Maternal homocysteine in pregnancy and offspring birthweight: epidemiological associations and Mendelian randomization analysis.

BACKGROUND Disturbed one-carbon (1-C) metabolism in the mother is associated with poor fetal growth but causality of this relationship has not been established. METHODS We studied the association between maternal total homocysteine and offspring birthweight in the Pune Maternal Nutrition Study (PMNS, Pune, India) and Parthenon Cohort Study (Mysore, India). We tested for evidence of causality within a Mendelian randomization framework, using a methylenetetrahydrofolatereductase (MTHFR) gene variant rs1801133 (earlier known as 677C→T) by instrumental variable and triangulation analysis, separately and using meta-analysis. RESULTS Median (IQR) homocysteine concentration and mean (SD) birthweight were 8.6 µmol/l (6.7,10.8) and 2642 g (379) in the PMNS and 6.0 µmol/l (5.1,7.1) and 2871 g (443) in the Parthenon study. Offspring birthweight was inversely related to maternal homocysteine concentration-PMNS: -22 g/SD [95% confidence interval (CI): (-50, 5), adjusted for gestational age and offspring gender]; Parthenon: -57 g (-92, -21); meta-analysis: -40 g (-62, -17)]. Maternal risk genotype at rs1801133 predicted higher homocysteine concentration [PMNS: 0.30 SD/allele (0.14, 0.46); Parthenon: 0.21 SD (0.02, 0.40); meta-analysis: 0.26 SD (0.14, 0.39)]; and lower birthweight [PMNS: -46 g (-102, 11, adjusted for gestational age, offspring gender and rs1801133 genotype); Parthenon: -78 g (-170, 15); meta-analysis: -61 g (-111, -10)]. Instrumental variable and triangulation analysis supported a causal association between maternal homocysteine concentration and offspring birthweight. CONCLUSIONS Our findings suggest a causal role for maternal homocysteine (1-C metabolism) in fetal growth. Reducing maternal homocysteine concentrations may improve fetal growth.

[1]  W. Fawzi,et al.  Vitamin B-12 supplementation during pregnancy and early lactation increases maternal, breast milk, and infant measures of vitamin B-12 status. , 2014, The Journal of nutrition.

[2]  Bonnie R. Joubert,et al.  Neonatal genome-wide methylation patterns in relation to birth weight in the Norwegian Mother and Child Cohort. , 2014, American journal of epidemiology.

[3]  E. Rush,et al.  Vitamin B12: one carbon metabolism, fetal growth and programming for chronic disease , 2014, European Journal of Clinical Nutrition.

[4]  R. Steegers-Theunissen,et al.  The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism. , 2013, Human reproduction update.

[5]  C. Yajnik,et al.  Influence of maternal vitamin B12 and folate on growth and insulin resistance in the offspring. , 2013, Nestle Nutrition Institute workshop series.

[6]  Susan K. Murphy,et al.  450K Epigenome-Wide Scan Identifies Differential DNA Methylation in Newborns Related to Maternal Smoking during Pregnancy , 2012, Environmental health perspectives.

[7]  A. Hofman,et al.  Homocysteine and folate concentrations in early pregnancy and the risk of adverse pregnancy outcomes: the Generation R Study , 2012, BJOG : an international journal of obstetrics and gynaecology.

[8]  S. Ring,et al.  DNA Methylation Patterns in Cord Blood DNA and Body Size in Childhood , 2012, PloS one.

[9]  D. Dunger,et al.  DNA methylation profiling at imprinted loci after periconceptional micronutrient supplementation in humans: results of a pilot randomized controlled trial , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  G. Chandak,et al.  Maternal one-carbon metabolism, MTHFR and TCN2 genotypes and neural tube defects in India. , 2011, Birth defects research. Part A, Clinical and molecular teratology.

[11]  A. Prentice,et al.  Season of Conception in Rural Gambia Affects DNA Methylation at Putative Human Metastable Epialleles , 2010, PLoS genetics.

[12]  H. Meltzer,et al.  Infant birth size is not associated with maternal intake and status of folate during the second trimester in Norwegian pregnant women. , 2010, The Journal of nutrition.

[13]  C. Fall,et al.  Multiple Micronutrient Supplementation during Pregnancy in Low-Income Countries: A Meta-Analysis of Effects on Birth Size and Length of Gestation , 2009, Food and nutrition bulletin.

[14]  J. Kumar,et al.  Single Nucleotide Polymorphisms in Homocysteine Metabolism Pathway Genes: Association of CHDH A119C and MTHFR C677T With Hyperhomocysteinemia , 2009, Circulation. Cardiovascular genetics.

[15]  E. Steegers,et al.  Periconceptional Maternal Folic Acid Use of 400 µg per Day Is Related to Increased Methylation of the IGF2 Gene in the Very Young Child , 2009, PloS one.

[16]  C. Yajnik.  Nutrient‐mediated teratogenesis and fuel‐mediated teratogenesis: Two pathways of intrauterine programming of diabetes , 2009, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[17]  D. Bhat,et al.  Vitamin B12 Status of Pregnant Indian Women and Cognitive Function in their 9-year-old Children , 2008, Food and nutrition bulletin.

