Abstract Ramadan is observed by 1.6 billion Muslims. In an accompanying article that uses data from the Nouna Health and Demographic Surveillance System in Burkina Faso, Schoeps et al. (Am J Epidemiol. 2018;187(10):2085–2092) find that exposure to Ramadan in early pregnancy is associated with an increased risk of mortality among children under age 5 years. Ramadan exposes observant individuals to a specific pattern of nutrition and other behaviors, including changes in sleep patterns. How these behaviors might result in child mortality is not yet understood, and the findings reported in this paper should be replicated in other settings. child mortality, famine, fasting, nutrition, prenatal exposure delayed effects, pregnancy A growing body of literature has identified pregnancy, particularly periconception and early pregnancy, as a window of plasticity during which interventions can impact the developing fetus and have consequences that persist throughout postnatal life. Early work by Barker et al. (1) and others identified that birth weight, a proxy measure of cumulative exposures incurred during pregnancy, was associated with a range of later health outcomes. It is widely recognized that birth weight is but a crude measure of exposure; therefore, identifying better markers of specific exposures, or indeed the exposures themselves, is critical if epidemiologists are to be able to isolate causal factors. Given its centrality in human development, nutrition has long been identified as one such key exposure, and there is a large body of literature relating maternal prepregnancy and pregnancy nutrition to birth weight and to later child outcomes. However, the challenges of identifying women prior to conception and of measuring dietary intakes, let alone the partitioning of the ingested energy and nutrients between the mother and the developing fetus, are legion; and, of course, maternal nutritional intakes cannot be studied in isolation from the context in which the pregnant woman is living, raising questions about whether the nutritional differences observed are in fact the relevant causal factor. Sometimes, however, that context provides enough of an exposure gradient that assessment of individual intakes becomes unnecessary. Studies of famines in the Netherlands, China, and Russia have exploited dramatic reductions in food availability at a population level to infer individual-level differences in the nutritional status of pregnant women, and have examined the consequences for their offspring (2–4). In particular, the circumstances of the Dutch famine of 1944–1945, in which food rations were below 1,000 kcal/day for approximately 5 months, allow examination of differences among those exposed at specific stages of their pregnancy (2). However, there is a perverse reverse problem—while a famine is, at its core, a lack of food supply at a population level, there are usually other accompanying social stressors, including violence, forced migration, weather extremes, and other factors, and hence the specific role of nutrition cannot always be isolated. The winter of 1944–1945 was especially cold in western Europe—this made the famine more severe by limiting the ability to transfer foods by canal to the famine area, while also increasing the energy demands for survival. And the decrease in fertility associated with famine-induced amenorrhea raises questions about selectivity of the resulting birth cohort. Sometimes the variation in food availability is less severe, yet more predictable. Sub-Saharan Africa has 2 primary seasons, with food availability being very different in the dry season and the rainy season. Prior research from the Gambia has shown that season of birth is associated with later mortality (5). Ramadan is a month in which observant Muslims refrain from eating or drinking during daylight hours, resulting in a change in the usual circadian patterns of ingestion and metabolism, which is superimposed on the seasonal food context. Based as it is on the lunar calendar, Ramadan starts 11 days earlier each year. Thus, given long enough, one can differentiate the impacts of seasonal food availability and of Ramadan fasting. In an elegant paper published in the Journal this month, Schoeps et al. (6) examine whether exposure to Ramadan in selected stages of pregnancy is associated with mortality among children under age 5 years. Several aspects of the study design are of interest to epidemiologists. The study was conducted among participants in the Nouna Health and Demographic Surveillance System, a well-characterized population of approximately 100,000 individuals in northwestern Burkina Faso, established in 1992. While Burkina Faso has an equatorial climate with distinct seasons that strongly impact food availability in subsistence farming areas such as Nouna without marked variation in day length or mean temperatures, the study authors exploited the 20 years of surveillance and the variation in the timing of Ramadan to reduce the potential impact of seasonality. But the study team also had one more ace up its sleeve: The surveilled population was approximately two-thirds Muslim and one-third Christian and other religions, and the non-Muslims do not fast, while they remain subject to any seasonal or other community-wide pressures on the food system and hence nutritional intakes. Schoeps et al. used a difference-in-differences approach, common in econometric analyses and in evaluation of community-level public health programs but perhaps not as widely used in epidemiology (7), to adjust for this background experience and to isolate the potential impact of Ramadan and its associated fasting behaviors on later outcomes (6). In the whole sample, Muslims experienced a 15% increase in the under-5 mortality rate, but Muslims and non-Muslims did not experience differences in their under-5-year mortality rates when there was no exposure to Ramadan in pregnancy, and Muslim women did not experience an increase in the under-5 mortality of their children when Ramadan occurred in the later stages of pregnancy. Specifically, the authors found that exposure to Ramadan in the periconception and early pregnancy periods was