We thank Drs. de Rooij (1) and Stein (2) for their thoughtful commentaries on our article (3). While the body of evidence linking Ramadan exposure during pregnancy to adverse outcomes has grown steadily over the past few years, we totally agree that there is still comparatively little known about the mechanisms involved. What changes occur in the functioning of specific organs or body systems? Do epigenetic changes occur in relevant genes? Are there moderators of the effects? Other studies on nutritional restrictions during pregnancy, such as the Dutch famine study (4) and work from the Gambia (5), provide a fertile ground for hypotheses on mechanisms, which now need to be tested for Ramadan. Prenatal famine exposure has been shown to affect a range of adverse health outcomes (6), including diabetes, coronary heart disease, breast cancer, schizophrenia, cognitive decline, and mortality later in life, and exposure to the Dutch famine has furthermore been shown to result in persistent epigenetic changes, in the insulin-like growth factor 2 gene (IGF2) (7) and at other locations (8–10), some of which mediate the famine’s effect on body mass index and triglycerides (11). Studies in rural Gambia found that conception during the rainy season (with less food availability but more varied food and higher maternal one-carbon micronutrient levels) was associated with increased methylation at metastable epialleles, including a putative tumor suppressor and modulator of innate immunity, the vault RNA 2-1 gene (VTRNA2-1) (12–14). Prenatal Ramadan exposure has by now been linked to various outcomes, including poorer cognitive performance, a higher prevalence of symptoms indicative of coronary heart disease and type 2 diabetes, and mental disabilities, as well as altered body composition. We have now found an association with mortality in children under 5 years of age (3), in a context where infectious diseases are a major cause of child death. This led us to speculate that prenatal Ramadan exposure affects the immune system. We agree that this needs to be corroborated by future studies including cause-specific mortality and markers of immune function, such as thymic size and lymphocyte subpopulation, as studied in the Gambia (15, 16), as well as epigenetic changes in immunity-relevant genes. We must be aware that the severe and prolonged nutritional restrictions present during famines can biologically work in a very different way than the intermittent nutritional restrictions imposed during Ramadan. And as both de Rooij (1) and Stein (2) point out, during famines there are also other simultaneous exposures, such as stress, that make it hard to disentangle what exactly caused the reported effects. During Ramadan, too, there may potentially be other, concurrent exposures besides caloric restriction, such as a change in sleeping patterns, dehydration, stress, and increased sugar intake during evenings or reduced micronutrient intake. Future research needs to determine the extent to which each of these indeed plays a role for pregnant women during Ramadan and establish their biological pathways. Moreover, several exposures may interact to produce an effect, or effects may be moderated by third variables—for example, daytime fasting may be less harmful when women refrain from physically straining activities or avoid copious consumption of sugar-rich foods at night. Finally, the studies on the Dutch famine, Ramadan in pregnancy, and others highlight that we can gain valuable insights from natural experiments where true experiments are not possible and observational data suffer from confounding—which extends far beyond the field of nutrition. Epidemiologists should systematically look for natural experiments and could also benefit from applying econometric methods (difference-in-differences, regression discontinuity, instrumental variables, etc.) more frequently in these situations, as these methods are specifically suited to getting closer to causality when only observational data are available. ACKNOWLEDGMENTS Author affiliations: Unit of Epidemiology and Biostatistics, Institute of Public Health, Heidelberg University, Heidelberg, Germany (Sabine Gabrysch); and Gutenberg School of Management and Economics, Johannes Gutenberg University, Mainz, Germany (Reyn van Ewijk). Conflict of interest: none declared. REFERENCES 1 de Rooij SR . Invited commentary: a matter of survival—the detrimental consequences of adverse early-life conditions . Am J Epidemiol . 2018 ; 187 ( 10 ): 2093 – 2094 . 2 Stein AD . Invited commentary: Ramadan, pregnancy, nutrition, and epidemiology . Am J Epidemiol . 2018 ; 187 ( 10 ): 2095 – 2097 . 3 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 . 4 Roseboom TJ , Painter RC , van Abeelen AF , et al. . Hungry in the womb: what are the consequences? Lessons from the Dutch famine . Maturitas . 2011 ; 70 ( 2 ): 141 – 145 . Google Scholar Crossref Search ADS PubMed 5 Moore SE . Early life nutritional programming of health and disease in The Gambia . J Dev Orig Health Dis . 2016 ; 7 ( 2 ): 123 – 131 . Google Scholar Crossref Search ADS PubMed 6 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 7 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 8 Tobi EW , Goeman JJ , Monajemi R , et al. . DNA methylation signatures link prenatal famine exposure to growth and metabolism . Nat Commun . 2014 ; 5 : 5592 . Google Scholar Crossref Search ADS PubMed 9 Tobi EW , Lumey LH , Talens RP , et al. . DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific . Hum Mol Genet . 2009 ; 18 ( 21 ): 4046 – 4053 . Google Scholar Crossref Search ADS PubMed 10 Tobi EW , Slieker RC , Stein AD , et al. . Early gestation as the critical time-window for changes in the prenatal environment to affect the adult human blood methylome . Int J Epidemiol . 2015 ; 44 ( 4 ): 1211 – 1223 . Google Scholar Crossref Search ADS PubMed 11 Tobi EW , Slieker RC , Luijk R , et al. . DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood . Sci Adv . 2018 ; 4 ( 1 ): eaao4364 . Google Scholar Crossref Search ADS PubMed 12 Dominguez-Salas P , Moore SE , Baker MS , et al. . Maternal nutrition at conception modulates DNA methylation of human metastable epialleles . Nat Commun . 2014 ; 5 : 3746 . Google Scholar Crossref Search ADS PubMed 13 Silver MJ , Kessler NJ , Hennig BJ , et al. . Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human epiallele responsive to periconceptional environment . Genome Biol . 2015 ; 16 : 118 . Google Scholar Crossref Search ADS PubMed 14 Waterland RA , Kellermayer R , Laritsky E , et al. . Season of conception in rural Gambia affects DNA methylation at putative human metastable epialleles . PLoS Genet . 2010 ; 6 ( 12 ): e1001252 . Google Scholar Crossref Search ADS PubMed 15 Collinson AC , Moore SE , Cole TJ , et al. . Birth season and environmental influences on patterns of thymic growth in rural Gambian infants . Acta Paediatr . 2003 ; 92 ( 9 ): 1014 – 1020 . Google Scholar Crossref Search ADS PubMed 16 Collinson AC , Ngom PT , Moore SE , et al. . Birth season and environmental influences on blood leucocyte and lymphocyte subpopulations in rural Gambian infants . BMC Immunol . 2008 ; 9 : 18 . 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: firstname.lastname@example.org. 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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