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ORIGINAL RESEARCH |
From the International Epidemiology Institute, Rockville, Maryland; Department of Medicine, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; Department of Medical Laboratory Science and Technology, Division of Clinical Pharmacology, and Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden; and Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Address reprint requests to: Lisa B. Signorello, ScD, International Epidemiology Institute, 1455 Research Boulevard, Suite 550, Rockville, MD 20850; E-mail: lisa{at}iei.ws.
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ABSTRACT |
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METHODS: We studied 101 women with normal karyotype spontaneous abortions and 953 pregnant women at 6–12 gestational weeks. Participants reported on caffeine intake and provided urine for phenotyping cytochrome P4501A2 (CYP1A2) activity and blood for genotyping N-acetylation (NAT2) status. We calculated odds ratios (OR) and 95% confidence intervals (CI) to evaluate the association between each of the two metabolic indices and spontaneous abortion risk and also the potential interaction between caffeine intake and metabolic activity on such risk. In calculating the associations between the metabolic indices and risk of spontaneous abortion, we had 80% power to detect an OR of 2.1, with a Type I error of 0.05.
RESULTS: Slow acetylators had a nonsignificantly increased risk for spontaneous abortion (OR 1.36, 95% CI 0.84, 2.21) and recurrent spontaneous abortion (OR 2.51, 95% CI 0.81, 7.76). In contrast, low CYP1A2 activity was associated with a significantly decreased risk for spontaneous abortion (OR 0.35, 95% CI 0.20, 0.63). Caffeine was a risk factor for spontaneous abortion among women with high, but not low, CYP1A2 activity (OR 2.42, 95% CI 1.01, 5.80 for 100–299 mg/day; OR 3.17, 95% CI 1.22, 8.22 for 300 mg/day or more, among women with high CYP1A2 activity).
CONCLUSION: The findings indicate that high CYP1A2 activity may increase the risk of spontaneous abortion, independently or by modifying the effect of caffeine. The results regarding NAT2 are less conclusive but suggest that slow acetylators may be at elevated risk of spontaneous abortion.
Spontaneous abortions occur as a result of chromosomal abnormalities in the fetus that are incompatible with survival (abnormal karyotype abortions), or when the viability of a chromosomally normal fetus cannot be sustained (normal karyotype abortions). An unknown proportion of the latter type may be preventable, as certain environmental exposures, including caffeine, may contribute to their risk.1 The measure of maternal exposure to caffeine is assumed to depend not only on the amount consumed, but also on the speed with which caffeine is metabolized and cleared from the body. Caffeine clearance rates vary widely among women and are also altered during pregnancy,2,3 and this variability could be a factor in determining susceptibility to the effects of caffeine on reproductive outcomes such as spontaneous abortion. Caffeine is primarily metabolized by the enzyme cytochrome P4501A2 (CYP1A2),4 but other enzymes, such as N-acetyltransferase 2 (NAT2), also participate in the further metabolism of caffeine.5 CYP1A2 is involved in the metabolism of numerous drugs4,6 and is an activator of procarcinogens.7 NAT2 is responsible for the acetylation polymorphism that determines whether individuals are slow or fast acetylators of a number of drugs and xenobiotics.8
Although numerous epidemiologic studies have been conducted to examine the effect of caffeine intake on spontaneous abortion risk,1,9 only one has been able to simultaneously account for metabolic activity,10 but this study could not distinguish between normal and abnormal karyotype fetuses. We recently reported the results from a large case-control study in Sweden, where we found that high caffeine intake (500 mg/day or more) was associated with a two-fold risk of normal karyotype spontaneous abortion in the first trimester of pregnancy.9 Biologic samples collected in that study have subsequently been used to estimate the activity levels of CYP1A2 and NAT2. We measured caffeine metabolites in the urine to arrive at an index of CYP1A2 activity (CYP1A2 phenotype) and also identified allelic variants of the NAT2 gene (NAT2 genotype). Both served as surrogate markers of caffeine clearance capacity. Our aim was to investigate whether these metabolic indices were themselves risk factors for normal karyotype spontaneous abortion and also whether they modified the effect of caffeine on abortion risk. Our a priori hypothesis was that slow metabolizers of caffeine (by either the CYP1A2 or NAT2 pathway) have a higher risk of spontaneous abortion and/or exhibit a stronger association between caffeine and spontaneous abortion.
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MATERIALS AND METHODS |
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Controls were randomly selected from pregnant women who were between 6–12 completed gestational weeks and were seeking prenatal care in Uppsala county. Of the 1037 women asked to participate as controls, 953 (92%) agreed to do so. Women in the control group were frequency matched to the 562 women in the case group by gestational week and area of residence (there are five municipalities in the county). All subjects in the control group underwent vaginal ultrasonography to verify the viability of the fetus.
