Maternal Consumption of Artificially Sweetened Beverages and Infant Weight Gain: Causal or Casual?

Inadultsandchildren,artificial sweeteners,alsoknownasnonnutritive sweeteners,may increase the riskofobesity andmetabolicdisorders.Much researchonnonnutritive sweetenershas focused on artificially sweetened beverages (ASBs) for several reasons: their consumption has increased over the last 30 years, they are the largest single contributor to overall intake of nonnutritive sweeteners,1,2 and they are a counterpart to the oft-implicated sugar-sweetened beverages (SSBs). Sweet taste is usually accompanied by energy intake, but this link is uncoupled by ASBs. Rodent3-6 and small acute human7,8 experiments suggest thatwhen oral or gut receptors are exposed to artificial sweeteners, hormonal signals between thegut and thebrainmaystimulate appetite and lead to weight gain. Investigators have also raised the possibility that artificial sweeteners may alter the gut microbiome in ways that are linked to cardiometabolic risk.6 Some epidemiologic studies9,10 have shown that thehigher the consumption of ASBs, the higher the subsequent risk of developing obesity and type 2 diabetes, yet the evidence is far from conclusive. Results of observational studies conflict with each other, and to our knowledge, no intervention trials in humans have found an obesogenic effect of consuming ASBs.11 Oneof themethodologic issues is the choice of a comparisongroup.PeoplegenerallydrinkASBsasa substitute forSSBs, not in addition to them. Therefore, whether a person drinks 1 beverage instead of another is an equally, if not more salient, question than whether a person simply drinks more of a particular beverage. Intervention trials address the real-world question of whether drinking ASBs instead of SSBs influencesweight-relatedoutcomes. Toour knowledge, trials published to date11-13 suggest a favorable, albeit modest, effect of ASBs onobesity prevention; theydonot indicateweight gain. In observational studies, it is also possible to analyze the effect of substituting 1 beverage for another. However, of 11 cohort studies11 addressing the association of ASBswith the risk of obesity in children and adults, none examined the substitution of ASBs for SSBs. Thus, addressing different questions—addition vs substitution of beverages—is an explanation for the apparent paradox of ASB intake being associated with higher risk for obesity in cohort studies but conferring lower risk in intervention trials. Another is confounding. Intake ofASBsmaybe associated with obesogenic risk factors including unhealthful lifestyle habits, which may themselves be the culprits in observedassociationswithweight gainordysmetabolism.10,11 On this background, we find the results reported by Azad et al14 in this issue of JAMAPediatrics to be intriguing. Studyingmore than 3000womenenrolled in theCanadianHealthy InfantLongitudinal Study, they found thatmothers’ daily consumption (vs no consumption) ofASBsduringpregnancywas associated with doubled odds of their infants being overweight after 1 year. This study,14 coupledwith 2 Scandinavian cohort studies15,16 suggesting a link between ASB intake and pretermbirth, raises questions about the advisability of pregnant women choosing to consume ASBs, for example, if they are trying to moderate gestational weight gain. However, we view the findings of Azad et al14 as preliminary. They did not address the question of substituting ASBs for SSBs, which themselves—perhaps surprisingly—were not associatedwith theoutcomes.Maternal intakeofASBswasassociatedwith prepregnancy bodymass index and gestational diabetes; adjusting for these and other confounders attenuatedobserved effects by about 40% (bodymass index z score: adjustedβ,0.22;95%CI,0.02-0.41; vsunadjustedβ,0.37;95% CI, 0.18-0.57). Substantial attenuation by observed covariates raises the possibility of residual confounding from inaccuratemeasurementaswell asunmeasuredconfounding from prenatalorpostnatal factorsassociatedwithbothmaternalASB intake and infant weight status. Mechanistically, the sweet-but-no-caloriesmechanism is unlikely toapplybecause the infant isnot thebeveragedrinker. Anymicrobiome-relatedmechanism is speculative, andother mechanisms,whichwould need to account for howmaternal consumption of ASBs is transduced into an obesogenic tendency in the fetus, are not apparent. Moreover, mechanisms mightdependonthechemical structureof thesweetener;Azad et al14 do not identify the sweeteners that their participants consumed. Despite these caveats, the findings of Azad et al14warrant attention and further research. Experimental studies in animals andsmall intervention trials amongpregnantwomencan exploremechanisms.Observational cohort studies should incorporate substitutionaswell as additionmodels andpayclose attention to confounding. Randomized clinical trials substitutingASBs for SSBsor, equallyvaluable,water forASBswould be particularly helpful. Pregnant women should drink more fluid than nonpregnant women to support higher circulating blood volume and Related article page 662 Opinion