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Caffeine consumption during pregnancy and association with late spontaneous abortion
Clinical Articles Caffeine consumption during pregnancy and association with late spontaneous abortion Wichit Srisuphan, Dr.P.H., and Michael B. Bracken, Ph.D. New Haven, Connecticut In a prospective cohort study, 3135 pregnant women were followed to evaluate the association of caffeine consumption during pregnancy with late first- and second-trimester spontaneous abortion. Almost 80% of pregnant women used some caffeine; among users the average daily intake was 99.3 mg from all sources. Sources of caffeine were nonherbal tea (used by 49.4% of women), coffee (41.2%), colas (35.0%), and drugs (6.6%). In all, 28% of pregnant women consumed ""151 mg of caffeine daily, and these "moderateto-heavy" caffeine users were significantly more likely to experience late first- or second-trimester spontaneous abortion when compared with nonusers and light users (0 to 150 mg). Demographic characteristics, reproductive and medical history, contraceptive use, and smoking and drinking habits were taken into consideration. The adjusted relative risk of miscarriage after moderate-to-heavy caffeine consumption was 1.73 (p = 0.03). Light caffeine use (1 to 150 mg daily) was associated with increased risk for spontaneous abortion only among women who aborted in their last pregnancy (RR = 4.18, p = 0.04). Replicative studies are necessary before the association of caffeine with spontaneous abortion can be confirmed. (AM J 0BSTET GYNECOL 1986;154:14-20.)
Key words: Caffeine, pregnancy, spontaneous abortion
Caffeine is listed in the Code of Federal Regulations as a multipurpose food substance that is generally recognized as safe. It can be found in cold tablets, allergy or analgesic preparations (15 to 64 mg/U), appetite suppressants (50 to 200 mg/U), and stimulants (100 to 200 mg!U). As a beverage, caffeine is ingested daily by a large segment of the American population as coffee (29 to 176 mg/cup), tea (8 to 107 mg/cup), cocoa (5 to 10 mg/cup), solid milk chocolate (6 mg/ounce), and cola beverages (32 to 65 mg/12 oz).' Less is known about caffeine consumption during pregnancy. In animals several studies have suggested a possible link of caffeine to birth defects, fetal resorption, and decreases in fetal weight. 2 Although the extrapolation of findings from animal studies to humans is not straightforward, the U.S. Food and Drug Administra-
From the Perinatal Epidemiology Unit of the Departments of Epidemiology and Public Health and Obstetrics and Gynecology, Yale University Medical School. Support for this study was provided by the National Center for Child Health and Human Development Award No. HD 11357. Received for publication june 24, 1985; revised October 10, 1985; accepted October 14, 1985. Reprint requests: Dr. Michael B. Bracken, Department of Epidemiology and Public Health, Yale University Medical School, 60 College St., New Haven, CT 06510.
14
tion cautions pregnant women to avoid caffeine or to use it sparingly. Caffeine is readily absorbed from the gastrointestinal tract and is rapidly distributed throughout all tissues as a function of water content. It also crosses the placenta.' In pregnant women the plasma half-life has been observed to increase to I 0.5 hours as compared to 2.5 to 4.5 hours in healthy adults.< The plasma halflife in the newborn infant ranges from 32 to 149 hours. 5 Potential effects of caffeine on fetal development may follow prolonged accumulation of caffeine in pregnant women and passage to the fetus which lacks enzymes necessary for the metabolism of caffeine until several days after birth. 5 Additionally, caffeine is known to increase adenosine-3' : 5' -cyclic monophosphate in cells and may interfere with fetal cell growth. Caffeine may act directly on nucleic acids, 6 since it is structurally similar to adenine and guanine, and result in chromosome aberrations. Another possible mechanism of caffeine action is by the increase of catecholamines, 7 which may restrict uteroplacental circulation through vasoconstriction and result in fetal hypoxia. Fetal deaths, decreases of fetal weight, fetal malformations, and shortened gestational age can follow fetat hypoxia. Existing human studies provide incomplete and conflicting results of the effect of caffeine consumed dur-
Caffeine and late spontaneous abortion
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Table I. Daily consumption of coffee, tea, and colas during pregnancy in the study population Coffee Frequency of use
n
Nonusers 1-3 cups/wk 4-6 cups/wk 1-2 cups/day 3-4 cups/day 5-10 cups/day 10+ cups/day Total
1843 422 154 553 139 22 2 3135
I
Tea
I
%
n
58.8 13.5 4.9 17.6 4.4 0.7 0.1 100.0
1586 594 209 585 129 25 7 3135
ing pregnancy on the risk for birth defects," preterm deliveries, 9• 11 and low birth weight. 10• 12 Only one study 9 reported a higher rate of spontaneous abortion among 16 women whose caffeine consumption during pregnancy was high (>600 mg). This study almost certainly used an unrepresentative sample of patients, since they had an unusually high stillbirth rate of 12.7%. Potential confounding variables were not controlled in the analysis and risks of moderate caffeine intake were not studied. The objectives of the present study are (1) to provide a detailed description of caffeine exposure in a large population of pregnant women and (2) to investigate the relationship between caffeine consumption during pregnancy and spontaneous abortion. Material and methods
Candidates for the study were all women who planned to be delivered at Yale New Haven Hospital and who sought care from 29 private physicians and health maintenance organizations in the New Haven area between May, 1980, and March, 1982. Each woman was interviewed during pregnancy by a trained interviewer with use of a standardized schedule. Information obtained included demographic characteristics, previous medical and obstetric history, smoking and drinking habits during pregnancy, and occupational exposure. Caffeine consumption was calculated from caffeinated coffee, tea, and colas (including all caffeinated soft drinks) with use of, respectively, 107 mg/serving, 34 mg/serving, and 4 7 mg/serving.' The names, numbers of days, times per day, and the weeks in gestation when prescription and nonprescription drugs were used during the first trimester of pregnancy were ascertained to identify those containing caffeine. Drug recall was enhanced by probing for 22 specific conditions (e.g., for control of nausea, for fluid retention, for diet or weight loss). Spontaneous abortion was defined as nondeliberate interruption of an intrauterine pregnancy of <28 weeks' gestation in which the fetus was dead when expelled. Gestational age at spontaneous abortion was
Colas
%
n
50.6 19.0 6.7 18.7 4.1 0.8 0.2 100.0
2037 617 194 219 50 13 5 3135
I
%
65.0 20.0 6.2 7.0 1.6 0.4 0.2 100.0
computed based on date of conception and the date of abortion. Date of conception was based on last menstrual period or physician's estimated due date for respondents when the last period was uncertain. Spontaneous abortions (n = 68) were identified from medical records and follow-up contacts with obstetricians and respondents. All miscarriages in the study occurred after interview and between 8 and 26 weeks' gestation. A total of 4073 women were eligible for the study. Women were considered ineligible for interview if they ( 1) were not pregnant at the time of interview, including women who spontaneously aborted or who were delivered before interview; (2) did not plan to deliver at our hospital; (3) demonstrated poor English comprehension; and (4) were familiar with the study. Of the eligible women, 473 refused to be interviewed, and 255 could not be reached to arrange an interview. For five subjects the interviewer considered the interview to be invalid. Interviews were completed on 3340 (82.0%) of eligible women. The pregnancy outcome of a further 86 women could not be ascertained, and 95 women were excluded because their gestational age at interview was >28 weeks and they were no longer at risk for spontaneous abortion. Some detail of caffeine consumption was lacking in 24 women, so we could not compute their average daily caffeine intake. The analysis uses 3135 subjects. Results
