Effect of Maternal Smoking and Coffee Consumption on the Risk of Having a Recognized Down Syndrome Pregnancy

Claudine P. Torfs and Roberta E. Christianson

From the California Birth Defects Monitoring Program, 1830 Embarcadero, Suite 100, Oakland, CA 94606-5226.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
To evaluate the possible effects of maternal smoking and caffeine or coffee consumption on the occurrence of a recognized pregnancy with Down syndrome, the authors analyzed data from a case-control study of 997 liveborn infants or fetuses with Down syndrome ascertained in California from 1991 to 1993 and 1,007 liveborn controls without a birth defect. Interviews with mothers covered demographic information, pregnancy, and medical history, with detailed questions on the use of tobacco, alcohol, and caffeinated beverages. All analyses were age-adjusted. High alcohol consumption (>=4 drinks/week) in the first month of pregnancy was associated with reduced risk for a recognized Down syndrome conceptus (odds ratio (OR) = 0.54; 95% confidence interval (CI): 0.34, 0.85). Maternal smoking during the periconceptional period was not associated with risk of recognized Down syndrome (OR = 1.04; 95% CI: 0.79, 1.37), but maternal consumption of four or more cups of coffee per day was inversely associated (OR = 0.63; 95% CI: 0.41, 0.96). In multivariate analysis, a significant interaction between coffee drinking and smoking was observed. The inverse association remained only for nonsmoking mothers who drank four or more cups of coffee per day (OR = 0.48; 95% CI: 0.28, 0.82). These results suggest that among nonsmoking mothers, high coffee consumption is more likely to reduce the viability of a Down syndrome conceptus than that of a normal conceptus.

abortion; alcohol drinking; caffeine; coffee; Down syndrome; fetal viability; pregnancy; smoking; spontaneous


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Maternal smoking and caffeine or coffee consumption are considered potential risk factors for early fetal loss (1GoGoGoGoGoGoGoGoGo–10Go). Consequently, there have been warnings about smoking and excessive use of caffeine during pregnancy for many years. It is thought that caffeine and substances in tobacco smoke may affect the survivability of the conceptus. Because trisomic fetuses are more susceptible to loss very early in pregnancy than are chromosomally normal fetuses (2Go, 11GoGoGo–14Go), maternal smoking and caffeine consumption may have a more deleterious, early effect on trisomic fetuses than on normal ones. If this were true, proportionately fewer mothers who smoked or consumed caffeine would be observed among pregnancies with a clinically recognized trisomic fetus than among pregnancies with a normal fetus.

The relation between smoking and consumption of caffeine during pregnancy is complex. Smokers tend to consume more caffeine than nonsmokers (15GoGo–17Go), and smoking speeds up the metabolism of caffeine (18GoGoGoGo–22Go), while pregnancy slows it down (18Go, 21Go). Thus, the independent and combined effects of caffeine and smoking must be considered.

This population-based case-control study examined the effect of the complex relation between tobacco smoking and coffee consumption on the risk of having a clinically recognized Down syndrome pregnancy, including live births, terminations, and spontaneous fetal losses.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The population
The California Birth Defects Monitoring Program is an active surveillance registry that monitors birth defects in a number of California counties representing over half of the state's yearly births. Abstractors inspect the obstetric, nursery, pediatric, and pathology logs of all birthing and pediatric tertiary care hospitals in the monitored counties and abstract the charts of all liveborn or stillborn infants who have a structural defect. Ascertainment of cases continues until the children reach 1 year of age. In addition, abstractors visit all genetic laboratories in the monitored counties to record all abnormal karyotypes; abortions with abnormal karyotypes are ascertained from this source or from hospital logs. Because most spontaneous abortions are not karyo-typed, trisomic abortions are not uniformly ascertained.

From July 1991 to December 1993, we conducted a case-control study of infants and fetuses with Down syndrome ascertained by the California Birth Defects Monitoring Program. During the same interval, abstractors obtained identifying information on liveborn infants without birth defects who were randomly chosen from the monitored birth population and frequency-matched by hospital of birth; those infants served as controls. Adopted infants were excluded, as were those whose mothers did not speak English or Spanish and those who resided outside of the monitored counties. Participants were administered a structured questionnaire by telephone; topics included maternal pregnancy and medical history, parental sociodemographic background, and use of tobacco, coffee, and alcohol.

