Ramadan Exposure In Utero and Child Mortality in Burkina Faso: Analysis of a Population-Based Cohort Including 41,025 Children

Ramadan Exposure In Utero and Child Mortality in Burkina Faso: Analysis of a Population-Based... Abstract Ramadan exposure in utero can be regarded as a natural experiment with which to study how nutritional conditions in utero influence susceptibility to disease later in life. We analyzed data from rural Burkina Faso on 41,025 children born between 1993 and 2012, of whom 25,093 were born to Muslim mothers. Ramadan exposure was assigned on the basis of overlap between Ramadan dates and gestation, creating 7 exclusive categories. We used proportional hazards regression with difference-in-differences analysis to estimate the association between Ramadan exposure at different gestational ages and mortality among children under 5 years of age. Under-5 mortality was 32 deaths per 1,000 child-years. Under-5 mortality among Muslims was 15% higher than that among non-Muslims (P < 0.001). In the difference-in-differences analysis, the occurrence of Ramadan during conception or the first or second trimester was associated with higher under-5 mortality rates among Muslims only. The mortality rates of children born to Muslim mothers were 33%, 29%, and 22% higher when Ramadan occurred during conception, the first trimester, and the second trimester, respectively, compared with children of non-Muslim mothers born at the same time (P = 0.01, P < 0.001, and P = 0.007). Having a Muslim mother was not associated with mortality when the child was not exposed to Ramadan, born during Ramadan, or exposed during the third trimester. Observance of Ramadan during early pregnancy can have detrimental consequences for the future health of the unborn child. child mortality, difference in differences, population-based cohort, prenatal exposure delayed effects, pregnancy, Ramadan, sub-Saharan Africa Editor’s note: Invited commentaries on this article appear on pages 2093 and 2095, and the authors’ response appears on page 2098. The first 9 months of life in utero are a crucial period for human development in which future health trajectories are set, determining physical and cognitive capabilities. Early pregnancy is a time when the developing organism is particularly vulnerable, as this is when organogenesis takes place, including development of the neural and immune systems and the shaping of endocrine and metabolic pathways (1). It is well established that some infections (including rubella virus), certain chemicals and drugs (most famously thalidomide), and deficiency in certain nutrients (e.g., folate and iodine) in early pregnancy can lead to serious fetal damage (2). There is also a growing body of evidence that nutrients, environmental chemicals, drugs, and infections can have more subtle effects on the developing organism in utero, presumably through epigenetic mechanisms. Such effects may show only later in life, a concept referred to as “developmental origins of health and disease” (3–5). The majority of studies on the topic have come from high- and middle-income countries and have focused on chronic diseases in later adulthood, such as diabetes and cardiovascular disease (6). There have been very few studies in low-income settings, although it would be of great interest to better understand developmental impacts on the immune system and infection-related mortality (7). When studying long-term effects of undernutrition in utero, researchers have employed natural experiments such as famines to avoid confounding by socioeconomic status and other factors (2, 8). The most famous is the study of the Dutch Hunger Winter of World War II, which showed that exposure to famine during gestation, especially early gestation, increases the risk of obesity, diabetes, coronary heart disease, breast cancer, mental illness, and cognitive decline later in life and increases later-life mortality rates (9–13). Other research has focused on other famines occurring during World War II, on 19th century famines, and on more recent famines such as those that took place during the Chinese Great Leap Forward (see Lumey et al. (8) for a review). One study that—like our study—focused on the association between nonfamine malnutrition and mortality exploited seasonal patterns of food availability in the Gambia, linking season of birth to smaller thymus size in children and to mortality in young adults (7). Another very particular natural experiment for studying the effects of undernutrition in utero is furnished by the Muslim tradition of daytime fasting during the holy month of Ramadan. The rotation of Ramadan through the year and the contrast with non-Muslim populations in the same location provides an opportunity to disentangle seasonal effects on fetal development (due to different availability of nutrients, as well as environmental and infectious exposures) from Ramadan effects. Studying the fetal health impacts of intermittent maternal fasting, as occurs during Ramadan, would shed light on potential long-term effects of relatively mild shocks experienced more commonly. Furthermore, effects of Ramadan fasting are relevant in their own right, given the high numbers of people affected each year. Most studies of intrauterine Ramadan exposure have focused on short-term outcomes such as low birth weight or preterm delivery, while fewer have looked beyond the immediate outcomes and studied longer-term outcomes, including cognitive abilities, body composition, symptoms of coronary heart disease and type 2 diabetes mellitus, and reduced work performance (14–20). To our knowledge, there have been no studies so far on the association between Ramadan exposure in utero and mortality outcomes in childhood or adulthood. We hypothesized that maternal observance of Ramadan during conception and early pregnancy may have negative impacts on the development of the fetus, leading to higher child mortality, especially in settings with high background levels of undernutrition among women and high infection-related child mortality. The aim of our study was to assess the influence of Ramadan exposure in utero at different gestational ages on mortality among children under 5 years of age in Burkina Faso. METHODS Study area and population This population-based cohort study was conducted using data from the Nouna Health and Demographic Surveillance System (HDSS) in northwestern Burkina Faso, which in 2012 comprised a population of nearly 100,000 inhabitants. The Nouna HDSS was established by an initial census carried out in 39 villages in 1992 (21). In 2000, 2 additional villages and the town of Nouna were included, and another 17 villages followed in 2004. The town of Nouna is a semiurban settlement with about 30,000 inhabitants, and the rural area around Nouna can be divided into 4 regions (22). The majority of inhabitants in the Nouna HDSS are Muslims (63%), while 32% are Christians, and a minority of 5% holds traditional beliefs. The study area is characterized by a sub-Sahelian climate with a dry season (November–May) and a rainy season (June–October). The majority of the population lives by subsistence farming; literacy rates are low, and there is seasonal food insecurity. More than one-quarter of children between 6 and 31 months of age are wasted (21, 23). Ramadan exposure During the month of Ramadan, which lasts about 30 days, healthy adult Muslims are obliged to abstain from eating and drinking (even water) between dawn and sunset. The Islamic lunar calendar is approximately 11 days shorter than the Gregorian calendar, so Ramadan occurs slightly earlier each year and rotates through the Gregorian year in about 33 years. For sick people and pregnant women, fasting during Ramadan is voluntary; however, they are supposed to make up for this exemption by fasting afterwards (24). While Ramadan is likely to affect fetal health through the fasting itself, other lifestyle changes taking place during Ramadan (including increased sugar intake and changes in sleeping patterns) may also be responsible for the association. Data from the Nouna HDSS do not contain information on individual Ramadan fasting, and we do not distinguish between the potential channels for associations. We assigned Ramadan exposure in utero based on a calculation of whether there was overlap between Ramadan and gestation, utilizing the date of birth in relation to the Ramadan dates and assuming a gestational period of 266 days, which is the average duration of a full-term human pregnancy. Our approach can be interpreted as an intention-to-treat analysis that helps avoid confounding due to self-selection of women into Ramadan-observant and nonobservant groups, which likely also differ in other ways. We differentiated Ramadan exposure into 7 exclusive categories: certainly not exposed, probably not exposed, conceived during Ramadan, Ramadan starting during the first, second, or third trimester, and born during Ramadan. Children in the category “probably not exposed” would not have experienced Ramadan in utero if their mothers had a normal 266-day pregnancy, as this would have started just after Ramadan. However, if they were born up to 20 days postterm, they could still have been exposed to Ramadan during conception (Figure 1). Figure 1. View largeDownload slide Assignment to prenatal Ramadan exposure by time of birth for children born in Nouna District, Burkina Faso, in 2011–2012. Assuming a gestation period of 266 days, one of 7 Ramadan exposure categories was assigned to each child. The asterisks (*) indicate birth dates, while black dots show the calculated dates of conception. The black boxes indicate the timing of Ramadan in 2010 and 2011. Mar, March; Jul, July; Nov, November. Figure 1. View largeDownload slide Assignment to prenatal Ramadan exposure by time of birth for children born in Nouna District, Burkina Faso, in 2011–2012. Assuming a gestation period of 266 days, one of 7 Ramadan exposure categories was assigned to each child. The asterisks (*) indicate birth dates, while black dots show the calculated dates of conception. The black boxes indicate the timing of Ramadan in 2010 and 2011. Mar, March; Jul, July; Nov, November. Statistical analysis Between 1993 and 2012, a total of 48,747 children were born alive in the Nouna HDSS. We excluded 7,520 children for whom the exact date of birth was unknown and 202 children for whom information on mother’s religion was missing; this resulted in a sample of 41,025 children for analysis. We calculated mortality rates in children of Muslim and non-Muslim mothers overall and stratified by the occurrence of Ramadan