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• W2032922308 abstract "Caffeine consumption has been equivocally associated with miscarriage, despite an absence of prospective longitudinal measurement of caffeine intake during sensitive windows of human development. In response to this critical data gap, we analyzed daily caffeine consumption while attempting pregnancy through 12 menstrual cycles at risk for pregnancy and found that caffeine consumption did not increase the risk or hazard of miscarriage, even after adjusting for relevant covariates. Caffeine consumption has been equivocally associated with miscarriage, despite an absence of prospective longitudinal measurement of caffeine intake during sensitive windows of human development. In response to this critical data gap, we analyzed daily caffeine consumption while attempting pregnancy through 12 menstrual cycles at risk for pregnancy and found that caffeine consumption did not increase the risk or hazard of miscarriage, even after adjusting for relevant covariates. A recent paper reignited concern that caffeine consumption during pregnancy was associated with miscarriage (1Weng X. Odouli R. Li D.K. Maternal caffeine consumption during pregnancy and the risk of miscarriage: a prospective cohort study.Am J Obstet Gynecol. 2008; 198 (e1–8): 279Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 2Grady D. Study sees caffeine possibly tied to miscarriages. New York Times. January 20, 2008.Google Scholar, 3March of Dimes. Caffeine in pregnancy 2008. Available at: http://www.marchofdimes.com/professionals/14332_1148.asp. Accessed August 20, 2008.Google Scholar) and quickly generated letters to the editors regarding the differential capture of caffeine by pregnancy outcome (4Signorello L.B. McLaughlin J.K. Caffeine and miscarriage: case closed?.Am J Obstet Gynecol. 2008; 199 ([letter]): e14-e15Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 5Lynch C.D. Klebanoff M.A. Louis G.M. Is caffeine use during pregnancy really unsafe?.Am J Obstet Gynecol. 2008; 199 ([letter]): e16Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). Surprisingly, a negative study published earlier in the year was largely overlooked (6Savitz D.A. Chan R.L. Herring A.H. Howards P.P. Hartmann K.E. Caffeine and miscarriage risk.Epidemiology. 2008; 19: 55-62Crossref PubMed Scopus (53) Google Scholar). Both papers were preceded by an equivocal literature relying on retrospective caffeine recall (7Bech B.H. Nohr E.A. Vaeth M. Henriksen T.B. Olsen J. Coffee and fetal death: a cohort study with prospective data.Am J Epidemiol. 2005; 162: 983-990Crossref PubMed Scopus (123) Google Scholar, 8Cnattingius S. Signorello L.B. Anneren G. Clausson B. Ekbom A. Ljunger E. et al.Caffeine intake risk of first-trimester spontaneous abortion.N Engl J Med. 2000; 343: 1839-1845Crossref PubMed Scopus (214) Google Scholar, 9Dlugosz L. Belanger K. Hellenbrand K. Holford T.R. Leaderer B. Bracken M.B. Maternal caffeine consumption and spontaneous abortion: a prospective cohort study.Epidemiology. 1996; 7: 250-255Crossref PubMed Scopus (75) Google Scholar, 10Signorello L.B. McLaughlin J.K. Maternal caffeine consumption and spontaneous abortion: a review of the epidemiologic evidence.Epidemiology. 2004; 15: 229-239Crossref PubMed Scopus (78) Google Scholar). We assessed caffeine consumption during sensitive windows of development in a prospective cohort study comprising women discontinuing contraception for the purpose of becoming pregnant and who were recruited from a larger study that focused on fish consumption and reproductive health (11Vena J.E. Buck G.M. Kostyniak P. Mendola P. Fitzgerald E. Sever L. et al.The New York Angler Cohort Study: exposure characterization and reproductive and developmental health.Toxicol Ind Health. 1996; 12: 327-334PubMed Google Scholar, 12Buck Louis G.M. Dmochowski J. Lynch C. Kostyniak P. McGuinness B.M. Vena J.E. Polychlorinated biphenyl serum concentrations, lifestyle and time-to-pregnancy.Hum Reprod. 