Literature Review - Systematic Research 4 Pages

ORIGINAL ARTICLE Reproductive epidemiology

Caffeine and caffeinated beverage consumption and risk of spontaneous abortion K.A. Hahn1,*, L.A. Wise1,2, K.J. Rothman1,3, E.M. Mikkelsen4, S.B. Brogly1, H.T. Sørensen1,4, A.H. Riis4, and E.E. Hatch1 1Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA 2Slone Epidemiology Center, Boston University, Boston, MA 02215, USA 3RTI Health Solutions, Research Triangle Park, NC 12194 USA 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark

*Correspondence address. E-mail: [email protected]

Submitted on December 9, 2014; resubmitted on February 18, 2015; accepted on February 26, 2015

study question: Is caffeine and caffeinated beverage consumption associated with the risk of spontaneous abortion (SAB)?

summary answer: While preconceptional caffeine consumption was not materially associated with an increased risk of SAB, consump- tion during early pregnancy was associated with a small increased risk of SAB, although the relation was not linear.

what is known already: Caffeine has been hypothesized as a risk factor for SAB since the 1980s; however, results from previous studies have been conflicting.

study design, size, duration: This prospective cohort study included 5132 Danish women planning pregnancy and enrolled from 2007 to 2010.

participants/materials, setting, methods: Participants were women who conceived after entry into the Snart-Gravid cohort and who were aged 18 – 40, in a stable relationship with a male partner, and did not use fertility treatments to conceive. Women reported their daily caffeine and caffeinated beverage consumption on questionnaires before conception and during early pregnancy. All exposure mea- surements were prospective with respect to outcome ascertainment. We estimated hazard ratios (HRs) of SAB for categories of caffeine con- sumption in milligrams (mg) per day and the corresponding 95% confidence intervals (CIs) using Cox proportional hazards regression models with gestational weeks as the time scale.

main results and the role of chance: There were 732 women (14.3%) who were identified as having a SAB. In the precon- ceptional period, caffeine consumption was not materially associated with SAB risk (HR comparing ≥300 with ,100 mg/day: 1.09; 95% CI: 0.89, 1.33). In early pregnancy, the HRs for 100 – 199, 200 – 299 and ≥300 mg/day of caffeine consumption were 1.62 (95% CI: 1.19, 2.22), 1.48 (95% CI: 1.03, 2.13) and 1.23 (95% CI: 0.61, 2.46), respectively, compared with that for ,100 mg/day.

limitations, reasons for caution: The observed results may be affected by non-differential exposure misclassification, reverse causation and residual confounding.

wider implications of the findings: This is the largest study to date of prospectively measured, preconception caffeine con- sumption and risk of SAB. We were able to reduce the likelihood of differential left truncation bias and recall bias present in other analyses.

study funding/competing interest(s): Snart-Gravid was funded by the NICHD (R21-050264). Dr. Hahn’s work was funded in part by the BU Reproductive, Perinatal, and Pediatric Epidemiology Training Grant NIH #T32HD052458. There are no competing interests.

Key words: caffeine / coffee / spontaneous abortion / cohort study

Introduction Caffeine crosses the placenta (Dlugosz and Bracken, 1992) and has a pro- longed metabolism in pregnant women (15.08 hour half-life) compared

with non-pregnant women (4.71 hour half-life). Fetuses eliminate caf- feine very slowly, suggesting that maternal caffeine ingestion could in- crease fetal caffeine levels exponentially (Brazier et al., 1983). Further, some studies (Lucero et al., 2001; Lawson et al., 2002; Kotsopoulos

& The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected]

Human Reproduction, Vol.30, No.5 pp. 1246 – 1255, 2015

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et al., 2009; Schliep et al., 2012) have shown that caffeine consumption alters endogenous hormone levels. In some studies, caffeine has been in- versely related to levels of estradiol and progesterone during the luteal phase of the menstrual cycle (Lawson et al., 2002; Kotsopoulos et al., 2009; Schliep et al., 2012) and positively related to sex hormone binding globulin (SHBG) (Kotsopoulos et al., 2009). Thus, hormonal changes related to caffeine consumption could plausibly affect the risk of spontaneous abortion (SAB).

Published results of studies examining the association between caf- feine and SAB risk have been conflicting (Fenster et al., 1991, 1997; Infante-Rivard et al., 1993; Mills et al., 1993; Dominguez-Rojas et al., 1994; Dlugosz et al., 1996; Cnattingius et al., 2000; Bech et al., 2005; Buss et al., 2006; Matijasevich et al., 2006; Savitz et al., 2008; Weng et al., 2008; Greenwood et al., 2010; Pollack et al., 2010), likely due to differences in study design and populations, outcome ascertainment, and exposure classification. Most previous studies of caffeine and SAB risk have focused on total caffeine intake from caffeinated beverage con- sumption during pregnancy. Some studies have also included chocolate (Wen et al., 2001) and caffeine from medications (Fenster et al., 1991; Cnattingius et al., 2000) while others have focused primarily on coffee (Armstrong et al., 1992; Dominguez-Rojas et al., 1994; Bech et al., 2005). In Danish prospective studies, the definition of high caffeine con- sumption has varied substantially, up to as much as ≥8 servings/day of coffee (Bech et al., 2005) and . 900 mg/day of caffeine (Tolstrup et al., 2003). However, several other studies have used a definition of ≥300 mg/day (Mills et al., 1993; Dlugosz et al., 1996; Fenster et al., 1997; Wen et al., 2001; Greenwood et al., 2010). Most prospective studies (Dlugosz et al., 1996; Fenster et al., 1997; Bech et al., 2005; Savitz et al., 2008; Weng et al., 2008; Greenwood et al., 2010) have en- rolled participants during early pregnancy and asked about caffeine con- sumption prior to the interview. This could lead to potential exposure misclassification, as well as differential left truncation bias. Prospective studies that have enrolled participants before pregnancy (Mills et al., 1993; Wen et al., 2001; Pollack et al., 2010) have been limited by small study sizes (431, 113 and 575, respectively).