during pregnancy. Because our study period included 20 years of observation, Ramadan did not fully rotate through the year (from February/March in 1992 to July/August in 2012), and thus Ramadan exposure varied by month of birth (see Web Figure 1, available at https://academic.oup.com/aje). We used a difference-in-differences analysis, comparing the association of Ramadan occurrence during pregnancy with mortality between non-Muslims and Muslims, under the assumption of a common seasonal trend. The inclusion of non-Muslims in the model served to purge any remaining seasonal mortality differences correlated with Ramadan that remained after adjustment for calendar month of birth (14). For details on the model assumptions and sensitivity analyses, refer to Web Appendix 1. We used 2-level multivariate Weibull proportional hazards regression to estimate the association between Ramadan exposure in utero and child survival up to age 5 years, with random intercepts at the mother level. Death between birth and 5 years of age was the event of interest. The time variable was time from birth to death, age 5 years, loss to follow-up, or the end of the study (December 31, 2012). After confirmation of the proportional hazards assumption for the main variables of interest through the use of Kaplan-Meier graphs, we first fitted a regression model without considering Ramadan timing, to estimate the association between religion and child mortality, using a binary variable indicating whether the mother was Muslim or non-Muslim. In a second regression model, we then added a variable indicating Ramadan occurrence during pregnancy, as well as a term for the interaction of Ramadan occurrence with the Muslim indicator variable. These interaction parameters were the coefficients of interest in our study. They can be interpreted as a comparison of mortality between exposed and unexposed Muslims after correcting for seasonality (by comparing with non-Muslims). Adjustment was made for year of birth (continuous variable), calendar month of birth, and region of residence. Stata version 14 (StataCorp LLC, College Station, Texas) was used for analysis, and SAS version 9.3 (SAS Institute, Inc., Cary, North Carolina) was used for creating the figures. All P values are 2-sided. In addition, stratified analyses were conducted for the 5 main regions of the study area (22) and for 3 different study periods. Besides the main outcome of under-5 mortality, we also studied infant mortality and mortality in children aged 1–4 years. To investigate in more detail the association between being conceived during Ramadan and mortality, we created 2 separate categories: exposure for at least 14 days and exposure for less than 14 days. RESULTS Our study included 41,025 children who were born to 20,709 mothers in the Nouna HDSS between January 1993 and December 2012, for whom mother’s religion and the precise date of birth were known. The majority of mothers in this sample were Muslim (61%), while 28% were Catholic, 5% were Protestant, and 6% had an animist religion or another religion. Between 1993 and 2012, there were 4,213 deaths among children under 5 years of age during 133,203 child-years at risk, corresponding to an overall mortality rate of 31.6 deaths per 1,000 child-years. Mortality rates were higher among Muslims (33.5 deaths per 1,000 child-years) than among non-Muslims (28.7 deaths per 1,000 child-years) (Table 1). Among non-Muslims, mortality rates were somewhat lower in children who were in utero during Ramadan as compared with children who were not. This was most likely due to seasonal variations in mortality that were correlated with Ramadan occurrence in our sample and that were previously described in the study area (25). This pattern was not apparent for children of Muslim mothers. Table 1. Numbers of Live Births, Numbers of Child Deaths, and Mortality Before 5 Years of Age, by Prenatal Ramadan Exposure and Religion, Among 41,025 Children From Nouna District, Burkina Faso, 1993–2012 Ramadan Exposure Category Muslims Non-Muslims Live Births No. of Child-Years No. of Child Deaths U5M Ratea Live Births No. of Child-Years No. of Child Deaths U5M Ratea No. % No. % Certainly not exposed 2,837 11.3 9,263 297 32.1 1,936 12.2 6,488 208 32.1 Probably not exposed 1,467 5.9 4,778 169 35.4 933 5.9 3,124 99 31.7 Conceived during Ramadan 2,150 8.6 6,983 252 36.1 1,338 8.4 4,485 119 26.5 Exposed during trimester 1 5,981 23.8 20,070 681 33.9 3,573 22.4 12,122 319 26.3 Exposed during trimester 2 6,058 24.1 19,183 632 32.9 3,791 23.8 11,960 319 26.7 Exposed during trimester 3 4,261 17.0 13,248 425 32.1 2,755 17.3 8,650 252 29.1 Born during Ramadan 2,339 9.3 7,586 262 34.5 1,606 10.1 5,263 179 34.0 Total 25,093 81,111 2,718 33.5 15,932 52,092 1,495 28.7 Ramadan Exposure Category Muslims Non-Muslims Live Births No. of Child-Years No. of Child Deaths U5M Ratea Live Births No. of Child-Years No. of Child Deaths U5M Ratea No. % No. % Certainly not exposed 2,837 11.3 9,263 297 32.1 1,936 12.2 6,488 208 32.1 Probably not exposed 1,467 5.9 4,778 169 35.4 933 5.9 3,124 99 31.7 Conceived during Ramadan 2,150 8.6 6,983 252 36.1 1,338 8.4 4,485 119 26.5 Exposed during trimester 1 5,981 23.8 20,070 681 33.9 3,573 22.4 12,122 319 26.3 Exposed during trimester 2 6,058 24.1 19,183 632 32.9 3,791 23.8 11,960 319 26.7 Exposed during trimester 3 4,261 17.0 13,248 425 32.1 2,755 17.3 8,650 252 29.1 Born during Ramadan 2,339 9.3 7,586 262 34.5 1,606 10.1 5,263 179 34.0 Total 25,093 81,111 2,718 33.5 15,932 52,092 1,495 28.7 Abbreviation: U5M, under-5 mortality. a Number of deaths per 1,000 child-years. Table 1. Numbers of Live Births, Numbers of Child Deaths, and Mortality Before 5 Years of Age, by Prenatal Ramadan Exposure and Religion, Among 41,025 Children From Nouna District, Burkina Faso, 1993–2012 Ramadan Exposure Category Muslims Non-Muslims Live Births No. of Child-Years No. of Child Deaths U5M Ratea Live Births No. of Child-Years No. of Child Deaths U5M Ratea No. % No. % Certainly not exposed 2,837 11.3 9,263 297 32.1 1,936 12.2 6,488 208 32.1 Probably not exposed 1,467 5.9 4,778 169 35.4 933 5.9 3,124 99 31.7 Conceived during Ramadan 2,150 8.6 6,983 252 36.1 1,338 8.4 4,485 119 26.5 Exposed during trimester 1 5,981 23.8 20,070 681 33.9 3,573 22.4 12,122 319 26.3 Exposed during trimester 2 6,058 24.1 19,183 632 32.9 3,791 23.8 11,960 319 26.7 Exposed during trimester 3 4,261 17.0 13,248 425 32.1 2,755 17.3 8,650 252 29.1 Born during Ramadan 2,339 9.3 7,586 262 34.5 1,606 10.1 5,263 179 34.0 Total 25,093 81,111 2,718 33.5 15,932 52,092 1,495 28.7 Ramadan Exposure Category Muslims Non-Muslims Live Births No. of Child-Years No. of Child Deaths U5M Ratea Live Births No. of Child-Years No. of Child Deaths U5M Ratea No. % No. % Certainly not exposed 2,837 11.3 9,263 297 32.1 1,936 12.2 6,488 208 32.1 Probably not exposed 1,467 5.9 4,778 169 35.4 933 5.9 3,124 99 31.7 Conceived during Ramadan 2,150 8.6 6,983 252 36.1 1,338 8.4 4,485 119 26.5 Exposed during trimester 1 5,981 23.8 20,070 681 33.9 3,573 22.4 12,122 319 26.3 Exposed during trimester 2 6,058 24.1 19,183 632 32.9 3,791 23.8 11,960 319 26.7 Exposed during trimester 3 4,261 17.0 13,248 425 32.1 2,755 17.3 8,650 252 29.1 Born during Ramadan 2,339 9.3 7,586 262 34.5 1,606 10.1 5,263 179 34.0 Total 25,093 81,111 2,718 33.5 15,932 52,092 1,495 28.7 Abbreviation: U5M, under-5 mortality. a Number of deaths per 1,000 child-years. To estimate the association between Ramadan exposure in utero and child mortality, we performed a difference-in-differences analysis to eliminate seasonal mortality differences through comparison with non-Muslims. In adjusted multilevel regression, children for whom Ramadan occurred during conception or the first or second trimester showed higher mortality rates (37%, 33%, and 25%, respectively) than children certainly not exposed, only among Muslims, as shown by the interaction terms (P = 0.03, P = 0.01, and P = 0.05, respectively), while exposure during the third trimester and at birth was not associated with increased mortality (Table 2). Table 2. Effect of Prenatal Ramadan Exposure on Mortality Before 5 Years of Age (Difference-in-Differences Analysis) Among 41,025 Children From Nouna District, Burkina Faso, 1993–2012 Parametera and Exposure Category HR 95% CI P Value Ramadan  Conceived vs. certainly not 0.86 0.69, 1.09 0.22  Trimester 1 vs. certainly not 0.88 0.73, 1.06 0.17  Trimester 2 vs. certainly not 0.91 0.76, 1.10 0.35  Trimester 3 vs. certainly not 0.92 0.76, 1.11 0.37  Born vs. certainly not 1.05 0.86, 1.29 0.63  Probably not vs. certainly not 0.99 0.77, 1.26 0.92 Mother is Muslim (yes vs. no) 0.97 0.81, 1.17 0.77 Ramadan × Muslim mother interactionb  Conceived vs. certainly not 1.37 1.03, 1.82 0.03  Trimester 1 vs. certainly not 1.33 1.06, 1.67 0.01  Trimester 2 vs. certainly not 1.25 1.00, 1.57 0.05  Trimester 3 vs. certainly not 1.10 0.87, 1.40 0.43  Born vs. certainly not 1.02 0.79, 1.34 0.86  Probably not vs. certainly not 1.14 0.83, 1.56 0.42 Year of birth (linear; per year since 1993) 0.96 0.95, 0.96 <0.001 Region of residence  Central vs. Nouna town 1.39 1.22, 1.58 <0.001  Northeast vs. Nouna town 1.94 1.74, 2.16 <0.001  Southeast vs. Nouna town 1.24 1.09, 1.40 0.001  Southwest vs. Nouna town 1.88 1.69, 2.09 <0.001 Parametera and Exposure Category HR 95% CI P Value Ramadan  Conceived vs. certainly not 0.86 0.69, 1.09 0.22  Trimester 1 vs. certainly not 0.88 0.73, 1.06 0.17  Trimester 2 vs. certainly not 0.91 0.76, 1.10 0.35  Trimester 3 vs. certainly not 0.92 0.76, 1.11 0.37  Born vs. certainly not 1.05 0.86, 1.29 0.63  Probably not vs. certainly not 0.99 0.77, 1.26 0.92 Mother is Muslim (yes vs. no) 0.97 0.81, 1.17 0.77 Ramadan × Muslim mother interactionb  Conceived vs. certainly not 1.37 1.03, 1.82 0.03  Trimester 1 vs. certainly not 1.33 1.06, 1.67 0.01  Trimester 2 vs. certainly not 1.25 1.00, 1.57 0.05  Trimester 3 vs. certainly not 1.10 0.87, 1.40 0.43  Born vs. certainly not 1.02 0.79, 1.34 0.86  Probably not vs. certainly not 1.14 0.83, 1.56 0.42 Year of birth (linear; per year since 1993) 0.96 0.95, 0.96 <0.001 Region of residence  Central vs. Nouna town 1.39 1.22, 1.58 <0.001  Northeast vs. Nouna town 1.94 1.74, 2.16 <0.001  Southeast vs. Nouna town 1.24 1.09, 1.40 0.001  Southwest vs. Nouna town 1.88 1.69, 2.09 <0.001 Abbreviations: CI, confidence interval; HR, hazard ratio. a Model: difference-in-differences analysis with a random intercept for mother; results were additionally adjusted for month of birth (estimates not displayed). b Interaction terms. Table 2. Effect of Prenatal Ramadan Exposure on Mortality Before 5 Years of Age (Difference-in-Differences Analysis) Among 41,025 Children From Nouna District, Burkina Faso, 1993–2012 Parametera and Exposure Category HR 95% CI P Value Ramadan  Conceived vs. certainly not 0.86 0.69, 1.09 0.22  Trimester 1 vs. certainly not 0.88 0.73, 1.06 0.17  Trimester 2 vs. certainly not 0.91 0.76, 1.10 0.35  Trimester 3 vs. certainly not 0.92 0.76, 1.11 0.37  Born vs. certainly not 1.05 0.86, 1.29 0.63  Probably not vs. certainly not 0.99 0.77, 1.26 0.92 Mother is Muslim (yes vs. no) 0.97 0.81, 1.17 0.77 Ramadan × Muslim mother interactionb  Conceived vs. certainly not 1.37 1.03, 1.82 0.03  Trimester 1 vs. certainly not 1.33 1.06, 1.67 0.01  Trimester 2 vs. certainly not 1.25 1.00, 1.57 0.05  Trimester 3 vs. certainly not 1.10 0.87, 1.40 0.43  Born vs. certainly not 1.02 0.79, 1.34 0.86  Probably not vs. certainly not 1.14 0.83, 1.56 0.42 Year of birth (linear; per year since 1993) 0.96 0.95, 0.96 <0.001 Region of residence  Central vs. Nouna town 1.39 1.22, 1.58 <0.001  Northeast vs. Nouna town 1.94 1.74, 2.16 <0.001  Southeast vs. Nouna town 1.24 1.09, 1.40 0.001  Southwest vs. Nouna town 1.88 1.69, 2.09 <0.001 Parametera and Exposure Category HR 95% CI P Value Ramadan  Conceived vs. certainly not 0.86 0.69, 1.09 0.22  Trimester 1 vs. certainly not 0.88 0.73, 1.06 0.17  Trimester 2 vs. certainly not 0.91 0.76, 1.10 0.35  Trimester 3 vs. certainly not 0.92 0.76, 1.11 0.37  Born vs. certainly not 1.05 0.86, 1.29 0.63  Probably not vs. certainly not 0.99 0.77, 1.26 0.92 Mother is Muslim (yes vs. no) 0.97 0.81, 1.17 0.77 Ramadan × Muslim mother interactionb  Conceived vs. certainly not 1.37 1.03, 1.82 0.03  Trimester 1 vs. certainly not 1.33 1.06, 1.67 0.01  Trimester 2 vs. certainly not 1.25 1.00, 1.57 0.05  Trimester 3 vs. certainly not 1.10 0.87, 1.40 0.43  Born vs. certainly not 1.02 0.79, 1.34 0.86  Probably not vs. certainly not 1.14 0.83, 1.56 0.42 Year of birth (linear; per year since 1993) 0.96 0.95, 0.96 <0.001 Region of residence  Central vs. Nouna town 1.39 1.22, 1.58 <0.001  Northeast vs. Nouna town 1.94 1.74, 2.16 <0.001  Southeast vs. Nouna town 1.24 1.09, 1.40 0.001  Southwest vs. Nouna town 1.88 1.69, 2.09 <0.001 Abbreviations: CI, confidence interval; HR, hazard ratio. a Model: difference-in-differences analysis with a random intercept for mother; results were additionally adjusted for month of birth (estimates not displayed). b Interaction terms. In the adjusted multilevel model that did not adjust for Ramadan occurrence during pregnancy, the mortality rate among Muslims was 15% higher (95% confidence interval: 7, 24) than that among non-Muslims (Table 3). From the model with Ramadan interaction terms, we calculated the mortality rate ratio for Muslims versus non-Muslims for each Ramadan exposure category. Children born to Muslim mothers who experienced Ramadan in utero during conception had a 33% higher mortality rate than children of non-Muslim mothers in utero during the same time period (hazard ratio (HR) = 0.97 for Muslim women vs. non-Muslim women outside Ramadan, multiplied with HR = 1.37 for the interaction; P = 0.01). For trimesters 1 and 2, the increases in mortality rates were 29% and 22% (P < 0.001 and P = 0.007), respectively (Table 3, Figure 2). Among children exposed to Ramadan in the third trimester, the difference in mortality between Muslims and non-Muslims was small, and there was no increased mortality for Muslim children born during Ramadan. Having a Muslim mother was not associated with mortality when not exposed to Ramadan (HR = 0.97, P = 0.74), and Ramadan occurrence was not associated with mortality among non-Muslims in the adjusted model (Table 2). Table 3. Mortality Before 5 Years of Age in Muslims Compared With Non-Muslims, by Prenatal Ramadan Exposure, Among 41,025 Children From Nouna District, Burkina Faso, 1993–2012 Prenatal Ramadan Exposure Calculationa HR 95% CI P Value Total (not considering Ramadan)b 1.15 1.07, 1.24 <0.001 Ramadan exposure categoryc  Certainly not exposed —d 0.97 0.81, 1.17 0.74  Probably not exposed 0.97 × 1.14 1.11 0.86, 1.43 0.43  Conceived during Ramadan 0.97 × 1.37 1.33 1.06, 1.66 0.01  Ramadan during trimester 1 0.97 × 1.33 1.29 1.12, 1.49 <0.001  Ramadan during trimester 2 0.97 × 1.26 1.22 1.06, 1.40 0.007  Ramadan during trimester 3 0.97 × 1.11 1.07 0.91, 1.26 0.39  Born during Ramadan 0.97 × 1.02 1.00 0.82, 1.21 0.98 Prenatal Ramadan Exposure Calculationa HR 95% CI P Value Total (not considering Ramadan)b 1.15 1.07, 1.24 <0.001 Ramadan exposure categoryc  Certainly not exposed —d 0.97 0.81, 1.17 0.74  Probably not exposed 0.97 × 1.14 1.11 0.86, 1.43 0.43  Conceived during Ramadan 0.97 × 1.37 1.33 1.06, 1.66 0.01  Ramadan during trimester 1 0.97 × 1.33 1.29 1.12, 1.49 <0.001  Ramadan during trimester 2 0.97 × 1.26 1.22 1.06, 1.40 0.007  Ramadan during trimester 3 0.97 × 1.11 1.07 0.91, 1.26 0.39  Born during Ramadan 0.97 × 1.02 1.00 0.82, 1.21 0.98 Abbreviations: CI, confidence interval; HR, hazard ratio. a Calculation of stratum HRs from the baseline HR and the interaction HR. b Survival analysis without Ramadan exposure (with a random intercept for mother; results were adjusted for year of birth, month of birth, region of residence, season at death, and sex of child). c Based on the full model shown in Table 2. d This value corresponds to the estimate for “mother is Muslim (yes vs. no)” as displayed in Table 2. Table 3. Mortality Before 5 Years of Age in Muslims Compared With Non-Muslims, by Prenatal Ramadan Exposure, Among 41,025 Children From Nouna District, Burkina Faso, 1993–2012 Prenatal Ramadan Exposure Calculationa HR 95% CI P Value Total (not considering Ramadan)b 1.15 1.07, 1.24 <0.001 Ramadan exposure categoryc  Certainly not exposed —d 0.97 0.81, 1.17 0.74  Probably not exposed 0.97 × 1.14 1.11 0.86, 1.43 0.43  Conceived during Ramadan 0.97 × 1.37 1.33 1.06, 1.66 0.01  Ramadan during trimester 1 0.97 × 1.33 1.29 1.12, 1.49 <0.001  Ramadan during trimester 2 0.97 × 1.26 1.22 1.06, 1.40 0.007  Ramadan during trimester 3 0.97 × 1.11 1.07 0.91, 1.26 0.39  Born during Ramadan 0.97 × 1.02 1.00 0.82, 1.21 0.98 Prenatal Ramadan Exposure Calculationa HR 95% CI P Value Total (not considering Ramadan)b 1.15 1.07, 1.24 <0.001 Ramadan exposure categoryc  Certainly not exposed —d 0.97 0.81, 1.17 0.74  Probably not exposed 0.97 × 1.14 1.11 0.86, 1.43 0.43  Conceived during Ramadan 0.97 × 1.37 1.33 1.06, 1.66 0.01  Ramadan during trimester 1 0.97 × 1.33 1.29 1.12, 1.49 <0.001  Ramadan during trimester 2 0.97 × 1.26 1.22 1.06, 1.40 0.007  Ramadan during trimester 3 0.97 × 1.11 1.07 0.91, 1.26 0.39  Born during Ramadan 0.97 × 1.02 1.00 0.82, 1.21 0.98 Abbreviations: CI, confidence interval; HR, hazard ratio. a Calculation of stratum HRs from the baseline HR and the interaction HR. b Survival analysis without Ramadan exposure (with a random intercept for mother; results were adjusted for year of birth, month of birth, region of residence, season at death, and sex of child). c Based on the full model shown in Table 2. d This value corresponds to the estimate for “mother is Muslim (yes vs. no)” as displayed in Table 2. Figure 2. View largeDownload slide Mortality under 5 years of age according to prenatal Ramadan exposure among children of Muslim mothers compared with children of non-Muslim mothers who were in utero during the same time period, Nouna District, Burkina Faso, 1993–2012. The hazard ratios were derived from an adjusted multilevel model (see Tables 2 and 3) that included 25,093 children born to Muslim mothers and 15,932 children born to non-Muslim mothers in Nouna District. They were calculated by dividing the under-5 mortality rates of Muslims by the under-5 mortality rates of non-Muslims. A hazard ratio of 1.3 means that under-5 mortality among Muslims was 30% higher than that among non-Muslims; a hazard ratio of 1.0 means that the mortality of Muslims and non-Muslims was the same; and hazard ratios below 1 signify lower mortality among Muslims. Vertical lines display 95% confidence intervals. Figure 2. View largeDownload slide Mortality under 5 years of age according to prenatal Ramadan exposure among children of Muslim mothers compared with children of non-Muslim mothers who were in utero during the same time period, Nouna District, Burkina Faso, 1993–2012. The hazard ratios were derived from an adjusted multilevel model (see Tables 2 and 3) that included 25,093 children born to Muslim mothers and 15,932 children born to non-Muslim mothers in Nouna District. They were calculated by dividing the under-5 mortality rates of Muslims by the under-5 mortality rates of non-Muslims. A hazard ratio of 1.3 means that under-5 mortality among Muslims was 30% higher than that among non-Muslims; a hazard ratio of 1.0 means that the mortality of Muslims and non-Muslims was the same; and hazard ratios below 1 signify lower mortality among Muslims. Vertical lines display 95% confidence intervals. In sensitivity analyses separating mortality during infancy from mortality later in childhood, Ramadan exposure during conception was associated with 68% higher infant mortality among Muslims than among non-Muslims (HR = 1.68, P = 0.004), while hazard ratios for infant mortality were 1.23 (P = 0.05) for first-trimester Ramadan occurrence and 1.17 (P = 0.13) for second-trimester Ramadan occurrence. In children aged 1–4 years, Ramadan exposure during the first (HR = 1.34, P = 0.002) and second (HR = 1.25, P = 0.02) trimesters was associated with a strong increase in mortality, but the association of Ramadan exposure during conception (HR = 1.11, P = 0.48) with mortality was weaker. When analyses were stratified by region of residence, the increased mortality rate in children exposed to Ramadan in utero was visible in all regions, with the strongest associations being seen in the Northeast and the Southwest, the regions with the highest child mortality. Because of the lower sample sizes, regional estimates were not significant at the 5% level, except for Ramadan exposure in the first or second trimester in the Southwest region, which had the largest number of children. Stratification by year of birth showed that the measures of association of Ramadan exposure with mortality during trimesters 1 and 2 were comparable between the 3 study periods (1993–1999, 2000–2006, and 2007–2012) and the association for being conceived during Ramadan was stronger during the most recent period. Among children exposed to Ramadan during conception, the association was stronger in children exposed for 14 days or more (HR = 1.45, P = 0.04). It was weaker and not significant for children exposed for less than 14 days (HR = 1.27, P = 0.21). DISCUSSION