2009; 24: 451-458Crossref PubMed Scopus (55) Google Scholar). The study cohort was restricted to women who reported in 1991 that they may be planning pregnancies in the next 5 years. In 1996, 2,637 women were recontacted, of which 244 (9%) reported planning pregnancies in the next 6 months, from which 113 women (46%) were enrolled. Fourteen women were already pregnant and were subsequently excluded from further participation. Women were interviewed by a nurse before first attempting pregnancy and instructed in the accurate use of the home pregnancy tests, reportedly capable of detecting ≤50 mIU/mL hCG on the date of expected menses. The fertile window was estimated using the Ogino-Knaus method of counting back 14 days from the end of the cycle (13Ogino K. Ovulationstermin und konzeptionstermin.Zentralbl F Gynak. 1930; 54: 464-479Google Scholar, 14Knaus H. Eine neue methods zur bestimmung des ovulationstermines.Zentralbl F Gynak. 1929; 53: 2193Google Scholar) and was broadly defined as commencing 5 days before the presumed date of ovulation and ending 2 days after ovulation. Women completed daily diaries on intercourse, menstruation, caffeine consumption (number of cups of coffee, tea, caffeinated soft drinks), alcohol consumption (number of drinks of beer, wine, wine coolers, hard liquor), and number of cigarettes smoked. Women were followed until hCG-confirmed pregnancy or up to 12 menstrual cycles with at least one act of sexual intercourse during the fertile window; 20 women withdrew from the study. Full human subject approval was granted, and all participants gave their informed consent. Caffeine, alcohol, and smoking data were standardized to a 28-day cycle to account for varying menstrual cycle lengths, reflecting the heterogeneity of both menstruation and couple fecundity as measured by time to pregnancy (TTP), and to prevent inflation in exposures for women with longer cycles. Standardization was derived by summing the daily number of cigarettes smoked and alcoholic and caffeinated beverages consumed, multiplying by 28 (assumed normal menstrual cycle length), and dividing by the number of observed days in each woman's cycle. Exposures for women who conceived in the first month (n = 19) were standardized to 28 days based on observed daily exposure data for the partially observed cycle. We assessed potential changes in acute caffeine exposure during sensitive windows (in relation to risk of pregnancy loss) by estimating the day of conception as having occurred 14 days and implantation 7 days before the woman's first positive pregnancy test. We formally assessed differences in caffeine consumption between the periovulatory period, defined as the 5 days before ovulation, the day of ovulation, and 2 days after ovulation, and the periimplantation period, which was defined as the subsequent 8 days, using the Wilcoxon signed rank test (15Gibbons J.D. Nonparametric statistical inference.2nd ed. Marcel Dekker, New York1985Google Scholar, 16Hollander M. Wolfe D.A. Nonparametric statistical methods. Wiley, New York1973Google Scholar). Using women as the unit of analysis, we stratified by gravidity and modeled standardized caffeine consumption and risk of pregnancy and miscarriage, adjusting for standardized cigarette smoking (continuous), standardized alcohol consumption (continuous), age (continuous), and history of prior spontaneous pregnancy loss (among gravid women; binary) using log-Poisson modeling (17Wacholder S. Binomial regression in GLIM: estimating risk ratios and risk differences.Am J Epidemiol. 1986; 123: 174-184PubMed Google Scholar, 18Zou G.A. modified Poisson regression approach to prospective studies with binary data.Am J Epidemiol. 2004; 159: 702-706Crossref PubMed Scopus (5392) Google Scholar). Using cycles as the unit of analysis, we estimated hazard of pregnancy loss using Cox proportional hazards regression with right censoring (19Cox D.R. Oakes D. Analysis of survival data. Chapman and Hall, London1984Google Scholar). Risk ratios (RRs) and hazard ratios (HRs) were estimated along with 95% confidence intervals (CIs). Pregnancy loss denoted both early (n = 10) and clinical (n = 4) losses in all analyses. To address the known clustering of pregnancy outcome (20Louis G.M. Dukic V. Heagerty P.J. Louis T.A. Lynch C.D. Ryan L.M. et al.Analysis of repeated pregnancy outcomes.Stat Methods Med Res. 2006; 15: 103-126Crossref PubMed Scopus (63) Google Scholar), we stratified by gravidity and assessed