The objective of this study was to examine SAB risk in relation to con- sumption of caffeine and caffeinated beverages during preconception and early pregnancy among women enrolled in a large prospective cohort study in Denmark.

Materials and Methods

Data collection The Snart-Gravid study is an Internet-based prospective cohort study of time to pregnancy. Recruitment began in 2007 when an advertisement was placed on a Danish health-related website (www.netdoktor.dk) and a coordinated media strategy was launched (Mikkelsen et al., 2009; Rothman et al., 2009; Huybrechts et al., 2010). Enrollment and primary data collection were conducted via a self-administered questionnaire on the study website (www.snart-gravid.dk). Contact with participants was maintained through the study website and e-mail.

Participants completed a consent form and an online screening question- naire to verify eligibility for enrollment. Eligible women were aged 18 – 40 years, residents of Denmark, in a stable relationship with a male partner, not using fertility treatment, and trying to become pregnant. Participants were required to provide a valid e-mail address and their Civil Personal Regis- tration (CPR) number, a unique 10-digit personal identification number

assigned to each Danish resident (Schmidt et al., 2014). After 38 months of recruitment, 5921 women had enrolled in the study. The study was approved by the Danish Data Protection Board and the Institutional Review Board of the Boston University Medical Campus.

The baseline questionnaire collected information on demographics, life- style and behavioral factors, and reproductive and medical history. Partici- pants were contacted every 2 months by e-mail with reminders to fill out a follow-up questionnaire. Follow-up questionnaires assessed changes in exposures and pregnancy status, including occurrence of any clinically recog- nized pregnancy losses. Follow-up continued until conception or for a maximum of 12 months. Women who were pregnant at the time of a follow- up questionnaire were asked to complete an early pregnancy questionnaire during their first trimester to assess any changes in exposures since concep- tion as well as pregnancy symptoms.

To obtain information on pregnancy outcomes among women in the cohort, we linked each woman’s CPR number to the Danish National Regis- try of Patients (DNRP) and the Danish Medical Birth Registry (DMBR). The DNRP provides information on hospitalizations and outpatient encounters (including SAB and therapeutic abortion) and the DMBR provides informa- tion on all live births and stillbirths after 22 gestational weeks (GW) (Kristen- sen et al., 1996; Lohse et al., 2010). International Classification of Disease (ICD), 10th edition, codes (DO03 for SAB and DO04 for therapeutic abor- tion) in the DNRP were used to identify pregnancy outcomes occurring among Snart-Gravid cohort members after the baseline enrollment date. A recent validation study comparing DNRP data on SABs with data from in- dividual medical records found that the registry information had a positive predictive value of 98.7% (Lohse et al., 2010).

Assessment of SAB Women who experienced a pregnancy loss after enrollment were asked to report the date of the loss and gestational weeks at time of loss (time since the last menstrual period (LMP)) on a study questionnaire. The DNRP also pro- vided information on SABs treated in hospital up to 22 gestational weeks and any therapeutic abortions, the dates of these events, and the gestational age at which the pregnancy ended. For pregnancy losses recorded in both the registry and on a questionnaire, we used data from the DNRP (based on either early ultrasound fetometry or LMP) to ascertain gestational week of pregnancy loss. In Denmark, the first pregnancy-related ultrasound is per- formed after about 12 weeks of gestation; gestational ages at SAB after this time are likely based on ultrasound. For SABs reported only on a Snart-Gravid follow-up questionnaire, gestational age was calculated as the number of weeks from the date of LMP to the date of pregnancy loss, rounded to the nearest whole week. For losses identified in both sources, the mean gesta- tional age reported on Snart-Gravid questionnaires was slightly lower than that recorded in the registry (6.8 (SD: 1.8) weeks versus 7.2 weeks (SD: 1.7)) and did not vary appreciably by caffeine exposure.

For 175 women, a pregnancy reported on a Snart-Gravid follow-up ques- tionnaire had no corresponding data recorded in the hospital or birth regis- tries. In these cases, we assumed that an early SAB had occurred. We used multiple imputation to impute a gestational age ≤12 weeks for each of these presumed SABs, under the assumption that later SABs would have been cap- tured by the hospital registry. Sensitivity analyses excluding these pregnancies produced similar results (not shown).

Assessment of caffeine and caffeinated beverage consumption Servings per week of caffeinated coffee (250 ml mug), decaffeinated coffee (250 ml mug), herbal/green tea (250 ml mug), black tea (250 ml mug), regular cola (500 ml bottle) and diet cola (500 ml bottle) were reported on the baseline, follow-up and early pregnancy questionnaires. We used the following formula, based on milligrams (mg) of caffeine per serving of

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each beverage as estimated in previous laboratory measurements (Caffeine content of food & drugs, 2014): total caffeine ¼ caffeinated coffee x (141 mg) + decaffeinated coffee x (5 mg) + black tea x (56 mg) + regular cola x (51 mg) + diet cola x (66 mg). Because the questionnaire did not dis- tinguish between consumption of herbal tea and green tea, we did not include this item in our caffeine formula. Daily servings of each beverage also were considered individually in our analyses. We calculated a conception date for each participant based on the date of LMP, date of SAB and gestational age at SAB. For the analysis of preconception caffeine consumption, we ana- lyzed exposure information that preceded the conception date. For those women who reported a pregnancy loss on a follow-up questionnaire, we relied on the most recent questionnaire before the reported loss for all ex- posure and covariate information. We analyzed data from the most recent questionnaire because pregnancy planners may change their caffeine con- sumption while attempting pregnancy (Lum et al., 2011). Early pregnancy caf- feine consumption was based on self-reported information from before the loss for the 61% of women who provided information on beverage consump- tion in their early pregnancy questionnaire and was imputed for all other women.