Specially trained midwives conducted in-person interviews using a structured questionnaire, and 90% of the cases were interviewed within 2 weeks after their spontaneous abortion diagnosis. All cases were interviewed within 7 weeks, whereas all subjects in the control group were interviewed within 6 days after enrolling in the study.
Subjects were asked to report specific sources of caffeine intake on a week-by-week basis, starting 4 weeks before their last menstrual period and ending in the last completed gestational week before they were identified. Caffeine sources included coffee (brewed, boiled, instant, and decaffeinated), tea (loose tea, tea bags, and herbal), cocoa, chocolate, soft drinks, and caffeine-containing medications. For coffee, tea, and cocoa, respondents were offered five frequency categories (none, one to two cups/day, three to four cups/day, five to six cups/day, and seven or more cups/day) and for coffee and tea, they were offered four cup sizes (1 dL, 1.5 dL, 2 dL, and 3 dL) from which to choose. Weekly soft drink intake was estimated by the women in cL.
Women also reported nausea on a week-by-week basis, assigning values for each week (0 = never; 1 = sometimes, but not daily; 2 = daily, but not all day; 3 = daily, all day), which were then averaged to arrive at a mean pregnancy nausea score.
Subjects were asked to provide both blood and urine samples, which were collected from the case group at the time of spontaneous abortion diagnosis and from the control group at the time of the interview. Approximately 10–12 mL of urine were collected in a tube containing 500-µL 1M HCl and then frozen at -20C until analysis. Urine samples were analyzed by a high performance liquid chromatography method as previously described.12 In brief, 100 µL of acidified urine were extracted with 5 mL of ethyl acetate/isopropanol (92:8 v/v), and 4 mL were evaporated under nitrogen stream before high-performance liquid chromatography. We used ultraviolet detection at 280 nm, gradient flow of acetate buffer:methanol (91:9 
70:30), and increased flow rate (1 mL/minute 2.5 mL/minute). Concentrations of the following four caffeine metabolites were measured: 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methyluric acid (1U), 1-methylxanthine (1X), and 1,7-dimethyluric acid (1,7U) (see Figure 1
for a depiction of the biotransformations involved in producing these metabolites).
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To determine smoking status, we measured plasma cotinine by gas chromatography using N-ethylnorcotinine as an internal standard.16 We defined smokers as women who had a plasma cotinine concentration above 15 ng/mL,17 but allowed self-reported daily smoking during all weeks of pregnancy to override missing plasma cotinine values.
Caffeine intake was estimated using the following conversion factors: 150 mL of coffee: brewed 115 mg, boiled 90 mg, and instant 60 mg; 150 mL of loose tea or tea bag: 39 mg (herbal tea 0 mg); 150 mL of soft (cola) drinks: 15 mg; 150 mL of cocoa: 4 mg; 1 g of chocolate bar: 0.3 mg; and a few drugs included 50–100 mg of caffeine per tablet.18 Total pregnancy caffeine intake was calculated as the sum of weekly caffeine intake from the time of estimated conception (ie, 2 weeks after the last menstrual period) through the last completed gestational week before enrollment. Mean daily caffeine intake during pregnancy was calculated as: (total pregnancy caffeine intake [mg])/(number of completed gestational weeks x 7 [days]). Coffee accounted for 79%, tea for 19%, and other sources for 2% of caffeine exposure in this study population.
The CYP1A2 phenotype was determined by using the concentrations of the four measured urinary metabolites of caffeine in the following equation: (AFMU + 1U + 1X)/(1,7U).19 This equation yielded a continuous numeric variable that was highly skewed to the right and was normalized by a log10 transformation. A log normal distribution for this and other CYP1A2 indices has been demonstrated in several studies.10,20,21 Low CYP1A2 activity was defined as having a log-transformed CYP1A2 index below the median value among the controls (0.73), and high CYP1A2 activity as being above the median.
Two sample t tests were used to compare the means of continuous variables, and Pearson 
2 tests were used to assess the statistical significance of associations between categorical variables. Unconditional logistic regression models were constructed to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between metabolic indices and spontaneous abortion risk and between caffeine and spontaneous abortion risk, while adjusting for potential confounders. In calculating the associations between the metabolic indices and the risk of spontaneous abortion, we had 80% power to detect an OR of 2.1, with a Type I error of 0.05. Some subanalyses focused on recurrent (two or more) spontaneous abortions as the outcome, and these analyses were restricted to women in the case group with at least one previous spontaneous abortion and to women in the control group who had no history of spontaneous abortion. Individual informed consent was obtained from all women, and the study was approved by the Ethics Committee of the Medical Faculty at Uppsala University.
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RESULTS |
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).
