The effect of caffeine on fetal survival has been of interest since the 1980s.1 The biologic rationale for this concern includes caffeine's ability to cross the placenta,2 the mother's decreased ability to metabolize caffeine later but not earlier in pregnancy,3,4 and the diverse pharmacologic effects of caffeine including increased levels of catecholamines and cellular cyclic adenosine monophosphate (AMP).5,6
Despite methodologic challenges,1 the association between caffeine and risk of miscarriage merits closer evaluation given the widespread consumption of caffeinated beverages and the frequency (and largely unknown causes) of pregnancy loss. We ascertained caffeine consumption in some detail as part of a study of pregnancy loss and disinfection by-products in water. Unlike most prior studies, we recorded information on caffeine consumption and pregnancy-related changes in consumption early in gestation and were able to stratify results by timing of losses relative to the timing of exposure assessment.
METHODS
Participant Recruitment and Data Collection
Between 2000 and 2004, we recruited women from Galveston (Texas), Memphis (Tennessee), and Raleigh (North Carolina) through public and private prenatal care providers as well as directly from the communities. Pregnant women at <12 weeks’ gestation who were 18 years of age or older were enrolled; in addition, women aged 18 to 45 who were trying to conceive for ≤6 months were identified and enrolled if they became pregnant. Although women were recruited when they were pregnant, some miscarriages had occurred by the time of interview. Details of the recruitment process are described elsewhere.7,8 Once pregnant, women were interviewed by telephone before 16 weeks’ gestation. Use of alcohol, drugs, and cigarettes; caffeine consumption; water exposure; medical history; and reproductive history were queried. An endovaginal ultrasound was performed if possible before 8 weeks’ gestation to date the pregnancy and assess fetal viability.
Miscarriage was defined as loss of a clinically recognized pregnancy at or before 20 completed weeks’ gestation from last menstrual period (LMP). We relied on self-reported LMP to define gestational age because the loss often occurred prior to the ultrasound and because for viable pregnancies, the estimated dates of conception from early ultrasound and LMP were highly concordant. Pregnancy outcomes were identified through self-report during follow-up and were confirmed by medical records or by vital records for live births and fetal deaths after 20 weeks’ gestation.
Assessment of Caffeine Intake
We assessed daily consumption of caffeinated beverages in a typical week, referred to as “current consumption”. For women who were still pregnant at the baseline interview, we asked this question at that time. We asked about consumption during pregnancy. For women who had already experienced a loss, “Current consumption” reflects exposure late in the first trimester. We inquired about caffeinated (brewed and instant) coffee, caffeinated (iced and hot) tea, and caffeinated soda consumption, including the number and size of cups consumed per day. We assigned cups of coffee and hot tea as small (4–10 oz), medium (12–14 oz), and large (16–24 oz). Iced tea was categorized as small (4–10 oz), medium (12–20 oz), and large (22–34 oz), and sodas as small (8–12 oz), medium (14–22 oz), and large (24–34 oz). Reported daily consumption of less than one cup or glass was set to half of a small cup. We assigned caffeine content to each caffeinated beverage9 using midpoints of the cup-size intervals to generate exposure indices. We evaluated total caffeine exposure from all sources and from coffee alone.
In addition to collecting data on current consumption, we also inquired about changes in consumption, including the amount and timing of any changes. Most women (92%) reported a change during pregnancy. When the day of the change was not provided (approximately 25% of those who reported changing) but the week could be estimated (ie, first, second, etc.), we assigned the day as the midpoint of that week; when only the month could be recalled, we assigned the midpoint of the month.
We considered 3 time points of caffeine exposure: Prepregnancy exposure; 4 weeks after LMP (after any changes associated with planning pregnancy) and current consumption at the time of the interview (or when still pregnant, for women who experienced losses). The third time period was presumably reflective of changes that occurred early in pregnancy, after the onset of any nausea and vomiting.
Statistical Methods
We used a discrete-time continuation ratio logistic survival model to estimate week-specific odds ratios for the probability of having a miscarriage in a given week, conditional on a woman still being pregnant at the beginning of that week. Women who were planning pregnancy were not included in the risk set for analysis until they enrolled following a positive pregnancy test. Women were followed from the day of enrollment up to 20 weeks’ gestation; possible outcomes were pregnancy survival to 20 weeks, miscarriage, or loss to follow-up. Coffee and caffeine consumption at each of the 3 time points was divided into 3 groups: none, less than or equal to the median among consumers at that time point, and above the median. In separate models, we compared those >75th percentile among consumers with those who consumed none.
