The Associations of Maternal Caffeine Consumption and Nausea with Spontaneous Abortion
Wen, Wanqing1; Shu, Xiao Ou1; Jacobs, David R. Jr.2; Brown, Judith E.2
From the 1Department of Medicine, Vanderbilt University, Nashville, TN, and 2Division of Epidemiology, University of Minnesota, Minneapolis, MN.
Address correspondence and reprint requests to: Wanqing Wen, Research Assistant Professor, Department of Medicine, School of Medicine, Vanderbilt University, 6th Floor, Medical Center East, Nashville, TN 37232-8300.
The research reported here was supported by National Institute of Child Health and Human Development Grant R01 HD19724.
Submitted October 22, 1999; final version accepted August 3, 2000.
To examine whether maternal caffeine consumption is associated with the risk of spontaneous abortion, we analyzed data from a population-based prospective study. The study population comprised 575 women delivering singleton livebirths and 75 women who had spontaneous abortions. The subjects were predominantly white, middle-class women enrolled before pregnancy. Study participants were traced to delivery of a liveborn, singleton infant or a spontaneous abortion. Of the 71 women who did not experience nausea, 29.6% had a spontaneous abortion, compared with 7.2% of 514 women who did experience nausea. Maternal caffeine consumption before pregnancy, or in women without nausea, did not increase the risk of spontaneous abortion, whereas maternal caffeine consumption during the first trimester after nausea started might increase risk of spontaneous abortion (risk ratio = 5.4, 95% confidence interval = 2.0–14.6 for caffeine consumption ≥300 mg per day compared with <20 mg per day). These results suggest that maternal caffeine consumption during pregnancy may influence fetal viability in women with nausea.
In 1980, the U.S. Food and Drug Administration recommended that pregnant women limit caffeine consumption to less than 400 mg per day, on the basis primarily of results of animal studies. 1 Results of epidemiologic studies on potential reproductive effects of caffeine consumption, however, have not been consistent. Although few data connect caffeine consumption with congenital malformations or preterm delivery, 2 the associations of caffeine consumption with spontaneous abortion, 3–8 as well as infertility 9–11 and low birth weight, remain controversial 5,6,12–16 despite numerous epidemiologic studies. Differences in study methods, a lack of control for nausea and vomiting, and limitations in assessment of caffeine consumption at different time points during pregnancy might account for the inconsistencies in the literature. 17–19
Nausea is one of the most common epiphenomena of pregnancy. Several previous studies have found that nausea is strongly associated with a decreased risk of spontaneous abortion. 20,21 Fenster et al22 have observed that women with nausea tend to reduce their caffeine consumption, and an association between caffeine consumption and spontaneous abortion may be an artifact caused by the relation of nausea with both spontaneous abortion and caffeine consumption.
We examined the relation of caffeine consumption and nausea with spontaneous abortion using data from the Diana Project, a population-based, prospective study that included 968 women enrolled before pregnancy.
Subjects and Methods
The data evaluated in this study originated from interviews, measurements, and questionnaires completed by participants in the Diana Project, which has been described in detail elsewhere. 23,24 Briefly, the primary aim of the Diana Project is to identify preconceptual and early-pregnancy exposures that are related to reproductive outcomes. Potential participants of the Diana Project were recruited during the years 1989–1992 from a population of women 22–35 years of age enrolled in Group Health, Inc., a health maintenance organization serving the greater Twin Cities area of Minnesota. Recruitment letters that described participant roles and eligibility criteria were sent in monthly waves to more than 28,000 women. Women were eligible for the study if they intended to become pregnant within the enrollment period; had not been attempting pregnancy for more than 3 months before enrollment; did not intend to use contraceptive methods during the study period; had no history of hypertension, renal disease, diabetes mellitus, heart disease, or infertility; and submitted a signed consent form. There was a total of 2,840 women who contacted the Diana Project in response to recruitment activities. Of these, 1,152 were determined to be eligible and returned a signed consent form. One hundred eighty-four of the 1,152 women became ineligible during the study owing to a change in plans for becoming pregnant or other reasons. Women completed a series of questionnaires monthly for the duration of the study and attended a study visit at their health maintenance organization clinic approximately every 3 months. Of the 968 women who remained eligible, 642 (66%) completed all required aspects of the study and 326 (34%) quit before completion of the study. Of these 326 women, various amounts of data from completed forms, study visits, and medical record abstractions were available. The data were included in analyses whenever the outcomes (livebirth or spontaneous abortion) applied. In this study, the final study group comprised 575 women delivering singleton livebirths and 75 women who had spontaneous abortions.