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We assessed the association between caffeine intake and metabolic activity using the control group (Table 2). CYP1A2 activity was inversely related to caffeine intake. Women with low CYP1A2 activity tended to have higher caffeine intake (300 mg/day or more), and women with high CYP1A2 activity tended to have lower caffeine intake (0–99 mg/day). This trend was evident among both smokers and nonsmokers (data not shown). Caffeine intake did not appear to be related to the NAT2 genotype.
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We calculated the association between each metabolic index and spontaneous abortion risk, adjusting for maternal age, gestational week, smoking, caffeine intake, and nausea score (Table 3). Alcohol intake was also tested as a potential confounding factor, but including it in the statistical models underlying Table 3 and Table 4 had no effect on the results (data not shown). Women with low CYP1A2 activity had a significant 65% reduction in risk (OR 0.35, 95% CI 0.20, 0.63). This association was attenuated (OR 0.78, 95% CI 0.27, 2.29) when we changed the outcome of interest to recurrent spontaneous abortion (data not shown). In contrast, women who were slow acetylators had a nonsignificantly increased risk of spontaneous abortion (OR 1.36, 95% CI 0.84, 2.21) (Table 3). A positive association between slow acetylation and recurrent spontaneous abortion was also observed, but again was not statistically significant (OR 2.51, 95% CI 0.81, 7.76) (data not shown).
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). A dose-related effect of caffeine intake on spontaneous abortion risk was evident among women with CYP1A2 activity above the median, but not below. Caffeine intake over 300 mg/day was associated with a three-fold increase in spontaneous abortion risk among women with high CYP1A2 activity (OR 3.17, 95% CI 1.22, 8.22), but with a nonsignificant deficit in risk among women with low CYP1A2 activity (OR 0.46, 95% CI 0.12, 1.73). Caffeine intake was positively associated with spontaneous abortion among both slow and fast acetylators. A significant effect of caffeine at the level of 100–299 mg/day was found for slow acetylators (OR 2.38, 95% CI 1.04, 5.49), but higher exposure (300 mg/day or more) was associated with a lower and nonsignificant OR (OR 1.65, 95% CI 0.67, 4.06). Small numbers prevented us from performing the analyses shown in Table 4 for the outcome of recurrent spontaneous abortion. |
DISCUSSION |
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Only one previous study has evaluated the effect of CYP1A2 activity on the risk of spontaneous abortion.10 In a case-control study based on 73 cases and 141 controls, Fenster et al10 found that CYP1A2 phenotype was related neither to abortion risk nor to recurrent abortion risk, and that there was no interaction between CYP1A2 phenotype and caffeine with respect to spontaneous abortion. However, phenotyping in that study was performed after pregnancy, and thus may not have accurately reflected enzyme activity during pregnancy.
No polymorphisms of functional significance for the CYP1A2 gene have been identified,3 and thus our present study and Fenster et al’s earlier study10 relied on phenotype data to characterize CYP1A2 activity. Phenotype data can impart information that may not be obtainable from genotype data, because environmental factors can have a large effect on metabolic activity. Regardless of the environmental factors contributing to the CYP1A2 activity level, the measured enzyme activity should nevertheless reflect the capacity for caffeine clearance and hence the ultimate caffeine load on the body. The speed of caffeine metabolism will also determine exposure to caffeine metabolites. We had hypothesized that any increase in risk of spontaneous abortion would be more likely among those with low CYP1A2 activity. However, our findings suggest instead that a metabolite(s) of caffeine may play a role in the etiology of spontaneous abortion. Currently, there is little evidence to evaluate this theory. However, a recent study that examined serum levels of one caffeine metabolite, paraxanthine, in relation to both early and late (up to 20 weeks) spontaneous abortion found an increased risk only among women in the top 5th percentile of paraxanthine levels.22 Another possible explanation for our counterintuitive finding regarding CYP1A2 stems from the fact that this enzyme is involved in the metabolic activation of numerous chemical carcinogens (eg, heterocyclic and aromatic amines and nitroaromatic compounds7) and in the biotransformation of many xenobiotics in addition to caffeine. Therefore, our results may reflect the interplay of various unmeasured factors that are possibly related to spontaneous abortion risk. The role of chance must also be considered as an explanation for the finding.
