Maternal caffeine consumption and childhood behavioural and neurocognitive development: A focused narrative review

Rationale: The majority of pregnant women regularly consume caffeine, a habit-forming substance of no nutritional value for mother or baby. Objectives: To examine evidence of association between maternal caffeine consumption and childhood behavioural and neurocognitive development, and to consider the soundness of current health guidance concerning the consumption of caffeine during pregnancy. Methods: Database searches identifi ed a large pool of peer-reviewed articles, which when culled for relevance yielded a modest corpus of animal and human research for inclusion in this focussed narrative review of potential caffeine-related threats to childhood behavioural and neurocognitive development. Results: High biological plausibility of potential harm from maternal caffeine exposure indicated by early animal research is confi rmed by more recent animal studies that sought to mimic human consumption patterns. Reported negative outcomes include increased neuronal network excitability and susceptibility to seizures in offspring, and disruptions to electrophysiological activity, learning, and memory. In contrast, human observational studies have yielded inconsistent fi ndings. Some studies have reported evidence of negative behavioural and neurocognitive outcomes, including hyperkinetic disorder, attention defi cit disorder, and intelligence level in preschooland elementary-aged children. Other studies, however, reported no associations with maternal caffeine consumption for similar parameters. Conclusions: Current understanding of caffeine-related increased risk of harm for childhood development is limited due to inconsistent fi ndings from human research. However, persistent reports of possible negative outcomes indicate high priority need for further research. In the meantime, the cumulative scientifi c evidence supports advice to pregnant women and women contemplating pregnancy to avoid caffeine. Review Article Maternal caffeine consumption and childhood behavioural and neurocognitive development: A focused narrative review

That maternal caffeine consumption remains commonplace is attributable, at least in part, to current health advice to women. The European Food Safety Authority [10], the United Kingdom National Health Service [11], and the American College of Obstetricians and Gynecologists [12] all advise that it is "safe" for pregnant women to consume up to 200 mg caffeine (the approximate equivalent of 2 cups of moderatestrength coffee) per day. Such advice persists despite reports of signifi cant dose-response associations suggestive of causation, including reports of no threshold of consumption below which associations between maternal caffeine consumption and adverse pregnancy outcomes are absent [8].
The diversity of adverse clinical outcomes is suggestive of potential disruption to key processes of foetal and child development.
Nevertheless, developmental processes associated with potential harm have only recently begun to attract concerted research attention. Accordingly, the main aim of the present focussed review was to examine evidence of association between maternal caffeine consumption and childhood behavioural and neurocognitive development, including potential for long lasting sequelae. A review at this time may help to stimulate further research to clarify inconsistencies in reported fi ndings, elucidate potential causal mechanisms, and identify directions for future research.
Notwithstanding the need for further research, a second aim of the present review was to consider the implications of recent empirical fi ndings for current health advice concerning maternal caffeine consumption.