Frequency of caffeine consumption during pregnancy. Nonherbal tea was the most frequently used caffeinated beverage (drunk by 49.4% of all respondents) followed by coffee (41.2%) and colas (35.0%) (Table I). Neither coffee nor tea drinking was reported by 30.7% of respondents and 21.9% did not drink coffee, tea, or colas. The average servings daily were tea, 0.6; coffee, 0.6; and colas, 0.3. The frequency for drinking three or more servings per day of coffee, tea, and colas was 5.2%, 5.1% and 2.2%, respectively. Overall, 6.6% of women used a caffeine-containing prescription or nonprescription drug at least once in the first trimester. Most of these women (95.1 %) used
16 Srisuphan and Bracken
January, !986 Am J Obstet Gynecol
Table II. Source and amount of average daily caffeine consumption by type of consumer
(n
=
(n
1292)
I
%
mg
143.7 20.1 16.2 5.1
77.6 10.9 8.7 2.8
185.1
100.0
Source
mg
Coffee Tea Colas Drugs Total
No coffee or tea used
No coffee used
Coffee used
= 1843)
I
(n
%
mg
21.2 13.4 4.5
54.2 34.4 11.5
39.1
100.0
only one caffeine-containing drug. Excedrin (64.8 mg of caffeine per unit) was the most frequently used caffeine-containing drug (by 23.7% of caffeine-drug users), followed by Anacin (32.5 mg of caffeine, 19.1% of users), Dristan (16.2 mg, 14.9% of users), Fiorinal (40 mg, 8.8% of users), and Dexatrim and Dietac (200 mg, 6.5% of users). However, these drugs were used sporadically; 54.6% used them for a period of I to 3 days and 23.7% for 4 to 14 days. In all, 652 women (20.8%) used no caffeine in pregnancy, 1604 (51.2%) were light (1 to 150 mg daily) caffeine users, and 879 (28.0%) were heavy (~151 mg daily) caffeine users. The source of caffeine for different consumers is shown in Table II. Characteristics of women who used caffeine during pregnancy. Daily caffeine consumption is categorized as none (0 mg), light (1 to 150 mg), and moderate-toheavy (~ 151 mg). Table III summarizes the demographic characteristics of women who used and did not use ~affeine during pregnancy. Moderate-to-heavy users are significantly more likely to be over 30 years of age, be white, have ~12 years of education, be relatively heavy users of alcohol (daily consumption of absolute alcohol of >0.25 ounces), be cigarette smokers, use marijuana during pregnancy, be in households whose head is a skilled or unskilled worker, and be interviewed beyond 12 weeks' gestation. Mothers not using any drugs during the first trimester, and Jewish women are significantly less likely to be caffeine users. Moderate-to-heavy caffeine users are significantly more likely to have higher gravidity and parity, be women with a history of spontaneous abortion, and be less likely to have a history of gynecologic surgery or any gynecologic condition. Menarcheal age, total numbers of prior induced abortions, interval from last pregnancy and history of any infertility treatment 12 months before pregnancy are not statistically different among the three caffeine exposure groups (Table IV). All contraceptive methods used during the month before conception, at the time of conception, or 1 month after conception were similar in the three caffeine use groups.
No coffee, tea, or colas used
= 963)
l
(n
= 685)
I
%
mg
12.5 3.7
77.3 22.7
3.9
100.0
16.2
100.0
3.9
100.0
%
Maternal characteristics associated with spontaneous abortion. Women who spontaneously aborted were significantly more likely to be over 30 years of age. Jewish women had a higher spontaneous abortion rate, but this increase is not statistically significant (p = 0.09 for Jewish versus non-Jewish). Marital status, education, religion, ethnic background, number of drugs used in the first trimester, medical conditions 12 months before pregnancy, any injury during pregnancy, diethylstilbestrol used by respondents' mother, cigarette smoking, alcohol, and marijuana use during pregnancy were not markedly different in the group with spontaneous abortions and in the group without them. As expected, women interviewed early in pregnancy were significantly more likely to subsequently abort. Spontaneous abortion rates were significantly higher in women who became pregnant (with the index pregnancy) within 6 months of the last pregnancy (p < 0.001) and with a history of gynecologic surgery (p = 0.03). Menarcheal age, gravidity, parity, history of any previous spontaneous abortion or induced abortion, any infertility treatment 12 months before the index pregnancy, and termination of the last pregnancy with a spontaneous abortion were not significantly different between the two groups. The use of pill, intrauterine device, foam, cream, jelly, suppository, diaphragm, rhythm, condom, and withdrawal were not significantly associated with spontaneous abortion. Frequency of spontaneous abortion and crude association with caffeine used. In all, 2.2% of the study subjects spontaneously aborted after the interview. The rate for non-caffeine users was 1.8%; for light caffeine users, 1.8%; and for moderate-to-heavy caffeine users, 3.1% (p = 0.096). Because of the similar spontaneous abortion rate in the no caffeine and light caffeine users, this group was combined (0 to 150 mg). The crude relative risk for spontaneous abortion of moderate-toheavy use (> 150 mg) was 1.69 (95% confidence intervals= 1.04 and 2.71, p = 0.030). Multivariate analysis of association between caffeine consumption during pregnancy and sponta-
Caffeine and late spontaneous abortion
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Table III. Maternal characteristics of caffeine users during pregnancy by average daily caffeine use Average daily caffeine exposure (mg) Characteristics Age :S30 years >30 years Marital status Currently married Not currently married Religion Catholic Protestant Jewish None Other Education (yr) <12 12 13-16 17+ Ethnic background White Nonwhite Occupation of head of household Higher executive, lesser professional Administrative personnel, technician Skilled or unskilled labor Gestational age at interview (wk) :S12 >12 No. of drugs used* 0 I
2+ Medical conditions 12 months before pregnancyt No Yes Injury during pregnancy No Yes Mothers exposed to diethylstilbestrol No Yes Uncertain Alcohol use during pregnancy None :s0.25 of absolute alcohol >0.25 of absolute alcohol No. of cigarettes smoked per day during pregnancy 0 1-10 II+ Marijuana use during pregnancy No Yes
151 +
Significance tests
52.9 46.9
25.4 34.5
t, = 26.94 p = 0.0001
20.7 21.9
51.4 47.9
27.9 30.2
x = 0.88
1606 1019 210 211 67
15.8 24.7 30.5 28.4 26.9
5l.l 52.0 51.9 45.5 50.8
33.1 23.3 17.6 26.1 22.4
148 785 1575 627
16.2 15.5 21.4 27.0
45.3 51.7 52.1 49.4
38.5 32.7 26.5 23.6
2873 257
29.2 20.1
51.5 47.1
28.4 23.7
X~=
1090 1080 954
23.5 21.7 16.6
52.1 49.4 52.3
24.2 29.0 3l.l
X~=
1875 1260
20.6 21.0
52.8 48.7
26.6 30.2
x§ = 6.13
968 988 1178
25.7 18.5 18.7
48.1 53.9 51.4
26.1 27.6 29.9
2776 359
2l.l 18.7
51.5 48.8
27.5 32.6
X~
2917 204
20.7 22.6
51.3 48.5
28.0 28.9
X~=
2590 29 481
21.2 31.0 17.9
51.2 48.3 51.9
27.6 20.7 31.2
804 2088 243
27.2 19.1 14.0
51.4 52.4 40.3
21.4 28.5 45.7
2259 433 405
24.1 14.3 9.1
54.0 49.0 38.0
21.9 36.7 52.8
2911 222
21.3 14.9
51.3 49.1
27.5 36.0
n
0
2226 909
21.7 18.6
2643 192
I
1-150
l
2
p
= 0.64
X~=
p
76.63
= 0.0001
X~=
p
p p
p
43.06
= 0.0001 12.13
= 0.002
22.30
= 0.0002
= 0.047
x; = 22.17 p p p
= 0.0002
= 4.35 = 0.11 0.63
= 0.73
x; = 6.18 p
= 0.19
x; = 70.29 p
= 0.0001
x; = p
X~=
p
195.57
= 0.0001 9.68
= 0.008
*Prescription and nonprescription drugs were included. tHeart or circulation problems, kidney problems, high blood pressure, sickle cell anemia, or other medical conditions.