Variable definitions
Sociodemographic variables used in this analysis included maternal race/ethnicity, age, and education. Ethnicity was classified as non-Hispanic White, Hispanic, African-American, and "other"; this classification was abridged to Hispanic and non-Hispanic categories for later analyses. Maternal age was considered as a continuous variable, because the occurrence of Down syndrome is known to vary substantially with maternal age. Mother's level of education was classified into three categories: less than high school completion, completion of high school or technical school, and any college attendance. The latter two groups were combined for the multivariate analysis. Gravidity was classified into 1–3 pregnancies and >=4 pregnancies. Parity and previous fetal losses were also evaluated. Maternal consumption of alcohol was recorded for the time preceding pregnancy and for three time intervals during pregnancy (month 1, months 2 and 3, and trimesters 2 and 3).

An alcoholic drink was defined as either a 12-ounce portion of beer, a 4-ounce glass of wine, or 1.5 ounces of hard liquor. We asked each mother how many drinks she usually consumed per week: 0, 1–3, or >=4. Given that the first month of pregnancy is the time when most concepti are lost (8Go), we selected that time period for analysis. Because no association with Down syndrome risk was observed for either 0 drinks per week or 1–3 drinks per week, these two categories were merged for the final model and compared with the category of four or more drinks per week.

We asked each mother if she had ever smoked cigarettes, the lifetime intervals during which she had smoked, and the quantity smoked during each interval. Because smoking cessation has a long term effect on the metabolism of caffeine (23Go) and because many women stopped smoking close to conception, we used the dichotomous variable "did not smoke within 3 months of conception" and "smoked within 3 months of conception." Women who quit smoking at an indeterminate time close to conception were placed in the "smoking" category.

To evaluate caffeine use, we asked mothers about their consumption of regular coffee, nonherbal tea, and caffeine-containing soft drinks around the time of conception, using four categories: 0, 1–3, 4–6, and >=7 cups or drinks per day. After we verified in all analyses that results for "1–3 cups per day" did not differ from results for "none," we recombined categories of coffee consumption as "three or fewer cups per day" and "four or more cups per day." Three cups of coffee is equivalent to approximately 300 mg of caffeine per day, a cutpoint at which interaction between smoking and high caffeine consumption has been observed in several of the previous studies on conception delay (24Go, 25Go). Since the questionnaire elicited not the exact number of cups or drinks consumed daily but rather the range, caffeine consumption could only be estimated using the midpoint of each range; eight cups or drinks was used to represent the open-ended interval of seven or more. To calculate caffeine intake, we multiplied these values by 100 mg, 50 mg, and 40 mg, the average amounts of caffeine per cup or drink of coffee, tea, and caffeinated soft drinks, respectively; these amounts have been used by several other researchers (24Go, 26Go, 27Go). The total amount of caffeine consumed by each woman daily was then derived by adding the amounts for coffee, tea, and soft drinks. No information was available on other sources of caffeine, such as medicines.

Statistical methods
We first examined each variable of interest separately via unconditional logistic regression, adjusting only for maternal age because of its strong effect on Down syndrome prevalence. All control variables were observed to be potential confounders and were retained in subsequent models. In further analyses, coffee consumption rather than caffeine consumption was chosen, because it was thought to be more exact than the crude estimates of caffeine equivalence and because coffee contains many compounds other than caffeine whose specific effects cannot be evaluated at present. We collapsed gravidity, ethnicity, education, coffee consumption, and alcohol consumption into binary variables after reviewing results from full multivariate models with expanded categories. Smoking and coffee consumption were then considered either in combination or with an interaction term. The final model analyzed all births and live births only. For all regressions, we used Proc Logistic in SAS (version 6.12) to compute odds ratios and related 95 percent confidence intervals (28Go).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Of the 1,197 cases and 1,296 controls eligible for this case-control study, 10 percent of the cases and 16.3 percent of the controls could not be located. An additional 6.4 percent of cases and 5.7 percent of controls refused to participate. We thus analyzed data on 997 (83 percent) cases and 1,007 (78 percent) controls after excluding seven mothers with incomplete interviews. The mean time interval between delivery and interview was 178 days for cases and 141 days for controls. Among the 997 interviewed case mothers, there were 687 live births, 13 spontaneous abortions, 18 stillbirths, and 279 elective terminations.

