommended maximum of pally those of the Diagnostic and Statistical Manual of Mental 15 43 200 mg caffeine per day. This narrative review was undertaken Disorders (DSM- V), caffeine has been labelled a 'drug of http://ebm.bmj.com/ for the dual purpose of (1) assessing current evidence concerning abuse'.44 Indeed, newborn infants of caffeine- consuming mothers caffeine- related pregnancy outcomes, and (2) determining whether have been reported to experience caffeine withdrawal symptoms current health advice concerning