Maternal Obesity, Overweight and Gestational Diabetes Affect the Offspring Neurodevelopment at 6 and 18 Months of Age – A Follow Up from the PREOBE Cohort

RESEARCH ARTICLE Maternal Obesity, Overweight and Gestational Diabetes Affect the Offspring Neurodevelopment at 6 and 18 Months of Age – A Follow Up from the PREOBE Cohort Francisco J. Torres-Espinola1, Staffan K Berglund1,2, Luz Mª García-Valdés1, Mª Teresa Segura1, Antonio Jerez1,3, Daniel Campos1, Rosario Moreno-Torres1, Ricardo Rueda4, Andrés Catena5, Miguel Pérez-García5, Cristina Campoy1,3*, PREOBE team¶ 1 Centre of Excellence for Paediatric Research EURISTIKOS, University of Granada, Granada, Spain, 2 Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden, 3 Department of Paediatrics, University of Granada, Granada, Spain, 4 R&D Department, Abbott Laboratories. Granada, Granada, Spain, 5 Mind, Brain and Behaviour International Research Centre (CIMCYC). University of Granada, Granada, Spain OPEN ACCESS Citation: Torres-Espinola FJ, Berglund SK, GarcíaValdés LM, Segura MT, Jerez A, Campos D, et al. (2015) Maternal Obesity, Overweight and Gestational Diabetes Affect the Offspring Neurodevelopment at 6 and 18 Months of Age – A Follow Up from the PREOBE Cohort. PLoS ONE 10(7): e0133010. doi:10.1371/journal.pone.0133010 Editor: Olivier Baud, Hôpital Robert Debré, FRANCE Received: May 4, 2015 Accepted: June 23, 2015 Published: July 24, 2015 Copyright: © 2015 Torres-Espinola et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper. Funding: This study was funded by Spanish Ministry of Innovation and Science. Junta de Andalucía: Excellence Projects (P06-CTS-02341); Spanish Ministry of Education (Grant no. SB2010-0025); Spanish Ministry of Economy and Competitiveness (BFU2012-40254-C03-01); Further support was received by Abbott Laboratories, Granada, Spain. The funders had no role in study design, data ¶ Membership of the PREOBE group is provided in the Acknowledgments. * Abstract Background Brain development in fetal life and early infancy is critical to determine lifelong performance in various neuropsychological domains. Metabolic pathologies such as overweight, obesity, and gestational diabetes in pregnant women are prevalent and increasing risk factors that may adversely affect long-term brain development in their offspring. Objective The objective of this research was to investigate the influence of maternal metabolic pathologies on the neurodevelopment of the offspring at 6 and 18 months of life. Design This was a prospective case-control study of 331 mother- and child pairs from Granada, Spain. The mothers were included during pregnancy into four groups according to their pregestational body mass index and their gestational diabetes status; overweight (n:56), obese (n:64), gestational diabetic (n:79), and healthy normal weight controls (n:132). At 6 months and 18 months we assessed the children with the Bayley III scales of neurodevelopment. Results At 6 months (n=215), we found significant group differences in cognition composite language, and expressive language. Post hoc test revealed unexpectedly higher scores in the PLOS ONE | DOI:10.1371/journal.pone.0133010 July 24, 2015 1 / 14 Maternal Obesity and Child Neurodevelopment collection and analysis, decision to publish, or preparation of the manuscript. The study was registered at www.ClinicalTrials.gov, identifier: NCT01634464). Competing Interests: The study was funded in part by Abbott Laboratories, Granada, Spain. There are no relevant declarations relating to employment, consultancy, patents, products in development, or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. obese group compared to the normal weight group and a similar trend in overweight and diabetic group. The effects on language remained significant after adjusting for confounders with an adjusted odds ratio for a value above median in composite language score of 3.3 (95% CI: 1.1, 10.0; p=0.035) for children of obese mothers. At 18 month (n=197), the offspring born to obese mothers had lost five points in language composite scores and the previous differences in language and cognition was replaced by a suggestive trend of lower gross motor scores in the overweight, obese, and diabetic groups. Conclusions Infants of obese mothers had a temporary accelerated development of cognition and language, followed by a rapid deceleration until 18 months of age, particularly of language scores. This novel observation prompts further confirmative studies to explore possible placental and neurodevelopmental mechanisms involved. Introduction The rates of obesity and diabetes have experienced exceptional increase during recent years in the developed world. In parallel, studies of how these diseases affect human health are prioritized [1, 2]. One important field of research is the influence of these pathologies on pregnant women and their offspring. It is well described that excessive weight before pregnancy, particularly in combination with rapid weight gain during pregnancy, can determine the occurrence of gestational diabetes [3], a well-known risk factor both to the mother and the fetus [4]. Gestational diabetes but also pre-gestational overweight and obesity in general, have been suggested to interact with the infant micronutrient status, birth anthropometrics and even with the offspring’s neurodevelopment [4–8]. Brain development in fetus and in early years of life is critical to determine lifelong performance in various neuropsychological domains such as cognition, language, and motor functions. It has been observed that the last trimester of pregnancy is un-arguably the most important period of neuronal determination, synaptogenesis and dendritic arborization [9– 11]. Thus, differences in the intrauterine environment at different stages of fetal life, may substantially determine long term neurodevelopment and brain performance [7, 9, 12, 13]. Maternal metabolic pathologies are possible examples of such differences. In recent years, several studies have suggested that children born to mothers with gestational diabetes present language delay, impaired recognition memory, poor motor development and neuropsychological impairment at different stages of childhood [4, 8, 14–19]. Furthermore, neurodevelopment of children is associated to maternal weight gain during pregnancy, to maternal pre-pregnancy body mass index (BMI) and to obesity [5, 20–22]. However, these studies show diverging results and as recently concluded in two reviews, most of them did not prospectively explore the effects on neurodevelopment before 20 months of life [23, 24]. The effect of obesity, overweight, and diabetes on the infants’ early (...truncated)