prior miscarriage among gravid women. Recognizing that women's behaviors may change in relation to timeliness in which she becomes pregnant, we assessed caffeine intake per cycle by women's intentions to change caffeine consumption as reported at the baseline interview. Sixty-eight women (86%) became pregnant, of which 54 (79%) had live births and 14 (21%) experienced pregnancy losses. Eleven women (14%) did not achieve pregnancy. The 79 women who fully completed the study contributed 419 menstrual cycles for the analysis, including 275 cycles contributed by women with pregnancies. No significant differences were observed for caffeine consumption or other study covariates and pregnancy outcome (data not shown). Parity, however, varied, with a significantly higher percentage of parous women having live births or having withdrawn compared with women with losses or no pregnancy (i.e., 83%, 77%, 57%, and 18%, respectively; P=.001). Twenty-two women reported a history of prior spontaneous pregnancy loss, including four infertile women (18%), two women with index losses (9%), 14 women with index births (64%), and two women who withdrew (9%). The daily mean number (±SD) of caffeinated beverages varied from a high among women who withdrew (1.9 ± 0.7) or had live births (1.8 ± 1.5) to a low for women experiencing miscarriage (0.8 ± 0.8). Caffeine consumption was not associated with becoming pregnant in adjusted models (RR 1.00, 95% CI 0.99–1.01), with increased miscarriage risk (RR 0.98, 95% CI 0.96–0.99), or with increased hazard of miscarriage (HR 0.97, 95% CI 0.95–1.00), even when stratifying by gravidity (Table 1). The absence of a caffeine effect suggests that infecundity or inability to conceive was not a competing risk for pregnancy loss. Caffeine consumption during sensitive windows was not associated with miscarriage risk nor was an effect seen when restricting analysis to nonsmoking women or when estimating the effect of previous pregnancy loss (HR 1.00, 95% CI 0.99–1.00). Few women changed caffeine consumption despite 44% reporting plans to reduce at baseline. Our findings agree with a recent cohort study that included preconception enrollment of some women and prospective measurement of caffeine consumption (6Savitz D.A. Chan R.L. Herring A.H. Howards P.P. Hartmann K.E. Caffeine and miscarriage risk.Epidemiology. 2008; 19: 55-62Crossref PubMed Scopus (53) Google Scholar).Table 1Risk ratios (RRs) for caffeine consumption and pregnancy loss and hazard ratios (HRs) for caffeine consumption and hazard of pregnancy loss (in days), stratified by gravidity.ModelRisk of pregnancy lossHazard of pregnancy lossnRR(95% CI)nHR(95% CI)Unadjusted All women660.98(0.96–0.99)660.97(0.95–1.00)Stratified by gravidity Nulligravid women130.98(0.95–1.00)130.98(0.94–1.01) Gravid women530.97(0.95–0.99)530.97(0.94–1.00)Adjusted All womenaAdjusted for age and average alcohol and cigarette consumption per standardized 28-day cycle.660.98(0.96–0.99)660.97(0.95–1.00)Stratified by gravidity Nulligravid womenaAdjusted for age and average alcohol and cigarette consumption per standardized 28-day cycle.130.98(0.95–1.01)130.98(0.94–1.02) Gravid womenbAdjusted for age, average alcohol and cigarette consumption per standardized 28-day cycle, and prior spontaneous pregnancy loss (yes/no).530.96(0.94–0.99)530.96(0.92–1.00)Note: Log-Poisson regression with empirical error variance was used to estimate the risk of pregnancy loss, and Cox proportional hazards regression with right censoring was used to estimate the hazard ratio, using the average number of daily cups of caffeinated beverages standardized to a 28-day menstrual cycle. CI = confidence interval.a Adjusted for age and average alcohol and cigarette consumption per standardized 28-day cycle.b Adjusted for age, average alcohol and cigarette consumption per standardized 28-day cycle, and prior spontaneous pregnancy loss (yes/no). Open table in a new tab Note: Log-Poisson regression with empirical error variance was used to estimate the risk of pregnancy loss, and Cox proportional hazards regression with right censoring was used to estimate the hazard ratio, using the average number of daily cups of caffeinated beverages standardized to a 28-day menstrual cycle. CI = confidence interval. Studies to date have largely assessed caffeine and TTP or miscarriage by asking pregnant women to recall consumption, raising concern about possible selection and recall biases (1Weng X. Odouli R. Li D.K. Maternal caffeine consumption during pregnancy and the risk of miscarriage: a prospective cohort study.Am J Obstet Gynecol. 