Population Attributable Fractions of Caffeine and Water Pipe on Low Birth Weight: A Population-Based Prospective Cohort Study in Iran

Background To estimate Population Attributable Fractions (PAFs) and Generalized Impact Fractions (GIFs) for LBW following scenarios to remove or decrease prenatal use of caffeine or water pipe. Methods Using data of 861 pregnant women from a population-based prospective cohort study in suburbs of Bandar Abbas city (2016-2018), PAFs and GIFs were calculated based on the relative risk scale. Practical interventional scenarios to reduce the exposure prevalence were developed for calculation of GIFs. Results The cumulative incidence of LBW was 16.1%. An estimated 19% (95%CI: 6, 30%) of LBW neonates was attributed to dietary caffeine intake of >100 mg/day and 11% (95%CI: 8,14%) to water pipe smoking. Action plans to reduce caffeine intake and water pipe smoking suggested an avoidable burden of LBW cases of approximately 10.7% (95% CI: 6.6, 25.3%) and 5.7% (95%CI: 5.0, 6.8%), respectively. than 100 mg/day in subjects with excessive intake of caffeine; and b) decrease prevalence of water pipe smoking to the estimated national prevalence (i.e. 3% among 25-54 years old Iranian women(7)). All the analyses were performed using Stata version 13 (Stata Corp., College Station, TX, USA). P-values less than 0.05 were considered statistically signicant for the nal model.


Introduction
Low Birth Weight (LBW), de ned as the birthweight below 2500 grams, is associated with increased morbidities and mortalities in neonates (1). Previous studies have shown that 5.0 to 8.0% of Iranian neonates were born with LBW each year while our previous study on the same study setting showed that nearly 12% of the pregnancies resulted in LBW infants (2). LBW, a consequence of inadequate fetal weight gain in utero, has been linked to a variety of interrelated risk factors, amongst them tobacco smoking and dietary indulgence in caffeine intake (3)(4)(5). Due to the causative effect of cigarette smoking on LBW, concern has been raised to possible effect of other types of tobacco consumption such as water pipe (6). The results of the latest STEPS survey in Iran showed that water pipe is a prevailed mode of smoking in the south of Iran, where women used it more frequently than the rest of the country (7). Detrimental effects of water pipe smoking on pregnancy outcomes have been reported previously (2,5,8). LBW is also linked to the excess intake of caffeine; whereas its adverse effect on pregnancy outcome has not been fully worked out (9)(10)(11). From the epidemiological point of view, the Population Attributable Fraction (PAF), de ned as the fraction of all cases of a particular health condition that is attributable to a speci c exposure, is an epidemiologic measure widely used to assess the public health impact of various exposures (12). However, interpretation of PAF relies heavily on interventions that can perfectly remove the exposure of interest. In other words, PAF interprets poorly for interventions for which success rate is below 100%. To overcome this conceptual pitfall, Generalized Impact Fraction (GIF), which calculates the change in the disease burden when a risk factor is altered, has been used by epidemiologists. While PAF simply studies complete elimination of a risk factor, GIF estimates the proportional reduction in disease incidence given a graded reduction in the prevalence of a risk factor (13). To the best of our knowledge, there is no epidemiologic evidence on the impact of designed interventions to prevent LBW by eliminating or reducing the level of caffeine intake and water pipe in Iran. Therefore, using data from a population-based prospective cohort study, the present paper estimated the anticipated incidence of LBW following interventions to reduce or eliminate the level of caffeine intake and water pipe.