Assessment of confounders Data on maternal age, parity, smoking status, prior SAB, alcohol consump- tion, physical activity, height and weight, and vocational training/education were self-reported on the baseline questionnaire. We estimated total meta- bolic equivalents (METs) per week by summing the METs from moderate physical activity (hours per week multiplied by 3.5 METs) and vigorous exer- cise (hours per week multiplied by 7.0 METs) (Jacobs et al., 1993). Body mass index (BMI) was calculated as kg/m2 and categorized as follows: ,20, 20 – 24, 25 – 29, ≥30. Study participants updated their smoking status and alcohol consumption on all subsequent follow-up questionnaires, in- cluding the early pregnancy questionnaire. We analyzed the covariate information from the questionnaire immediately before the pregnancy loss. The categories used for each confounder examined were as follows: age (18 – 24, 25 – 29, 30 – 34, ≥35 years), smoking status (non-smoker, ,10 cigarettes/day, ≥10 cigarettes/day), alcohol consumption (0, 1, 2, 3 – 6, 7 or more drinks/week), prior SAB (yes/no), physical activity (,10, 10 – 19, 20 – 39, ≥40 METs/week), vocational training/education (none, semi- skilled/basic training, ≤4 years, .4 years), parity (nulliparous, 1 birth, .1 birth), BMI (,20, 20 – 24, 25 – 29, ≥30 kg/m2).

Study population The present analysis focuses on women with a clinically recognized preg- nancy conceived after enrollment in Snart-Gravid. We excluded 126 who did not live in Denmark after enrollment, 10 women who did not provide a valid CPR, and 653 (11%) women who did not conceive after enrollment in the cohort (indicated by absence of any pregnancy reported on the follow- up questionnaires or recorded in the registries).

Data analysis We assessed the relationships between consumption of total caffeine and in- dividual caffeinated beverages and SAB risk separately during preconception and early pregnancy, using a time-to-event analysis. Time to SAB was mea- sured in gestational weeks. We categorized caffeine consumption as ,100, 100 – 199, 200 – 299 and ≥300 mg per day based on a previous manu- script from the Snart-Gravid study (Hatch et al., 2012) and similar categories examined in other caffeine and SAB studies (Dlugosz et al., 1996; Fenster et al., 1997; Wen et al., 2001; Greenwood et al., 2010). The categories of daily caffeinated beverage consumption were 0, 1, 2 and ≥3 servings for coffee and 0, 1 and ≥2 servings for cola, black tea and herbal/green tea. We examined the shape and magnitude of the relation between daily caffeine

consumption and SAB risk using restricted cubic splines (Durrleman and Simon, 1989).

We used Cox proportional hazards regression models, with gestational weeks as the time scale, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for caffeine and caffeinated beverage consumption associated with SAB. We assumed that there was a true but unknown ordering for tied event times and used the ‘exact’ option in SAS PROC PHREG (Therneau and Grambsch, 2000), which takes into account all possible orderings of event times. The HR is approximately equal to the average per-week risk of SAB for the exposed category divided by the corresponding risk for the reference cat- egory. Therapeutic abortions were censored at the week of pregnancy termin- ation and pregnancies lasting more than 22 weeks were censored at 22 weeks.

We identified potential confounders from variables associated both with SAB and caffeine consumption in our data. We also considered covariates meeting the criteria for confounding based on a review of the literature and the assessment of causal graphs (Rothman et al., 2008). Covariates included in both the preconception and early pregnancy models were maternal age, cigarette smoking, previous SAB, parity, vocational training/education, and physical activity. The preconception model also was adjusted for alcohol con- sumption. Models for the individual beverages (coffee, cola, herbal/green, and black tea) were mutually adjusted for each other (Willett, 1998).

In secondary analyses, we stratified the data by waiting time to pregnancy (TTP), smoking status and BMI. Because it has been reported that women with viable pregnancies may experience more severe nausea symptoms and aver- sion to caffeinated beverages, we stratified our analyses on reported nausea during early pregnancy (‘Have you experienced nausea or vomiting with this preg- nancy?’). In addition, we examined the relationship between caffeine consump- tion and SAB as a dichotomous outcome using log-binomial models.

The etiology of pregnancy loss likely differs for early and late losses (Savitz et al., 2002; United States. Congress. Office of Technology Assessment., 1985), especially by karyotype, so we also examined the relationship between preconception caffeine consumption and timing of losses (loss during ,8 weeks of gestation and loss during ≥8 weeks of gestation). The choice of 8 weeks as a cut point for evaluating the timing of pregnancy loss was based on karyotype data showing a higher proportion of chromosomal abnormalities prior to 8 weeks (Klein and Stein, 1987). For this analysis, preg- nant women were at risk for having an early loss, but only women who were still carrying a fetus by the end of 7 weeks were at risk for having a late loss (≥8 weeks). Those who were part of the first risk calculation but not part of the second are those women who experienced an SAB or a therapeutic abortion before 8 weeks of gestation. The risk period for the ‘late loss’ analysis began at 8 gestational weeks.

