American Journal of Epidemiology Vol. 155, No. 1 : 32-37
Copyright © 2002 by The Johns Hopkins University School of Hygiene and Public Health
ORIGINAL CONTRIBUTIONS |
Maternal Serum Caffeine Metabolites and Small-for-Gestational Age Birth
Division of Epidemiology, Statistics and Prevention Research, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
Center for Human Toxicology, University of Utah, Salt Lake City, UT.
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ABSTRACT |
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To determine whether the third-trimester maternal serum concentration of paraxanthine, caffeine's primary metabolite, is associated with delivery of a small-for-gestational age infant (birth weight less than the 10th percentile for gestational age, gender, and ethnicity) and whether this association differs by smoking, the authors studied 2,515 women who participated in the Collaborative Perinatal Project from 1959 to 1966. The women provided a third-trimester serum sample and had been controls for a nested case-control study of spontaneous abortion. The mean serum paraxanthine concentration was greater in women who gave birth to small-for-gestational age infants (754 ng/ml) than to appropriately grown infants (653 ng/ml, p = 0.02). However, the linear trend for increasing serum paraxanthine concentration to be associated with increasing risk of small-for-gestational age birth was confined to women who also smoked (p = 0.03). There was no association between paraxanthine and fetal growth in nonsmokers (p = 0.48). Adjustment for maternal age, prepregnant weight, education, parity, ethnicity, and the number of cigarettes smoked per day did not alter the results substantially, although the p value for trend among smokers increased to 0.07. The authors conclude that maternal third-trimester serum paraxanthine concentration, which reflects caffeine consumption, was associated with a higher risk of reduced fetal growth, particularly among women who smoked.
caffeine; fetus; infant; newborn; pregnancy outcome
Abbreviations: CI, confidence interval; OR, odds ratio; SGA, small for gestational age
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The literature on the association between maternal caffeine consumption during pregnancy and infant size at birth is large, but inconsistent. In particular, caffeine consumption has been associated with low birth weight (1
–5), reduced gestational age-adjusted birth weight (1, 6), and intrauterine growth restriction (2, 4, 7). Other studies have not found caffeine consumption to increase the risk of these outcomes, especially after adjustment for confounders such as maternal smoking, alcohol consumption, and age (8–12). Most investigators have not observed an increased risk of shortened gestation among women who consumed caffeine.(1, 2, 7, 10, 13). An interaction of caffeine and cigarette use on fetal growth has been reported in three studies, in which the growth-restricting effect of maternal caffeine use was greater among or was restricted to the infants of women who also smoked during pregnancy (7, 14, 15).
The reasons for these inconsistent results may include prospective versus retrospective assessment of caffeine consumption, timing of assessment of intake and changes during pregnancy, size of the study (particularly the number of women who consumed large amounts of caffeine), and difficulties of assessing caffeine intake by questionnaire. Factors to be considered in the assessment of caffeine intake include sources (coffee, tea, soft drinks, chocolate, and medication), method of preparation, and cup or portion size (16). However, even with direct measurement of caffeine intake, wide interindividual differences in caffeine metabolism produced a correlation between measured intake and 24-hour integrated serum caffeine concentration of only 0.41 (16). The authors are aware of only one study of caffeine and fetal growth that utilized a biomarker of caffeine intake, third-trimester serum caffeine concentration. No association was observed between this concentration and fetal growth (15). However, the serum concentration of caffeine exhibits wide, short-term fluctuation during the day, depending on very recent intake (16). In contrast, the serum concentration of paraxanthine, caffeine's primary metabolite in humans, fluctuates less throughout the day (16) and, therefore, may be a better marker of caffeine intake than the concentration of caffeine. This report describes the results of an analysis of the association between the serum concentration of paraxanthine and the delivery of a small-for-gestational age (SGA) infant.
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MATERIALS AND METHODS |
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Subjects were selected from among women who enrolled in the Collaborative Perinatal Project when they registered for prenatal care at 12 sites across the United States from 1959 to 1966 (17
). The women were followed for the remainder of the pregnancy according to a standard protocol that included collection of serum at registration, at approximate 2-month intervals during pregnancy, and at delivery. No information about caffeine intake was collected. The subjects of this report had originally been chosen as controls for a nested case-control study of serum caffeine metabolites and spontaneous abortion (18). As such, they had given birth to a liveborn infant of at least 28 weeks' gestation, had registered for prenatal care at less than 20 weeks' gestation, and had been from the same clinical site and had had serum drawn on the same day of gestation as a woman who had experienced a spontaneous abortion.