neous abortion. Variables associated with both caffeine exposure and miscarriage at the p < 0.10 level of significance were considered potential confounding factors. These were gestational age at interview, maternal age, prior gynecologic surgery, member of Jewish religion, and last pregnancy ending with a spontaneous
abortion. Several classifications of average daily caffeine consumption were used to test for an association with spontaneous abortion. First daily caffeine consumption was trichotomized as none, light (l to 150 mg), and moderate-to-heavy(;:;,: 151 mg), and a multiple logistic regression model was fit to the data. This pro-
18 Srisuphan and Bracken
January, 1986 Am J Obstet Gynecol
Table IV. Maternal obstetric history by levels of caffeine exposure and significance tests Levels of caffeine exposure (mg) Obstetric history Menarcheal age (yr) <12 12-13 14+ Gravidity 1 2 3 Parity :S[
2+ Previous spontaneous abortion 0 I
2+ Previous induced abortion 0 I 2+ Spontaneous abortion in last pregnancy Never pregnant No Yes Induced abortion in last pregnancy Never pregnant No Yes Interval from last pregnancy s6 months >6 months Gynecologic condition 12 months before pregnancy* No Yes Infertility treatment 12 months before pregnancy No Yes Gynecologic surgeryt No Yes
I
I
+
Significance tests
n
0
684 1796 625
21.1 20.4 21.8
48.4 52.6 50.2
30.7 26.8 27.8
xi= 4.59 p = 0.35
946 1!13 1075
24.7 20.5 17.7
52.9 52.6 48.2
22.4 27.0 34.1
X~= 40.38
p
= 0.0001
2574 56!
21.8 16.2
52.3 46.2
26.0 37.6
X~
= 32.55 = 0.0001
1618 445 126
18.4 19.6 26.2
52.0 49.7 33.3
29.6 30.8 40.5
xi = 16.44 p = 0.0025
1572 492 125
17.7 22.8 22.4
51.2 48.1 49.6
31.1 29.! 28.0
xl = p =
943 1843 345
24.8 18.3 23.2
52.8 51.5 44.6
22.4 30.2 32.2
xi= 29.92 p = 0.0001
943 1803 386
24.8 17.8 25.1
52.8 50.8 48.7
22.4 31.4 26.2
xi= p =
199 1950
22.1 !8.7
48.2 50.8
29.7 30.5
x! = 1.36 p = 0.50
2340 795
!9.4 24.8
50.9 51.8
29.6 23.4
X~
2957 178
20.5 26.4
51.2 51.1
28.4 22.5
X~= 4.94
2333 802
!9.7 24.1
52.7 46.6
27.6 29.3
x! = p =
1-150
151
p
p p
7.30 0.13
38.07 0.0001
= 16.40 = 0.0003 = 0.08 10.47 0.005
*Vaginal infections, venereal disease, or pelvic inflammatory disease. tCaesarean section, induced abortion, or dilatation and curettage given as an abortion procedure are not included.
vided adjusted relative risks that take into account other confounding factors. Moderate-to-heavy use was associated with a twofold increased risk of spontaneous abortion (relative risk = 1.95, p = 0.07). Light caffeine use was not by itself associated with an increased rate of spontaneous abortion except among women who also had a history of spontaneous abortion in their last pregnancy. These women had a fourfold increase in spontaneous abortion (relative risk = 4.18, p = 0.04). Next we dichotomized the sample's caffeine use as none and light (0 to 150 mg) and moderate-to-heavy (~ 151 mg). The multiple logistic regression analysis for this classification of caffeine is shown in Table V. Moderate-to-heavy caffeine use was significantly associated with an increased risk of spontaneous abortion (relative risk = l. 73, p = 0.03), as was maternal age over 30 and the methodologic variable-gestational age at interview in the first trimester.
A third multiple logistic regression analysis was used to examine the effect of increasing daily caffeine consumption in 50 mg increments on risk for spontaneous abortion. There was no significant elevation of the adjusted relative risks for caffeine at 150 mg per day or less. At levels > 150 mg per day there was a marked increase in the adjusted relative risk for miscarriage, but caffeine consumption of >200 mg did not further increase risk. An attempt was made to identify the particular source of caffeine that might be associated with spontaneous abortion. However, the number of women in each category is frequently too small to detect other than large effects. Those whose caffeine source was from coffee alone had an increased risk of miscarriage over those whose source was tea alone or colas alone (eRR of 2.0, l.l, and 1.3, respectively); however, these associations are not statistically significant.