Maternal characteristics are shown in table 1. The distributions by maternal age, race/ethnicity, education, and gravidity are quite different for cases and controls. Among cases, Hispanics were overrepresented and African Americans underrepresented. Cases occurred more frequently among mothers with less than a high school education and among mothers with four or more pregnancies. The strong association between mother's age and Down syndrome is clearly shown in table 1: There are more than twice as many controls with mothers aged <=30 years than there are cases (71.1 percent vs. 34.9 percent). Consumption of four or more alcoholic drinks per week during the first month of pregnancy was observed slightly more often among controls than among cases. The proportions of mothers who consumed four or more cups of coffee per day or who smoked were very similar for cases and controls. Less than 20 percent of the mothers drank caffeinated tea, and the small proportions who consumed four or more caffeinated sodas per day were slightly more likely to be control mothers than case mothers. Among smokers, only six case mothers and two control mothers also used other forms of tobacco.


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TABLE 1. Distribution (%) of maternal characteristics for 997 Down syndrome cases and 1,007 controls, California, 1991–1993

 
Table 2 gives the odds ratios for single variables, adjusted only for mother's age. Two variables associated with an increased risk of Down syndrome were having less than a high school education and being of Hispanic ethnicity. High gravidity and high parity were also risk factors for Down syndrome. Given that there were many nulliparous women who had undergone pregnancy termination, we chose gravidity rather than parity for the analysis after verifying that the proportions of prior pregnancy losses were the same for both cases and controls. Consumption of four or more cups of coffee per day was associated with a reduced risk of Down syndrome (odds ratio (OR) = 0.63; 95 percent confidence interval (CI): 0.41, 0.96). Mothers who consumed 1–3 cups of coffee per day had the same risk as those who did not consume any coffee. These two categories were then combined in all subsequent reported analyses. High levels of consumption of tea and soft drinks (not shown in table 2) had odds ratios less than 1.0 (for tea, OR = 0.85 (95 percent CI: 0.35, 2.10); for soft drinks, OR = 0.87 (95 percent CI: 0.57, 1.31)). Although the risk of Down syndrome was similarly decreased for both categories of high daily consumption of coffee, the relation did not reach significance for mothers who drank seven or more cups per day, presumably because of small numbers. These two categories were merged in subsequent analyses. The odds ratios for caffeine consumption exhibited the same trend as those for coffee consumption; coffee consumption was then used in all subsequent analyses. Maternal smoking around the time of conception was not associated with the risk of having a recognized Down syndrome pregnancy. Consuming four or more alcoholic drinks per week during the first month of pregnancy was associated with a reduced risk for Down syndrome (OR = 0.54; 95 percent CI: 0.34, 0.85).


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TABLE 2. Age-adjusted odds ratio for having a recognized pregnancy with Down syndrome, according to various maternal characteristics, California, 1991–1993

 
Table 3 outlines the results of the multivariate analysis that included an interaction term for smoking and coffee consumption. Five cases and four controls with unknown values were excluded from the multiple regression analyses of all births. The odds ratios for the following variables remained significant when all births were considered: high coffee consumption among nonsmokers, less than a high school education, Hispanic ethnicity, and single year of age. After adjustment for other variables, the effects of high gravidity and consumption of four or more alcoholic drinks per week remained but dropped below the level of significance. The interaction between smoking and heavy coffee consumption was highly significant (p <= 0.01). A repetition of this analysis limited to live births further reduced the odds ratios for coffee and alcohol consumption; all previously significant associations remained, and the associations with high alcohol consumption and high gravidity became significant.


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TABLE 3. Adjusted odds ratio* for having a recognized pregnancy with Down syndrome, according to various maternal characteristics, California, 1991–1993

 

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TABLE 4. Adjusted odds ratio for having a recognized pregnancy with Down syndrome, according to maternal smoking-coffee consumption category (all birth outcomes), California, 1991–1993