Potential confounders included maternal age, race/ethnicity, education, marital status, income, smoking, alcohol use, body mass index, age at menarche, employment status, diabetes, miscarriage history, induced abortion history, vitamin use, and nausea and vomiting in early pregnancy. Covariates were retained in the final model if they were predictive of the outcome based on a P value of <0.20, or if they changed effect estimates for the exposure of interest by ≥10% when excluded from the model. Increased risk was found for women who were older, non-Hispanic, highly educated, unmarried, alcohol users, and nonusers of vitamins, as well as those lacking nausea and vomiting; those covariates were included in the final models.
Of the 2766 women enrolled in the study, 32 withdrew and 227 were excluded for other reasons, including being greater than 12 weeks’ gestation at enrollment based on study ultrasound, being unreachable by telephone for more than 7 weeks, or moving out of the study area. Additionally, second or third study pregnancies (n = 69), multiple gestations (n = 23), and women with inconsistent or invalid essential data (n = 8) were excluded from the analysis, leaving a total of 2407 pregnancies. There were 258 miscarriages (74 [29%] before the interview and 184 [71%] after the interview), 2112 live births, and 37 women who contributed person-time of observation but had unknown pregnancy outcomes.
RESULTS
Study participants were predominantly from Raleigh or Memphis (83%), included a substantial proportion of black women (32%), represented a range of education and income levels, and contained few smokers (5%) or alcohol users (2%) (Table 1). Sizable proportions were overweight (24%) or obese (21%). Prior miscarriage was reported by 21%, and prior induced abortion by 18%. A higher proportion of the pregnancy losses occurred before the interview, as opposed to after, among women from Memphis, older mothers, women with higher education and income, alcohol users, nonusers of vitamins, and those without nausea or vomiting.
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TABLE 1: Demographic, Health Behavior, and Pregnancy History of Women Included in Analysis, by Timing of Interview and Pregnancy Outcome
Among women who had live births, 33% of women reported that they drank coffee prior to pregnancy. The proportion of daily coffee drinkers declined to 15% at the time of the interview; overall caffeine intake diminished as well (Table 2). Caffeinated soda, iced tea, and coffee all contributed substantially to caffeine intake. Coffee consumption did not decrease more notably among women reporting nausea and vomiting in early pregnancy compared with those who did not have nausea and vomiting (data not shown).
TABLE 2: Coffee and Total Caffeine Consumption Among Women Included in the Analysis, by Timing of Interview and Pregnancy Outcome
Coffee consumption before LMP was highly correlated with consumption 4 weeks after LMP (r = 0.80), but the correlation was lower with consumption at the time of the interview (r = 0.53). Total caffeine showed similar patterns (r = 0.82 and r = 0.53, respectively). Coffee and total caffeine consumption were highly correlated with one another prepregnancy (r = 0.86) and at 4 weeks after LMP (r = 0.82), but less so at the time of the interview (r = 0.64).
Among all women, coffee and caffeine consumption at all 3 time points were unrelated to the overall risk of miscarriage (Table 3), with all adjusted odds ratios between 0.7 and 1.3. The most suggestively elevated odds ratios were for total caffeine above the median and above the 75th percentile at the time of the interview, with odds ratios of 1.2 and 1.3, respectively. Analyses of losses before the interview (Table 4), for whom there is greater susceptibility to biased reporting of exposure, yielded evidence of a positive association with coffee and caffeine exposure around the time of the interview, but the results were imprecise. When analyses were restricted to losses after the interview (Table 5), the results were uniformly close to the null except for a single, imprecise measure.
TABLE 3: All Pregnancy Loss (n = 258). Unadjusted and Adjusted Odds Ratios Relating Coffee and Caffeine Consumption at 3 Time Points to the Risk of Miscarriage (Before or After Interview), Contrasting the Following Consumption Categories: None, Below or Equal to the Median, Above the Median, and Above the 75th Percentile. All Study Participants
TABLE 4: Pregnancy Loss Before Interview (n = 74). Unadjusted and Adjusted Odds Ratios Relating Coffee and Caffeine Consumption at 3 Time Points to the Risk of Miscarriage Before Interview, Contrasting the Following Consumption Categories: None, Below or Equal to the Median, Above the Median, and Above the 75th Percentile
TABLE 5: Pregnancy Loss After Interview (n = 184). Unadjusted and Adjusted Odds Ratios Relating Coffee and Caffeine Consumption to the Risk of Miscarriage After Interview, Contrasting None, Below or Equal to the Median, Above the Median, and Above the 75th Percentile
DISCUSSION
These data show little evidence for associations between coffee or caffeine consumption prior to or early in pregnancy and the risk of miscarriage. Relative to previous studies, our population had modest levels of coffee and caffeine intake, with median coffee intake of 350 mg/d prior to and early in pregnancy, and 200 mg/d at the time of the interview among those who consumed any caffeine. The median levels of caffeine consumption before and during pregnancy among those who had some exposure were modest relative to previous studies, equivalent to 1.1 to 1.7 seven-oz cups of brewed coffee per day prior to pregnancy and 4 weeks post-LMP. This restricted our ability to examine possible effects above the 300 to 400 mg/d range addressed in a number of previous studies.1 Our study population may be more health-conscious than those in previous studies because we enrolled volunteers who sought prenatal care early or were planning a pregnancy. This selectivity or the geographic location of the study may account for the relatively low level of coffee and caffeine consumption. Whereas some studies report elevated risks at levels in the range that we were able to examine (<300 mg/d),10–13 most did not.14–18 Classification of previous studies based on timing of caffeine assessment (during vs. after pregnancy) does not provide clear evidence that timing of assessment is predictive of results, with both suggestively positive12,17 and negative16,18 studies among those with early assessment.
Given our observed null association, a key question concerns potential biases that may have masked an underlying causal effect. One potential source of error is misclassification of coffee and caffeine intake. We did not account for caffeine from chocolate or medications, and there is substantial variability in the dose of caffeine resulting from different beverage preparation methods.19 Thus, even if self-reported consumption of “cups of coffee per day” and the “cup sizes” were accurate, the inferred dose of caffeine using standard conversion tables9 would be subject to error that is nondifferential by outcome.
The exposure window of interest falls shortly before conception and extends into the earliest weeks of pregnancy, a time of marked change in behavior, making a single assessment of limited value. We assessed caffeine use in some detail earlier in pregnancy than most previous studies, but our assessment could be subject to erroneous recall of the timing and nature of changes. Caffeine assessment preceded 67% of miscarriages, limiting the potential for recall bias. Women who were interviewed after miscarriage reported elevated levels of coffee and caffeine intake during pregnancy compared with women who had losses after the interview. The elevated consumption could reflect recall bias or true differences, perhaps due to decreased nausea and thus increased consumption after fetal demise but before recognition of the loss, or erroneously reporting on their intake after the loss was known to have occurred. In addition to concerns about exposure assessment, our inability to isolate subsets of pregnancy losses based on karyotypes may mask a modest effect among chromosomally distinctive subsets.14
Nausea in early pregnancy is strongly predictive of fetal survival,20–23 presumably indicative of hormonal changes that support continued pregnancy. Nausea also affects dietary habits, often resulting in aversion to coffee. Thus, there has been a concern that caffeine consumption would decline among women who have nausea (and a more favorable prognosis) relative to those who do not have nausea, resulting in an artifactual positive association between caffeine and pregnancy loss.24 In our study, we did not find a differential decline in caffeine in relation to reported nausea and vomiting, with all women reporting markedly decreasing coffee and caffeine from prior to pregnancy through the course of pregnancy. Adjustment for nausea and vomiting did not affect the measures of association between coffee or caffeine and miscarriage risk.
The assessment of coffee and caffeine use early in pregnancy, before most losses had occurred, should minimize the potential for outcome-related differences in actual or reported exposure. When we restricted losses to those that occurred after the interview, presumably eliminating recall bias resulting from having had a loss, the results remained null. It should be noted, however, that all women were reporting retrospectively with regard to caffeine intake prior to pregnancy and at 4 weeks post LMP. While studies in populations that combine early assessment of caffeine with a higher exposure range would yield more informative results pertaining to higher doses, these data provide evidence to suggest that, within the lower range examined, caffeine intake is not associated with risk of miscarriage.
ACKNOWLEDGMENTS
We thank Christina Makarushka, Project Manager, and Yanfang Jiang, Staff Programmer, for their contributions.
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