Materials And Methods
The present study used data from the rst two phases of a prospective cohort study entitled "A population-based prospective cohort study to identify contributors of mother and child health in suburban communities" in Bandar Abbas city, which is abbreviated as Bandar Abbas Pregnancy Cohort (BAPC Therefore, data of 861 live singleton pregnancies (mean +SD gestational age at recruitment: 22.62+9.66 weeks) was included in the analysis (Figure 1). The main outcome of the study was LBW, de ned as birth weight below 2,500 grams (1). The main exposures were water pipe smoking and caffeine intake during pregnancy both were measured on the rst phase of the BAPC.
Water pipe smoking during pregnancy (Yes regular/Yes often/No) was measured by a checklist recommended by the WHO (15) and was merged into Yes/No answers. The checklist was validated by a group of healthcare professionals and epidemiologists while the reliability was checked on a subset of BAPC subjects (n=25, Cronbach`s alpha=0.78). The checklist also contained additional information on age at smoking initiation, smoking duration, and number of water pipe sessions per day, and an "important covariate" was determined as whether the change in the exposure effect estimate from adjusting for the covariate falls outside an interval of practical equivalence; e.g., 0.91 < RR a /RR u < 1.1 (which is the 10%-change rule for the risk ratio modi ed to be proportionally symmetric) (19). Based on the CIE strategy, duration of water pipe smoking, maternal education, intake of iron supplement, infant sex, preterm birth, history of LBW infant, and monthly expenditure were included in the nal regression model. RR a for the effects of the main exposures on LBW were calculated using Modi ed Poisson regression models (20). The Miettinen formula was applied to calculate PAFs for caffeine intake and water pipe smoking (12,21). Accordingly, we estimated the PAF from the estimated RR a derived from the modi ed Poisson regression model for the exposure of interest (water pipe smoking and caffeine intake, both as dichotomous variables). The prevalence of exposure among cases (p c ) was estimated as 22.3% for water pipe smoking and 67.63% for caffeine intake equal or more than 100 mg/day. The PAF nally estimated as: PAF = p c (1 −1/RR) (12).
GIFs were calculated using the following formula: Where, P i denoted the proportion of the population in exposure category i (fact) (8.59% for water pipe, 56.98% for high caffeine intake). P i` denoted the proportion of the population in exposure category after an intervention or other change (counter fact).
Therefore, P i` for water pipe was set as 3% as the estimated national prevalence of water pipe. To set P i` for caffeine intake, we used the recommended dose of 100 mg/day caffeine in pregnancy by the world health organization as the safe threshold; hence, we hypothesized that an effective intervention would successfully decrease the proportion of women with high intake of caffeine to 14.9%. Finally, RR a denoted adjusted relative risk derived from the modi ed Poisson regression model (13). GIFs were calculated based on a series of proposed action plans for: a) decrease caffeine intake to less than 100 mg/day in subjects with excessive intake of caffeine; and b) decrease prevalence of water pipe smoking to the estimated national prevalence (i.e. 3% among 25-54 years old Iranian women (7)). All the analyses were performed using Stata version 13 (Stata Corp., College Station, TX, USA). P-values less than 0.05 were considered statistically signi cant for the nal model.

Results
Out of 861 newborns, one hundred and thirty-nine (16.14%) were LBW, while the incidence of LBW was higher in illiterate/ elementary education group (21.1%), those with no prenatal intake of iron supplementation (19.3%), and those with a history of LBW newborn (24.5%). Overall, 482 (56%) of the pregnant women reported intake of more than 100 mg/day caffeine, among whom the three most frequently reported sources of caffeine were black tea (43.3%), soft drinks (33.8%), and instant coffee (19%). Compared to the group with normal caffeine intake, the proportion of LBW neonates was signi cantly higher in mothers with high caffeine intake during pregnancy (13.2% vs. 18.4%, p=0.038). Sixty-nine (8.59%) pregnant women reported water pipe smoking, with an aver age of 1.87 sessions per day. Compared to non-smokers, the proportion of LBW neonates was signi cantly higher in mothers who smoked water pipe during pregnancy (14.27% vs. 37.68%, p<0.001). Additionally, the mean (SD) of water pipe smoking duration was 6.7 (30.8) months. The mean (SD) duration of water pipe smoking was signi cantly higher in mothers with LBW neonates (11.8 (43) vs. 5.8 (27) in normal-weight neonates, P=0.01) (

Discussion
The present study used data of 861 live singleton births from the BAPC study. Sixteen percent of neonates were born with LBW while one-third of them were preterm as well. The incidence of LBW in our sample of suburban residents was higher than the estimate by the UNICEF (8%) and previous studies in Iran (5,22,23).
Overall, 73% of the study subjects reported consumption dietary caffeine on any dose during their current pregnancy while the average dose of caffeine was 104.7 mg/day. By de ning the threshold for the safety dose of caffeine as 100 mg/day (17), we found that 56% of our study subjects reported excessive intake of caffeine. We also observed that women belonging to lower educational and socio-economic groups and those who used water pipe reported higher doses of caffeine intake. The estimated dose of caffeine intake in our study was similar to the reports from the US and Poland (24,25). The primary sources of dietary caffeine in our study; however, disagreed with the reports from the developed countries. While black tea (60%) and soft drinks (44%) were the predominant sources of caffeine intake in our study, black coffee was the dominant source of caffeine intake in the developed world. This discrepancy can be attributed to social and cultural context. Differences in weather circumstances and availability and affordability of black tea and soft drinks advertise their consumption over other sources of caffeine (e.g. coffee or chocolate). Nevertheless, due to the lack of national estimates on the pattern of caffeine intake in Iran, we are unable to provide a valid comparison on caffeine consumption in our sample of pregnant women to the general population. Our study showed that consumption of more than 100 mg/day caffeine signi cantly increased the risk of LBW, which was consistent with the results of previous studies (10,26). We used one-week dietary recall to measure daily intake of caffeine during pregnancy. Due to many exogenous and endogenous factors, it is likely that the measured dose of caffeine did not necessarily re ect the actual concentration of metabolites in the woman`s body (27). Moreover, we are aware that the amount of caffeine in beverages is heavily determined by methods of beverage preparation; therefore, non-differential misclassi cation bias for the measured dose of caffeine is likely (9).
The self-reported prevalence of water pipe smoking during pregnancy was 8% among the study subjects, which was higher than previous estimates in Iran (7,28); yet similar to the estimates from countries of Arabian Peninsula (29,30).
Consistent with previous reports (31, 32), we found that water pipe smoking during pregnancy signi cantly increased the risk of LBW.
The nal hypothesis of our study was the extent to which partial or complete removal of either exposures of interest would reduce the risk of LBW. To answer that, we calculated PAF, which is de ned as the fraction of all cases of an adverse condition in a population that is attributable to a speci c exposure (12). We estimated that 11% and 19% of LBW cases would be prevented if interventions to eliminate water pipe smoking or dietary caffeine intake were to be implemented, respectively. In order to interpret PAF using our observational data, we must assume that removal of the study exposures did not affect or alter the distribution of other risk factors for LBW (such as cigarette smoking instead of water pipe). We also must assume that there was no bias in the study design and data analysis, which means that the estimated effects were adjusted for all measured confounders (12). The estimate of PAF only applies to interventions that can successfully and completely remove the exposure of interest, while such successful interventions, especially in lifestyle factors, are scarce. For this reason and to calculate the impact of partially successful interventions, we developed real-time scenarios and calculated GIF, which measures the reduced fraction of cases that would result from changing the current level of the exposure to some modi ed level (13). The rst intervention was designed to decrease the proportion of women with high intake of caffeine among pregnant women whose daily caffeine consumption was above that level. By doing so, 19% of LBW neonates would be prevented. The second scenario aimed to decrease the marginal prevalence of water pipe to the estimated national level of 3% among women. Implementation of such program would result in 11% reduction in LBW cases.
This study used data from a population-based sample to nd the extent to which various preventive interventions on caffeine intake and water pipe smoking would in uence the risk of LBW. Despite the high generalizability of population-based samples, our results should be translated carefully. We restricted our study subjects to women who had conception without medical assistance and had no history of infertility, hence our sample might be a healthier sample compared to the general population of women at reproductive age (33). Caution must be taken if the estimated effects of water pipe smoking and caffeine intake are to be generalized to women who had prior history of infertility or medically-assisted conception. Moreover, generalization of the estimated PAF requires similar distribution of the outcome as well as valid estimates for the exposure effects in the target population (12). The possible mediation effect of preterm birth in causal pathway between exposures of interest and LBW is another crucial note to keep in mind. Whether preterm birth lies in the causal pathway from water pipe or caffeine to LBW is not clear yet. Nonetheless, the likelihood of this association is acknowledged and we recommend caution in using the results of our study to preterm infants.
The present study was one of the rst prospective epidemiologic studies to investigate public health impacts of caffeine and water pipe on reproductive outcomes in Iran. It used data from a prospective cohort project, while the suitability of prospective epidemiological studies to investigate pregnancy outcomes has been well-documented (33,34).
Some limitations worth mentioning as well. We calculated the risk of LBW based on a risk set of total live births, whereas, the true theoretical risk set is de ned as the total of successful conceptions. Therefore, the estimated risk of LBW might be in ated due to exclusion of unsuccessful pregnancies from the denominator (33). Furthermore, questionnaire-based data was used to estimate the prevalence of water pipe based on a systematic review done by Akl et.al (35). Nevertheless, estimation of the exact dose of substance absorption following water pipe smoking is not practical due to the lack of a ubiquitous standard tool. Therefore, the estimated magnitude and effects of water pipe on pregnancy outcomes might be different from previous results partly because of using various de nitions and data collection tools. Additionally, we did not measure the chronic use of water pipe as an important predictor of fetal growth. This was because of the inconclusive evidence regarding such association at the time of the BAPC development. Therefore, our results only apply to water pipe use during pregnancy rather than continuous water pipe smoking.

Conclusions
Our study showed that water pipe smoking and excess consumption of dietary caffeine during pregnancy could decrease birth weight in deprived communities in the south of Iran. A notable proportion of LBW neonates can possibly be prevented by eliminating dietary caffeine and water pipe from pregnant women. Practical community-based action plans to control water pipe and to prevent excess intake of caffeine among pregnant women would substantially reduce LBW burden in the south of Iran.