Studies that have charted within-person caffeine clearance rates in response to differing test doses of caffeine have provided some evidence that caffeine may exhibit dose-dependent kinetics, such that the rate of caffeine metabolism may decrease with increasing doses of caffeine.23,24 Denaro et al23 observed a decline in clearance capacity of 22% after an increase in caffeine dose from 4.2 to 12 mg/kg body weight per day, and Cheng et al24 reported a similar decline of 29% after escalating single oral doses of caffeine from 70 to 300 mg. The significant inverse association we observed between caffeine intake and CYP1A2 phenotype could be further evidence for this type of dose-dependent metabolism of caffeine, but without an experimental design using repeated measurements in the subjects, this evidence is equivocal. If high caffeine intake does dampen CYP1A2 activity, this may increase overall exposure to caffeine but might also work to counteract any potential detrimental effects of caffeine metabolites, making the assessment of any cause-effect relationship between caffeine and spontaneous abortion very complex. The uncertainty surrounding caffeine pharmacokinetics is an additional hindrance to the interpretation of our CYP1A2 results.
We did not employ a standardized caffeine challenge protocol in this study, as is typical when using caffeine as a probe for CYP1A2 activity,3 for a number of reasons. First, we could not compel the women in the control group to ingest a test amount of caffeine, which we hypothesized may have harmful effects on the pregnancy. Under these circumstances, the women in the case group could also not be subjected to such a protocol because using different methods to assess case and control phenotype may lead to noncomparability of the data. Also, subjects in both the case and control groups were not aware of the fact that caffeine was the study’s primary exposure of interest. The random sampling of urine predictably resulted in a large amount of missing phenotype data among those who abstained from caffeine and those who had not ingested caffeine in the recent 1 or 2 days. However, the use of spot urine testing per se is unlikely to have introduced any bias. We recently conducted a validation study to assess the comparability of randomly collected urine samples and standardized sampling methods using a strict caffeine challenge protocol, and the correlation between the two CYP1A2 phenotype values was 0.91.12 This and other results from the validation study demonstrated that CYP1A2 phenotyping using random urine testing could be successful in populations with widespread caffeine consumption, such as in Sweden.
Hirvonen et al25 and Mendola et al26 previously reported that genotypically slow acetylators had a 40–60% and 20%, respectively, increased risk for recurrent spontaneous abortion. Likewise, Fenster et al10 found that phenotypically slow acetylators had a 60% increased risk for recurrent spontaneous abortion. As in the present analysis, none of these earlier findings were statistically significant, but the consistency with which this association has been reported merits consideration. We observed a substantially stronger association between NAT2 status and recurrent spontaneous abortion (a nonsignificant 150% increased risk for slow acetylators), which may be attributed to the fact that we were able to perform fetal karyotyping and exclude abnormal karyotype abortions. Using cases that are nonviable regardless of the effects of environmental pregnancy exposures would dilute any true associations that may exist. We believe that despite the greater effort and cost involved, it is important that future studies of spontaneous abortion distinguish between normal and abnormal karyotypes to improve interpretability and avoid bias.
We found that caffeine intake as low as 100–299 mg/ day was associated with a doubled risk for spontaneous abortion among slow acetylators, but among fast acetylators, no association with caffeine was observed below an exposure of 300 mg/day. The higher OR at 100–299 mg/day than at 300 mg/day or more among slow acetylators is likely a chance finding, but given the high prevalence of slow acetylators (ranging from 25% in Asian populations to 70% in white populations13,15,27), the public health importance of any effect at doses below 300 mg/day could be considerable.
Recall bias must always be considered as a potential problem in case-control studies. Women in the case group, because they experienced a spontaneous abortion, may have been more likely to report their caffeine intake more thoroughly, or even in an exaggerated fashion. However, an earlier analysis of data from this study9 provided important evidence indicating that such recall bias was unlikely to have occurred. Specifically, we found an association between caffeine and spontaneous abortion among women with normal karyotype fetuses, but not among women with abnormal karyotype fetuses. If it were true that women in the case group were over-reporting their caffeine intake, then any type of miscarriage (normal or abnormal karyotype) would be associated with caffeine because karyotyping results were not known until long after the interview.
This study was of limited size but has a number of strengths, including the availability of karyotype classification, the thorough and weekly reporting of source-specific caffeine intake in early pregnancy, the relatively high intake of caffeine among the study subjects, and the ability to phenotype CYP1A2 activity during the first trimester of pregnancy. The findings from this investigation suggest that variation in metabolic activity may influence spontaneous abortion risk independently and/or by interacting with caffeine exposure. The direction of our CYP1A2 results was unexpected and contrary to the a priori hypothesis, but the NAT2 results were in line with our hypothesis and do support some earlier investigations. Most of our analyses relied on small numbers, producing statistically imprecise estimates of relative risk that should be interpreted with caution. They do indicate, however, that further study of caffeine metabolism and normal karyotype spontaneous abortion is warranted.
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Footnotes |
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We kindly acknowledge the work carried out by Dr. F. Kylenstierna and colleagues at Pharmacia Corporation, Helsinborg, Sweden, for conducting the cotinine laboratory analyses.
Received May 16, 2001. Received in revised form July 20, 2001. Accepted August 2, 2001.
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