Using 20 years of surveillance data from northwestern Burkina Faso, we detected a strong association between having been exposed to Ramadan in utero and under-5 mortality. This association was present from conception to the second trimester, and particularly strong during early pregnancy, when the mortality rate of children born to Muslim mothers was around 30% higher than that among children of non-Muslim mothers born at the same time. The 15% higher mortality seen in children of Muslim mothers overall was entirely explained by Ramadan exposure, as having a Muslim mother was not associated with mortality when the pregnancy occurred outside of Ramadan. For our analysis, we assigned children of Muslim mothers as being exposed to Ramadan without having actual information on maternal fasting, as in an intention-to-treat analysis. Use of this approach avoids confounding by health issues associated with decreased fasting adherence and increased child mortality. However, if a substantial proportion of Muslim women did not adhere to Ramadan fasting during pregnancy, our results would underestimate the true association due to nondifferential misclassification. Another source of misclassification is pregnancy duration. For the Ramadan exposure assignment, we assumed a gestational age of 266 days for all children. There are, however, natural variations in gestational age at birth, and only about 50% of children are born within 7 days of the estimated due date (26). Some children born at higher gestational ages will have been classified as not exposed to Ramadan, even though they were actually exposed during conception. To ensure that our comparison category was “certainly not exposed to Ramadan,” we created a separate category of children “probably not exposed,” capturing possible exposure in very early pregnancy among children born 1–20 days postterm. A different issue is children who were born early—that is, who were in utero for less than 266 days. These children might have been assigned Ramadan exposure during conception or the beginning of trimester 1, even though they were actually not exposed to Ramadan at all. The categorization of the certainly-not-exposed children (born just before Ramadan) was not affected by this, because a shorter gestation would not lead to an overlap with Ramadan. Thus, any misclassification of pregnancy duration would only have led to an attenuation of the measures of association. If some women planned their pregnancies to avoid an overlap with Ramadan, this could have introduced bias. If this group was less vulnerable for some reason, this could have artificially increased our estimates. Such behavior should be more likely in Muslim women, because there is less reason for non-Muslims to avoid an overlap with Ramadan. Our sensitivity analyses provided no evidence for such pregnancy planning (Web Appendix 1), and previous research comparing Muslims who were pregnant during a Ramadan with those who were not found no differences in education, smoking behavior, health, or income (14–16, 19, 27), suggesting that Muslims generally do not plan their pregnancies in such a way that they avoid overlap with a Ramadan. The majority of studies on the association between Ramadan fasting and health of the offspring have focused on immediate outcomes such as birth weight and preterm delivery and have mostly found no associations (28–32). Even though low birth weight is associated with increased child mortality (33), the effect of Ramadan fasting on child mortality presumably does not act via birth weight but through an impact on the developing immune system, which is in line with the impacts of seasonality on thymus size reported from the Gambia (6). While undernutrition in utero can lead to intrauterine growth restriction that is measurable as low birth weight, as well as to epigenetic changes influencing later disease risk (9), the systems affected and the time(s) at which this shows in life will depend on the types of nutrients missing and the exact timing of undernutrition during pregnancy. For example, persons exposed to the Dutch Hunger Winter in early pregnancy had normal birth weight but suffered from a higher burden of disease as adults (9). Previous studies on long-term outcomes showed that children who were exposed to Ramadan in utero had lower academic performance (14, 15) and were more likely to suffer from learning disabilities (27), suggesting an impact on the developing nervous system. There is also evidence from Indonesia linking Ramadan exposure in utero to adult body size (17), to lower nurse-rated general adult health, and to higher prevalence of slow-healing wounds and chest pain (symptoms indicative of diabetes and coronary heart disease) (19). In line with our study, the great majority of studies on long-term outcomes of Ramadan exposure showed stronger associations if children were exposed early in pregnancy, during the time of conception and the first trimester (14, 17, 20, 34). This is biologically plausible and consistent with our knowledge on fetal programming (1, 35). An alternative explanation for the stronger associations in early pregnancy is a higher adherence to fasting during this time, especially when women are not yet aware of the pregnancy (28, 34). In pregnant women, fasting leads to increases in levels of free fatty acids and ketones and decreases in blood glucose after a relatively short period of time (12–18 hours), a process called “accelerated starvation” (36). Because of its location close to the equator, the durations of fasting periods in Burkina Faso are roughly constant over the years (around 13 hours). At the same time, preexisting undernutrition and physical labor in a hot climate may exacerbate fasting effects. Intermittent exposure to decreased glucose and increased ketone levels, the balance of calories from proteins and carbohydrates, and deficiencies in crucial micronutrients can be responsible for adverse effects on fetal health (35). From our data, however, it is impossible to say whether the association between Ramadan and mortality is due to the lack of food and water intake during the daytime or due to other lifestyle changes related to Ramadan, such as overall reduced calorie intake, increased sugar and fat intake, decreased intake of micronutrient-rich foods, changes in sleeping patterns, or other factors. The developing immune system is particularly vulnerable to maternal malnutrition in the first trimester through a range of mechanisms: micronutrient deficiencies directly affecting thymus development and hematopoiesis, impaired maternal immune transfer altering the fetal immune system’s trajectory, and maternal glucocorticoids suppressing fetal thymus and lymphocyte development as well as influencing the development of the fetal hypothalamic-pituitary-adrenal axis (37). Especially in sub-Saharan Africa, where infectious diseases (pneumonia, diarrhea, malaria) are still a major cause of under-5 mortality (38), alterations in the functioning of the immune system can be expected to influence child survival. Our finding that periconceptional Ramadan exposure was most strongly linked to mortality, and mainly to infant mortality rather than later child mortality, could mean that impacts incurred during the embryo’s formative phase are particularly severe and kill earlier or that they disrupt immune mechanisms that are important for maternal immune transfer, which is particularly relevant in infancy before vaccination takes effect. However, given our limited statistical power in subanalyses, results of the stratified analyses should not be overinterpreted. To shed more light on the mechanisms involved, it would be helpful to study cause-specific mortality and to investigate epigenetic changes where such data are available. Finally, because sex differences in immune response and in fetal programming are common (39–42), we plan to investigate effect modification by child sex as soon as newer years of surveillance data become available. In conclusion, we found that Ramadan exposure in early pregnancy leads to a 30% increase in child mortality in rural Burkina Faso, a setting where infectious causes of child mortality dominate. This suggests that changes in nutrient intake and/or lifestyle which are far less dramatic than those that occur during a famine or hunger season can have long-lasting detrimental effects on child health, which might act through impacts on immune system development (6). Besides its contribution to knowledge on the developmental origins of disease and causes of child mortality, our finding is relevant for the 1.6 billion Muslims globally, tens of millions of whom get pregnant each year. According to Islam, pregnant women are exempt from fasting during Ramadan if they are worried about their health or the health of their unborn child (24), but it has been shown in several settings that many women still fast (43–47). Conception and early pregnancy seem to be the most vulnerable periods, which complicates matters, as it would imply abstaining from fasting while trying to get pregnant and in a period when women may not yet want to reveal their pregnancy status. Furthermore, our finding may be important to women of other faiths who fast and to all women, because meal-skipping and dieting during pregnancy are common in nonreligious pregnant women as well (18, 48, 49). Even though the effect of Ramadan fasting on child mortality is probably restricted to high-mortality settings, long-term health and cognitive effects may also affect people in high-income settings. ACKNOWLEDGMENTS Author affiliations: Unit of Epidemiology and Biostatistics, Institute of Public Health, Heidelberg University, Heidelberg, Germany (Anja Schoeps, Gisela Kynast-Wolf, Sabine Gabrysch); Gutenberg School of Management and Economics, Johannes Gutenberg University, Mainz, Germany (Reyn van Ewijk); and Centre de Recherche en Santé de Nouna, Nouna, Burkina Faso (Eric Nebié, Pascal Zabré, Ali Sié). This work benefitted from support provided by the German Research Foundation to R.v.E. (grant 260639091) and to the Nouna Health and Demographic Surveillance System (research grant SFB 544 (“Control of Tropical Infectious Diseases”), 1999–2011). Conflict of interest: none declared. Abbreviations HDSS Health and Demographic Surveillance System HR hazard ratio REFERENCES 1 Ramakrishnan U , Grant F , Goldenberg T , et al. . Effect of women’s nutrition before and during early pregnancy on maternal and infant outcomes: a systematic review . 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Ramadan Exposure In Utero and Child Mortality in Burkina Faso: Analysis of a Population-Based Cohort Including 41,025 Children