[18]  Hein Putter,et al.  Persistent epigenetic differences associated with prenatal exposure to famine in humans , 2008, Proceedings of the National Academy of Sciences.

[19]  C. Yajnik,et al.  Maternal nutrition, intrauterine programming and consequential risks in the offspring , 2008, Reviews in Endocrine and Metabolic Disorders.

[20]  J. Selhub.  Public Health Significance of Elevated Homocysteine , 2008, Food and nutrition bulletin.

[21]  P. Elliott,et al.  Common Variation in the FTO Gene Alters Diabetes-Related Metabolic Traits to the Extent Expected Given Its Effect on BMI , 2008, Diabetes.

[22]  Oxford Journal.  Vitamin B12 and folate deficiency in later life , 2008 .

[23]  J. Craigon,et al.  DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status , 2007, Proceedings of the National Academy of Sciences.

[24]  D. Bhat,et al.  Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study , 2007, Diabetologia.

[25]  W. Fawzi,et al.  Low maternal vitamin B12 status is associated with intrauterine growth retardation in urban South Indians , 2006, European Journal of Clinical Nutrition.

[26]  A. Ekström,et al.  Folate, vitamin B12, and homocysteine levels in South Asian women with growth‐retarded fetuses , 2005, Acta obstetricia et gynecologica Scandinavica.

[27]  S. Lewis,et al.  Meta-analysis of MTHFR 677C→ T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate? , 2005, BMJ : British Medical Journal.

[28]  M. Pearce,et al.  An investigation of folate-related genetic factors in the determination of birthweight. , 2005, Paediatric and perinatal epidemiology.

[29]  C. Fall,et al.  Glucose tolerance in pregnancy in South India: relationships to neonatal anthropometry , 2005, Acta obstetricia et gynecologica Scandinavica.

[30]  L. Smeeth,et al.  For Personal Use. Only Reproduce with Permission from Elsevier Ltd Homocysteine and Stroke: Evidence on a Causal Link from Mendelian Randomisation , 2022 .

[31]  C. Fall,et al.  Maternal total homocysteine concentration and neonatal size in India. , 2005, Asia Pacific journal of clinical nutrition.

[32]  A. Smith,et al.  Facts and recommendations about total homocysteine determinations: an expert opinion. , 2004, Clinical chemistry.

[33]  R. Waterland,et al.  Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. , 2004, Nutrition.

[34]  Ken P Kleinman,et al.  A nearly continuous measure of birth weight for gestational age using a United States national reference , 2003, BMC pediatrics.

[35]  C. A. Newsome,et al.  Is birth weight related to later glucose and insulin metabolism?—a systematic review , 2003, Diabetic medicine : a journal of the British Diabetic Association.

[36]  C. Yajnik,et al.  Neonatal anthropometry: the thin–fat Indian baby. The Pune Maternal Nutrition Study , 2003, International Journal of Obesity.

[37]  S. Ebrahim,et al.  'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? , 2003, International journal of epidemiology.

[38]  Olaf Stanger,et al.  Interactions of Homocysteine, Nitric Oxide, Folate and Radicals in the Progressively Damaged Endothelium , 2003, Clinical chemistry and laboratory medicine.

[39]  S. Vollset,et al.  Plasma total cysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. , 2000, The American journal of clinical nutrition.

[40]  H. Refsum,et al.  Homocysteine and methylmalonic acid levels in pregnant Nepali women. Should cobalamin supplementation be considered? , 2001, European Journal of Clinical Nutrition.

[41]  S. Vollset,et al.  Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. , 2001, The American journal of clinical nutrition.

[42]  Asawari N. Kanade,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. , 2001, The Journal of nutrition.

[43]  P. Ueland,et al.  Biological and clinical implications of the MTHFR C677T polymorphism. , 2001, Trends in pharmacological sciences.

[44]  Anne-Lise Bjørke Monsen,et al.  Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study. , 2000, The American journal of clinical nutrition.

[45]  J. Hodgkin,et al.  Seven types of pleiotropy. , 1998, The International journal of developmental biology.

[46]  M. Shipchandler,et al.  Rapid, fully automated measurement of plasma homocyst(e)ine with the Abbott IMx analyzer. , 1995, Clinical chemistry.

[47]  R. Matthews,et al.  A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase , 1995, Nature Genetics.

[48]  C Osmond,et al.  Fetal and infant growth and impaired glucose tolerance at age 64. , 1991, BMJ.

[49]  B. Kelleher,et al.  Microbiological assay for vitamin B12 performed in 96-well microtitre plates. , 1991, Journal of clinical pathology.

[50]  L. Berstein,et al.  WEIGHT IN INFANCY AND DEATH FROM ISCHAEMIC HEART DISEASE , 1989, The Lancet.

[51]  D. Horne,et al.  Lactobacillus casei microbiological assay of folic acid derivatives in 96-well microtiter plates. , 1988, Clinical chemistry.

[52]  A. Harris,et al.  Carboplatin/cisplatin , 2012, Reactions Weekly.

[53]  S. O'broin,et al.  Microbiological assay for vitamin B12 with use of a colistin-sulfate-resistant organism. , 1987, Clinical chemistry.

[54]  A. Petrie,et al.  Vitamin B12 Status in Pregnancy among Immigrants to Britain , 1973, British medical journal.