Volume 154 !';umber l
Comment Before the results of this investigation are discussed, some limitations need to be noted. First, although the study has a relatively high response rate of 82% of eligible patients, selection bias may occur if women elect to participate based on their caffeine consumption. However, the study was introduced to women as a study of "factors influencing the health of women during pregnancy and their newborn infants" and caffeine was not specifically mentioned. It is unlikely, therefore, that women selectively participated in the study based on their caffeine consumption. Second, the results of the study are limited to only late first- and second-trimester miscarriage. This study therefore cannot evaluate the risk of caffeine consumption during pregnancy on early first-trimester spontaneous abortions. Third, the results are limited to patients seeking their antenatal care at private obstetrical practices and health maintenance organizations. Fourth, although only 86 women (2.7%) were lost to follow-up after interviewing, they could bias the result if these women had a differential rate of spontaneous abortion and caffeine use. However, attrition loss is unlikely to be a major problem, since the average daily caffeine consumption and demographic characteristics of mothers lost to follow-up were not different from mothers who stayed in the study. Fifth, a number of potential confounding variables, for example, maternal illness during the index pregnancy, are not included in the study. Mothers who have some illness, that is, gastrointestinal or cardiovascular problems that may predispose them to spontaneously abort might be advised to avoid or limit caffeine consumption. Such a bias would spuriously reduce the risk estimates for caffeine. In the present prospective study, recall bias could not occur because women were interviewed before knowing their pregnancy outcomes. Sixth, information concerning caffeine consumption is ascertained at the time of interview and cannot necessarily be assumed to remain constant throughout the entire pregnancy. However, a retrospective study at the same hospital' 1 found that average coffee and tea consumption for the first, second, and third trimesters of pregnancy are almost the same. Our estimate that 2.2% of pregnancies end in late first- and second-trimester spontaneous abortion in the study may appear somewhat low. However, if the early spontaneous abortions before interview are included, the rate of 7.2% for spontaneous abortion is not low for a prospective study; those reviewed by Kline and Stein 13 ranged from 3.6% to 9.7%. The finding that 79.2% of the study population was exposed to some caffeine is comparable to the estimate of 74% from the GRAS Survey, 14 which did not include caffeine from drugs. The proportions of those who drink coffee (41.2%)
Caffeine and late spontaneous abortion
19
Table V. Adjusted relative risks and the significance levels of moderately heavy caffeine users and all potential confounding variables Factors
Intercept Moderately heavy caffeine users Maternal age, 31 + years Gestational age at interview s: 12 weeks Jewish Prior gynecologic surgery Spontaneous abortion in last pregnancy
Adjusted relative risks
O.Dl
p value
1.73
0.00 0.03
1.72 2.53
0.03 0.002
1.82 1.43 1.45
0.12 0.19 0.29
or tea (49.4%) are somewhat lower than in one previous study but similar to others. 10· 11 Comparison of the average daily servings for coffee and tea of the earlier Yale study 11 with the present one suggests pregnant women may have reduced coffee and tea consumption rather than having stopped completely (average daily servings in 1980 to 82 of 0.6 for coffee and 0.6 for tea versus 1.1 for coffee and 1.0 for tea in 1977). It is unlikely that the average daily caffeine intake reported in this study is under reported. Overall, 6.6% of the study population used at least one caffeine-containing drug during the first trimester of pregnancy. The figure is comparable to that of 10.7% use by pregnant women in the first 4 months' gestation as reported in the Collaborative Perinatal Project, 15 which collected data between 1959 and 1965. The finding that daily caffeine exposure at the 1 to 150 mg level did not significantly increase the risk for spontaneous abortion whereas it did for the > 150 mg level may be interpreted in at least three ways. First, caffeine may have a threshold effect around 150 mg. Ingestion of daily caffeine of < 150 mg may not sufficiently affect the fetus to cause fetal death through interference with cell division, cell growth, or uteroplacental circulation. Second, smoking increases demethylation of caffeine in humans, 16 which may reduce the plasma half-life of caffeine and increase its rate of elimination. In this study, smokers are significantly more likely to be caffeine users. Therefore, the effect of caffeine at 1 to 150 mg/day on spontaneous abortion in smokers may be diminished. Third, fetal effects may come from coffee consumption rather than caffeine per se. In this study, coffee is a major source of caffeine in moderate-to-heavy caffeine users (72%) but not in light caffeine users (26%). Benzo (a) pyrene and chlorogenic acid, found in roast coffee, 17 may increase risk for spontaneous abortion. Both caffeinated and decaffeinated instant and roast coffee, but not tea or cocoa, have recently been found to contain an opiate receptor antagonist with binding activity clearly separable from
20 Srisuphan and Bracken
caffeine. 18 The hypothesis that some component of coffee other than caffeine may be associated with spontaneous abortion should be tested in future research. Women who have experienced spontaneous abortion in their last pregnancy are known to be at increased risk for subsequent spontaneous abortion. In these women light caffeine use may further increase their susceptibility. This must be considered a preliminary observation, however, since prior miscarriage did not further significantly increase spontaneous abortion risks among moderate-to-heavy caffeine users. This is the first population-based study to report an association of caffeine with an increased risk of late first- and second-trimester spontaneous abortion. Although the effect of caffeine is consistent in all the statistical models we used, not all analyses achieved conventional statistical significance. Thus, additional studies are needed before the association of caffeine with spontaneous abortion can be more definitively evaluated. REFERENCES 1. Bunker ML, McWilliams M. Caffeine content of common beverages. J Am Diet Assoc 1979;74:28. 2. Collins TFX. Update to review of caffeine studies. FDA By-Lines 1981;1:19-24. 3. Mirkin BL, Singh S. Placental transfer of pharmacologically active molecules. In: Mirkin BL, ed. Perinatal pharmacology and therapeutics, New York: Academic Press, 1976:1-69. 4. Knutti R, Rothweiler H, Schlatter C. The effect of pregnancy on the pharmacokinetics of caffeine. Arch Toxicol 1982;5(suppl): 187-92.
January, 1986 Am J Obstet Gynecol
5. Horning MG, Stratton C, Nowlin J, et al. Placental transfer of drugs. In: Boreus LO, ed. Fetal pharmacology. New York: Raven Press, 1973:355. 6. Wethersbee PS, Lodge JR. Caffeine: its direct and indirect influence on reproduction. J Reprod Med 1977:19:55-63. 7. Anton AH. Catecholamines during pregnancy and their effects on the fetus. Pediatr Adolesc Endocrinol 1979; 5:110-25. 8. Rosenberg L, Mitchell A, Shapiro S, et al. Selected birth defects in relation to caffeine-containing beverages. JAMA 1982;247:1429-32. 9. Wethersbee PS, Olsen LK, Lodge JR. Caffeine and pregnancy: a retrospective study. Postgrad Med 1977;62:649. 10. Linn S, Schoenbaum SC, Monson RR, et al. No association between coffee consumption and adverse outcomes of pregnancy. N EnglJ Med 1982;306:141-5. 11. Berkowitz GS, Holford TR, Berkowitz RL. Effects of cigarette smoking, alcohol, coffee and tea consumption on preterm delivery. Early Hum Dev 1982;7:349-50. 12. van den Berg BJ. Epidemiologic observations of prematurity: effects of tobacco, coffee and alcohol. In: Reed DM, Stanley F.J, eds. The epidemiology of prematurity. Baltimore: Urban & Schwarzenberg, 1977:157-77. 13. Kline J, Stein Z. Spontaneous abortion (miscarriage). In: Bracken MB, ed. Perinatal epidemiology. New York: Oxford University Press, 1984:23-51. 14. Graham DM. Caffeine: its identity, dietary sources, intake and biological effects. Nutr Rev 1978;36:99. 15. Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton, Massachusetts: PSG Publishing Company, 1977:462. 16. Kaplan R. Caffeine: an update. Drug Chern Toxicol 1981;4:311-29. 17. Kuratsume M, Hueper WC. Polycyclic aromatic hydrocarbons in coffee soots. JNCI 1958;20:37-51. 18. Boublik .JH, Quinn MJ, Clements JA, Herington AC, Wynne KN, Funder JW. Caffeine contains potent opiate receptor binding activity. Nature 1983;30 1:246-8.