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Abstract

Abstract Ramadan exposure in utero can be regarded as a natural experiment with which to study how nutritional conditions in utero influence susceptibility to disease later in life. We analyzed data from rural Burkina Faso on 41,025 children born between 1993 and 2012, of whom 25,093 were born to Muslim mothers. Ramadan exposure was assigned on the basis of overlap between Ramadan dates and gestation, creating 7 exclusive categories. We used proportional hazards regression with difference-in-differences analysis to estimate the association between Ramadan exposure at different gestational ages and mortality among children under 5 years of age. Under-5 mortality was 32 deaths per 1,000 child-years. Under-5 mortality among Muslims was 15% higher than that among non-Muslims (P < 0.001). In the difference-in-differences analysis, the occurrence of Ramadan during conception or the first or second trimester was associated with higher under-5 mortality rates among Muslims only. The mortality rates of children born to Muslim mothers were 33%, 29%, and 22% higher when Ramadan occurred during conception, the first trimester, and the second trimester, respectively, compared with children of non-Muslim mothers born at the same time (P = 0.01, P < 0.001, and P = 0.007). Having a Muslim mother was not associated with mortality when the child was not exposed to Ramadan, born during Ramadan, or exposed during the third trimester. Observance of Ramadan during early pregnancy can have detrimental consequences for the future health of the unborn child. child mortality, difference in differences, population-based cohort, prenatal exposure delayed effects, pregnancy, Ramadan, sub-Saharan Africa Editor’s note: Invited commentaries on this article appear on pages 2093 and 2095, and the authors’ response appears on page 2098. The first 9 months of life in utero are a crucial period for human development in which future health trajectories are set, determining physical and cognitive capabilities. Early pregnancy is a time when the developing organism is particularly vulnerable, as this is when organogenesis takes place, including development of the neural and immune systems and the shaping of endocrine and metabolic pathways (1). It is well established that some infections (including rubella virus), certain chemicals and drugs (most famously thalidomide), and deficiency in certain nutrients (e.g., folate and iodine) in early pregnancy can lead to serious fetal damage (2). There is also a growing body of evidence that nutrients, environmental chemicals, drugs, and infections can have more subtle effects on the developing organism in utero, presumably through epigenetic mechanisms. Such effects may show only later in life, a concept referred to as “developmental origins of health and disease” (3–5). The majority of studies on the topic have come from high- and middle-income countries and have focused on chronic diseases in later adulthood, such as diabetes and cardiovascular disease (6). There have been very few studies in low-income settings, although it would be of great interest to better understand developmental impacts on the immune system and infection-related mortality (7). When studying long-term effects of undernutrition in utero, researchers have employed natural experiments such as famines to avoid confounding by socioeconomic status and other factors (2, 8). The most famous is the study of the Dutch Hunger Winter of World War II, which showed that exposure to famine during gestation, especially early gestation, increases the risk of obesity, diabetes, coronary heart disease, breast cancer, mental illness, and cognitive decline later in life and increases later-life mortality rates (9–13). Other research has focused on other famines occurring during World War II, on 19th century famines, and on more recent famines such as those that took place during the Chinese Great Leap Forward (see Lumey et al. (8) for a review). One study that—like our study—focused on the association between nonfamine malnutrition and mortality exploited seasonal patterns of food availability in the Gambia, linking season of birth to smaller thymus size in children and to mortality in young adults (7). Another very particular natural experiment for studying the effects of undernutrition in utero is furnished by the Muslim tradition of daytime fasting during the holy month of Ramadan. The rotation of Ramadan through the year and the contrast with non-Muslim populations in the same location provides an opportunity to disentangle seasonal effects on fetal development (due to different availability of nutrients, as well as environmental and infectious exposures) from Ramadan effects. Studying the fetal health impacts of intermittent maternal fasting, as occurs during Ramadan, would shed light on potential long-term effects of relatively mild shocks experienced more commonly. Furthermore, effects of Ramadan fasting are relevant in their own right, given the high numbers of people affected each year. Most studies of intrauterine Ramadan exposure have focused on short-term outcomes such as low birth weight or preterm delivery, while fewer have looked beyond the immediate outcomes and studied longer-term outcomes, including cognitive abilities, body composition, symptoms of coronary heart disease and type 2 diabetes mellitus, and reduced work performance (14–20). To our knowledge, there have been no studies so far on the association between Ramadan exposure in utero and mortality outcomes in childhood or adulthood. We hypothesized that maternal observance of Ramadan during conception and early pregnancy may have negative impacts on the development of the fetus, leading to higher child mortality, especially in settings with high background levels of undernutrition among women and high infection-related child mortality. The aim of our study was to assess the influence of Ramadan exposure in utero at different gestational ages on mortality among children under 5 years of age in Burkina Faso. METHODS Study area and population This population-based cohort study was conducted using data from the Nouna Health and Demographic Surveillance System (HDSS) in northwestern Burkina Faso, which in 2012 comprised a population of nearly 100,000 inhabitants. The Nouna HDSS was established by an initial census carried out in 39 villages in 1992 (21). In 2000, 2 additional villages and the town of Nouna were included, and another 17 villages followed in 2004. The town of Nouna is a semiurban settlement with about 30,000 inhabitants, and the rural area around Nouna can be divided into 4 regions (22). The majority of inhabitants in the Nouna HDSS are Muslims (63%), while 32% are Christians, and a minority of 5% holds traditional beliefs. The study area is characterized by a sub-Sahelian climate with a dry season (November–May) and a rainy season (June–October). The majority of the population lives by subsistence farming; literacy rates are low, and there is seasonal food insecurity. More than one-quarter of children between 6 and 31 months of age are wasted (21, 23). Ramadan exposure During the month of Ramadan, which lasts about 30 days, healthy adult Muslims are obliged to abstain from eating and drinking (even water) between dawn and sunset. The Islamic lunar calendar is approximately 11 days shorter than the Gregorian calendar, so Ramadan occurs slightly earlier each year and rotates through the Gregorian year in about 33 years. For sick people and pregnant women, fasting during Ramadan is voluntary; however, they are supposed to make up for this exemption by fasting afterwards (24). While Ramadan is likely to affect fetal health through the fasting itself, other lifestyle changes taking place during Ramadan (including increased sugar intake and changes in sleeping patterns) may also be responsible for the association. Data from the Nouna HDSS do not contain information on individual Ramadan fasting, and we do not distinguish between the potential channels for associations. We assigned Ramadan exposure in utero based on a calculation of whether there was overlap between Ramadan and gestation, utilizing the date of birth in relation to the Ramadan dates and assuming a gestational period of 266 days, which is the average duration of a full-term human pregnancy. Our approach can be interpreted as an intention-to-treat analysis that helps avoid confounding due to self-selection of women into Ramadan-observant and nonobservant groups, which likely also differ in other ways. We differentiated Ramadan exposure into 7 exclusive categories: certainly not exposed, probably not exposed, conceived during Ramadan, Ramadan starting during the first, second, or third trimester, and born during Ramadan. Children in the category “probably not exposed” would not have experienced Ramadan in utero if their mothers had a normal 266-day pregnancy, as this would have started just after Ramadan. However, if they were born up to 20 days postterm, they could still have been exposed to Ramadan during conception (Figure 1). Figure 1. View largeDownload slide Assignment to prenatal Ramadan exposure by time of birth for children born in Nouna District, Burkina Faso, in 2011–2012. Assuming a gestation period of 266 days, one of 7 Ramadan exposure categories was assigned to each child. The asterisks (*) indicate birth dates, while black dots show the calculated dates of conception. The black boxes indicate the timing of Ramadan in 2010 and 2011. Mar, March; Jul, July; Nov, November. Figure 1. View largeDownload slide Assignment to prenatal Ramadan exposure by time of birth for children born in Nouna District, Burkina Faso, in 2011–2012. Assuming a gestation period of 266 days, one of 7 Ramadan exposure categories was assigned to each child. The asterisks (*) indicate birth dates, while black dots show the calculated dates of conception. The black boxes indicate the timing of Ramadan in 2010 and 2011. Mar, March; Jul, July; Nov, November. Statistical analysis Between 1993 and 2012, a total of 48,747 children were born alive in the Nouna HDSS. We excluded 7,520 children for whom the exact date of birth was unknown and 202 children for whom information on mother’s religion was missing; this resulted in a sample of 41,025 children for analysis. We calculated mortality rates in children of Muslim and non-Muslim mothers overall and stratified by the occurrence of Ramadan during pregnancy. Because our study period included 20 years of observation, Ramadan did not fully rotate through the year (from February/March in 1992 to July/August in 2012), and thus Ramadan exposure varied by month of birth (see Web Figure 1, available at https://academic.oup.com/aje). We used a difference-in-differences analysis, comparing the association of Ramadan occurrence during pregnancy with mortality between non-Muslims and Muslims, under the assumption of a common seasonal trend. The inclusion of non-Muslims in the model served to purge any remaining seasonal mortality differences correlated with Ramadan that remained after adjustment for calendar month of birth (14). For details on the model assumptions and sensitivity analyses, refer to Web Appendix 1. We used 2-level multivariate Weibull proportional hazards regression to estimate the association between Ramadan exposure in utero and child survival up to age 5 years, with random intercepts at the mother level. Death between birth and 5 years of age was the event of interest. The time variable was time from birth to death, age 5 years, loss to follow-up, or the end of the study (December 31, 2012). After confirmation of the proportional hazards assumption for the main variables of interest through the use of Kaplan-Meier graphs, we first fitted a regression model without considering Ramadan timing, to estimate the association between religion and child mortality, using a binary variable indicating whether the mother was Muslim or non-Muslim. In a second regression model, we then added a variable indicating Ramadan occurrence during pregnancy, as well as a term for the interaction of Ramadan occurrence with the Muslim indicator variable. These interaction parameters were the coefficients of interest in our study. They can be interpreted as a comparison of mortality between exposed and unexposed Muslims after correcting for seasonality (by comparing with non-Muslims). Adjustment was made for year of birth (continuous variable), calendar month of birth, and region of residence. Stata version 14 (StataCorp LLC, College Station, Texas) was used for analysis, and SAS version 9.3 (SAS Institute, Inc., Cary, North Carolina) was used for creating the figures. All P values are 2-sided. In addition, stratified analyses were conducted for the 5 main regions of the study area (22) and for 3 different study periods. Besides the main outcome of under-5 mortality, we also studied infant mortality and mortality in children aged 1–4 years. To investigate in more detail the association between being conceived during Ramadan and mortality, we created 2 separate categories: exposure for at least 14 days and exposure for less than 14 days. RESULTS Our study included 41,025 children who were born to 20,709 mothers in the Nouna HDSS between January 1993 and December 2012, for whom mother’s religion and the precise date of birth were known. The majority of mothers in this sample were Muslim (61%), while 28% were Catholic, 5% were Protestant, and 6% had an animist religion or another religion. Between 1993 and 2012, there were 4,213 deaths among children under 5 years of age during 133,203 child-years at risk, corresponding to an overall mortality rate of 31.6 deaths per 1,000 child-years. Mortality rates were higher among Muslims (33.5 deaths per 1,000 child-years) than among non-Muslims (28.7 deaths per 1,000 child-years) (Table 1). Among non-Muslims, mortality rates were somewhat lower in children who were in utero during Ramadan as compared with children who were not. This was most likely due to seasonal variations in mortality that were correlated with Ramadan occurrence in our sample and that were previously described in the study area (25). This pattern was not apparent for children of Muslim mothers. Table 1. Numbers of Live Births, Numbers of Child Deaths, and Mortality Before 5 Years of Age, by Prenatal Ramadan Exposure and Religion, Among 41,025 Children From Nouna District, Burkina Faso, 1993–2012 Ramadan Exposure Category Muslims Non-Muslims Live Births No. of Child-Years No. of Child Deaths U5M Ratea Live Births No. of Child-Years No. of Child Deaths U5M Ratea No. % No. % Certainly not exposed 2,837 11.3 9,263 297 32.1 1,936 12.2 6,488 208 32.1 Probably not exposed 1,467 5.9 4,778 169 35.4 933 5.9 3,124 99 31.7 Conceived during Ramadan 2,150 8.6 6,983 252 36.1 1,338 8.4 4,485 119 26.5 Exposed during trimester 1 5,981 23.8 20,070 681 33.9 3,573 22.4 12,122 319 26.3 Exposed during trimester 2 6,058 24.1 19,183 632 32.9 3,791 23.8 11,960 319 26.7 Exposed during trimester 3 4,261 17.0 13,248 425 32.1 2,755 17.3 8,650 252 29.1 Born during Ramadan 2,339 9.3 7,586 262 34.5 1,606 10.1 5,263 179 34.0 Total 25,093 81,111 2,718 33.5 15,932 52,092 1,495 28.7 Ramadan Exposure Category Muslims Non-Muslims Live Births No. of Child-Years No. of Child Deaths U5M Ratea Live Births No. of Child-Years No. of Child Deaths U5M Ratea No. % No. % Certainly not exposed 2,837 11.3 9,263 297 32.1 1,936 12.2 6,488 208 32.1 Probably not exposed 1,467 5.9 4,778 169 35.4 933 5.9 3,124 99 31.7 Conceived during Ramadan 2,150 8.6 6,983 252 36.1 1,338 8.4 4,485 119 26.5 Exposed during trimester 1 5,981 23.8 20,070 681 33.9 3,573 22.4 12,122 319 26.3 Exposed during trimester 2 6,058 24.1 19,183 632 32.9 3,791 23.8 11,960 319 26.7 Exposed during trimester 3 4,261 17.0 13,248 425 32.1 2,755 17.3 8,650 252 29.1 Born during Ramadan 2,339 9.3 7,586 262 34.5 1,606 10.1 5,263 179 34.0 Total 25,093 81,111 2,718 33.5 15,932 52,092 1,495 28.7 Abbreviation: U5M, under-5 mortality. a Number of deaths per 1,000 child-years. Table 1. Numbers of Live Births, Numbers of Child Deaths, and Mortality Before 5 Years of Age, by Prenatal Ramadan Exposure and Religion, Among 41,025 Children From Nouna District, Burkina Faso, 1993–2012 Ramadan Exposure Category Muslims Non-Muslims Live Births No. of Child-Years No. of Child Deaths U5M Ratea Live Births No. of Child-Years No. of Child Deaths U5M Ratea No. % No. % Certainly not exposed 2,837 11.3 9,263 297 32.1 1,936 12.2 6,488 208 32.1 Probably not exposed 1,467 5.9 4,778 169 35.4 933 5.9 3,124 99 31.7 Conceived during Ramadan 2,150 8.6 6,983 252 36.1 1,338 8.4 4,485 119 26.5 Exposed during trimester 1 5,981 23.8 20,070 681 33.9 3,573 22.4 12,122 319 26.3 Exposed during trimester 2 6,058 24.1 19,183 632 32.9 3,791 23.8 11,960 319 26.7 Exposed during trimester 3 4,261 17.0 13,248 425 32.1 2,755 17.3 8,650 252 29.1 Born during Ramadan 2,339 9.3 7,586 262 34.5 1,606 10.1 5,263 179 34.0 Total 25,093 81,111 2,718 33.5 15,932 52,092 1,495 28.7 Ramadan Exposure Category Muslims Non-Muslims Live Births No. of Child-Years No. of Child Deaths U5M Ratea Live Births No. of Child-Years No. of Child Deaths U5M Ratea No. % No. % Certainly not exposed 2,837 11.3 9,263 297 32.1 1,936 12.2 6,488 208 32.1 Probably not exposed 1,467 5.9 4,778 169 35.4 933 5.9 3,124 99 31.7 Conceived during Ramadan 2,150 8.6 6,983 252 36.1 1,338 8.4 4,485 119 26.5 Exposed during trimester 1 5,981 23.8 20,070 681 33.9 3,573 22.4 12,122 319 26.3 Exposed during trimester 2 6,058 24.1 19,183 632 32.9 3,791 23.8 11,960 319 26.7 Exposed during trimester 3 4,261 17.0 13,248 425 32.1 2,755 17.3 8,650 252 29.1 Born during Ramadan 2,339 9.3 7,586 262 34.5 1,606 10.1 5,263 179 34.0 Total 25,093 81,111 2,718 33.5 15,932 52,092 1,495 28.7 Abbreviation: U5M, under-5 mortality. a Number of deaths per 1,000 child-years. To estimate the association between Ramadan exposure in utero and child mortality, we performed a difference-in-differences analysis to eliminate seasonal mortality differences through comparison with non-Muslims. In adjusted multilevel regression, children for whom Ramadan occurred during conception or the first or second trimester showed higher mortality rates (37%, 33%, and 25%, respectively) than children certainly not exposed, only among Muslims, as shown by the interaction terms (P = 0.03, P = 0.01, and P = 0.05, respectively), while exposure during the third trimester and at birth was not associated with increased mortality (Table 2). Table 2. Effect of Prenatal Ramadan Exposure on Mortality Before 5 Years of Age (Difference-in-Differences Analysis) Among 41,025 Children From Nouna District, Burkina Faso, 1993–2012 Parametera and Exposure Category HR 95% CI P Value Ramadan  Conceived vs. certainly not 0.86 0.69, 1.09 0.22  Trimester 1 vs. certainly not 0.88 0.73, 1.06 0.17  Trimester 2 vs. certainly not 0.91 0.76, 1.10 0.35  Trimester 3 vs. certainly not 0.92 0.76, 1.11 0.37  Born vs. certainly not 1.05 0.86, 1.29 0.63  Probably not vs. certainly not 0.99 0.77, 1.26 0.92 Mother is Muslim (yes vs. no) 0.97 0.81, 1.17 0.77 Ramadan × Muslim mother interactionb  Conceived vs. certainly not 1.37 1.03, 1.82 0.03  Trimester 1 vs. certainly not 1.33 1.06, 1.67 0.01  Trimester 2 vs. certainly not 1.25 1.00, 1.57 0.05  Trimester 3 vs. certainly not 1.10 0.87, 1.40 0.43  Born vs. certainly not 1.02 0.79, 1.34 0.86  Probably not vs. certainly not 1.14 0.83, 1.56 0.42 Year of birth (linear; per year since 1993) 0.96 0.95, 0.96 <0.001 Region of residence  Central vs. Nouna town 1.39 1.22, 1.58 <0.001  Northeast vs. Nouna town 1.94 1.74, 2.16 <0.001  Southeast vs. Nouna town 1.24 1.09, 1.40 0.001  Southwest vs. Nouna town 1.88 1.69, 2.09 <0.001 Parametera and Exposure Category HR 95% CI P Value Ramadan  Conceived vs. certainly not 0.86 0.69, 1.09 0.22  Trimester 1 vs. certainly not 0.88 0.73, 1.06 0.17  Trimester 2 vs. certainly not 0.91 0.76, 1.10 0.35  Trimester 3 vs. certainly not 0.92 0.76, 1.11 0.37  Born vs. certainly not 1.05 0.86, 1.29 0.63  Probably not vs. certainly not 0.99 0.77, 1.26 0.92 Mother is Muslim (yes vs. no) 0.97 0.81, 1.17 0.77 Ramadan × Muslim mother interactionb  Conceived vs. certainly not 1.37 1.03, 1.82 0.03  Trimester 1 vs. certainly not 1.33 1.06, 1.67 0.01  Trimester 2 vs. certainly not 1.25 1.00, 1.57 0.05  Trimester 3 vs. certainly not 1.10 0.87, 1.40 0.43  Born vs. certainly not 1.02 0.79, 1.34 0.86  Probably not vs. certainly not 1.14 0.83, 1.56 0.42 Year of birth (linear; per year since 1993) 0.96 0.95, 0.96 <0.001 Region of residence  Central vs. Nouna town 1.39 1.22, 1.58 <0.001  Northeast vs. Nouna town 1.94 1.74, 2.16 <0.001  Southeast vs. Nouna town 1.24 1.09, 1.40 0.001  Southwest vs. Nouna town 1.88 1.69, 2.09 <0.001 Abbreviations: CI, confidence interval; HR, hazard ratio. a Model: difference-in-differences analysis with a random intercept for mother; results were additionally adjusted for month of birth (estimates not displayed). b Interaction terms. Table 2. Effect of Prenatal Ramadan Exposure on Mortality Before 5 Years of Age (Difference-in-Differences Analysis) Among 41,025 Children From Nouna District, Burkina Faso, 1993–2012 