Caffeine pharmacology: Relevant mechanisms of action
Caffeine is readily distributed throughout the body, and achieves peak plasma concentrations within approximately 40-60 minutes [13]. The drug crosses the placenta, exposing the developing fetus to concentrations similar to systemic levels in the mother [14,15]. Metabolism is principally by cytochrome P450 enzymes (monooxygenase and xanthine oxidase) in the liver, involving processes that are undeveloped in newborns and acquired during the fi rst year of life [16,17]. Consequently, whereas adult caffeine elimination half-life is generally about 5 hours, 80 hours is typical of newborns [16].
Caffeine exerts a variety of pharmacological actions at diverse sites, both centrally and peripherally. These actions are due mostly to competitive blockade of the neuromodulator adenosine, with A 1 and A 2A receptors appearing to be the primary targets [18]. Effects include maintenance of transmitter release in the CNS (anti-somnolent effect), constriction of cerebral and coronary blood vessels, renal diuresis, respiratory bronchodilation, and gastrointestinal acid secretion [19][20][21].
A 1 and A 2A receptors also interact in functionally important ways with dopamine receptors [22,23], with caffeine serving to stimulate secretion of the catecholamine stress hormones of epinephrine and norepinephrine [24]. In turn, elevated catecholamine levels have the potential to increase placental vasoconstriction and fetal heart rate [25], leading to impaired fetal oxygenation [26].
Acknowledgment of the high theoretical plausibility of fetal harm due to maternal caffeine consumption was the main impetus for early experimental studies with rodents (mice, rats, rabbits). A range of caffeine-induced gross fetal abnormalities was reported, including cleft palate, ectrodactyly (absent or deformed digits), and skeletal malformations [27][28][29][30]. Responding to such reports, the United States Food and Drug Administration issued a warning advising pregnant women to restrict or eliminate coffee consumption [31].
The warning elicited wide discussion, including strenuous representation from caffeine-beverage industries [32].  [39], and in another study 25% of a cohort of pregnant Dutch women reported consuming more than 250 mg caffeine per day [40].
Importantly, of numerous potential adverse pregnancy outcomes, gross morphological abnormality (i.e., "frank" teratogenicity) is but one category, attention to which may have unduly infl uenced current health guidelines [1,7,9]. As mentioned above, an extensive body of scientifi c evidence from human observational studies and meta-analyses has emerged independently of early studies of caffeine-related teratogenicity [8]. containing beverages of "coffee", "tea", "cola", "energy drink", and "maté"). The search terms for the exposure period were "maternal" and "pregnancy". Other sources of caffeine, such as chocolate (including confectionaries, cake, and hot drink), cocoa, and decaffeinated coffee and tea were not included as specifi c search terms, as they generally represent a negligible fraction of total daily caffeine consumed.
Moreover, studies of caffeine beverages frequently include results for the aforementioned "other" sources (sometimes reported for purposes of comparison with the main sources), thereby contributing to the likelihood of information from low-caffeine sources, where relevant, being included as part of the present review. Additionally, it was assumed that the term "caffeine" would capture relevant studies (if any) that had examined a substantial source of caffeine other than those identifi ed by the specifi c search terms employed here. The search was further refi ned by inclusion of terms relevant to the key "development"/"developmental" outcomes of interest.

Experimental studies with rodents
Early experiments with rodents provided strong confi rmation of high biological plausibility for harm from maternal caffeine exposure, with consistent reports of disruption to behavioural and neurocognitive development [41][42][43]. For example, Grimm  [41] "low" dose of 0.15 mg/ml and possibly the "medium" dose of 0.30 mg/ ml, could be considered comparable to reputed "moderate" and "safe" levels of exposure during human pregnancy.
In that vein, the 0.45 mg/ml dose would be comparable to intake widely considered "high", but not uncommon, among pregnant women. Table 1 summarises key fi ndings from fi ve rodent studies published since 2009 that satisfi ed the aforementioned selection criteria for inclusion in the current narrative review. In contrast to the Grimm and Frieder [41] study, in which exposure was limited to the latter stages of pregnancy, Soellner, et al. [50] exposed pregnant rat dams to either plain tap water or caffeinated tap water throughout gestation. The level of caffeine exposure was estimated to be the human equivalent of 2 to 3 cups of coffee per day. Adult male and female offspring of dams exposed to caffeine during pregnancy exhibited memory and learning impairments in object recognition and spatial learning tasks. The fi ndings were interpreted as suggesting developmental changes in the expression and/or function of adenosine receptors within the hippocampus and prefrontal cortex leading to long-term alterations in memory and learning. Long-term effects were also reported by Silva et al. [48] who exposed mouse dams to 0.30 mg/ml caffeine in drinking water throughout gestation and lactation. Compared to untreated controls, adult offspring of treated animals showed increased excitability in hippocampal circuits and associated sequelae including increased susceptibility to seizures.
Fazeli, et al. [51] also reported increased seizure susceptibility in a study in which caffeine in drinking water was intended to mimic human consumption of approximately three cups of coffee per day. Compared to control offspring, formation and activity of cortical networks was found to be impaired in offspring of caffeine-exposed mouse dams. In another study that sought to mimic human consumption patterns with the use of 0.30 mg/ml caffeine in drinking water, Zappettini, et al. [52] were careful to parallel human exposure before and during pregnancy until full-term birth, taking account of both the time span of caffeine exposure and amount of caffeine consumed. Electrophysiological recordings of hippocampal CA1 pyramidal cells in vitro revealed caffeinerelated changes likely to increase the risk for early onset of dementia-associated pathology. In addition, Li et al. [49] reported that expression of adenosine A 1 and A 2A receptors was impaired in fetal and neonatal brain among offspring of rat dams exposed to 20 mg/kg caffeine (compared to saline) administered twice daily via subcutaneous injection. The same study also reported that learning and memory were impaired in adult offspring exposed to caffeine in utero.  Pregnant rat dams were exposed via drinking water to the human equivalent of 2 to 3 cups of coffee per day throughout pregnancy, and offspring were compared to the offspring of caffeine-free dams.
Compared to untreated controls, adult male and female offspring of caffeine-exposed dams exhibited impaired cognition, including 24-h memory retention in novel object recognition and spatial learning in a maze task. Findings were suggestive of developmental changes in the adenosine-receptor functioning in the hippocampus and prefrontal cortex, leading to long-term alterations in memory and learning. Silva, et al. 2013 Effects of maternal exposure to caffeine, as an adenosine modulator, on offspring neural development.
Offspring of mouse dams exposed to 0.30 mg/ml caffeine via drinking water during pregnancy and lactation were compared to offspring of caffeine-free dams.
Compared to untreated controls, caffeine-exposed offspring showed delayed migration and insertion of g-aminobutyric acid (GABA) neurons into the hippocampal circuitry during the fi rst postnatal week, and increased neuronal network excitability and susceptibility to seizures. Adult offspring displayed loss of hippocampal GABA neurons and cognitive defi cits.
Fazeli, et al. 2017 The construction and activity of cortical networks in offspring of dams exposed to effects of caffeine during pregnancy and the early postnatal period.
Caffeine was added to the drinking water of female mice to mimic daily consumption of 3 cups of coffee in humans.
Compared to controls, caffeine-exposed offspring showed impaired brain development, including altered construction of GABAergic neuronal networks in the primary visual cortex at postnatal days 6-7; increased synaptic activity in vitro and elevated network activity in vivo in the primary visual cortex; altered in vivo hippocampal network activity from the neonatal period until adulthood; and increased seizure susceptibility.
Li, et al. 2018 Effects of maternal caffeine exposure on neurocognitive functions.
Rat dams received subcutaneous injections of 20 mg/kg caffeine (compared to saline) twice daily throughout pregnancy. Fetal and offspring body and brain weight were measured, learning-and memoryrelated receptors were measured, and learning and memory were tested in adult offspring.
Compared to untreated controls, caffeine-exposed offspring showed fetal growth restriction, and longterm impairment in learning and memory; intrauterine programming dysfunction of adenosine receptors; and impairment of subunits of down-stream protein-binding systems in fetal, neonatal, and adult brain.