We used multiple imputation methods to impute missing covariates, exposures, and outcome information (Zhou et al., 2001). Missing covariate data ranged from 0% for maternal age, time to pregnancy, and smoking status to 44% for number of glasses of dessert wine during early pregnancy. We imputed individual early pregnancy beverage frequencies for 2016 parti- cipants (39%). Missing data for preconception beverages ranged from 2% for coffee to 5% for decaf coffee. We used PROC MI to create 5 imputed data- sets based on 46 variables in the imputation model. We combined coeffi- cients and standard errors across the imputed datasets using PROC MIANALYZE. See Supplementary Table SI for details on percent missingness for the variables included in the imputation model.

Departures from the proportional hazards assumption were assessed with log survivor plots. SAS statistical software (version 9.3, SAS Institute) was used for all analyses.

Results Among the 5132 women who conceived after enrolling in Snart-Gravid, 732 (14.3%) were identified as having an SAB. Overall, 25% of SABs were

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recorded only in the DNRP, 36% of SABs were reported only on a follow- up questionnaire, 15% of SABs were documented in both sources and 24% were pregnancies reported on a follow-up questionnaire but with no outcome information (live birth, SAB, therapeutic abortion) in either the DNRP or the DMBR.

Baseline characteristics of study participants are presented in Table I. Preconception and early pregnancy caffeine consumption were asso- ciated with parity, higher education and cigarette smoking; preconcep- tion caffeine consumption was also positively associated with alcohol consumption.

Most caffeine intake was from coffee; the Pearson correlation coeffi- cient between servings of coffee consumed per day and total preconcep- tion caffeine consumption was 0.96. The correlation between number of

servings of coffee consumed per day during early pregnancy and total caf- feine consumed during early pregnancy was 0.92, and the correlation between preconception caffeine consumption and caffeine consumption during early pregnancy was 0.48.

After adjustment for all covariates, the HRs for preconception caffeine consumption of 100 – 299, 200 – 299 and ≥300 mg/day compared with ,100 mg/day were 1.00 (95% CI: 0.81, 1.23), 1.19 (95% CI: 0.96, 1.49) and 1.09 (95% CI: 0.89, 1.33), respectively (Table II). Figure 1 displays the relation between preconception caffeine consumption and risk of SAB by gestational week using a restricted cubic spline. The figure indicates little association between SAB risk and caffeine consumption at levels above 200 mg/day, consistent with the categorical results. Drinking ≥3 ser- vings of coffee per day versus not drinking coffee was associated with a

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Table I Baseline characteristicsa of 5132 women according to daily preconception and early pregnancy consumption of caffeine from the first imputed dataset.

Preconception caffeine consumption (mg/day) Early pregnancy caffeine consumption (mg/day)

<100 100 – 199 200 – 299 ≥300 <100 100 – 199 200 – 200 ≥300

Parity (%)

Nulliparous 67.9 66.7 69.8 63.5 67.8 67.7 66.5 59.3

1 Birth 24.9 24.9 22.7 27.1 24.6 24.6 24.5 29.4

.1 births 7.3 8.5 7.5 9.6 7.6 7.8 9.0 11.3

Vocational training/education (%)

No vocational training 12.2 12.2 11.1 12.3 11.7 9.8 13.8 17.6

Semi-skilled/basic training 16.7 16.7 14.1 13.9 16.5 15.6 14.4 11.8

Higher education (≤4 years) 53.0 50.3 47.4 47.3 51.3 49.5 49.3 47.0 Higher education (.4 years) 18.1 20.8 27.4 26.4 20.6 25.1 22.6 23.6

Smoking status (%)

Non-smokers 85.3 79.4 80.2 66.8 88.8 88.1 74.8 70.3

,10 cigarettes/day 8.5 10.5 11.5 16.8 11.2 11.9 25.2 29.7

10 or more cigs/day 6.2 10.1 8.4 16.4

Body mass index (kg/m2) (%)

,20 15.2 14.2 14.9 14.8 14.5 15.4 16.6 14.7

20 – 24.9 50.0 52.7 58.0 54.1 52.3 53.6 51.0 54.9

25 – 29.9 20.8 20.5 20.3 20.4 20.6 20.1 20.6 18.4

≥30 14.1 12.7 6.8 10.6 12.6 10.9 11.8 12.0 Alcohol categories (%)

0 drinks per week 42.6 32.3 27.3 21.2 99.9 100 99.5 98.7

1 drink/week 16.2 14.6 15.6 11.9 0.1 0 0.5 1.3

2 drinks/week 14.7 13.7 15.5 16.2 0 0 0 0

3 – 6 drinks/week 20.8 29.5 30.4 34.9 0 0 0 0

≥7 drinks/week 5.8 10.0 11.1 15.8 0 0 0 0 METs categories (%)

,10 METs 16.6 15.3 15.2 14.5 16.0 14.3 15.0 17.7

10 – 19 METs 32.8 32.9 29.1 32.7 33.4 31.1 27.9 31.9

20 – 39 METs 34.2 34.9 36.9 37.2 33.7 37.9 40.1 35.1

≥40 METs 16.4 16.8 18.9 15.6 16.9 16.7 17.1 15.4 Time to pregnancy ≥6 months (%) 57.5 57.0 53.9 54.2 55.4 56.0 61.1 52.2

aCharacteristics are presented as percentages within levels of caffeine consumption based on the first dataset resulting from multiple imputation, and are standardized to the age distribution of the cohort at baseline.

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slightly increased risk of SAB (HR: 1.23; 95% CI: 0.89, 1.72), but con- sumption of other caffeinated beverages was not consistently associated with SAB risk.