The primary hypothesis of this analysis was that the mean concentration of paraxanthine, caffeine's primary metabolite, in the first serum specimen drawn after 182 days' (26 weeks') gestation would be elevated in women who gave birth to an SGA infant compared with those who gave birth to an infant not SGA. Early third-trimester serum was chosen because this is the time of rapid fetal growth in weight. Because the growth-restricting effect of maternal caffeine consumption has been noted in several previous publications (7, 14, 15) to be greater in women who also smoked, the interaction was evaluated between serum paraxanthine and smoking as reported by the woman at the prenatal visit closest in time to the date when the serum was obtained.
SGA was defined as a birth weight less than the tenth percentile for maternal ethnicity and infant gender. The ethnicity-specific standards of Cunningham et al. (19) and Williams et al. (20) were used for women who were Black, White, or Asian. However, the Hispanic women on whom these standards were based were predominantly of Mexican descent, while the Hispanic women in the Collaborative Perinatal Project were primarily of Puerto Rican descent. Therefore, SGA status for the infants of Puerto Rican women was determined from standards based on mainland United States births to women of Puerto Rican descent as recorded in United States birth certificate files from 1990–1994 (Dr. John Kiely, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Maryland, personal communication, 1997).
A detailed description of the assay methods has been published previously (21). Serum was assayed during 1997–1999 for caffeine, paraxanthine, theophylline, and theobromine by using high-performance liquid chromatography. The limit of quantitation was established at 50 ng/ml for caffeine and paraxanthine; the limit of detection was 25 ng/ml. The intra- and interassay coefficients of variation were less than 6.9 percent at 200, 800, and 2,000 ng/ml. The laboratory was masked to the pregnancy outcome; serum from women who gave birth to SGA infants was distributed equally throughout the assay batches, and the order of the samples within each batch was determined by a computerized random number generator.
Continuous variables were compared by using the Student t test or analysis of variance, categorical variables were compared by using the chi-square test, and ordered categorical variables were evaluated for linear trend and departure from linearity with the Cochran test for trend. The standard deviation of serum paraxanthine was proportional to the mean, violating the assumptions of the t test and analysis of variance. Although log-transformation of paraxanthine solved this problem, the results using log-transformed data were not substantially different from the untransformed results, so only untransformed results are presented. Adjusted odds ratios were derived from multiple logistic regression. Factors entered into the model were those generally accepted as being associated with reduced fetal growth.
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RESULTS |
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There were 2,816 pregnancies resulting in liveborn infants selected as controls for the study of spontaneous abortion; 2,659 of these women had serum drawn at 26 or more weeks' gestation. SGA status could not be determined for 15 children due to a gestational age of more than 44 completed weeks or to missing birth weight, gender, or maternal ethnicity. In addition, there was insufficient volume of serum for assay or the sample could not be located for 96 subjects, and there were 33 twin pregnancies, leaving 2,515 pregnancies for analysis.
Among the 2,515 studied pregnancies, 222 (8.8 percent) children were SGA, and 2,293 were not SGA. The associations between various maternal characteristics and the delivery of an SGA infant are presented in table 1. SGA infants were more commonly born to women who smoked; women with fewer years of education; those with first births; and those who were younger, shorter, and lighter. The occurrence of SGA did not differ significantly among women of different ethnicities or among the 12 study centers (p = 0.34, data not shown).
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Factors associated with serum paraxanthine concentration are shown in table 2. Serum paraxanthine concentrations were higher in women who were older, those of higher parity, and those who smoked and were lower in African-American women. Serum paraxanthine was negatively, but weakly, correlated with maternal prepregnant weight among women who gave birth to infants who were not SGA (r = -0.066, p = 0.002), but not among women who gave birth to infants who were SGA (r = -0.018, p = 0.80).
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The mean serum paraxanthine concentration was significantly higher among women who gave birth to SGA infants compared with those who gave birth to infants that were not SGA (754 vs. 653 ng/ml, p = 0.02). For the remainder of the analyses, serum paraxanthine was categorized by using the same values as previously published to maintain consistency with the previous report (18
). When categorized this way, there was a statistically significant linear trend (p = 0.02) for increasing paraxanthine category to be associated with an increased risk of SGA; the departure from linearity was not statistically significant (p = 0.56). However, this trend was confined to smokers (p = 0.03); there was no significant association between serum paraxanthine and SGA among women who did not smoke (p = 0.48). The interaction between serum paraxanthine category as a continuous variable and smoking as a dichotomous variable was of borderline statistical significance (p = 0.05). The percent of SGA infants according to maternal serum paraxanthine and smoking status is shown in figure 1. Among women who were not current smokers, the trend for increasing serum paraxanthine was not significant regardless of whether women had never smoked (p = 0.63, n = 991) or had smoked in the past (p = 0.49, n = 471).