2019
The long-term consequences of early-life exposure to caffeine for Alzheimer's disease-like pathology.
The study employed a rodent model of Alzheimer's disease (THY-Tau22 transgenic mice). The exposure schedule involved caffeine in drinking water intended to mimic the amount and time span of the human consumption of caffeine before and throughout gestation. Caffeine-exposed offspring showed defi cits in spatial learning and memory earlier than untreated controls; and disordered electrophysiological recordings suggestive of early onset of Alzheimer's disease-like pathology.
Human observational studies Linnet, et al. 2009 Associations between maternal coffee exposure and risk of hyperkinetic disorder and attention defi cit hyperactivity disorder (ADHD).
A prospective cohort study of 24,068 Danish children, including 88 children aged 3-12 years with hyperkinetic disorder and/or ADHD.
High maternal caffeine consumption (10+ cups of coffee per day) reported at 16 weeks of gestation was associated with a threefold increased risk of hyperkinetic disorder and ADHD. After adjustment for confounders, the risk decreased to RR 2.3 (95% CI 0.9-5.9) and was no longer statistically signifi cant. Bekkhus, et al. 2010 Associations between maternal caffeine consumption and inattention/overactivity suggestive of ADHD.
A prospective cohort study of 25,343 Norwegian mothers and their 18-month-old children.
After adjustment for potential confounders, caffeine in the form of soft drinks but not coffee or tea, reported at 17 and 30 weeks of gestation, was found to be associated with inattention/overactivity. Loomans, et al. 2012 Associations between maternal caffeine consumption and offspring behavioural problems.
A prospective cohort study in The Netherlands of 3,439 children assessed at age 5-6 years for mother-and teacher-reported problem behaviour.
After adjustment for potential confounders, maternal caffeine consumption reported at 16 weeks of gestation was not associated with a higher risk for behaviour problems or with suboptimal prosocial behaviour. In summary, recent animal studies confi rm the decadeslong inference of high biological plausibility for potential harm from maternal caffeine exposure. The studies summarised in Table 1 report a wide range of caffeine-related disruption to brain function and structure, and associated developmental impairment in behaviour and cognition. Whereas there may have been a tendency to discount earlier similar fi ndings due to pregnant animals being exposed to levels of caffeine in excess of those typical of human consumption patterns, the studies summarised in Table 1 were careful to use regimens of caffeine intake intended to mimic typical human exposure. As such, recent animal fi ndings are important in raising awareness of potential negative effects for child development due to maternal caffeine consumption. In a study of 3,439 Dutch children, Loomans et al. [40] reported that maternal caffeine consumption was unrelated to mother and teacher ratings of ADHD-related behaviour among children aged 5 to 6 years. Absence of association was also reported by Klebanoff and Keim [55] [57] reported that high maternal caffeine consumption (defi ned as 8+ cups of coffee per day) assessed at 15 weeks of pregnancy was associated with increased risk for a range of behavioural and psychiatric disorders including ADHD-related behaviour.