HRs for total caffeine consumption during early pregnancy of 100 – 199, 200 – 299 and ≥300 mg/day compared with ,100 mg/day were 1.62 (95% CI: 1.19, 2.22), 1.49 (95% CI: 1.03, 2.13) and 1.23 (95% CI: 0.61, 2.46), respectively (Table II). The relationship between early pregnancy caffeine consumption and SAB risk by gestational week is displayed in Fig. 2 using a restricted cubic spline. The figure is consistent with the findings from categorical analyses and shows that the risk of SAB increases to a peak around 200 mg/day followed by a decline in risk of SAB with higher levels of intake. Consuming less than 2 but more than 0 servings of coffee, black tea, and herbal/green tea during early pregnancy was associated with increased risks of SAB compared with 0 servings of the respective beverages, but the high- est categories of each beverage (≥2 servings/day) were not asso- ciated with an increased risk (Table II). After adjustment for preconception consumption, the early pregnancy estimates did not change: ,100 mg/day: reference; 100 – 199 mg/day HR: 1.65 (95% CI: 1.21, 2.24); 200 – 299 mg/day HR: 1.53 (95% CI: 0.96, 2.43); ≥300 mg/day HR: 1.29 (95% CI: 0.56, 2.97).

When SAB was analyzed as a dichotomous variable using log-binomial regression, the observed risk ratios approximated the HRs from Cox proportional hazards regression (See Supplementary Table SII).

Risk of SAB ≥8 weeks of gestation was higher among women who consumed ≥300 mg/day of caffeine preconception (HR: 1.40; 95% CI: 1.00, 1.96) compared with women who consumed ,100 mg/day (Table III). The risk of late SAB was also higher among women who con- sumed 1 serving or ≥2 servings of coffee per day compared with none preconception; HRs were 1.13 (95% CI: 0.82, 1.55) and 1.32 (95% CI: 0.87, 2.01), respectively. The HRs for preconception caffeine and SAB before 8 weeks of gestation were 0.96 (95% CI: 0.73, 1.27) for 100 – 199 mg/day, 1.27 (95% CI: 0.97, 1.67) for 200 – 299 mg/day, and 0.93 (95% CI: 0.72, 1.22) for ≥300 mg/day. The HR for an early SAB among women drinking ≥2 servings of herbal/green tea/day was 0.67 (95% CI: 0.39, 1.16) compared with no herbal/green tea consumption.

Results for caffeine consumption stratified by TTP, smoking and BMI are presented in Supplementary Table SIII. The relation between precon- ception caffeine and risk of SAB was similar among smokers and non-smokers but the observed HRs were higher among women with a BMI ,25 than those with a BMI ≥25 and among women with a TTP ≥6 months versus those with a TTP ,6 months. Preconception

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Table II Hazard ratios for the association of spontaneous abortion (SAB) with consumption of caffeine and caffeinated beverages.

Preconception consumption Early pregnancy consumption

N SABa

Total GWa Crude Adjustedb HR (95% CI)

N SABa

Total GWa Crude Adjustedb HR (95% CI)

Caffeine (mg/day)

,100 327 48 500 1.00 (Reference) 392 66 210 1.00 (Reference)

100 – 199 122 17 484 1.04 1.00 (0.81, 1.23) 93 10 417 1.67 1.62 (1.19, 2.22)

200 – 299 112 13 498 1.24 1.19 (0.96, 1.49) 164 15 375 1.66 1.48 (1.03, 2.13)

≥300 171 20 819 1.22 1.09 (0.89, 1.33) 83 8299 1.46 1.23 (0.61, 2.46) Coffee (servings/day)c

0 295 43 254 1.00 (Reference) 488 77 622 1.00 (Reference)

,1 – 1 325 44 039 1.08 1.01 (0.86, 1.20) 220 18 706 1.54 1.38 (0.88, 2.17)

2 67 8580 1.15 1.02 (0.77, 1.35) 24 3973 0.80 0.66 (0.28, 1.52)

≥3 45 4428 1.46 1.23 (0.89, 1.72) Cola (servings/day)c

0 276 36 236 1.00 (Reference) 661 91 867 1.00 (Reference)

,1 – 1 448 62 995 0.95 0.95 (0.81, 1.11) 68 7859 1.11 1.02 (0.67, 1.56)

≥2 8 1070 1.01 0.94 (0.46, 1.92) 3 575 0.74 0.73 (0.18, 2.87) Black tea (servings/day)c

0 403 55 446 1.00 (Reference) 574 84 549 1.00 (Reference)

,1 – 1 312 41 618 1.05 1.06 (0.91, 1.24) 152 14 327 1.54 1.51 (1.18, 1.92)

≥2 17 3237 0.77 0.73 (0.45, 1.19) 6 1425 0.90 0.87 (0.38, 2.03) Herbal/green tea (servings/day)c

0 461 62 180 1.00 (Reference) 566 81 932 1.00 (Reference)

,1 – 1 245 33 676 0.97 0.97 (0.83, 1.14) 157 15 977 1.27 1.28 (0.88, 1.85)

≥2 26 4445 0.81 0.76 (0.51, 1.14) 9 2392 0.60 0.60 (0.25, 1.43)

aFrequencies and gestational weeks (GW) from the first imputation dataset. bAdjusted for maternal age, physical activity, parity, BMI, vocational training/education, smoking and prior SAB. The preconception model also includes alcohol consumption. cEstimates for coffee, cola, black tea and green/herbal tea are mutually adjusted for each other.

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coffee consumption also had a stronger association with SAB among women with a TTP ≥6 months than among women trying for ,6 months. Higher preconception consumption of cola was associated with an increased risk of SAB among smokers but a decreased risk among non-smokers (Supplementary Table SIII). The associations between SAB and black and herbal/green tea consumption were con- sistent across strata of TTP, smoking and BMI. Associations between early pregnancy caffeine and caffeinated beverage consumption and risk of SAB were similar across strata of TTP, smoking and BMI.

