Impacts of Caffeine during Pregnancy

Abstract

Epidemiological studies have revealed that caffeine consumption during pregnancy is associated with adverse gestational outcomes, yet the underlying mechanisms remain obscure. Recent animal studies with physiologically relevant dosages have begun to dissect adverse effects of caffeine during pregnancy with respect to oviduct contractility, embryo development, uterine receptivity, and placentation that jointly contribute to pregnancy complications. Interestingly, caffeine's effects are highly variable between individual animals under well-controlled experimental settings, suggesting the possibility of epigenetic regulation of these phenotypes, in addition to genetic variants. Moreover, caffeine exposure during sensitive windows of pregnancy may induce epigenetic changes in the developing fetus or even the germ cells to cause adult-onset diseases in subsequent generations. We discuss these research frontiers in light of emerging data.

Keywords: caffeine; embryo development; embryo implantation; epigenetic inheritance; epigenetic variation; oviductal transport.

Figure 1.. Maternal Caffeine Intake Compromises Pregnancy and Birth Outcomes.

(A) In humans, caffeine intake during pregnancy may give rise to pregnancy complications, such as miscarriage [4,17], fetal growth restriction [5,12], and low birth weight [–24], which would also increase the risk of overweight and impaired cognitive development in childhood [–27]. (B) Potential mechanisms for the effects of caffeine as revealed by a rodent model. Current studies show that maternal caffeine exposure not only severely disrupts embryo implantation but also disrupts ongoing midterm fetal growth and development, resulting in pregnancy loss, low birth weight, and impaired brain development in offspring on postnatal day 6 (P6) [–38,55]. Abbreviations: GABA, γ-aminobutyric acid; IUGR, intrauterine growth retardation.

Figure 2.. Interindividual Variability in Caffeine Response.

Postulated models underpinning the highly variable individual response to caffeine exposure. (A) Women showed different responses to caffeine exposure during pregnancy [5,8,9,45,46]. (B) The effects of caffeine might be regulated by multiple factors in vivo, including the ability to metabolize caffeine (determined by the rate-limiting enzyme CYP1A2) and cellular targets (mainly through ADORA1/A2A), or regulated through modulators associated with pregnancy and fetal development, all of which modify the outcome of pregnancy for individual women after caffeine exposure. Abbreviations: ADORA1, adenosine A1 receptor; ADORA2A, adenosine A2A receptor; CYP1A2, cytochrome P450 1A2.

Figure 3.. In Utero Caffeine Exposure Triggers Adult-Onset Diseases and Transmits Adverse Effects into Subsequent Generations.

Caffeine can freely cross the blood–placenta barrier and thus exposes the fetus. Exposure to caffeine during pregnancy can induce long-term health disorders in subsequent generations [11,55,59]. Compromised maternal caffeine metabolism, disrupted placenta development, and an abnormal uterine environment may affect fetal development as well as the offspring’s health (F1), which may also influence the primordial germ cells (PGCs) of the developing fetus and transfer diseases, such as cardiomyopathy, to the F2 descendants. Abbreviations: IUGR, intrauterine growth retardation; HPA axis, hypothalamic-pituitary-adrenal axis.

Figure I.

Genetic Variation and Epigenetic Factors may Contribute to CYP1A2-Mediated Interindividual Variability in Caffeine Response.