Maternal Caffeine Consumption and Racial Disparities in Fetal Telomere Length

1. Introduction

Telomeres are DNA-based regions that cap the end of chromosomes to prevent degradation of essential genes involved in cell replication. Telomeres progressively shorten, and cells become susceptible to degradation as the shortening occurs, which is the result of low telomerase levels (an enzyme that elongates chromosomes by adding TTAGGG sequences).1 As telomere length can strongly predict chromosomal aging and long-term health outcomes, researchers have aimed to explore the association between dietary factors and telomere length. Caffeine, a stimulant found in foods (tea, coffee, soft drinks, chocolate, and over-the-counter medications), is believed to influence telomere length at a cellular level. Evident in laboratory studies conducted with yeast, caffeine appears to act through the phosphoinositide 3-kinase-related protein kinases Tel1 and MEc1, which are known regulators of telomere length.2 Several studies provide contradictory findings regarding the influence of caffeine on telomere length. In a study by Liu et al. among 4,780 female nurses who reported coffee consumption, the investigators found that telomere length increased with elevated levels of caffeine consumption.3 However, in a separate study by Tucker et al., researchers found that for each 100 mg of caffeine consumed, telomeres were 35.4 base pairs shorter.4 This same study found that coffee consumption within this population was positively associated with longer telomere length.4 These inconsistent findings indicate the need to continue examining the association while taking into account additional confounding factors as well as population subgroups, such as pregnant women, where caffeine consumption may be detrimental to the development of a healthy fetus.5

A major gap in knowledge is the impact of caffeine consumption within a pregnant population. During pregnancy, caffeine clearance from the mother’s blood slows down significantly. A study by Wierzejeska et al. found that caffeine consumed by a pregnant woman passes through the placenta to the fetus freely.6 In another study by Torstein et al., researchers found that high caffeine intake in the third trimester may be a risk factor for fetal growth restriction, in particular, if the fetus is a boy.7 Current recommendations from the World Health Organization (WHO) advise pregnant women to limit total caffeine consumption to less than 300 mg per day.8 The American Congress of Obstetricians and Gynecologists (ACOG) reported that moderate caffeine consumption of less than 200 mg per day during pregnancy does not appear to be a risk factor for miscarriage or preterm births.9 Caffeine restrictions during pregnancy are based on several studies that have shown poor fetal outcomes, such as low birth weight babies and spontaneous abortions resulting from high caffeine intake prenatally.8-11 The identification of risk factors for shorter telomere length, especially during fetal development, would provide important information essential for making caffeine consumption recommendations on a global scale. In addition to the unknown influence of caffeine consumption on fetal telomere length, several studies have found that certain factors are associated with shorter telomere lengths. Previous research found that maternal-perceived stress during pregnancy was associated with shorter telomere length.1 However, there is paucity of data on the differential effects of caffeine consumption by race/ethnicity.

2. Materials and Methods

A prospective cohort study was conducted by the University of South Florida (USF) Morsani College of Medicine from July 2011 to September 2012. The study enrolled pregnant women in labor at Tampa General Hospital (TGH) in Tampa, Florida, USA. TGH admits patients for delivery who are socioeconomically disadvantaged, racially/ethnically diverse, and primarily uninsured or insured with Medicaid. Inclusion criteria for study participants required being over the age of 18, with a primary language of English or Spanish, and delivering full-term single live birth with no congenital malformations. A food history questionnaire (FHQ) was provided to the study participants, which was completed before hospital discharge. Informed consent was obtained, and the study was approved by the institutional review boards at USF and TGH.1

3. Results

Fifty-seven (59.4%) of 96 maternal-fetal dyads with their corresponding fetal T/S ratios were included in this analysis, and pairs with T/S ratios greater than three or negative were excluded. The mean maternal age was 25.5 years (SD=5.19, range 18 – 39). Among the mothers, 35.7% were White; 30.4% were Black; 25.0% were Hispanic, and 8.9% were Other. About 80.7% of the study population was covered by private health insurance, and 19.3% were on Medicaid or uninsured. Regarding marital status, 71.9% of the women were single, and 28.1% were married. About 71.9% of the mothers reported two or fewer previous pregnancies. The mean blood caffeine level (mg) was 117.3 (range 0 – 940.9). Among the mothers, 77.2% had a caffeine level of less than 200 mg, consistent with ACOG recommendations, and 89.5% had a blood caffeine level of less than 300 mg, consistent with WHO recommendations. The mean gestational age of the newborns at delivery was 39.5 weeks (standard deviation = 1.31, range 37 – 42). All newborns were delivered during the third trimester. The mean newborn birthweight was 3381.4 grams (range 2101 – 4510) (Table 1).