Human observational studies
In the same study that reported no association for ADHD-related behaviour, Klebanoff and Keim [55] found no association between maternal caffeine consumption and intelligence quotient (IQ) in children aged 4 and 7 years.
Conversely, Galéra et al. [6] reported a signifi cant association between maternal caffeine consumption and lower IQ among 1,083 French children aged 5.5 years. Reasons for the discrepant fi ndings were debated in an exchange of letters without the respective groups [58,59] reaching agreement. Bernard, et al. [58] reasoned that a combination of the two sets of results Galéra, et al. 2015 Associations between maternal caffeine consumption and impaired cognitive development in offspring.
A prospective cohort study of 1,083 French mother-child pairs followed from pregnancy to when the children were aged 5.5 years.
After adjustment for potential confounders, there was a signifi cant caffeine-related association with reduced childhood IQ of nearly one full IQ point per additional 100 mg/day of maternal caffeine intake assessed before pregnancy and after delivery.

Klebanoff and Keim 2015
Associations between maternal serum paraxanthine (the primary metabolite of caffeine) and offspring IQ and problem behaviour.
A prospective cohort study in the United States of 2,197 children assessed at ages 4 and 7 years.
After adjustment for potential confounders, no statistically signifi cant associations were reported between maternal serum paraxanthine, measured at "early pregnancy" (<20 weeks) and "third trimester" (>26 weeks), and either IQ or problem behaviour.
Del-Ponte, et al. 2016 Associations between maternal consumption of caffeine during pregnancy and childhood ADHD.
A prospective cohort study of 3,485 Brazilian children assessed at age 11 years.
After adjustment for potential confounders, maternal caffeine consumption, assessed by interview after delivery, was not associated with ADHD. Mikkelsen, et al. 2017 Associations between maternal caffeine consumption and offspring behavioural and psychiatric disorders.
A prospective cohort study of 47,491 Danish mother-child pairs.
After adjustment for potential confounders, maternal caffeine consumption reported at 15 weeks gestation was reported to be associated with increased risk of a range of behavioural and psychiatric disorders. Berglundh, et al. 2021 Associations between maternal caffeine consumption and childhood neurodevelopment.
A prospective cohort study of 64,189 Norwegian children assessed at ages 6 and 18 months, and 3, 5 and 8 years.
After adjustment for potential confounders, maternal caffeine consumption reported at 22 weeks of gestation yielded no consistent associations with childhood neurodevelopment at any age. Christensen, et al. 2021 Associations between maternal caffeine consumption and childhood neurodevelopment.
A prospective cohort study in the United States of 9,157 children assessed at 9-10 years using magnetic resonance imaging (MRI).
After adjustment for potential confounders, MRI revealed caffeine-related alterations in brain microstructures associated with maternal caffeine consumption reported "throughout gestation". supported the conclusion that a causal link exists between high caffeine exposure and lower childhood IQ. In reply, Klebanoff and Keim [59] reiterated their belief "that the amount of caffeine consumed by most pregnant women . . . is not likely to be associated with reduced child cognition" (p. 873).