Key words: Caffeine, pregnancy, spontaneous abortion
Caffeine is listed in the Code of Federal Regulations as a multipurpose food substance that is generally recognized as safe. It can be found in cold tablets, allergy or analgesic preparations (15 to 64 mg/U), appetite suppressants (50 to 200 mg/U), and stimulants (100 to 200 mg!U). As a beverage, caffeine is ingested daily by a large segment of the American population as coffee (29 to 176 mg/cup), tea (8 to 107 mg/cup), cocoa (5 to 10 mg/cup), solid milk chocolate (6 mg/ounce), and cola beverages (32 to 65 mg/12 oz).' Less is known about caffeine consumption during pregnancy. In animals several studies have suggested a possible link of caffeine to birth defects, fetal resorption, and decreases in fetal weight. 2 Although the extrapolation of findings from animal studies to humans is not straightforward, the U.S. Food and Drug Administra-
From the Perinatal Epidemiology Unit of the Departments of Epidemiology and Public Health and Obstetrics and Gynecology, Yale University Medical School. Support for this study was provided by the National Center for Child Health and Human Development Award No. HD 11357. Received for publication june 24, 1985; revised October 10, 1985; accepted October 14, 1985. Reprint requests: Dr. Michael B. Bracken, Department of Epidemiology and Public Health, Yale University Medical School, 60 College St., New Haven, CT 06510.
14
tion cautions pregnant women to avoid caffeine or to use it sparingly. Caffeine is readily absorbed from the gastrointestinal tract and is rapidly distributed throughout all tissues as a function of water content. It also crosses the placenta.' In pregnant women the plasma half-life has been observed to increase to I 0.5 hours as compared to 2.5 to 4.5 hours in healthy adults.< The plasma halflife in the newborn infant ranges from 32 to 149 hours. 5 Potential effects of caffeine on fetal development may follow prolonged accumulation of caffeine in pregnant women and passage to the fetus which lacks enzymes necessary for the metabolism of caffeine until several days after birth. 5 Additionally, caffeine is known to increase adenosine-3' : 5' -cyclic monophosphate in cells and may interfere with fetal cell growth. Caffeine may act directly on nucleic acids, 6 since it is structurally similar to adenine and guanine, and result in chromosome aberrations. Another possible mechanism of caffeine action is by the increase of catecholamines, 7 which may restrict uteroplacental circulation through vasoconstriction and result in fetal hypoxia. Fetal deaths, decreases of fetal weight, fetal malformations, and shortened gestational age can follow fetat hypoxia. Existing human studies provide incomplete and conflicting results of the effect of caffeine consumed dur-
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Table I. Daily consumption of coffee, tea, and colas during pregnancy in the study population Coffee Frequency of use
n
Nonusers 1-3 cups/wk 4-6 cups/wk 1-2 cups/day 3-4 cups/day 5-10 cups/day 10+ cups/day Total
1843 422 154 553 139 22 2 3135
I
Tea
I
%
n
58.8 13.5 4.9 17.6 4.4 0.7 0.1 100.0
1586 594 209 585 129 25 7 3135
ing pregnancy on the risk for birth defects," preterm deliveries, 9• 11 and low birth weight. 10• 12 Only one study 9 reported a higher rate of spontaneous abortion among 16 women whose caffeine consumption during pregnancy was high (>600 mg). This study almost certainly used an unrepresentative sample of patients, since they had an unusually high stillbirth rate of 12.7%. Potential confounding variables were not controlled in the analysis and risks of moderate caffeine intake were not studied. The objectives of the present study are (1) to provide a detailed description of caffeine exposure in a large population of pregnant women and (2) to investigate the relationship between caffeine consumption during pregnancy and spontaneous abortion. Material and methods
Candidates for the study were all women who planned to be delivered at Yale New Haven Hospital and who sought care from 29 private physicians and health maintenance organizations in the New Haven area between May, 1980, and March, 1982. Each woman was interviewed during pregnancy by a trained interviewer with use of a standardized schedule. Information obtained included demographic characteristics, previous medical and obstetric history, smoking and drinking habits during pregnancy, and occupational exposure. Caffeine consumption was calculated from caffeinated coffee, tea, and colas (including all caffeinated soft drinks) with use of, respectively, 107 mg/serving, 34 mg/serving, and 4 7 mg/serving.' The names, numbers of days, times per day, and the weeks in gestation when prescription and nonprescription drugs were used during the first trimester of pregnancy were ascertained to identify those containing caffeine. Drug recall was enhanced by probing for 22 specific conditions (e.g., for control of nausea, for fluid retention, for diet or weight loss). Spontaneous abortion was defined as nondeliberate interruption of an intrauterine pregnancy of <28 weeks' gestation in which the fetus was dead when expelled. Gestational age at spontaneous abortion was
Colas
%
n
50.6 19.0 6.7 18.7 4.1 0.8 0.2 100.0
2037 617 194 219 50 13 5 3135
I
%
65.0 20.0 6.2 7.0 1.6 0.4 0.2 100.0
computed based on date of conception and the date of abortion. Date of conception was based on last menstrual period or physician's estimated due date for respondents when the last period was uncertain. Spontaneous abortions (n = 68) were identified from medical records and follow-up contacts with obstetricians and respondents. All miscarriages in the study occurred after interview and between 8 and 26 weeks' gestation. A total of 4073 women were eligible for the study. Women were considered ineligible for interview if they ( 1) were not pregnant at the time of interview, including women who spontaneously aborted or who were delivered before interview; (2) did not plan to deliver at our hospital; (3) demonstrated poor English comprehension; and (4) were familiar with the study. Of the eligible women, 473 refused to be interviewed, and 255 could not be reached to arrange an interview. For five subjects the interviewer considered the interview to be invalid. Interviews were completed on 3340 (82.0%) of eligible women. The pregnancy outcome of a further 86 women could not be ascertained, and 95 women were excluded because their gestational age at interview was >28 weeks and they were no longer at risk for spontaneous abortion. Some detail of caffeine consumption was lacking in 24 women, so we could not compute their average daily caffeine intake. The analysis uses 3135 subjects. Results
Frequency of caffeine consumption during pregnancy. Nonherbal tea was the most frequently used caffeinated beverage (drunk by 49.4% of all respondents) followed by coffee (41.2%) and colas (35.0%) (Table I). Neither coffee nor tea drinking was reported by 30.7% of respondents and 21.9% did not drink coffee, tea, or colas. The average servings daily were tea, 0.6; coffee, 0.6; and colas, 0.3. The frequency for drinking three or more servings per day of coffee, tea, and colas was 5.2%, 5.1% and 2.2%, respectively. Overall, 6.6% of women used a caffeine-containing prescription or nonprescription drug at least once in the first trimester. Most of these women (95.1 %) used