Parametera and Exposure Category HR 95% CI P Value Ramadan  Conceived vs. certainly not 0.86 0.69, 1.09 0.22  Trimester 1 vs. certainly not 0.88 0.73, 1.06 0.17  Trimester 2 vs. certainly not 0.91 0.76, 1.10 0.35  Trimester 3 vs. certainly not 0.92 0.76, 1.11 0.37  Born vs. certainly not 1.05 0.86, 1.29 0.63  Probably not vs. certainly not 0.99 0.77, 1.26 0.92 Mother is Muslim (yes vs. no) 0.97 0.81, 1.17 0.77 Ramadan × Muslim mother interactionb  Conceived vs. certainly not 1.37 1.03, 1.82 0.03  Trimester 1 vs. certainly not 1.33 1.06, 1.67 0.01  Trimester 2 vs. certainly not 1.25 1.00, 1.57 0.05  Trimester 3 vs. certainly not 1.10 0.87, 1.40 0.43  Born vs. certainly not 1.02 0.79, 1.34 0.86  Probably not vs. certainly not 1.14 0.83, 1.56 0.42 Year of birth (linear; per year since 1993) 0.96 0.95, 0.96 <0.001 Region of residence  Central vs. Nouna town 1.39 1.22, 1.58 <0.001  Northeast vs. Nouna town 1.94 1.74, 2.16 <0.001  Southeast vs. Nouna town 1.24 1.09, 1.40 0.001  Southwest vs. Nouna town 1.88 1.69, 2.09 <0.001 Parametera and Exposure Category HR 95% CI P Value Ramadan  Conceived vs. certainly not 0.86 0.69, 1.09 0.22  Trimester 1 vs. certainly not 0.88 0.73, 1.06 0.17  Trimester 2 vs. certainly not 0.91 0.76, 1.10 0.35  Trimester 3 vs. certainly not 0.92 0.76, 1.11 0.37  Born vs. certainly not 1.05 0.86, 1.29 0.63  Probably not vs. certainly not 0.99 0.77, 1.26 0.92 Mother is Muslim (yes vs. no) 0.97 0.81, 1.17 0.77 Ramadan × Muslim mother interactionb  Conceived vs. certainly not 1.37 1.03, 1.82 0.03  Trimester 1 vs. certainly not 1.33 1.06, 1.67 0.01  Trimester 2 vs. certainly not 1.25 1.00, 1.57 0.05  Trimester 3 vs. certainly not 1.10 0.87, 1.40 0.43  Born vs. certainly not 1.02 0.79, 1.34 0.86  Probably not vs. certainly not 1.14 0.83, 1.56 0.42 Year of birth (linear; per year since 1993) 0.96 0.95, 0.96 <0.001 Region of residence  Central vs. Nouna town 1.39 1.22, 1.58 <0.001  Northeast vs. Nouna town 1.94 1.74, 2.16 <0.001  Southeast vs. Nouna town 1.24 1.09, 1.40 0.001  Southwest vs. Nouna town 1.88 1.69, 2.09 <0.001 Abbreviations: CI, confidence interval; HR, hazard ratio. a Model: difference-in-differences analysis with a random intercept for mother; results were additionally adjusted for month of birth (estimates not displayed). b Interaction terms. In the adjusted multilevel model that did not adjust for Ramadan occurrence during pregnancy, the mortality rate among Muslims was 15% higher (95% confidence interval: 7, 24) than that among non-Muslims (Table 3). From the model with Ramadan interaction terms, we calculated the mortality rate ratio for Muslims versus non-Muslims for each Ramadan exposure category. Children born to Muslim mothers who experienced Ramadan in utero during conception had a 33% higher mortality rate than children of non-Muslim mothers in utero during the same time period (hazard ratio (HR) = 0.97 for Muslim women vs. non-Muslim women outside Ramadan, multiplied with HR = 1.37 for the interaction; P = 0.01). For trimesters 1 and 2, the increases in mortality rates were 29% and 22% (P < 0.001 and P = 0.007), respectively (Table 3, Figure 2). Among children exposed to Ramadan in the third trimester, the difference in mortality between Muslims and non-Muslims was small, and there was no increased mortality for Muslim children born during Ramadan. Having a Muslim mother was not associated with mortality when not exposed to Ramadan (HR = 0.97, P = 0.74), and Ramadan occurrence was not associated with mortality among non-Muslims in the adjusted model (Table 2). Table 3. Mortality Before 5 Years of Age in Muslims Compared With Non-Muslims, by Prenatal Ramadan Exposure, Among 41,025 Children From Nouna District, Burkina Faso, 1993–2012 Prenatal Ramadan Exposure Calculationa HR 95% CI P Value Total (not considering Ramadan)b 1.15 1.07, 1.24 <0.001 Ramadan exposure categoryc  Certainly not exposed —d 0.97 0.81, 1.17 0.74  Probably not exposed 0.97 × 1.14 1.11 0.86, 1.43 0.43  Conceived during Ramadan 0.97 × 1.37 1.33 1.06, 1.66 0.01  Ramadan during trimester 1 0.97 × 1.33 1.29 1.12, 1.49 <0.001  Ramadan during trimester 2 0.97 × 1.26 1.22 1.06, 1.40 0.007  Ramadan during trimester 3 0.97 × 1.11 1.07 0.91, 1.26 0.39  Born during Ramadan 0.97 × 1.02 1.00 0.82, 1.21 0.98 Prenatal Ramadan Exposure Calculationa HR 95% CI P Value Total (not considering Ramadan)b 1.15 1.07, 1.24 <0.001 Ramadan exposure categoryc  Certainly not exposed —d 0.97 0.81, 1.17 0.74  Probably not exposed 0.97 × 1.14 1.11 0.86, 1.43 0.43  Conceived during Ramadan 0.97 × 1.37 1.33 1.06, 1.66 0.01  Ramadan during trimester 1 0.97 × 1.33 1.29 1.12, 1.49 <0.001  Ramadan during trimester 2 0.97 × 1.26 1.22 1.06, 1.40 0.007  Ramadan during trimester 3 0.97 × 1.11 1.07 0.91, 1.26 0.39  Born during Ramadan 0.97 × 1.02 1.00 0.82, 1.21 0.98 Abbreviations: CI, confidence interval; HR, hazard ratio. a Calculation of stratum HRs from the baseline HR and the interaction HR. b Survival analysis without Ramadan exposure (with a random intercept for mother; results were adjusted for year of birth, month of birth, region of residence, season at death, and sex of child). c Based on the full model shown in Table 2. d This value corresponds to the estimate for “mother is Muslim (yes vs. no)” as displayed in Table 2. Table 3. Mortality Before 5 Years of Age in Muslims Compared With Non-Muslims, by Prenatal Ramadan Exposure, Among 41,025 Children From Nouna District, Burkina Faso, 1993–2012 Prenatal Ramadan Exposure Calculationa HR 95% CI P Value Total (not considering Ramadan)b 1.15 1.07, 1.24 <0.001 Ramadan exposure categoryc  Certainly not exposed —d 0.97 0.81, 1.17 0.74  Probably not exposed 0.97 × 1.14 1.11 0.86, 1.43 0.43  Conceived during Ramadan 0.97 × 1.37 1.33 1.06, 1.66 0.01  Ramadan during trimester 1 0.97 × 1.33 1.29 1.12, 1.49 <0.001  Ramadan during trimester 2 0.97 × 1.26 1.22 1.06, 1.40 0.007  Ramadan during trimester 3 0.97 × 1.11 1.07 0.91, 1.26 0.39  Born during Ramadan 0.97 × 1.02 1.00 0.82, 1.21 0.98 Prenatal Ramadan Exposure Calculationa HR 95% CI P Value Total (not considering Ramadan)b 1.15 1.07, 1.24 <0.001 Ramadan exposure categoryc  Certainly not exposed —d 0.97 0.81, 1.17 0.74  Probably not exposed 0.97 × 1.14 1.11 0.86, 1.43 0.43  Conceived during Ramadan 0.97 × 1.37 1.33 1.06, 1.66 0.01  Ramadan during trimester 1 0.97 × 1.33 1.29 1.12, 1.49 <0.001  Ramadan during trimester 2 0.97 × 1.26 1.22 1.06, 1.40 0.007  Ramadan during trimester 3 0.97 × 1.11 1.07 0.91, 1.26 0.39  Born during Ramadan 0.97 × 1.02 1.00 0.82, 1.21 0.98 Abbreviations: CI, confidence interval; HR, hazard ratio. a Calculation of stratum HRs from the baseline HR and the interaction HR. b Survival analysis without Ramadan exposure (with a random intercept for mother; results were adjusted for year of birth, month of birth, region of residence, season at death, and sex of child). c Based on the full model shown in Table 2. d This value corresponds to the estimate for “mother is Muslim (yes vs. no)” as displayed in Table 2. Figure 2. View largeDownload slide Mortality under 5 years of age according to prenatal Ramadan exposure among children of Muslim mothers compared with children of non-Muslim mothers who were in utero during the same time period, Nouna District, Burkina Faso, 1993–2012. The hazard ratios were derived from an adjusted multilevel model (see Tables 2 and 3) that included 25,093 children born to Muslim mothers and 15,932 children born to non-Muslim mothers in Nouna District. They were calculated by dividing the under-5 mortality rates of Muslims by the under-5 mortality rates of non-Muslims. A hazard ratio of 1.3 means that under-5 mortality among Muslims was 30% higher than that among non-Muslims; a hazard ratio of 1.0 means that the mortality of Muslims and non-Muslims was the same; and hazard ratios below 1 signify lower mortality among Muslims. Vertical lines display 95% confidence intervals. Figure 2. View largeDownload slide Mortality under 5 years of age according to prenatal Ramadan exposure among children of Muslim mothers compared with children of non-Muslim mothers who were in utero during the same time period, Nouna District, Burkina Faso, 1993–2012. The hazard ratios were derived from an adjusted multilevel model (see Tables 2 and 3) that included 25,093 children born to Muslim mothers and 15,932 children born to non-Muslim mothers in Nouna District. They were calculated by dividing the under-5 mortality rates of Muslims by the under-5 mortality rates of non-Muslims. A hazard ratio of 1.3 means that under-5 mortality among Muslims was 30% higher than that among non-Muslims; a hazard ratio of 1.0 means that the mortality of Muslims and non-Muslims was the same; and hazard ratios below 1 signify lower mortality among Muslims. Vertical lines display 95% confidence intervals. In sensitivity analyses separating mortality during infancy from mortality later in childhood, Ramadan exposure during conception was associated with 68% higher infant mortality among Muslims than among non-Muslims (HR = 1.68, P = 0.004), while hazard ratios for infant mortality were 1.23 (P = 0.05) for first-trimester Ramadan occurrence and 1.17 (P = 0.13) for second-trimester Ramadan occurrence. In children aged 1–4 years, Ramadan exposure during the first (HR = 1.34, P = 0.002) and second (HR = 1.25, P = 0.02) trimesters was associated with a strong increase in mortality, but the association of Ramadan exposure during conception (HR = 1.11, P = 0.48) with mortality was weaker. When analyses were stratified by region of residence, the increased mortality rate in children exposed to Ramadan in utero was visible in all regions, with the strongest associations being seen in the Northeast and the Southwest, the regions with the highest child mortality. Because of the lower sample sizes, regional estimates were not significant at the 5% level, except for Ramadan exposure in the first or second trimester in the Southwest region, which had the largest number of children. Stratification by year of birth showed that the measures of association of Ramadan exposure with mortality during trimesters 1 and 2 were comparable between the 3 study periods (1993–1999, 2000–2006, and 2007–2012) and the association for being conceived during Ramadan was stronger during the most recent period. Among children exposed to Ramadan during conception, the association was stronger in children exposed for 14 days or more (HR = 1.45, P = 0.04). It was weaker and not significant for children exposed for less than 14 days (HR = 1.27, P = 0.21). DISCUSSION Using 20 years of surveillance data from northwestern Burkina Faso, we detected a strong association