Data included in this analysis were collected prospectively in part through mailed questionnaires that included vital data, smoking status, alcohol intake, medication/drug use, and taste and odor changes. Dietary intake was assessed using the Willett food frequency questionnaire. 25 Women completed the vital data questionnaires once and the food frequency questionnaire three times, then every 3 months until conception occurred, and then monthly during pregnancy. Other forms (for example, tobacco use, illness record, etc) were completed monthly from enrollment to the end of the study. Medical records were used to abstract information regarding parity; spontaneous abortion; and newborn weight, length, head circumference, sex, and Apgar scores. The abstraction was done by a trained and supervised research staff.
Caffeine content was assigned to beverages as follows: regular coffee, 139.2 mg per cup; tea, 64.0 mg per cup; cola, 46.0 mg per 12 oz, hot chocolate, 16.0 mg per cup; and caffeinated diet soda, 46.0 mg per cup. Caffeine content of products that contain chocolate (for example, brownies and chocolate syrup) was also included in total caffeine intake.
Information about caffeine intake was ascertained by the monthly food frequency questionnaire. 25 Mean caffeine consumption per day was calculated for each month. Four categories of consumption were defined (<20, 20–99, 100–299, and ≥300 mg per day), which are similar to those used in other studies. 6,16 Nausea status (yes/no) and its duration (days) were recorded monthly. Analyses on spontaneous abortion included mean daily caffeine consumption before pregnancy, in the first trimester of the pregnancy, or up to the date of spontaneous abortion if it occurred before the end of the first trimester; analyses were further stratified by timing of the caffeine consumption in relation to occurrence of nausea.
We calculated the risk of spontaneous abortion for each category of risk predictor by dividing the number of women who had a spontaneous abortion by the total number of women in the corresponding group. We used the Mantel-Haenszel procedure 26,27 to estimate risk ratios and their 95% confidence intervals (95% CIs). We considered some demographic factors, smoking and alcohol drinking, and other selected characteristics of women under study such as parity and body mass index as potential confounding factors (Table 1) because of their reported relation to maternal caffeine consumption and spontaneous abortion. We used logistic regression models to obtain adjusted associations controlling for potential confounding factors. We evaluated confounding by comparing unadjusted estimates of associations with adjusted estimates. Because we found no important confounding, we only present unadjusted associations in this paper. To show trend, we present spline-smoothed trend curves using a method described by Greenland. 28
Table 1 presents the risk of spontaneous abortion by selected characteristics of women in the Diana project including sociodemographic status, smoking, alcohol intake, parity, and prepregnancy body mass index [weight (kg) per height (m)2]. The vast majority of study participants were white (more than 96%) and middle class. The risk of spontaneous abortion was associated little with race, education, household income, parity, maternal age, smoking, and alcohol consumption at enrollment, as well as prepregnancy weight height and body mass index. Women who were never employed for pay had lower risk of spontaneous abortion (risk ratio = 0.2, 95% CI = 0.1–0.9).
Table 2 shows that, compared with 71 women who did not experience nausea, the 514 women who reported nausea during the first trimester of the pregnancy were less likely to abort (7.2%vs 29.6%). Among those reporting nausea, duration of nausea was shorter in those who aborted than in those who delivered a liveborn infant (mean, 4.8 vs 9.4 days).
Despite an average reduction in caffeine intake during the first trimester of the pregnancy, the risk of spontaneous abortion was higher among women who reported relatively higher caffeine consumption (Table 3). As compared with caffeine consumption of <20 mg per day, risk ratios for spontaneous abortion associated with consumption of 20–99, 100–299, ≥300 mg caffeine daily were 1.5 (95% CI = 0.8–2.7), 2.0 (95% CI = 1.0–4.1), and 2.5 (95% CI = 1.0–6.4), respectively. Stratifying caffeine consumption during the first trimester by nausea status, we found that the association between spontaneous abortion and caffeine consumption was restricted to the period after nausea started (the median caffeine consumption was 32.6 mg per day in the abortion group vs 17.9 mg per day in the livebirth group; risk ratio = 5.4 (95% CI = 2.0–14.6) for caffeine consumption ≥300 mg per day compared with <20 mg per day). Neither caffeine consumption before nausea in women who ever reported nausea nor caffeine consumption in women who never reported nausea was materially associated with an increased risk of spontaneous abortion. We further examined caffeine consumption during the month after nausea started among subjects who reported nausea at least 2 months in a row (indicating that the spontaneous abortion probably did not occur after the first month’s episode of nausea). Although only 21 cases of spontaneous abortion remained in this analysis, the association was similar to that among all 34 spontaneous abortions that occurred in women who experienced nausea. Figure 1 presents the spline-smoothed trend of associations between the risk of spontaneous abortion and maternal caffeine consumption during the first trimester in three different situations that is, overall caffeine intake during the first trimester, ignoring nausea status (curve indicated by “1st trimester”) caffeine intake before nausea or in women who never reported nausea (curve indicated by “No nausea”) and caffeine intake after occurrence of nausea (curve indicated by “After nausea”). As presented in Figure 1, the first trimester curve showed an increasing trend of the risk of spontaneous abortion as maternal caffeine consumption rose. A more striking trend was observed for the After nausea curve. The No nausea curve showed a slight trend of decreasing risk of spontaneous abortion with increasing maternal caffeine consumption.
Findings from studies of the association between caffeine intake and spontaneous abortion have been inconsistent. 3–8 Infante-Rivard et al3 demonstrated in a case-control study that caffeine intake was associated with an increased risk of fetal loss. A positive association between caffeine intake and spontaneous abortion was also found in a prospective cohort study 4 and a meta-analysis. 5 In a cohort of 431 women enrolled within 21 days of conception, however, Mills et al6 reported that moderate caffeine consumption was not associated with an increased risk of spontaneous abortion. No relation of caffeine consumption with spontaneous abortion was reported by another case-control study 7 and a prospective study. 8 The disparity in the results of these studies can, in part, be explained by the difference in exposure ascertainment (for example, retrospectively or prospectively, nausea ascertained or not) and in sociodemographic characteristics and other risk factors between different study populations. 17,18 For example, the women in the Mills et al6 study were well educated and of middle to upper income, whereas the Infante-Rivard et al3 study included poorer women, about one-fourth of whom smoked.
In this prospective study, we found that caffeine consumption before pregnancy did not increase the risk of spontaneous abortion, but caffeine consumption during the first trimester of the pregnancy appeared to be associated with an elevated risk, and the risk became higher as caffeine consumption rose. Further analysis of caffeine consumption during the first trimester by nausea status showed a more obvious dose-response relation between the risk of spontaneous abortion and caffeine consumption after occurrence of nausea in women who reported nausea.
Previous studies have shown that nausea predicts a lower risk of spontaneous abortion. 21,22 It was found in the Fenster et al22 study that heavy caffeine consumers (>300 mg per day) reporting nausea had a twofold risk of spontaneous abortion (adjusted odds ratio = 2.10, 95% CI = 1.20–3.70) compared with women who did not report nausea. In this study, we found that (1) both occurrence and duration of nausea predict a lower risk of spontaneous abortion, and (2) spontaneous abortion was more likely to occur with higher caffeine consumption after nausea started.
Feinster et al22 raised an issue that the association seen in women reporting nausea and high caffeine use may have been an artifact of nauseated women being more likely to decrease caffeine consumption during pregnancy, but women who had a spontaneous abortion with shorter pregnancies may have had less opportunity to do so. Stein and Susser 29 argued against a causal association between caffeine consumption and spontaneous abortion in women reporting nausea, referring to the accepted concept that nausea indicates a concurrently surviving pregnancy. When pregnancy fails, nausea and other discomforts fade or disappear and caffeine consumption resumes. As such, nausea may be less frequent and caffeine consumption higher in pregnancies that end in spontaneous abortion than in those carried to term. Nevertheless, we found that caffeine consumption during the first month after nausea started was still associated with an increased risk of spontaneous abortion among women who reported nausea on at least two monthly questionnaires, implying continued fetal viability after the first bout of nausea. This finding implies that the higher caffeine consumption is unlikely to be the consequence of disappearance of nausea due to fetal death. It is hard to clarify fully the causal association between caffeine consumption and spontaneous abortion, because the exact timing of the fetal demise is unclear. We speculate, however, that in women who have a viable fetus and experienced nausea during pregnancy, caffeine consumption might influence their fetal viability. It is possible that caffeine consumption may result in a decrease of estrogen level, 30 which could allay discomfort of pregnancy, decrease the severity and duration of nausea, and subsequently increase the risk of spontaneous abortion. The caffeine and spontaneous abortion association may also be an effect of some unmeasured factors, such as severity of nausea, because nausea of differing severity may differentially affect caffeine consumption. 22
Our study has several advantages, including a prospective design, enrollment of study participants at the time of planning pregnancy, and monthly recording of caffeine consumption and other exposures. These procedures reduced recall bias, provided relatively accurate information about timing and amount of caffeine intake, enabled us to analyze the effect of caffeine consumption before conception and during various periods of pregnancy on spontaneous abortion, and to examine the effect of nausea on the relation between caffeine consumption and spontaneous abortion. One consequence of the restrictive subject recruitment used here, however, was small study size, resulting in low precision, particularly in analyses of subgroups.
In summary, our study suggests that spontaneous abortion is unrelated to maternal caffeine consumption before conception, before nausea starts in the first trimester of the pregnancy, or in women who did not experience nausea. Maternal caffeine consumption after nausea starts in the first trimester was associated with an increased risk of spontaneous abortion.
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