16 Srisuphan and Bracken
January, !986 Am J Obstet Gynecol
Table II. Source and amount of average daily caffeine consumption by type of consumer
(n
=
(n
1292)
I
%
mg
143.7 20.1 16.2 5.1
77.6 10.9 8.7 2.8
185.1
100.0
Source
mg
Coffee Tea Colas Drugs Total
No coffee or tea used
No coffee used
Coffee used
= 1843)
I
(n
%
mg
21.2 13.4 4.5
54.2 34.4 11.5
39.1
100.0
only one caffeine-containing drug. Excedrin (64.8 mg of caffeine per unit) was the most frequently used caffeine-containing drug (by 23.7% of caffeine-drug users), followed by Anacin (32.5 mg of caffeine, 19.1% of users), Dristan (16.2 mg, 14.9% of users), Fiorinal (40 mg, 8.8% of users), and Dexatrim and Dietac (200 mg, 6.5% of users). However, these drugs were used sporadically; 54.6% used them for a period of I to 3 days and 23.7% for 4 to 14 days. In all, 652 women (20.8%) used no caffeine in pregnancy, 1604 (51.2%) were light (1 to 150 mg daily) caffeine users, and 879 (28.0%) were heavy (~151 mg daily) caffeine users. The source of caffeine for different consumers is shown in Table II. Characteristics of women who used caffeine during pregnancy. Daily caffeine consumption is categorized as none (0 mg), light (1 to 150 mg), and moderate-toheavy (~ 151 mg). Table III summarizes the demographic characteristics of women who used and did not use ~affeine during pregnancy. Moderate-to-heavy users are significantly more likely to be over 30 years of age, be white, have ~12 years of education, be relatively heavy users of alcohol (daily consumption of absolute alcohol of >0.25 ounces), be cigarette smokers, use marijuana during pregnancy, be in households whose head is a skilled or unskilled worker, and be interviewed beyond 12 weeks' gestation. Mothers not using any drugs during the first trimester, and Jewish women are significantly less likely to be caffeine users. Moderate-to-heavy caffeine users are significantly more likely to have higher gravidity and parity, be women with a history of spontaneous abortion, and be less likely to have a history of gynecologic surgery or any gynecologic condition. Menarcheal age, total numbers of prior induced abortions, interval from last pregnancy and history of any infertility treatment 12 months before pregnancy are not statistically different among the three caffeine exposure groups (Table IV). All contraceptive methods used during the month before conception, at the time of conception, or 1 month after conception were similar in the three caffeine use groups.
No coffee, tea, or colas used
= 963)
l
(n
= 685)
I
%
mg
12.5 3.7
77.3 22.7
3.9
100.0
16.2
100.0
3.9
100.0
%
Maternal characteristics associated with spontaneous abortion. Women who spontaneously aborted were significantly more likely to be over 30 years of age. Jewish women had a higher spontaneous abortion rate, but this increase is not statistically significant (p = 0.09 for Jewish versus non-Jewish). Marital status, education, religion, ethnic background, number of drugs used in the first trimester, medical conditions 12 months before pregnancy, any injury during pregnancy, diethylstilbestrol used by respondents' mother, cigarette smoking, alcohol, and marijuana use during pregnancy were not markedly different in the group with spontaneous abortions and in the group without them. As expected, women interviewed early in pregnancy were significantly more likely to subsequently abort. Spontaneous abortion rates were significantly higher in women who became pregnant (with the index pregnancy) within 6 months of the last pregnancy (p < 0.001) and with a history of gynecologic surgery (p = 0.03). Menarcheal age, gravidity, parity, history of any previous spontaneous abortion or induced abortion, any infertility treatment 12 months before the index pregnancy, and termination of the last pregnancy with a spontaneous abortion were not significantly different between the two groups. The use of pill, intrauterine device, foam, cream, jelly, suppository, diaphragm, rhythm, condom, and withdrawal were not significantly associated with spontaneous abortion. Frequency of spontaneous abortion and crude association with caffeine used. In all, 2.2% of the study subjects spontaneously aborted after the interview. The rate for non-caffeine users was 1.8%; for light caffeine users, 1.8%; and for moderate-to-heavy caffeine users, 3.1% (p = 0.096). Because of the similar spontaneous abortion rate in the no caffeine and light caffeine users, this group was combined (0 to 150 mg). The crude relative risk for spontaneous abortion of moderate-toheavy use (> 150 mg) was 1.69 (95% confidence intervals= 1.04 and 2.71, p = 0.030). Multivariate analysis of association between caffeine consumption during pregnancy and sponta-
Caffeine and late spontaneous abortion
Volume 154 Number I
17
Table III. Maternal characteristics of caffeine users during pregnancy by average daily caffeine use Average daily caffeine exposure (mg) Characteristics Age :S30 years >30 years Marital status Currently married Not currently married Religion Catholic Protestant Jewish None Other Education (yr) <12 12 13-16 17+ Ethnic background White Nonwhite Occupation of head of household Higher executive, lesser professional Administrative personnel, technician Skilled or unskilled labor Gestational age at interview (wk) :S12 >12 No. of drugs used* 0 I
2+ Medical conditions 12 months before pregnancyt No Yes Injury during pregnancy No Yes Mothers exposed to diethylstilbestrol No Yes Uncertain Alcohol use during pregnancy None :s0.25 of absolute alcohol >0.25 of absolute alcohol No. of cigarettes smoked per day during pregnancy 0 1-10 II+ Marijuana use during pregnancy No Yes
151 +
Significance tests
52.9 46.9
25.4 34.5
t, = 26.94 p = 0.0001
20.7 21.9
51.4 47.9
27.9 30.2
x = 0.88
1606 1019 210 211 67
15.8 24.7 30.5 28.4 26.9
5l.l 52.0 51.9 45.5 50.8
33.1 23.3 17.6 26.1 22.4
148 785 1575 627
16.2 15.5 21.4 27.0
45.3 51.7 52.1 49.4
38.5 32.7 26.5 23.6
2873 257
29.2 20.1
51.5 47.1
28.4 23.7
X~=
1090 1080 954
23.5 21.7 16.6
52.1 49.4 52.3
24.2 29.0 3l.l
X~=
1875 1260
20.6 21.0
52.8 48.7
26.6 30.2
x§ = 6.13
968 988 1178
25.7 18.5 18.7
48.1 53.9 51.4
26.1 27.6 29.9
2776 359
2l.l 18.7
51.5 48.8
27.5 32.6
X~
2917 204
20.7 22.6
51.3 48.5
28.0 28.9
X~=
2590 29 481
21.2 31.0 17.9
51.2 48.3 51.9
27.6 20.7 31.2
804 2088 243
27.2 19.1 14.0
51.4 52.4 40.3
21.4 28.5 45.7
2259 433 405
24.1 14.3 9.1
54.0 49.0 38.0
21.9 36.7 52.8
2911 222
21.3 14.9
51.3 49.1
27.5 36.0
n
0
2226 909
21.7 18.6
2643 192
I
1-150
l
2
p
= 0.64
X~=
p
76.63
= 0.0001
X~=
p
p p
p
43.06
= 0.0001 12.13
= 0.002
22.30
= 0.0002
= 0.047
x; = 22.17 p p p
= 0.0002
= 4.35 = 0.11 0.63
= 0.73
x; = 6.18 p
= 0.19
x; = 70.29 p
= 0.0001
x; = p
X~=
p
195.57
= 0.0001 9.68
= 0.008
*Prescription and nonprescription drugs were included. tHeart or circulation problems, kidney problems, high blood pressure, sickle cell anemia, or other medical conditions.