A lower proportion of women who experienced nausea had an SAB (10.7%) compared with women who did not experience nausea (21.1%); the total prevalence of nausea in early pregnancy was 66%. Table IV displays the hazard ratios for risk of SAB stratified by nausea symptoms. The mean mg/day of caffeine consumed decreased from pre- conception to early pregnancy (183 versus 81 mg/day, SD 216.9 and 133.1, respectively). After adjusting for gestational age at the early pregnancy questionnaire, women who experienced nausea during early pregnancy decreased their caffeine consumption by an average of 107 mg/day and women who did not report nausea decreased their caf- feine consumption by 95 mg/day. The observed hazard ratios were similar among women who experienced symptoms of nausea and those who did not.

Discussion In the present study, women who consumed high amounts of caffeine during early pregnancy, or who changed consumption from low to high between preconception and early pregnancy, had a slightly increased risk of SAB. However, the association between drinking individual caf- feinated drinks during early pregnancy and the risk of SAB was inconsist- ent. We observed an increased risk of SAB after ≥8 weeks of gestation among women who consumed higher levels of caffeine during the pre- conception period. We also observed an increased risk of SAB at all ges- tational ages among women with a TTP ≥6 months. Our finding that high levels of caffeine consumption during early pregnancy were associated with a higher risk of SAB is consistent with most (Dlugosz et al., 1996; Fenster et al., 1997; Wen et al., 2001; Bech et al., 2005; Weng et al., 2008; Greenwood et al., 2010) but not all (Mills et al., 1993; Savitz et al., 2008; Pollack et al., 2010), prospective studies. A prospective cohort study of 575 pregnancy planners (Wen et al., 2001) demonstrated a 2.5-fold increase in the risk of SAB among women who consumed 300 or more mg/day of caffeine during pregnancy compared with women who consumed ,20 mg (HR: 2.5; 95% CI: 1.0, 6.4). This study was con- ducted in a very small cohort of women and may have missed early SABs due to reliance on medical record review to ascertain birth outcomes. In a cohort of 2407 women interviewed before 12 weeks of gestation, Savitz et al. (2008) reported little indication of an increased risk of SAB with caffeine or coffee consumption when the exposure was measured prospectively. However, they were unable to assess caffeine consump- tion before the index SAB for 33% of women in their cohort and analyses among all women. Among the remainder of the women, they observed an increased risk of SAB with increasing amounts of reported coffee intake, a result the authors attributed to recall bias. A nested case – control study using prospective data from Denmark (Tolstrup et al., 2003) found an increased risk of SAB among women who consumed 75 – 300 mg/day of caffeine (OR: 1.26; 95% CI: 0.77, 2.06); however, in some cases, the exposure was ascertained up to 2 years before the

Figure 1 Association between preconception caffeine consumption and risk of spontaneous abortion (SAB) among all women in the Snart- Gravid cohort, fitted by a restricted cubic spline. Adjusted for maternal age, parity, BMI, alcohol consumption, smoking, vocational training/ education and prior SAB. Five knots at the 5th, 25th, 50th, 75th and 95th percentiles (0, 36, 104, 251 and 600 mg/day).

Figure 2 Association between early pregnancy caffeine consumption and risk of spontaneous abortion (SAB) fitted by a restricted cubic spline. Adjusted for maternal age, parity, BMI, smoking, vocational train- ing/education and prior SAB. Three knots at 0, 130 and 300 mg/day.

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index pregnancy. Other prospective studies (Dlugosz et al., 1996; Fenster et al., 1997; Savitz et al., 2008; Weng et al., 2008) that examined relationships between caffeinated beverage consumption and SAB risk have reported inconsistent associations. An analysis of coffee consump- tion during early pregnancy among participants in the Danish National Birth Cohort (Bech et al., 2005) showed that 55% of the cohort abstained from drinking coffee during pregnancy. The risk of SAB among women who drank eight or more servings of coffee per day was 1.59 times as high as the risk among abstainers (HR: 1.59; 95% CI: 1.19, 2.13). However, SABs were ascertained only through the registry and exposure information was collected at Week 16. These study weaknesses could have led to missed early losses and recall bias.

The present study did not collect daily readings of human chorionic go- nadotrophin (hCG), the earliest biologic marker of implantation, so it is inevitable that some early SABs were not identified. This limitation is common to most SAB studies. Missing early losses would have induced bias if caffeine consumption affected early losses differently than later losses. Women who were lost to follow-up or who became pregnant long after completing Snart-Gravid may have had an intervening SAB or may have changed their caffeine consumption habits before the pregnancy that we analyzed which would potentially lead to exposure misclassification. The proportion of missed losses is expected to be

smaller within a population of pregnancy planners than among the general population because pregnancy planners are presumably more observant of menstrual cycles. In support of this theory, 96% of Snart- Gravid participants who conceived during the study reported using home pregnancy tests to confirm their pregnancies (Wise et al., 2011).