Three GLMs were run to fit the data in R using three different cut-off points for caffeine (sample mean, WHO recommendation, and ACOG recommendation) and T/S ratios. The first GLM using mean caffeine consumption (Figure 1) did not find a statistically significant association between the mean T/S ratio and mean maternal caffeine level. However, both GLM models that included ACOG and WHO recommendations cut-off points for caffeine found that caffeine was statistically associated with longer telomere lengths (p<0.05) (Figure 2). Older maternal age (p<0.001) was significantly associated with shorter telomere length, whereas sodium intake (p<0.05)”white” race (p<0.001) and “other” race (p<0.001) were associated with longer telomere length (Figure 2).

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Figure 1

Regression Coefficients of Caffeine Effect on Telomere Length Stratified by Cutoff Point for Caffeine (Sample Mean, WHO Recommendation, and ACOG Recommendation)

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Figure 2

Regression Coefficients of Other Variable Effects on Telomere Length Stratified by Cutoff Point for Caffeine (Sample Mean, WHO Recommendation, and ACOG Recommendation)

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4. Discussion

This study suggests that high maternal caffeine intake and other factors including race, may be associated with increased fetal telomere length, whereas advanced maternal age may be associated with shortened fetal telomere lengths. The finding that caffeine food history questionnaire dietary levels were positively associated with telomere length suggests that caffeine consumption during pregnancies may have long term implications from a chromosomal perspective. It is unclear why certain races/ethnicities were associated with longer telomere length. However, there may be certain health disparities within certain racial populations that may predispose infants to premature chromosomal aging. Drury et al. found significant differences in telomere length between African American infants who weighed significantly less than white infants at birth, yet had significantly longer telomere length than White infants (p=0.01), with the strongest association observed in Black female infants.18 In addition, research has also found that high caffeine intake during the third trimester of pregnancy may be a risk for fetal growth retardation, in particular, if the fetus is male.7 However, the gender of the fetus was not provided in our study, and as such we were unable to examine the role of fetal gender on telomere length.

We found that maternal age may be associated with shorter telomeres. This is consistent with the literature, which has reported that maternal age is weakly associated with telomere terminal restriction fragment (TRF) length in white blood cells in newborns.19 In addition, Prescott et al. found that paternal age, which was not available for this study, may be associated with fetal telomere length.20 However, both paternal and maternal ages may be confounded by one another as a mother may be more likely to choose a partner close to her age.

Based on the results of this study, if the sample population were to be increased to include babies with congenital defects and those who were excluded for complications, we might have detected a stronger association between caffeine and telomere length. The association between sodium and telomere length, in addition to caffeine, suggests the need for future studies to examine the role of diet during the third trimester of pregnancy on fetal telomere length.

5. Conclusion and Global Health Implications

This study identifies the need for further research to examine the association between fetal telomere length and caffeine consumption during pregnancy (i.e., fetal and maternal caffeine serum levels). Higher caffeine intake and certain racial categories may have a protective effect on fetal telomere length, suggesting that caffeine consumption during pregnancy may have long-term implications for fetal development. This study reinforced the literature in that maternal age was shown to have a significant association with shortened fetal telomere length. The racial/ethnic differences in telomere length found in this study warrant the conduct of larger studies to further delineate these associations.

The relationship between caffeine consumption and telomere length promises to be an avenue for exploring the impact of coffee consumption on pregnancy outcomes. Apart from water and tea, coffee is the third most consumed drink in the world.21 The findings in this study are, therefore, of global importance because it provides additional information that could inform future recommendations of prenatal caffeine consumption at the global level.