neous abortion. Variables associated with both caffeine exposure and miscarriage at the p < 0.10 level of significance were considered potential confounding factors. These were gestational age at interview, maternal age, prior gynecologic surgery, member of Jewish religion, and last pregnancy ending with a spontaneous
abortion. Several classifications of average daily caffeine consumption were used to test for an association with spontaneous abortion. First daily caffeine consumption was trichotomized as none, light (l to 150 mg), and moderate-to-heavy(;:;,: 151 mg), and a multiple logistic regression model was fit to the data. This pro-
18 Srisuphan and Bracken
January, 1986 Am J Obstet Gynecol
Table IV. Maternal obstetric history by levels of caffeine exposure and significance tests Levels of caffeine exposure (mg) Obstetric history Menarcheal age (yr) <12 12-13 14+ Gravidity 1 2 3 Parity :S[
2+ Previous spontaneous abortion 0 I
2+ Previous induced abortion 0 I 2+ Spontaneous abortion in last pregnancy Never pregnant No Yes Induced abortion in last pregnancy Never pregnant No Yes Interval from last pregnancy s6 months >6 months Gynecologic condition 12 months before pregnancy* No Yes Infertility treatment 12 months before pregnancy No Yes Gynecologic surgeryt No Yes
I
I
+
Significance tests
n
0
684 1796 625
21.1 20.4 21.8
48.4 52.6 50.2
30.7 26.8 27.8
xi= 4.59 p = 0.35
946 1!13 1075
24.7 20.5 17.7
52.9 52.6 48.2
22.4 27.0 34.1
X~= 40.38
p
= 0.0001
2574 56!
21.8 16.2
52.3 46.2
26.0 37.6
X~
= 32.55 = 0.0001
1618 445 126
18.4 19.6 26.2
52.0 49.7 33.3
29.6 30.8 40.5
xi = 16.44 p = 0.0025
1572 492 125
17.7 22.8 22.4
51.2 48.1 49.6
31.1 29.! 28.0
xl = p =
943 1843 345
24.8 18.3 23.2
52.8 51.5 44.6
22.4 30.2 32.2
xi= 29.92 p = 0.0001
943 1803 386
24.8 17.8 25.1
52.8 50.8 48.7
22.4 31.4 26.2
xi= p =
199 1950
22.1 !8.7
48.2 50.8
29.7 30.5
x! = 1.36 p = 0.50
2340 795
!9.4 24.8
50.9 51.8
29.6 23.4
X~
2957 178
20.5 26.4
51.2 51.1
28.4 22.5
X~= 4.94
2333 802
!9.7 24.1
52.7 46.6
27.6 29.3
x! = p =
1-150
151
p
p p
7.30 0.13
38.07 0.0001
= 16.40 = 0.0003 = 0.08 10.47 0.005
*Vaginal infections, venereal disease, or pelvic inflammatory disease. tCaesarean section, induced abortion, or dilatation and curettage given as an abortion procedure are not included.
vided adjusted relative risks that take into account other confounding factors. Moderate-to-heavy use was associated with a twofold increased risk of spontaneous abortion (relative risk = 1.95, p = 0.07). Light caffeine use was not by itself associated with an increased rate of spontaneous abortion except among women who also had a history of spontaneous abortion in their last pregnancy. These women had a fourfold increase in spontaneous abortion (relative risk = 4.18, p = 0.04). Next we dichotomized the sample's caffeine use as none and light (0 to 150 mg) and moderate-to-heavy (~ 151 mg). The multiple logistic regression analysis for this classification of caffeine is shown in Table V. Moderate-to-heavy caffeine use was significantly associated with an increased risk of spontaneous abortion (relative risk = l. 73, p = 0.03), as was maternal age over 30 and the methodologic variable-gestational age at interview in the first trimester.
A third multiple logistic regression analysis was used to examine the effect of increasing daily caffeine consumption in 50 mg increments on risk for spontaneous abortion. There was no significant elevation of the adjusted relative risks for caffeine at 150 mg per day or less. At levels > 150 mg per day there was a marked increase in the adjusted relative risk for miscarriage, but caffeine consumption of >200 mg did not further increase risk. An attempt was made to identify the particular source of caffeine that might be associated with spontaneous abortion. However, the number of women in each category is frequently too small to detect other than large effects. Those whose caffeine source was from coffee alone had an increased risk of miscarriage over those whose source was tea alone or colas alone (eRR of 2.0, l.l, and 1.3, respectively); however, these associations are not statistically significant.