A common problem for any study relying on self-reported caffeinated beverage intake is misclassification of total caffeine consumption. The caffeine content can differ based on the brewing method of coffees and teas, the coffee beans and tea leaves themselves, and the batch of cola (Bracken et al., 2002). Although we inquired about the number of daily servings of beverages with a specific volume, actual serving size and portion consumed are unknown. A previous study of reproductive- aged women indicated that a food frequency questionnaire similar to the one administered to the Snart-Gravid cohort was effective for ranking and categorizing participants according to caffeinated beverage intake, but not as precise for estimating total intake in milligrams as a daily diary or 24 h recalls (Schliep et al., 2013). In addition, we could not account for caffeine from sources like chocolate consumption, other caffeinated beverages such as energy drinks or caffeine-containing medications, because the questionnaire did not include these items. This lack of information most likely resulted in an underestimate of total caf- feine consumed. Further, the Snart-Gravid questionnaire included green

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Table III Hazard ratios for the association of caffeine and caffeinated beverage consumption before pregnancy with early (<8 weeks) and late spontaneous abortion (SAB).

Early SAB <8 weeks Late SAB ≥8 weeks

N SABa

Total GWa Crude Adjustedb HR (95% CI)

N SABa

Total GWa Crude Adjustedb HR (95% CI)

Caffeine (mg/day)

,100 216 1401 1.00 (Reference) 111 47 099 1.00 (Reference)

100 – 199 80 521 0.99 0.96 (0.73, 1.27) 42 16 963 1.14 1.07 (0.72, 1.57)

200 – 299 77 491 1.28 1.27 (0.97, 1.67) 35 13 007 1.15 1.05 (0.69, 1.60)

≥300 97 621 1.02 0.93 (0.72, 1.22) 74 20 198 1.65 1.40 (1.00, 1.96) Coffee (servings/day)c

0 204 1284 1.00 (Reference) 91 41 970 1.00 (Reference)

,1 – 1 199 1324 1.00 0.96 (0.76, 1.21) 126 42 715 1.25 1.13 (0.82, 1.55)

≥2 67 426 1.09 0.98 (0.71, 1.35) 45 12 582 1.61 1.32 (0.87, 2.01) Cola (servings/day)c

0 168 1059 1.00 (Reference) 108 35 177 1.00 (Reference)

,1 – 1 296 1933 0.99 0.99 (0.80, 1.23) 152 61 062 0.90 0.88 (0.65, 1.20)

≥2 6 42 1.07 1.02 (0.41, 2.50) 2 1028 0.89 0.79 (0.19, 3.36) Black tea (servings/day)c

0 255 1678 1.00 (Reference) 148 53 768 1.00 (Reference)

,1 – 1 203 1274 1.08 1.11 (0.91, 1.34) 109 40 344 0.99 0.99 (0.76, 1.29)

≥2 12 82 0.83 0.80 (0.44, 1.45) 5 3155 0.66 0.60 (0.24, 1.50) Herbal/green tea (servings/day)c

0 305 1990 1.00 (Reference) 156 60 190 1.00 (Reference)

,1 – 1 151 949 0.93 0.95 (0.78, 1.17) 94 32 727 1.03 1.01 (0.76, 1.33)

≥2 14 95 0.69 0.67 (0.39, 1.16) 12 4350 1.00 0.90 (0.46, 1.75)

aFrequencies and gestational weeks (GW) from the first imputation dataset. bAdjusted for maternal age, physical activity, parity, vocational training/education, BMI, alcohol consumption, smoking and prior SAB. cEstimates for coffee, cola, black tea and herbal/green tea are mutually adjusted for each other.

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tea and herbal tea in the same question and we coded them as not con- tributing to the total caffeine intake in this manuscript. This would lead to an underestimate of total caffeine intake.

Misclassification of caffeine intake is unlikely to depend on SAB status, so any misclassification is likely to be non-differential. Non-differential misclassification of the exposure would likely bias estimated effects in the highest category toward the null and bias estimates in the middle cat- egories of consumption in an unpredictable manner. This may help to explain the non-linear association observed between caffeine consump- tion during early pregnancy and SAB. Another methodologic challenge arises from the fact that coffee and other caffeinated beverages contain myriad chemicals (Higdon and Frei, 2006; Ferruzzi, 2010) with unknown effects. In addition, even for women consuming identical amounts of caffeine, individual variation in caffeine metabolism due to genetic polymorphisms in the CYP1A2 and NAT2 genes affects the amount of caffeine in circulation (Grosso and Bracken, 2005).

All caffeine exposure data in the present study was ascertained prior to the occurrence of SAB, thereby eliminating potential for recall bias. Nevertheless, data on caffeine intake were collected at only one point in time during pregnancy. Depending on when the woman recognized her pregnancy and the time when the follow-up questionnaires were completed (every 2 months), the information on early pregnancy caffeine consumption and pregnancy symptoms could be collected at different

gestational ages for each participant. The median gestational age at com- pletion of the early pregnancy questionnaire was 10 weeks. Because we did not collect exposure information during each month of pregnancy, we were unable to produce month-specific estimates of the association between caffeine consumption and SAB. If fetal demise occurred during a pregnancy but was still undetected at the time of the early pregnancy questionnaire, it is possible that the participant’s lack of aversion to caf- feine would affect her consumption habits (Stein and Susser, 1991), resulting in reverse causation. The observed changes in caffeine con- sumption from preconception to early pregnancy could be due to aver- sion to coffee/caffeine from pregnancy symptoms or due to a perceived health benefit. We were unable to separate these two reasons for a change in consumption, as the Snart-Gravid questionnaire did not include a question on this topic. Another prospective cohort study of pregnancy planners, Pregnancy Study Online (PRESTO), found that of the 61.9% of participants who decreased caffeine consumption during pregnancy, only 12% did so because of nausea; most women (56%) decreased consumption because they were worried about the effects of caffeine on the baby (L. Wise, personal communication).

An issue that has affected studies such as ours is residual confounding by smoking, especially if women are concerned about being stigmatized for smoking and are thus less likely to report their true exposure levels. Potential residual confounding from smoking would inflate the observed

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Table IV Hazard ratios for the association of spontaneous abortion (SAB) with caffeine and caffeinated beverage consumption during early pregnancy stratified by nausea symptoms during early pregnancy.