between having been exposed to Ramadan in utero and under-5 mortality. This association was present from conception to the second trimester, and particularly strong during early pregnancy, when the mortality rate of children born to Muslim mothers was around 30% higher than that among children of non-Muslim mothers born at the same time. The 15% higher mortality seen in children of Muslim mothers overall was entirely explained by Ramadan exposure, as having a Muslim mother was not associated with mortality when the pregnancy occurred outside of Ramadan. For our analysis, we assigned children of Muslim mothers as being exposed to Ramadan without having actual information on maternal fasting, as in an intention-to-treat analysis. Use of this approach avoids confounding by health issues associated with decreased fasting adherence and increased child mortality. However, if a substantial proportion of Muslim women did not adhere to Ramadan fasting during pregnancy, our results would underestimate the true association due to nondifferential misclassification. Another source of misclassification is pregnancy duration. For the Ramadan exposure assignment, we assumed a gestational age of 266 days for all children. There are, however, natural variations in gestational age at birth, and only about 50% of children are born within 7 days of the estimated due date (26). Some children born at higher gestational ages will have been classified as not exposed to Ramadan, even though they were actually exposed during conception. To ensure that our comparison category was “certainly not exposed to Ramadan,” we created a separate category of children “probably not exposed,” capturing possible exposure in very early pregnancy among children born 1–20 days postterm. A different issue is children who were born early—that is, who were in utero for less than 266 days. These children might have been assigned Ramadan exposure during conception or the beginning of trimester 1, even though they were actually not exposed to Ramadan at all. The categorization of the certainly-not-exposed children (born just before Ramadan) was not affected by this, because a shorter gestation would not lead to an overlap with Ramadan. Thus, any misclassification of pregnancy duration would only have led to an attenuation of the measures of association. If some women planned their pregnancies to avoid an overlap with Ramadan, this could have introduced bias. If this group was less vulnerable for some reason, this could have artificially increased our estimates. Such behavior should be more likely in Muslim women, because there is less reason for non-Muslims to avoid an overlap with Ramadan. Our sensitivity analyses provided no evidence for such pregnancy planning (Web Appendix 1), and previous research comparing Muslims who were pregnant during a Ramadan with those who were not found no differences in education, smoking behavior, health, or income (14–16, 19, 27), suggesting that Muslims generally do not plan their pregnancies in such a way that they avoid overlap with a Ramadan. The majority of studies on the association between Ramadan fasting and health of the offspring have focused on immediate outcomes such as birth weight and preterm delivery and have mostly found no associations (28–32). Even though low birth weight is associated with increased child mortality (33), the effect of Ramadan fasting on child mortality presumably does not act via birth weight but through an impact on the developing immune system, which is in line with the impacts of seasonality on thymus size reported from the Gambia (6). While undernutrition in utero can lead to intrauterine growth restriction that is measurable as low birth weight, as well as to epigenetic changes influencing later disease risk (9), the systems affected and the time(s) at which this shows in life will depend on the types of nutrients missing and the exact timing of undernutrition during pregnancy. For example, persons exposed to the Dutch Hunger Winter in early pregnancy had normal birth weight but suffered from a higher burden of disease as adults (9). Previous studies on long-term outcomes showed that children who were exposed to Ramadan in utero had lower academic performance (14, 15) and were more likely to suffer from learning disabilities (27), suggesting an impact on the developing nervous system. There is also evidence from Indonesia linking Ramadan exposure in utero to adult body size (17), to lower nurse-rated general adult health, and to higher prevalence of slow-healing wounds and chest pain (symptoms indicative of diabetes and coronary heart disease) (19). In line with our study, the great majority of studies on long-term outcomes of Ramadan exposure showed stronger associations if children were exposed early in pregnancy, during the time of conception and the first trimester (14, 17, 20, 34). This is biologically plausible and consistent with our knowledge on fetal programming (1, 35). An alternative explanation for the stronger associations in early pregnancy is a higher adherence to fasting during this time, especially when women are not yet aware of the pregnancy (28, 34). In pregnant women, fasting leads to increases in levels of free fatty acids and ketones and decreases in blood glucose after a relatively short period of time (12–18 hours), a process called “accelerated starvation” (36). Because of its location close to the equator, the durations of fasting periods in Burkina Faso are roughly constant over the years (around 13 hours). At the same time, preexisting undernutrition and physical labor in a hot climate may exacerbate fasting effects. Intermittent exposure to decreased glucose and increased ketone levels, the balance of calories from proteins and carbohydrates, and deficiencies in crucial micronutrients can be responsible for adverse effects on fetal health (35). From our data, however, it is impossible to say whether the association between Ramadan and mortality is due to the lack of food and water intake during the daytime or due to other lifestyle changes related to Ramadan, such as overall reduced calorie intake, increased sugar and fat intake, decreased intake of micronutrient-rich foods, changes in sleeping patterns, or other factors. The developing immune system is particularly vulnerable to maternal malnutrition in the first trimester through a range of mechanisms: micronutrient deficiencies directly affecting thymus development and hematopoiesis, impaired maternal immune transfer altering the fetal immune system’s trajectory, and maternal glucocorticoids suppressing fetal thymus and lymphocyte development as well as influencing the development of the fetal hypothalamic-pituitary-adrenal axis (37). Especially in sub-Saharan Africa, where infectious diseases (pneumonia, diarrhea, malaria) are still a major cause of under-5 mortality (38), alterations in the functioning of the immune system can be expected to influence child survival. Our finding that periconceptional Ramadan exposure was most strongly linked to mortality, and mainly to infant mortality rather than later child mortality, could mean that impacts incurred during the embryo’s formative phase are particularly severe and kill earlier or that they disrupt immune mechanisms that are important for maternal immune transfer, which is particularly relevant in infancy before vaccination takes effect. However, given our limited statistical power in subanalyses, results of the stratified analyses should not be overinterpreted. To shed more light on the mechanisms involved, it would be helpful to study cause-specific mortality and to investigate epigenetic changes where such data are available. Finally, because sex differences in immune response and in fetal programming are common (39–42), we plan to investigate effect modification by child sex as soon as newer years of surveillance data become available. In conclusion, we found that Ramadan exposure in early pregnancy leads to a 30% increase in child mortality in rural Burkina Faso, a setting where infectious causes of child mortality dominate. This suggests that changes in nutrient intake and/or lifestyle which are far less dramatic than those that occur during a famine or hunger season can have long-lasting detrimental effects on child health, which might act through impacts on immune system development (6). Besides its contribution to knowledge on the developmental origins of disease and causes of child mortality, our finding is relevant for the 1.6 billion Muslims globally, tens of millions of whom get pregnant each year. According to Islam, pregnant women are exempt from fasting during Ramadan if they are worried about their health or the health of their unborn child (24), but it has been shown in several settings that many women still fast (43–47). Conception and early pregnancy seem to be the most vulnerable periods, which complicates matters, as it would imply abstaining from fasting while trying to get pregnant and in a period when women may not yet want to reveal their pregnancy status. Furthermore, our finding may be important to women of other faiths who fast and to all women, because meal-skipping and dieting during pregnancy are common in nonreligious pregnant women as well (18, 48, 49). Even though the effect of Ramadan fasting on child mortality is probably restricted to high-mortality settings, long-term health and cognitive effects may also affect people in high-income settings. ACKNOWLEDGMENTS Author affiliations: Unit of Epidemiology and Biostatistics, Institute of Public Health, Heidelberg University, Heidelberg, Germany (Anja Schoeps, Gisela Kynast-Wolf, Sabine Gabrysch); Gutenberg School of Management and Economics, Johannes Gutenberg University, Mainz, Germany (Reyn van Ewijk); and Centre de Recherche en Santé de Nouna, Nouna, Burkina Faso (Eric Nebié, Pascal Zabré, Ali Sié). This work benefitted from support provided by the German Research Foundation to R.v.E. (grant 260639091) and to the Nouna Health and Demographic Surveillance System (research grant SFB 544 (“Control of Tropical Infectious Diseases”), 1999–2011). Conflict of interest: none declared. Abbreviations HDSS Health and Demographic Surveillance System HR hazard ratio REFERENCES 1 Ramakrishnan U , Grant F , Goldenberg T , et al. . Effect of women’s nutrition before and during early pregnancy on maternal and infant outcomes: a systematic review . 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Journal

American Journal of EpidemiologyOxford University Press

Published: Oct 1, 2018

References

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