2008; 198 (e1–8): 279Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 7Bech B.H. Nohr E.A. Vaeth M. Henriksen T.B. Olsen J. Coffee and fetal death: a cohort study with prospective data.Am J Epidemiol. 2005; 162: 983-990Crossref PubMed Scopus (123) Google Scholar, 10Signorello L.B. McLaughlin J.K. Maternal caffeine consumption and spontaneous abortion: a review of the epidemiologic evidence.Epidemiology. 2004; 15: 229-239Crossref PubMed Scopus (78) Google Scholar, 21Bolumar F. Olsen J. Rebagliato M. Bisanti European Study Group on Infertility and SubfecundityCaffeine intake and delayed conception: a European multicenter study on infertility and subfecundity.Am J Epidemiol. 1997; 145: 324-334Crossref PubMed Scopus (128) Google Scholar). In the present study, 10 out of 14 pregnancy losses would have been missed without preconception enrollment of women. Caffeine consumption has been measured differently, with some authors estimating risk by daily milligrams (mg) of caffeine (22Bech B.H. Nohr E.A. Vaeth M. Henriksen T.B. Olsen J. Coffee and fetal death: a cohort study with prospective data.Am J Epidemiol. 2005; 162: 983-990Crossref PubMed Scopus (62) Google Scholar) or by source (21Bolumar F. Olsen J. Rebagliato M. Bisanti European Study Group on Infertility and SubfecundityCaffeine intake and delayed conception: a European multicenter study on infertility and subfecundity.Am J Epidemiol. 1997; 145: 324-334Crossref PubMed Scopus (128) Google Scholar, 23Joesoef M.R. Beral V. Rolfs R.T. Aral S.O. Cramer P.W. Are caffeinated beverages risk factors for delayed conception?.Lancet. 1990; 335: 136-137Abstract PubMed Scopus (81) Google Scholar). Only 24% of women in our cohort who failed to become pregnant or who had live births reported consuming more than three caffeinated beverages daily, which is approximately equivalent to >300 mg of daily caffeine, assuming higher caffeine content for coffee than tea or soft drinks (24Bunker M.L. McWilliams M. Caffeine content of common beverages.J Am Diet Assoc. 1979; 74: 28-32PubMed Google Scholar). Earlier studies have associated caffeine intake of >300 mg per day with miscarriage risk (22Bech B.H. Nohr E.A. Vaeth M. Henriksen T.B. Olsen J. Coffee and fetal death: a cohort study with prospective data.Am J Epidemiol. 2005; 162: 983-990Crossref PubMed Scopus (62) Google Scholar, 25Tolstrup J.S. Kjaer S.K. Munk C. Madsen L.B. Ottensen B. Bergholt T. et al.Does caffeine and alcohol intake before pregnancy predict the occurrence of spontaneous abortion?.Hum Reprod. 2003; 18: 2704-2710Crossref PubMed Scopus (60) Google Scholar). The extent to which the present findings may be generalizable to women with unplanned pregnancies is uncertain, particularly because the latter group is at risk for adverse pregnancy outcomes (26Mohllajee A.P. Curtis K.M. Morrow B. Marchbanks P.A. Pregnancy intention and its relationship to birth and maternal outcomes.Obstet Gynecol. 2007; 109: 678-686Crossref PubMed Scopus (190) Google Scholar). However, we are unaware of any data to support systematic differences in day-specific caffeine consumption by women's pregnancy intentions. Moreover, women's daily reporting of caffeine consumption in the present cohort was most likely unaffected by intentions to change behaviors, given that women were unaware of their eventual pregnancy outcome. These findings have important methodologic limitations, including potential measurement error in caffeine intake, less exposure data on women who conceived during the first cycle compared with women requiring more time, and the highest consumption among women who withdrew from the study, albeit amounts similar to women with live births. In sum, we found no evidence that caffeine consumption increases miscarriage risk among women with light or moderate caffeine consumption." @default.
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