 
Table 4 shows the risk of Down syndrome stratified by level of coffee consumption and smoking after adjustment for all retained variables. The category of nonsmokers with daily coffee consumption of three cups or less was used as the referent group. We observed a significantly reduced risk of Down syndrome for heavy coffee drinkers who did not smoke (OR = 0.48; 95 percent CI: 0.28, 0.82) but not for heavy coffee drinkers who smoked (OR = 1.64; 95 percent CI: 0.80, 3.36). For smokers who consumed less coffee, the odds ratio was close to 1. These results demonstrate the strong interaction observed between smoking and high coffee consumption.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this large case-control study, we were able to obtain a more representative age distribution of recognized Down syndrome cases by including elective terminations. However, we were unable to include early spontaneous abortions which go undetected yet form a large proportion of Down syndrome concepti. Wilcox et al. (8Go) observed that miscarriage occurred in 25 percent of all pregnancies in the first 6 weeks after the last menstrual period. Eiben et al. (13Go), in a study of 750 abortuses older than 4 weeks' gestation, noted that 54.1 percent of those spontaneously aborted before the 12th week of gestation had abnormal karyotypes, with trisomies predominating. Snijders et al. (29Go) observed the age-specific prevalence of Down syndrome at birth to be 54 percent lower than its prevalence in fetuses karyotyped at 9–14 weeks' gestation, the decrease being associated with a high early fetal loss rate. We ascertained only nine spontaneous abortions of less than 15 weeks' gestation; thus, our case-control study included less than half of the Down syndrome fetuses originally conceived.

To overcome any bias introduced by comparing Down syndrome cases that included fetal losses with liveborn controls, we repeated our multivariate analysis including only liveborn cases. Although the increase in risk with each additional year of mother's age dropped from 15 percent to 10 percent, it confirmed and strengthened other associations and allows comparison of our results with those of studies limited to live births.

A limitation of our study stems from our use of maternal self-reports of smoking and coffee drinking as proxies for actual biologic levels of nicotine and caffeine. Furthermore, we preferred to use the single estimate of cups of coffee consumed as opposed to the rough estimates of caffeine contained in those cups. However, there is no reason to believe that cases and controls would have reported their consumption of coffee or other beverages differentially.

In our study, the proportion of infants with Down syndrome who were Hispanic was higher than the proportion of Hispanics among controls. Two other California studies have observed significantly higher rates of Down syndrome among Hispanics (30Go, 31Go).

Our observation that having less than a high school education was associated with a nearly 50 percent increase in Down syndrome (OR = 1.50; 95 percent CI: 1.17, 1.91) was unexpected. This association was not observed in the data from the Collaborative Perinatal Project presented by Hook and Cross (32Go) or in the studies by Sigler et al. (33Go) and Stoll et al. (34Go). However, in 1974, Harlap (35Go), in Israel, observed an increased rate of Down syndrome among families with a lower standard of living as defined by father's education. Because 76 percent of our mothers with less than a high school education were foreign-born, place of birth was added to the regression analysis, but the association remained unchanged. Perhaps education in our data set represented a broader spectrum of socioeconomic levels than those usually observed in other studies in the United States and abroad.

High gravidity (>=4 pregnancies) and high parity have long been suspected of being associated with Down syndrome (36Go). Källen (37Go) and Schimmel et al. (38Go) reported that grand multiparas have a higher risk for a Down syndrome live birth. In our study, in multivariate analysis limited to live births, the association was confirmed for high gravidity (OR = 1.41; 95 percent CI: 1.10, 1.80) and parity (data not shown); but when all births were included, the odds ratio dropped to 1.15 (95 percent CI: 0.92, 1.45), which suggests that high gravidity may influence either the survival of the fetus or a mother's choice to terminate her pregnancy. Källen's data (Go) support the latter suggestion.

After adjustment for other risk factors, maternal consumption of four or more alcoholic drinks per week during the first month of pregnancy had a moderate inverse relation with Down syndrome (OR = 0.66; 95 percent CI: 0.41, 1.06). Maternal alcohol consumption has previously been associated with increases in spontaneous fetal loss (1Go, 2Go, 10Go, 39Go, 40Go). This association, and the fact that the odds ratio was reduced further when only live births were analyzed, suggests that alcohol consumption has a stronger effect on the trisomic fetus than on the normal fetus or that mothers who use alcohol are more likely to terminate pregnancies with a Down syndrome conceptus.

Heavy coffee consumption (>=4 cups/day) was inversely associated with the occurrence of a recognized Down syndrome pregnancy, suggesting that mothers who consumed caffeine at levels of >=400 mg/day were more likely to miscarry a Down syndrome fetus. Other investigators (41Go), basing their evaluation of coffee consumption on serum levels of paraxanthine, a metabolite of caffeine, have suggested that a high level of caffeine intake is a moderate risk factor for spontaneous abortion.

In our data, maternal smoking without high coffee consumption was not a risk factor for Down syndrome. Several small studies (32Go, 42Go) reported a nonsignificant inverse association of maternal smoking with Down syndrome risk which Källen (43Go), in a larger study, could not confirm. None of these studies controlled for caffeine intake.