associated with a 22%–30% increase in the under-5 mortality rate. Epidemiologists, when faced with a statistical association, often attempt to identify, and rule out, alternative explanations. The sample size itself was large, with 41,025 births for which date of birth was known exactly; of those 41,025 births, 4,213 children died prior to the censoring date. The authors controlled for long-term mortality trends through the inclusion of a year-of-birth variable. Indeed, there was an overall trend towards a reduction of mortality with time. Although they were not able to completely rule out a season × Ramadan interaction, as they had less than a full 33-year cycle of data available to them, any seasonal factors that impact child mortality should have been netted out through the experience of the non-Muslims, who would not have fasted. The association was observed across the geographic regions within the surveillance system. A key consideration is whether knowledge of the occurrence of Ramadan might have affected the timing of attempts to conceive, and whether the timing of pregnancy might have been differential by factors that are related to the risk of infant and child mortality. There was no suggestion of this in the data. Notably, the association was stronger for infant mortality and somewhat lower for postinfant mortality. The biological explanation for the finding is less clear. Ramadan is not, in and of itself, a psychologically stressful period. Unlike the Dutch famine, where food shortages were closely related to changes in maternal weight gain in pregnancy (8) and size at birth (9), and unlike the experience of the Gambia, where there is also an annual “hungry season” that is associated with postchildhood infectious disease mortality (5), it is not clear that Ramadan in fact results in any meaningful changes in net food intake or resting metabolic rate (10). The major behavioral change is in the timing of food intake, and therefore to some extent in the patterns of other behaviors engaged in during the month, including physical activity and sleep. Changes in drinking patterns may have resulted in mild dehydration (11). The authors hypothesize that the intermittent fasting of Ramadan affects the developing immune system (6). However, they do not provide details on specific causes of death in their population, nor do they provide any information on markers of immune function that might support this conjecture. Ramadan is observed by most of the world’s 1.6 billion Muslims. If, indeed, something about being conceived during Ramadan is raising mortality risks, this potentially affects a large proportion of the world’s population and is deserving of further study. Advising couples to refrain from attempts to conceive in the month or months before Ramadan is premature based on this single study. One hopes that further research will replicate this finding in other settings, perhaps those in which the seasonal context results in marked differences in temperature or day length over the 33-year cycle, to identify an epigenetic signal that results from this particular set of behaviors—as has been demonstrated in the context of severe, acute exposure to famine (12)—allowing exploration of any underlying mechanisms. ACKNOWLEDGMENTS Author affiliation: Hubert Department of Global Health, Rollins School of Public Heath, Emory University, Atlanta, Georgia (Aryeh D. Stein). Conflict of interest: none declared. REFERENCES 1 Barker DJ , Osmond C , Golding J , et al. . Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease . BMJ . 1989 ; 298 ( 6673 ): 564 – 567 . Google Scholar Crossref Search ADS PubMed 2 Lumey LH , Stein AD , Susser E . Prenatal famine and adult health . Annu Rev Public Health . 2011 ; 32 : 237 – 262 . Google Scholar Crossref Search ADS PubMed 3 Li C , Lumey LH . Exposure to the Chinese famine of 1959–61 in early life and long-term health conditions: a systematic review and meta-analysis . Int J Epidemiol . 2017 ; 46 ( 4 ): 1157 – 1170 . Google Scholar Crossref Search ADS PubMed 4 Stanner SA , Bulmer K , Andrès C , et al. . Does malnutrition in utero determine diabetes and coronary heart disease in adulthood? Results from the Leningrad siege study, a cross sectional study . BMJ . 1997 ; 315 ( 7119 ): 1342 – 1348 . Google Scholar Crossref Search ADS PubMed 5 Moore SE , Cole TJ , Poskitt EM , et al. . Season of birth predicts mortality in rural Gambia . Nature . 1997 ; 388 ( 6641 ): 434 . Google Scholar Crossref Search ADS PubMed 6 Schoeps A , van Ewijk R , Kynast-Wolf G , et al. . Ramadan exposure in utero and child mortality in Burkina Faso: analysis of a population-based cohort including 41,025 children . Am J Epidemiol . 2018 ; 187 ( 10 ): 2085 – 2092 . 7 Dimick JB , Ryan AM . Methods for evaluating changes in health care policy: the difference-in-differences approach . JAMA . 2014 ; 312 ( 22 ): 2401 – 2402 . Google Scholar Crossref Search ADS PubMed 8 Stein AD , Ravelli AC , Lumey LH . Famine, third-trimester pregnancy weight gain, and intrauterine growth: the Dutch Famine Birth Cohort Study . Hum Biol . 1995 ; 67 ( 1 ): 135 – 150 . Google Scholar PubMed 9 Stein AD , Zybert PA , van de Bor M , et al. . Intrauterine famine exposure and body proportions at birth: the Dutch Hunger Winter . Int J Epidemiol . 2004 ; 33 ( 4 ): 831 – 836 . Google Scholar Crossref Search ADS PubMed 10 Lessan N , Saadane I , Alkaf B , et al. . The effects of Ramadan fasting on activity and energy expenditure . Am J Clin Nutr . 2018 ; 107 ( 1 ): 54 – 61 . Google Scholar Crossref Search ADS PubMed 11 Mulyani EY , Hardinsyah , Briawan D , et al. . Hydration status of pregnant women in West Jakarta . Asia Pac J Clin Nutr . 2017 ; 26 ( suppl 1 ): S26 – S30 . Google Scholar PubMed 12 Heijmans BT , Tobi EW , Stein AD , et al. . Persistent epigenetic differences associated with prenatal exposure to famine in humans . Proc Natl Acad Sci U S A . 2008 ; 105 ( 44 ): 17046 – 17049 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: email@example.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
American Journal of Epidemiology – Oxford University Press
Published: Oct 1, 2018
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