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Neither African-American (adjusted odds ratio (OR) = 0.96, 95 percent confidence interval (CI): 0.67, 1.37) nor other non-White (adjusted OR = 0.68, 95 percent CI: 0.35, 1.30) ethnicity was associated with giving birth to an SGA infant. Maternal prepregnant weight (adjusted OR = 0.98 per pound increase, 95 percent CI: 0.98, 0.99), age (adjusted OR = 0.97 per year increase, 95 percent CI: 0.94, 0.99), and education (adjusted OR = 0.93 per year increase, 95 percent CI: 0.88, 0.98) were associated with this outcome. The adjusted ORs were 0.68 (95 percent CI: 0.46, 0.99) for second-born children, 0.74 (95 percent CI: 0.47, 1.15) for third-born children, and 1.53 for fourth and later-born children (95 percent CI: 0.99, 2.42) compared with firstborn children.
The odds ratios were stratified by maternal smoking status and adjusted for maternal age, ethnicity, parity, education, and prepregnant weight. There was no clear linear trend for increasing serum paraxanthine concentration to be associated with SGA births among nonsmokers (p for trend = 0.77). However, among all smokers, there was a significant (p = 0.03) linear trend of increasing risk for SGA with increasing serum paraxanthine concentration. The Pearson correlation between serum paraxanthine and the number of cigarettes smoked per day was 0.31 (p < 0.0001), and the crude odds ratio for giving birth to an SGA infant among smokers was 1.02 per cigarette smoked per day (p = 0.01). When the actual number of cigarettes per day was included in the model for women who smoked, the p value for trend of increasing risk of SGA with increasing paraxanthine increased to 0.065. The results of the analyses stratified by smoking and adjusted for maternal age, ethnicity, parity, education, maternal prepregnancy weight, and (for smokers) number of cigarettes smoked per day are presented in figure 2. When the above analysis was repeated utilizing serum caffeine instead of paraxanthine, no association with reduced fetal growth was observed (data not shown).
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There was a statistically significant linear trend for the mean gestation at delivery to be prolonged as the third-trimester serum paraxanthine concentration increased (p = 0.002, data not shown). Similarly, the linear trend for a reduction in preterm (<37 completed weeks' gestation) birth with increasing category of paraxanthine was significant (p = 0.01). However, as is noted in table 2, African-American women on average had lower serum paraxanthine concentrations than did other women; they also had shorter gestations (data not shown). When the mean gestation at delivery and the fraction of births that was preterm were adjusted for maternal ethnicity by analysis of covariance and logistic regression, respectively, these trends were virtually eliminated (p = 0.94 and 0.99, respectively). Analyses stratified by maternal ethnicity confirmed these results. Therefore, serum paraxanthine was not associated with duration of pregnancy after maternal ethnicity was controlled. Furthermore, in contrast to the results of the fetal growth analysis, there was no evidence of an interaction between serum paraxanthine and smoking on the occurrence of preterm birth (p = 0.36 for interaction between smoking and the paraxanthine categories entered as a continuous variable in a logistic regression model that included terms for maternal ethnicity).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This study found that increasing third-trimester serum paraxanthine concentration was associated with an increasing risk of giving birth to an SGA infant, in agreement with several previous studies that found reported maternal caffeine intake to be associated with the delivery of an SGA or a low birth weight infant (1
–7). Based on the time during pregnancy when cigarette smoking has maximal effect on fetal growth (22), the a priori hypothesis of this analysis was that third-trimester serum paraxanthine would be maximally associated with fetal growth. However, if caffeine acted by a different mechanism than tobacco, the third trimester might not be the optimal time to assay this compound. The mechanism by which caffeine might influence fetal growth is not known. However, when caffeine has been administered therapeutically to treat apnea in preterm infants, oxygen consumption and energy expenditure were noted to increase and growth rate to slow (23), providing biologic plausibility for a fetal growth-restricting effect of third-trimester caffeine.
The increased risk of serum paraxanthine was confined to women who smoke, and adjustment for the actual number of cigarettes smoked per day did not change the results substantially. The marginally statistically significant interaction between paraxanthine and smoking is also in agreement with several previous studies of reported caffeine intake (7, 14, 15). However, the number of cigarettes per day was determined by questionnaire in this study. Although, in this cohort, women were generally honest in reporting their smoking habit, the trend for increasing risk of SGA with increasing paraxanthine concentration might have been further blunted had maternal serum cotinine been assayed (24).