Interaction between maternal smoking and various levels of coffee or caffeine consumption have been studied by others for various pregnancy outcomes that do not include Down syndrome. Some have observed a significant interaction (15Go, 24Go, 25Go, 44Go) and others have not (5Go, 6Go, 16Go, 27Go, 45Go). In order to evaluate the biologic plausibility of an interaction between maternal smoking and high caffeine consumption, we reviewed the metabolism of caffeine and nicotine. Nicotine is metabolized to cotinine by the enzyme CYP2A6, a cytochrome P-450 enzyme that has genetic variants (46Go). Cotinine, in turn, appears to have a longer half-life in African Americans than in Whites (47GoGo–49Go), which further suggests genetic differences in nicotine metabolism. Caffeine metabolism is widely variable depending on the activity of several enzymes, including CYP1A2, xanthine oxidase, and N-acetyltransferase-2 (22Go). Racial differences in xanthine oxidase activity have been observed (22Go). Caffeine metabolism is also strongly affected by tobacco smoking (20GoGo–22Go). Smoking is thought to accelerate the clearance of caffeine from the body through the induction of hepatic cytochrome P-450 enzymes that increase N-demethylation (18Go, 19Go). When people stop smoking, their serum caffeine levels increase by 250 percent or more (23Go). Clearance of caffeine from the body is slowed down considerably by pregnancy and reaches its lowest point in the third trimester (21Go). Caffeine readily crosses the placenta and builds up in all fetal tissues at higher levels than in adult tissues (50Go, 51Go). Because smoking speeds up caffeine metabolism, it seems plausible that a given dose of caffeine would have a stronger effect in nonsmokers than in smokers, as suggested by our results; furthermore, this type of interaction could vary according to the genetic makeup of the population studied.

Coffee consumption increases with maternal age (15Go, 16Go, 18Go) as well as with smoking. We therefore split our population into two age groups and repeated the analyses, also adjusting by single year of mother's age. High coffee consumption was associated with reduced risks for Down syndrome in both groups, but the effects were stronger in older mothers.

To explore further the relation between spontaneous abortion and high coffee consumption, we examined the outcome of previous pregnancies of case and control mothers who did not smoke, assuming that the mothers' coffee drinking habits would not have changed much over time. Case and control mothers who were high coffee consumers each had previous spontaneous abortion rates (23.2 percent and 23.0 percent, respectively) approximately 50 percent higher than those of mothers who consumed less coffee.

If, during the interval of greatest loss (before 15 weeks' gestation), Down syndrome fetuses are more vulnerable to caffeine or alcohol consumed by the mother than are fetuses of normal karyotype, one would expect a higher rate of Down syndrome fetal loss among users of these substances. The proportion of users would then be decreased among subsequently recognized cases, as postulated by Khoury et al. (52Go). Because more than 99 percent of our cases were detected after 15 weeks' gestation and fewer cases than expected were observed among mothers who had high coffee or alcohol consumption, we propose that our observations are consistent with this expectation. Smoking was not directly associated with a reduction in Down syndrome, but among mothers who smoked and were heavy coffee drinkers, smoking appeared to reverse the effects of coffee, possibly by speeding up its metabolism and clearance from the body. Additional factors such as genetic differences in enzyme variants or unrecognized confounders may have contributed to these findings.

Because the proportion of heavy coffee drinkers in our population was small, the overall effect of coffee among nonsmokers on the prevalence of Down syndrome was quite small. Nevertheless, our findings are consistent with the hypothesis that, in nonsmokers, caffeine (or other substances contained in coffee), when consumed at high levels (>=4 cups/day), increases the probability of an early Down syndrome fetal loss. Our study also emphasizes the need to consider the interaction between coffee consumption and smoking in studies pertaining to pregnancy.


    ACKNOWLEDGMENTS
 
Financial support (grant 2RT0080) was provided by the Cigarette and Tobacco Surtax Fund of the State of California through the Tobacco-Related Disease Research Program of the University of California.

The authors thank Dr. M. Khoury for assistance in sampling of controls and the data collection specialists for their dedication to excellence.


    NOTES
 
(Reprint requests to Dr. Claudine P. Torfs at this address (e-mail: cptorfs{at}cbdmp.org)).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication April 14, 1999. Accepted for publication January 12, 2000.