Citation
Unfortunately, inconsistencies in fi ndings continue to characterise the most recent research. Berglundh, et al. [60] examined the association between maternal caffeine consumption and impaired neurodevelopment, including motor development, behaviour problems, and language diffi culties, among 64,189 Norwegian children aged 6 and 18 months, and 3, 5 and 8 years, and found no consistent associations. Conversely, Christensen, et al. [61] in the United States, examined maternal caffeine consumption and regional brain microstructure among 9,157 children aged 9 to 10 years.
Maternal exposure to caffeine was measured dichotomously to create an exposed group of women who reported consuming caffeine more than once a week throughout pregnancy and a group comprised of women who reported consuming caffeine less than once a week. Magnetic resonance imaging (MRI) indicated microstructure alterations of "critical fi bre tracts" among children of the exposed group of mothers compared with children of control mothers,  Table 1, all adjusted for cigarette smoking, and all but one [61] adjusted for alcohol consumption.

Limitations and inconsistencies among human observational studies
Recall bias in relation to amount of caffeine consumed during pregnancy has long been offered as a possible source of confounding, especially by commentators with caffeineindustry affi liations [62][63][64][65][66]. However, as with many recent studies concerning clinical outcomes associated with maternal caffeine consumption [8], all of the observational studies summarised in

Public-health advice
Even in the absence of other information, the status of caffeine as a common habit-forming substance of no nutritional value to either mother or baby is a clear indicator of the need to adopt a cautionary approach when framing public-health advice about consuming the drug during pregnancy. In respect of potential harm to childhood behavioural and neurocognitive development, fi ndings from animal studies add substantial additional grounds for concern. On the other hand, the relative paucity of human observational studies, and especially the many contradictory results among the few that have been conducted, preclude defi nitive conclusions. However, whereas contradictory fi ndings may incline some commentators to be dismissive, precisely the opposite inclination is warranted.
The core empirical fact concerning potential caffeine-related developmental harm is that some studies have reported null results whereas others have not. Therefore, unless and until maternal caffeine consumption is consistently shown to be without risk to childhood development, persistent intermittent empirical fi ndings of harm should fi gure prominently in health advice for mothers and mothers-to-be.  [68]. Instead of continuing to condone the consumption of reputedly "safe" amounts of caffeine during pregnancy, the new Guidelines state that women "who could be or who are pregnant should consult their healthcare providers for advice concerning caffeine consumption" (p. 118).
We may guess that this revised advice is an attempt at compromise, refl ecting growing awareness of the many and increasing reports of harm associated with maternal caffeine consumption. However, the revised DGAC [68] guidance is disappointing at least, and even shocking in its prevarication. said that is has no opinion. In so doing, the DGAC has opted to transfer responsibility for advice about maternal caffeine consumption to an amorphous and countless number of individual "healthcare providers", the large majority of whom may be assumed to possess neither the required expertise nor any clear means for mustering an informed opinion.

Future research
Whereas current knowledge is limited concerning caffeinerelated risks to childhood behavioural and neurocognitive development, there are many facts about maternal caffeine consumption that are far from uncertain. As discussed above, there is high biological plausibility for potential harm; there is consistent evidence from animal research of harm to behavioural and neurocognitive development among offspring (summarised in Table 1); and extensive evidence from human observational research and meta-analyses of harm for diverse clinical pregnancy outcomes [8]. The inconsistent fi ndings described herein (and summarised in Table 1) from human observational studies of childhood behavioural and neurocognitive development serve, at the very least, to indicate the high-priority need for more and better-controlled studies in this area.
For the present, it is not possible to be hig hly prescriptive as to what constitutes better-controlled studies in this relatively undeveloped fi eld. Animal experimentation offers the substantial advantage of permitting controlled manipulations of caffeine exposure and should be pursued so as inform researchers about potentially important human sites of caffeine-related harm (e.g., impaired development of critical brain structures). Alas, comparable levels of experimental control, such as may be achieved in ran domised controlled trials, although theoretically possible, are unlikely to be conducted in practice due to the questionable ethicality of conducting such trials with pregnant women [8,69].
Consequently, advances in the fi eld are likely to depend on continued epidemiological investigation. Here, much benefi t would accrue were gre ater standardisation achieved in relation to the use of reliable and validated measurement protocols for assessing caffeine exposure, such as has been in use for some time in the Norwegian Mother and Child Cohort Study [70,71]. Similarly, continued attention to the control of potential confounders is strongly advised, including where possible the use of biological indicators of exposure, not only for caffeine, but also for nicotine and alcohol.

Conclusion
There are strong grounds for eschewing the complacency that may be said to characterise much current public-health advice about maternal caffeine consumption. Taken as a whole, the cumulative scientifi c evidence supports advice to pregnant women and women contemplating pregnancy to avoid caffeine.