Maternal vitamin B12, folate during pregnancy and neurocognitive outcomes in young adults of the Pune Maternal Nutrition Study (PMNS) prospective birth cohort: study protocol

Rishikesh V Behere, Gopikrishna Deshpande, Souvik Kumar Bandyopadhyay, Chittaranjan Yajnik, Rishikesh V Behere, Gopikrishna Deshpande, Souvik Kumar Bandyopadhyay, Chittaranjan Yajnik

Abstract

Introduction: The Developmental Origins of Health and Disease (DOHaD) hypothesis proposes that intrauterine and early life exposures significantly influence fetal development and risk for disease in later life. Evidence from prospective birth cohorts suggests a role for maternal B12 and folate in influencing neurocognitive outcomes in the offspring. In the Indian setting, B12 deficiency is common during the pregnancy while rates of folate deficiency are lower. The long-term influences of maternal nutrition during the pregnancy on adult neurocognitive outcomes have not been examined. The Pune Maternal Nutrition Study (PMNS) is a preconceptional birth cohort into its 24th year and is considered a unique resource to study the DOHaD hypothesis. We found an association between maternal B12 status in pregnancy and child's neurocognitive status at 9 years of age. We now plan to assess neurocognitive function and MRI measurements of brain structural-functional connectivity at young adult age to study its association with maternal nutritional exposures during the pregnancy.

Methods and analysis: As part of ongoing prospective follow-up in young adults of the PMNS at the Diabetes Unit, KEM Hospital Research Center, Pune India, the following measurements will be done: neurocognitive performance (Standardised Tests of Intelligence, Verbal and Visual Memory, Attention and Executive Functions), temperament (Adult Temperament Questionnaire), psychopathology (Brief Symptom Inventory and Clinical Interview on Mini Neuropsychiatric Interview 7.0). Brain MRI for structural T1, resting-state functional connectivity and diffusion tensor imaging will be performed on a subset of the cohort (selected based on exposure to a lower or higher maternal B12 status at 18 weeks of pregnancy).

Ethics and dissemination: The study is approved by Institutional ethics committee of KEM Hospital Research Center, Pune. The results will be shared at national and international scientific conferences and published in peer-reviewed scientific journals.

Trial registration number: NCT03096028.

Keywords: magnetic resonance imaging; nutrition & dietetics; public health.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
Understanding neurocognitive development using a life course approach in the PMNS. PMNS, Pune Maternal Nutrition Study.
Figure 2
Figure 2
Selection of subjects from the PMNS cohort for the study. PMNS, Pune Maternal Nutrition Study.