The Collaborative Perinatal Project collected no information on maternal caffeine intake, and it is therefore not possible to relate these results to an amount of caffeine consumption. Nonsmokers metabolize caffeine less rapidly than do smokers (25), and it has been reported previously that at a given amount of caffeine intake, the serum paraxanthine concentration is higher among nonsmokers than among smokers (21). This suggests that nonsmokers also metabolize paraxanthine less rapidly than do smokers. Therefore, when smokers and nonsmokers are compared, serum paraxanthine may be a better measure of biologic dose than is reported intake, but the interaction with smoking may have differed had caffeine exposure been determined by reported intake instead of serum paraxanthine.
In confirmation of previous studies of reported maternal caffeine consumption, our study noted that serum paraxanthine was not associated with gestational age at delivery after controlling for maternal ethnicity (1, 2, 7, 10, 13). Only one previous study utilized a biomarker for caffeine consumption, the maternal serum caffeine concentration (15). That study found that while reported caffeine intake was associated with a reduction in fetal growth, particularly among smokers, the serum caffeine concentration was not. However, serum caffeine fluctuates rapidly throughout the day, depending on very recent intake; serum paraxanthine is more stable (16).
Reported caffeine intake has been noted previously to be associated with a greater reduction in fetal growth among smokers than among nonsmokers (7, 14, 15). An additional study reported a similar interaction between caffeine and tobacco on the occurrence of preterm birth (26). Most other previous studies do not note whether a synergistic effect between caffeine and smoking was evaluated (1, 3, 5, 12). Only three studies (2, 4, 10) evaluated this interaction and found it not to be significant. In addition, one study noted that caffeine was not associated with fetal growth in nonsmokers but included too few smokers to evaluate the association in these women (8), and another noted that although caffeine was associated with reduced fetal growth in both smokers and nonsmokers, the association was of greater magnitude in nonsmokers (6). Neither of these two studies specifically tested for an interaction. The mechanism for a caffeine-tobacco interaction is unclear. Caffeine has been reported to decrease intervillous blood flow (27); one mechanism by which smoking is believed to reduce fetal growth is by increasing maternal carboxyhemoglobin, thereby inhibiting the oxygen-carrying capacity of hemoglobin (28). Perhaps these mechanisms operate synergistically in vivo.
This study has several strengths. Per capita coffee consumption peaked in the United States in 1962 and has since declined, particularly among persons under age 40 years (29). Therefore, this study is likely to have included relatively larger numbers of women with high serum paraxanthine concentrations than would be observed in more recent cohorts of pregnant women. The highest paraxanthine concentration observed among women who attended prenatal care in Birmingham, Alabama, during the 1980s was 1,165 ng/ml (24), which would correspond approximately to the 80–90 percentile in our study. In addition, nearly half of the study women in this study reported smoking in the third trimester. Roughly equal numbers of smokers and nonsmokers increase the power to demonstrate an interaction between caffeine use and smoking.
A weakness of this study is that although the half-lives of both caffeine and paraxanthine are prolonged in the third trimester (approximately 10 hours) compared with the nonpregnant state (2–5 hours) (30) and although the serum concentration of paraxanthine is relatively stable throughout the day, paraxanthine is a marker of short-term caffeine intake. Day-to-day variation of caffeine intake by people will reduce the statistical power of this study. However, although the authors are unaware of any data to confirm this, it is generally believed that, as with tobacco, caffeine intake is relatively constant from day to day. This would strengthen the utility of paraxanthine as a biomarker for caffeine intake. The characteristics found to be associated with lower serum paraxanthine concentrations (African-American race, young age, low parity, greater weight, and nonsmoking) have been reported previously to be associated with lower caffeine intake during pregnancy (1, 2, 7, 10). This suggests that paraxanthine was an appropriate marker for caffeine intake and that the compound was stable during extended storage.
In conclusion, increasing serum paraxanthine concentration during the third trimester was found to be associated with increasing risk of fetal growth restriction, but only among women who smoked. This suggests that use of caffeine is unlikely to affect fetal growth in the vast majority of women who do not smoke during pregnancy.
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ACKNOWLEDGMENTS |
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Supported by contract NO1-HD-7-3262 from the National Institutes of Health.
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NOTES |
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Reprint requests to Dr. Mark A. Klebanoff, Division of Epidemiology, Statistics and Prevention Research, National Institute of Child Health and Human Development, National Institutes of Health, 6100 Building, Room 7B05, Bethesda, MD 20892–7510 (e-mail mk90h{at}nih.gov).
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