Coffee in Health and Disease Prevention http://dx.doi.org/10.1016/B978-0-12-409517-5.00049-8 © 2015 Elsevier Inc. All rights reserved. 443 CHAPTER 49 Coffee-Induced Neural Tube Defects Gianfranco Carlomagno 1, 3 , Sara De Grazia 1, 3 , Alberto Vaiarelli 2 , Vittorio Unfer 1 1 A.G.UN.CO. Obstetrics and Gynecology Center, Rome, Italy; 2 Reproductive Medicine Unit, University Hospital, Messina, Italy; 3 R&D Dept. LO.LI Pharma s.r.l, Rome, Italy List of Abbreviations NTD Neural tube defect PKC Protein kinase C IP3 Inositol triphosphate DAG Diacylglycerol MRC-UK Medical Research Council of the United Kingdom NAT2 N-acetyltransferase 2 PONTI Prevention of NTDs by inositol 49.1 INTRODUCTION Caffeine is a naturally occurring compound, and it is probably one of the most frequently used pharma- cologically active substance in the world (Table 49.1). Because of its wide consumption, the public and the sci- entific communities have expressed interest in studying the potential for caffeine to produce adverse effects on human health. 1 Although a clear consensus on the negative effects of caffeine has not been reached, several epidemiological studies have been associated with health problems such as coronary heart diseases and hypertension as well as reproductive and developmental adverse effects. In par- ticular, delayed conception, spontaneous abortion, and other reproductive and developmental malformations have been reported. 2–5 Neural tube defects (NTDs) are complex congenital malformations of the central nervous system occurring within 8 weeks from conception. During embryogenesis, the central nervous system normally develops as a flat sheet of cells that subsequently rolls up and fuses shut to form the hollow neural tube: NTDs arise when this process of neural tube closure is disrupted. 6 As pregnancy progresses, exposure to the amniotic fluid environment leads to neurodegeneration so that, at the time of birth, the exposed brain, spinal cord, or both are severely damaged. 7 Although substantial advances have been made in the prevention and treatment of these malformations, NTDs remain a substantial public health problem, occurring in 0.5–2 per 1000 pregnan- cies, depending on geographic region and ethnic group. Moreover, the recurrence risk goes up to 2–3% in subse- quent pregnancies among couples who had a previous case of NTDs. NTDs are generally classified in two main groups, defined as “open” and “closed” NTDs, depending on whether lesions are covered by skin or not. In general terms, cranial defects are usually lethal before or at birth, whereas spina bifida is compatible with postna- tal life being associated with various grades of physi- cal and developmental disabilities. 8 NTDs result from defective primary neurulation (anencephaly, open spina bifida, and craniorachischisis), secondary neu- rulation (skin-covered spinal dysraphism), or post- neurulation disorders (other malformations, such as encephalocele). 9 Several studies have been carried out to understand the etiology of NTDs; however, there is still considerable discussion regarding the etiology of NTDs and genetic, environmental, and joint factors (Table 49.2). 10 Several observations support the fact that genetic factors are involved in the formation of NTDs and that chromosomal anomalies can be associated with these kinds of congenital malformations in between 2% and 16% of isolated NTDs. In addition to genetic factors, it has been reported that teratogenic insults such as drug use and exposure to infection during pregnancy, mater- nal micronutrient deficiencies, and metabolic conditions represent environmental factors involved in the etiology of NTDs. In this context, caffeine seems to play a key role in impairing nutrient absorption as well as in interacting with biologic pathways involved in NTDs development.