N SABa

Total GWa Nauseab N SABa

Total GWa No Nauseab

Caffeine (mg/day)

,100 210 47 301 1.00 (Reference) 182 18 909 1.00 (Reference)

100 – 199 50 7067 1.66 (1.18, 2.33) 43 3350 1.45 (0.89, 2.37)

200 – 299 72 8936 1.34 (0.82, 2.17) 92 6439 1.31 (0.90, 1.91)

≥300 31 4608 1.18 (0.51, 2.73) 52 3691 1.00 (0.51, 1.96) Coffee (servings/day)c

0 262 55 006 1.00 (Reference) 226 22 616 1.00 (Reference)

,1 – 1 96 10 840 1.24 (0.74, 2.07) 124 7866 1.26 (0.77, 2.08)

≥2 5 2066 0.45 (0.07, 3.09) 19 1907 0.60 (0.29, 1.26) Cola (servings/day)c

0 321 62 566 1.00 (Reference) 340 29 301 1.00 (Reference)

,1 – 1 40 4952 1.16 (0.63, 2.13) 28 2907 0.80 (0.47, 1.34)

≥2 2 394 0.82 (0.13, 5.28) 1 181 0.54 (0.08, 3.87) Black tea (servings/day)c

0 286 57 793 1.00 (Reference) 288 26 756 1.00 (Reference)

,1 – 1 74 9305 1.53 (1.10, 2.13) 78 5022 1.42 (1.08, 1.85)

≥2 3 814 1.11 (0.30, 4.10) 3 611 0.57 (0.19, 1.74) Herbal/green tea (servings/day)c

0 284 55 815 1.00 (Reference) 282 26 117 1.00 (Reference)

,1 – 1 76 10 688 1.36 (0.86, 2.14) 81 5289 1.20 (0.78, 1.85)

≥2 3 1409 0.49 (0.12, 1.92) 6 983 0.61 (0.23, 1.62)

aFrequencies and gestational weeks (GW) from the first imputation dataset. bAdjusted models include maternal age, physical activity, parity, vocational training/education, BMI, smoking and prior spontaneous abortion. The preconception model also includes alcohol consumption. cEstimates for coffee, cola, black tea and herbal/green tea are mutually adjusted for each other.

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HRs because smoking is positively associated with caffeine consumption and SAB. The Internet-based methodology of the Snart-Gravid study may reduce reluctance to report smoking, compared with face-to-face interviewing, but such reporting errors are unlikely to be completely eliminated (van Gelder et al., 2010). In a secondary analysis to determine the presence of an interaction between caffeine consumption and smoking, we did not find departure from additivity based on the relative excess risk due to interaction.

We collected outcome data from two data sources, thereby reducing the potential for dependent misclassification between exposure and outcome. Nevertheless, because non-registry-based information on the exposure and covariates were collected using a self-administered questionnaire, misclassification of these variables may be correlated with each other and lead to residual confounding (Rothman et al., 2008).

Caffeine consumption has been shown to alter endogenous hormone levels in some studies (Lucero et al., 2001; Kotsopoulos et al., 2009; Schliep et al., 2012) and, in turn, these alterations in hormones could affect the risk of SAB. Lawson et al. (2002) enrolled pregnant women 9 weeks after LMP in their study and found that coffee consumption was inversely associated with hCG and estrone-3-glucuronide, a metabolite of estradiol. Other studies have reported that caffeine is inversely asso- ciated with luteal phase total and free estradiol (Kotsopoulos et al., 2009) and positively associated with luteal phase progesterone (Kotsopoulos et al., 2009) and early follicular phase estradiol (Lucero et al., 2001). Kirkinen et al. (1983) and (Weathersbee and Lodge, 1977) also demon- strated that caffeine consumption during pregnancy increases levels of catecholamines and cellular cyclic adenosine monophosphate that may affect blood flow to the fetus through vasodilation pathways. Many of the prior examinations of caffeine consumption and hormone levels focus on non-pregnant women. Because physiologic processes change greatly during pregnancy, the associations between caffeine and hormone concentrations still have not been fully established.

In summary, we found that preconception caffeine consumption was not appreciably associated with SAB overall. Consumption of caffeine during early pregnancy was associated with a slightly higher risk of SAB, but there was little evidence of a dose – response relation. Our study is the largest to date to enroll participants during preconception and was able to reduce the likelihood of differential left truncation bias and recall bias. However, the observed results may still be affected by reverse causation, residual confounding, especially from smoking, and non-differential misclassification of exposure.

Supplementary data Supplementary data are available at http://humrep.oxfordjournals.org.

Acknowledgements We would like to thank Drs David Savitz and Shruthi Mahalingaiah for their review of the methods and early results of the manuscript. We would also like to acknowledge Tina Christensen for her role in the re- cruitment of the Snart-Gravid participants.

Authors’ roles H.T.S., E.E.H., L.A.W., E.M.M., K.J.R., A.H.R.: study concept and design. E.M.M., A.H.R., H.T.S.: data acquisition. K.A.H., E.E.H., L.A.W., E.M.M.,

S.B.B., K.J.R.: analysis and interpretation of the data. K.A.H.: statistical analysis, preparing the manuscript. All authors contributed to the critical revisions of the article and have approved the final version.

Funding Snart-Gravid was funded by the NICHD (R21-050264). Dr. Hahn’s work was funded in part by the BU Reproductive, Perinatal, and Pediatric Epi- demiology Training Grant NIH #T32HD052458.

Conflict of interest None declared.

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