Volume 154 !';umber l
Comment Before the results of this investigation are discussed, some limitations need to be noted. First, although the study has a relatively high response rate of 82% of eligible patients, selection bias may occur if women elect to participate based on their caffeine consumption. However, the study was introduced to women as a study of "factors influencing the health of women during pregnancy and their newborn infants" and caffeine was not specifically mentioned. It is unlikely, therefore, that women selectively participated in the study based on their caffeine consumption. Second, the results of the study are limited to only late first- and second-trimester miscarriage. This study therefore cannot evaluate the risk of caffeine consumption during pregnancy on early first-trimester spontaneous abortions. Third, the results are limited to patients seeking their antenatal care at private obstetrical practices and health maintenance organizations. Fourth, although only 86 women (2.7%) were lost to follow-up after interviewing, they could bias the result if these women had a differential rate of spontaneous abortion and caffeine use. However, attrition loss is unlikely to be a major problem, since the average daily caffeine consumption and demographic characteristics of mothers lost to follow-up were not different from mothers who stayed in the study. Fifth, a number of potential confounding variables, for example, maternal illness during the index pregnancy, are not included in the study. Mothers who have some illness, that is, gastrointestinal or cardiovascular problems that may predispose them to spontaneously abort might be advised to avoid or limit caffeine consumption. Such a bias would spuriously reduce the risk estimates for caffeine. In the present prospective study, recall bias could not occur because women were interviewed before knowing their pregnancy outcomes. Sixth, information concerning caffeine consumption is ascertained at the time of interview and cannot necessarily be assumed to remain constant throughout the entire pregnancy. However, a retrospective study at the same hospital' 1 found that average coffee and tea consumption for the first, second, and third trimesters of pregnancy are almost the same. Our estimate that 2.2% of pregnancies end in late first- and second-trimester spontaneous abortion in the study may appear somewhat low. However, if the early spontaneous abortions before interview are included, the rate of 7.2% for spontaneous abortion is not low for a prospective study; those reviewed by Kline and Stein 13 ranged from 3.6% to 9.7%. The finding that 79.2% of the study population was exposed to some caffeine is comparable to the estimate of 74% from the GRAS Survey, 14 which did not include caffeine from drugs. The proportions of those who drink coffee (41.2%)
Caffeine and late spontaneous abortion
19
Table V. Adjusted relative risks and the significance levels of moderately heavy caffeine users and all potential confounding variables Factors
Intercept Moderately heavy caffeine users Maternal age, 31 + years Gestational age at interview s: 12 weeks Jewish Prior gynecologic surgery Spontaneous abortion in last pregnancy
Adjusted relative risks
O.Dl
p value
1.73
0.00 0.03
1.72 2.53
0.03 0.002
1.82 1.43 1.45
0.12 0.19 0.29
or tea (49.4%) are somewhat lower than in one previous study but similar to others. 10· 11 Comparison of the average daily servings for coffee and tea of the earlier Yale study 11 with the present one suggests pregnant women may have reduced coffee and tea consumption rather than having stopped completely (average daily servings in 1980 to 82 of 0.6 for coffee and 0.6 for tea versus 1.1 for coffee and 1.0 for tea in 1977). It is unlikely that the average daily caffeine intake reported in this study is under reported. Overall, 6.6% of the study population used at least one caffeine-containing drug during the first trimester of pregnancy. The figure is comparable to that of 10.7% use by pregnant women in the first 4 months' gestation as reported in the Collaborative Perinatal Project, 15 which collected data between 1959 and 1965. The finding that daily caffeine exposure at the 1 to 150 mg level did not significantly increase the risk for spontaneous abortion whereas it did for the > 150 mg level may be interpreted in at least three ways. First, caffeine may have a threshold effect around 150 mg. Ingestion of daily caffeine of < 150 mg may not sufficiently affect the fetus to cause fetal death through interference with cell division, cell growth, or uteroplacental circulation. Second, smoking increases demethylation of caffeine in humans, 16 which may reduce the plasma half-life of caffeine and increase its rate of elimination. In this study, smokers are significantly more likely to be caffeine users. Therefore, the effect of caffeine at 1 to 150 mg/day on spontaneous abortion in smokers may be diminished. Third, fetal effects may come from coffee consumption rather than caffeine per se. In this study, coffee is a major source of caffeine in moderate-to-heavy caffeine users (72%) but not in light caffeine users (26%). Benzo (a) pyrene and chlorogenic acid, found in roast coffee, 17 may increase risk for spontaneous abortion. Both caffeinated and decaffeinated instant and roast coffee, but not tea or cocoa, have recently been found to contain an opiate receptor antagonist with binding activity clearly separable from
20 Srisuphan and Bracken
caffeine. 18 The hypothesis that some component of coffee other than caffeine may be associated with spontaneous abortion should be tested in future research. Women who have experienced spontaneous abortion in their last pregnancy are known to be at increased risk for subsequent spontaneous abortion. In these women light caffeine use may further increase their susceptibility. This must be considered a preliminary observation, however, since prior miscarriage did not further significantly increase spontaneous abortion risks among moderate-to-heavy caffeine users. This is the first population-based study to report an association of caffeine with an increased risk of late first- and second-trimester spontaneous abortion. Although the effect of caffeine is consistent in all the statistical models we used, not all analyses achieved conventional statistical significance. Thus, additional studies are needed before the association of caffeine with spontaneous abortion can be more definitively evaluated. REFERENCES 1. Bunker ML, McWilliams M. Caffeine content of common beverages. J Am Diet Assoc 1979;74:28. 2. Collins TFX. Update to review of caffeine studies. FDA By-Lines 1981;1:19-24. 3. Mirkin BL, Singh S. Placental transfer of pharmacologically active molecules. In: Mirkin BL, ed. Perinatal pharmacology and therapeutics, New York: Academic Press, 1976:1-69. 4. Knutti R, Rothweiler H, Schlatter C. The effect of pregnancy on the pharmacokinetics of caffeine. Arch Toxicol 1982;5(suppl): 187-92.
January, 1986 Am J Obstet Gynecol
5. Horning MG, Stratton C, Nowlin J, et al. Placental transfer of drugs. In: Boreus LO, ed. Fetal pharmacology. New York: Raven Press, 1973:355. 6. Wethersbee PS, Lodge JR. Caffeine: its direct and indirect influence on reproduction. J Reprod Med 1977:19:55-63. 7. Anton AH. Catecholamines during pregnancy and their effects on the fetus. Pediatr Adolesc Endocrinol 1979; 5:110-25. 8. Rosenberg L, Mitchell A, Shapiro S, et al. Selected birth defects in relation to caffeine-containing beverages. JAMA 1982;247:1429-32. 9. Wethersbee PS, Olsen LK, Lodge JR. Caffeine and pregnancy: a retrospective study. Postgrad Med 1977;62:649. 10. Linn S, Schoenbaum SC, Monson RR, et al. No association between coffee consumption and adverse outcomes of pregnancy. N EnglJ Med 1982;306:141-5. 11. Berkowitz GS, Holford TR, Berkowitz RL. Effects of cigarette smoking, alcohol, coffee and tea consumption on preterm delivery. Early Hum Dev 1982;7:349-50. 12. van den Berg BJ. Epidemiologic observations of prematurity: effects of tobacco, coffee and alcohol. In: Reed DM, Stanley F.J, eds. The epidemiology of prematurity. Baltimore: Urban & Schwarzenberg, 1977:157-77. 13. Kline J, Stein Z. Spontaneous abortion (miscarriage). In: Bracken MB, ed. Perinatal epidemiology. New York: Oxford University Press, 1984:23-51. 14. Graham DM. Caffeine: its identity, dietary sources, intake and biological effects. Nutr Rev 1978;36:99. 15. Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton, Massachusetts: PSG Publishing Company, 1977:462. 16. Kaplan R. Caffeine: an update. Drug Chern Toxicol 1981;4:311-29. 17. Kuratsume M, Hueper WC. Polycyclic aromatic hydrocarbons in coffee soots. JNCI 1958;20:37-51. 18. Boublik .JH, Quinn MJ, Clements JA, Herington AC, Wynne KN, Funder JW. Caffeine contains potent opiate receptor binding activity. Nature 1983;30 1:246-8.