References

    1. Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull 2001:60–5.
    1. Fleming TP, Watkins AJ, Velazquez MA, et al. . Origins of lifetime health around the time of conception: causes and consequences. Lancet 2018;391:1842–52. 10.1016/S0140-6736(18)30312-X
    1. Schlotz W, Phillips DIW. Fetal origins of mental health: evidence and mechanisms. Brain Behav Immun 2009;23:905–16. 10.1016/j.bbi.2009.02.001
    1. Gilchrist C, Cumberland A, Walker D, et al. . Intrauterine growth restriction and development of the hippocampus: implications for learning and memory in children and adolescents. Lancet Child Adolesc Health 2018;2:755–64. 10.1016/S2352-4642(18)30245-1
    1. Langen CD, Muetzel R, Blanken L, et al. . Differential patterns of age-related cortical and subcortical functional connectivity in 6-to-10 year old children: a connectome-wide association study. Brain Behav 2018;8:e01031. 10.1002/brb3.1031
    1. Liu J, Chen Y, Stephens R, et al. . Hippocampal functional connectivity development during the first two years indexes 4-year working memory performance. Cortex 2021;138:165–77. 10.1016/j.cortex.2021.02.005
    1. Yoon YB, Shin W-G, Lee TY, et al. . Brain structural networks associated with intelligence and visuomotor ability. Sci Rep 2017;7:2177. 10.1038/s41598-017-02304-z
    1. Yajnik CS, Deshmukh US. Maternal nutrition, intrauterine programming and consequential risks in the offspring. Rev Endocr Metab Disord 2008;9:203–11. 10.1007/s11154-008-9087-z
    1. Misra UK, Kalita J, Das A. Vitamin B12 deficiency neurological syndromes: a clinical, MRI and electrodiagnostic study. Electromyogr Clin Neurophysiol 2003;43:57–64.
    1. Yajnik CS, Deshmukh US. Fetal programming: maternal nutrition and role of one-carbon metabolism. Rev Endocr Metab Disord 2012;13:121–7. 10.1007/s11154-012-9214-8
    1. Magnus P. The norwegian mother and child cohort study (MoBa)–new research possibilities. Norsk epidemiologi 2007;17. 10.5324/nje.v17i2.132
    1. Jacka FN, Ystrom E, Brantsaeter AL, et al. . Maternal and early postnatal nutrition and mental health of offspring by age 5 years: a prospective cohort study. J Am Acad Child Adolesc Psychiatry 2013;52:1038–47. 10.1016/j.jaac.2013.07.002
    1. Roza SJ, van Batenburg-Eddes T, Steegers EAP, et al. . Maternal folic acid supplement use in early pregnancy and child behavioural problems: the generation R study. Br J Nutr 2010;103:445–52. 10.1017/S0007114509991954
    1. Schlotz W, Jones A, Phillips DIW, et al. . Lower maternal folate status in early pregnancy is associated with childhood hyperactivity and peer problems in offspring. J Child Psychol Psychiatry 2010;51:594–602. 10.1111/j.1469-7610.2009.02182.x
    1. Ars CL, Nijs IM, Marroun HE, et al. . Prenatal folate, homocysteine and vitamin B12 levels and child brain volumes, cognitive development and psychological functioning: the generation R Study. Br J Nutr 2019;122:S1–9. 10.1017/S0007114515002081
    1. Surén P, Roth C, Bresnahan M, et al. . Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA 2013;309:309–6. 10.1001/jama.2012.155925
    1. Steenweg-de Graaff J, Ghassabian A, Jaddoe VWV, et al. . Folate concentrations during pregnancy and autistic traits in the offspring. the generation R study. Eur J Public Health 2015;25:431–3. 10.1093/eurpub/cku126
    1. Veena SR, Gale CR, Krishnaveni GV, et al. . Association between maternal nutritional status in pregnancy and offspring cognitive function during childhood and adolescence; a systematic review. BMC Pregnancy Childbirth 2016;16:220. 10.1186/s12884-016-1011-z
    1. Behere RV, Deshmukh AS, Otiv S, et al. . Maternal vitamin B12 status during pregnancy and its association with outcomes of pregnancy and health of the offspring: a systematic review and implications for policy in India. Front Endocrinol 2021;12:619176. 10.3389/fendo.2021.619176
    1. Smith GD, Ebrahim S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003;32:1–22. 10.1093/ije/dyg070
    1. Bonilla C, Lawlor DA, Taylor AE, et al. . Vitamin B-12 status during pregnancy and child's IQ at age 8: a mendelian randomization study in the avon longitudinal study of parents and children. PLoS One 2012;7:e51084. 10.1371/journal.pone.0051084
    1. Samuel TM, Duggan C, Thomas T, et al. . Vitamin B(12) intake and status in early pregnancy among urban south Indian women. Ann Nutr Metab 2013;62:113–22. 10.1159/000345589
    1. Pathak P, Kapil U, Yajnik CS, et al. . Iron, folate, and vitamin B12 stores among pregnant women in a rural area of haryana state, India. Food Nutr Bull 2007;28:435–8. 10.1177/156482650702800409
    1. Yajnik CS, Deshpande SS, Jackson AA, et al. . Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune maternal nutrition study. Diabetologia 2008;51:29–38. 10.1007/s00125-007-0793-y
    1. Behere RV, Yajnik CS. Low vitamin B-12-high folate status in adolescents and pregnant women may have deleterious effects on health of the offspring. Am J Clin Nutr 2021;113:1057–9. 10.1093/ajcn/nqab007
    1. Bailey R, Jun S, Murphy L, et al. . High folate and vitamin low B12 status: potential interactions with cognitive function among U.S. older adults, NHANES 2011–2014. Curr Dev Nutr 2020;4:1189. 10.1093/cdn/nzaa057_005
    1. Sable P, Dangat K, Kale A, et al. . Altered brain neurotrophins at birth: consequence of imbalance in maternal folic acid and vitamin B₁₂ metabolism. Neuroscience 2011;190:127–34. 10.1016/j.neuroscience.2011.05.010
    1. Sable P, Kale A, Joshi A. Maternal micronutrient imbalance alters gene expression of BDNF, NGF, TrkB and CREB in the offspring brain at an adult age. Int J Dev Neurosci 2014:34–24. 10.1016/j.ijdevneu.2014.01.003
    1. Yajnik CS, Chandak GR, Joglekar C, et al. . Maternal homocysteine in pregnancy and offspring birthweight: epidemiological associations and Mendelian randomization analysis. Int J Epidemiol 2014;43:1487–97. 10.1093/ije/dyu132
    1. Bhate V, Deshpande S, Bhat D, et al. . Vitamin B12 status of pregnant Indian women and cognitive function in their 9-year-old children. Food Nutr Bull 2008;29:249–54. 10.1177/156482650802900401
    1. Rao S, Yajnik CS, Kanade A, et al. . Intake of micronutrient-rich foods in rural Indian mothers is associated with the size of their babies at birth: pune maternal nutrition study. J Nutr 2001;131:1217–24. 10.1093/jn/131.4.1217
    1. Kumaran K, Yajnik P, Lubree H, et al. . The pune rural intervention in young adolescents (PRIYA) study: design and methods of a randomised controlled trial. BMC Nutr 2017;3:41.10.1186/s40795-017-0143-5
    1. Lanka P, Deshpande G. Combining prospective acquisition correction (PACE) with retrospective correction to reduce motion artifacts in resting state fMRI data. Brain Behav 2019;9:e01341. 10.1002/brb3.1341
    1. Lanka P, Deshpande G. Resting state fMRI data from subjects scanned with the EPI-PACE (echoplanar imaging - prospective acquisition correction) sequence. Data Brief 2018;20:2072–5. 10.1016/j.dib.2018.01.089
    1. Perlis RH, Haneuse SJPA, Rubenfeld GD, et al. . Reporting clinical studies affected by the COVID-19 pandemic: guidelines for authors. JAMA Netw Open 2021;4:e2036155. 10.1001/jamanetworkopen.2020.36155
    1. Nongmaithem SS, Joglekar CV, Krishnaveni GV, et al. . GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians. Hum Mol Genet 2017;26:2589. 10.1093/hmg/ddx156

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa