Skip to main content Accessibility help
×
Home

The determinants of maternal homocysteine in pregnancy: findings from the Ottawa and Kingston Birth Cohort

  • Shazia H Chaudhry (a1) (a2) (a3), Monica Taljaard (a1) (a3), Amanda J MacFarlane (a4) (a5), Laura M Gaudet (a1) (a2) (a3), Graeme N Smith (a6) (a7), Marc Rodger (a1) (a3), Ruth Rennicks White (a1) (a2), Mark C Walker (a1) (a2) (a3) and Shi Wu Wen (a1) (a2) (a3)...

Abstract

Objective:

Observational studies have linked elevated homocysteine to vascular conditions. Folate intake has been associated with lower homocysteine concentration, although randomised controlled trials of folic acid supplementation to decrease the incidence of vascular conditions have been inconclusive. We investigated determinants of maternal homocysteine during pregnancy, particularly in a folic acid-fortified population.

Design:

Data were from the Ottawa and Kingston Birth Cohort of 8085 participants. We used multivariable regression analyses to identify factors associated with maternal homocysteine, adjusted for gestational age at bloodwork. Continuous factors were modelled using restricted cubic splines. A subgroup analysis examined the modifying effect of MTHFR 677C>T genotype on folate, in determining homocysteine concentration.

Setting:

Participants were recruited in Ottawa and Kingston, Canada, from 2002 to 2009.

Participants:

Women were recruited when presenting for prenatal care in the early second trimester.

Results:

In 7587 participants, factors significantly associated with higher homocysteine concentration were nulliparous, smoking and chronic hypertension, while factors significantly associated with lower homocysteine concentration were non-Caucasian race, history of a placenta-mediated complication and folic acid supplementation. Maternal age and BMI demonstrated U-shaped associations. Folic acid supplementation of >1 mg/d during pregnancy did not substantially increase folate concentration. In the subgroup analysis, MTHFR 677C>T modified the effect of folate status on homocysteine concentration.

Conclusions:

We identified determinants of maternal homocysteine relevant to the lowering of homocysteine in the post-folic acid fortification era, characterised by folate-replete populations. A focus on periconceptional folic acid supplementation and improving health status may form an effective approach to lower homocysteine.

Copyright

Corresponding author

*Corresponding author: Email swwen@ohri.ca

References

Hide All
1.The Homocysteine Studies Collaboration (2002) Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA J Am Med Assoc 288, 20152023.10.1001/jama.288.16.2015
2.Wald, DS, Morris, JK & Wald, NJ (2011) Reconciling the evidence on serum homocysteine and ischaemic heart disease: a meta-analysis. PLoS One 6, e16473.10.1371/journal.pone.0016473
3.Vollset, SE, Refsum, H, Irgens, LMet al. (2000) Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study. Am J Clin Nutr 71, 962968.10.1093/ajcn/71.4.962
4.Bergen, NE, Jaddoe, VW, Timmermans, Set al. (2012) Homocysteine and folate concentrations in early pregnancy and the risk of adverse pregnancy outcomes: the Generation R Study. BJOG 119, 739751.10.1111/j.1471-0528.2012.03321.x
5.Dodds, L, Fell, DB, Dooley, KCet al. (2008) Effect of homocysteine concentration in early pregnancy on gestational hypertensive disorders and other pregnancy outcomes. Clin Chem 54, 326334.10.1373/clinchem.2007.097469
6.Mignini, LE, Latthe, PM, Villar, Jet al. (2005) Mapping the theories of preeclampsia: the role of homocysteine. Obstet Gynecol 105, 411425.10.1097/01.AOG.0000151117.52952.b6
7.Hogeveen, M, Blom, HJ & den Heijer, M (2012) Maternal homocysteine and small-for-gestational-age offspring: systematic review and meta-analysis. Am J Clin Nutr 95, 130136.10.3945/ajcn.111.016212
8.Refsum, H, Nurk, E, Smith, ADet al. (2006) The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutr 136, Suppl. 6, 1731S1740S.10.1093/jn/136.6.1731S
9.Jacques, PF, Bostom, AG, Wilson, PWFet al. (2001) Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 73, 613621.10.1093/ajcn/73.3.613
10.Clarke, R, Halsey, J, Lewington, Set al. (2010) Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 170, 16221631.
11.Martí-Carvajal, AJ, Solà, I & Lathyris, D (2017) Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev 8, CD006612.
12.Sayyah-melli, M, Ghorbanihaghjo, A, Alizadeh, Met al. (2016) The effect of high dose folic acid throughout Pregnancy on Homocysteine (Hcy) concentration and pre-eclampsia: a randomized clinical trial. PLoS One 11, e0154400.10.1371/journal.pone.0154400
13.Holmes, MV, Newcombe, P, Hubacek, JAet al. (2011) Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet 378, 584594.10.1016/S0140-6736(11)60872-6
14.Clarke, R, Bennett, DA, Parish, Set al. (2012) Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med 9, e1001177.10.1371/journal.pmed.1001177
15.Shere, M, Kapur, BM & Koren, G (2015) Folate status of women in Toronto: implications of folate fortification and supplementation. Can J Public Health 106, e509e513.10.17269/CJPH.106.5109
16.Dasarathy, J, Gruca, LL, Bennett, Cet al. (2010) Methionine metabolism in human pregnancy. Am J Clin Nutr 91, 357365.10.3945/ajcn.2009.28457
17.Blom, HJ & Smulders, Y (2011) Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis 34, 7581.10.1007/s10545-010-9177-4
18.Salway, JG (1999) Metabolism at a Glance. Malden, MA: Blackwell Science Publishing.
19.Sibani, S, Leclerc, D, Weisberg, ISet al. (2003) Characterization of mutations in severe methylenetetrahydrofolate reductase deficiency reveals an FAD-responsive mutation. Hum Mutat 21, 509520.10.1002/humu.10193
20.Murphy, MM, Scott, JM, McPartlin, JMet al. (2002) The pregnancy-related decrease in fasting plasma homocysteine is not explained by folic acid supplementation, hemodilution, or a decrease in albumin in a longitudinal study 1–3. Am J Clin Nutr 76, 614619.10.1093/ajcn/76.3.614
21.Walker, MC, Smith, GN, Perkins, SLet al. (1999) Changes in homocysteine levels during normal pregnancy. Am J Obstet Gynecol 180, 660664.10.1016/S0002-9378(99)70269-3
22.Walker, MC, Finkelstein, SA, Rennicks White, Ret al. (2011) The Ottawa and Kingston (OaK) Birth Cohort: development and achievements. J Obstet Gynaecol Canada 33, 11241133.10.1016/S1701-2163(16)35080-0
23.Selhub, J, Jacques, PF, Rosenberg, IHet al. (1999) Serum total homocysteine concentrations in the third National Health and Nutrition Examination survey (1991–1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann Intern Med 131, 331339.10.7326/0003-4819-131-5-199909070-00003
24.Kahn, SR, Platt, R, McNamara, Het al. (2009) Inherited thrombophilia and preeclampsia within a multicenter cohort: the Montreal Preeclampsia study. Am J Obstet Gynecol 200, 151.e1151.e9.10.1016/j.ajog.2008.09.023
25.van Buuren, S & Groothuis-oudshoorn, K (2011) Mice: multivariate imputation by chained equations in R. J Stat Softw 45, 167.
26.Harrell, FE Jr (2016) Rms: Regression Modeling Strategies. R Packag version 4.5-0. https://cran.r-project.org/package=rms (accessed January 2019).
27.Harrell, FE (2015) Regression Modeling Strategies with Applications to Linear Models, Logistic and Ordinal Regression, and Survival Analysis, 2nd ed.Springer Series in Statistics. New York: Springer.10.1007/978-3-319-19425-7
28.Harrell, FE Jr & With contributions from Charles Dupont and many others (2016) Hmisc: Harrell Miscellaneous. R Packag version 3.17-4. https://cran.r-project.org/package=Hmisc (accessed January 2019).
29.Graffelman, J (2015) Exploring diallelic genetic markers: the HardyWeinberg package. J Stat Softw 63, 122.
30.Sorensen, TK, Malinow, MR, Williams, MAet al. (1999) Elevated second-trimester serum homocyst(e)ine levels and subsequent risk of preeclampsia. Gynecol Obstet Invest 48, 98103.10.1159/000010148
31.Polat, M, Biberoglu, EH, Guler, Iet al. (2016) Coexistence of preeclampsia and inherited thrombophilia in Turkish pregnant women. Turkish J Med Sci 46, 10941100.10.3906/sag-1502-132
32.Onalan, R, Onalan, G, Gunenc, Zet al. (2006) Combining 2nd-trimester maternal serum homocysteine levels and uterine artery Doppler for prediction of preeclampsia and isolated intrauterine growth restriction. Gynecol Obstet Invest 61, 142148.10.1159/000090432
33.World Health Organization (2012) Serum and red blood cell folate concentrations for assessing folate status in populations. Vitamin and Mineral Nutrition Information System. Document: WHO/NMH/NHD/EPG/15.01. http://apps.who.int/iris/bitstream/10665/75584/1/WHO_NMH_NHD_EPG_12.1_eng (accessed January 2019).
34.Bernette, C & Vickers, A (2012) Against quantiles: categorization of continuous variables in epidemiologic research, and its discontents. BMC Med Res Methodol 12, 21.10.1186/1471-2288-12-21
35.Fedorov, V, Mannino, F & Zhang, R (2009) Consequences of dichotomization. Pharm Stat 8, 5061.10.1002/pst.331
36.Royston, P, Altman, DG & Sauerbrei, W (2006) Dichotomizing continuous predictors in multiple regression: a bad idea. Stat Med 25, 127141.10.1002/sim.2331
37.Jacques, PF, Rosenberg, IH, Rogers, Get al. (1999) Serum total homocysteine concentrations in adolescent and adult Americans: results from the third National Health and Nutrition Examination survey. Am J Clin Nutr 69, 482489.10.1093/ajcn/69.3.482
38.Nygard, O, Vollset, SE, Refsum, Het al. (1995) Total plasma homocysteine and cardiovascular risk profile. The Hordland homocysteine study. JAMA 274, 15261533.10.1001/jama.1995.03530190040032
39.Jin, H, Cheng, H, Chen, Wet al. (2018) An evidence-based approach to globally assess the covariate-dependent effect of the MTHFR single nucleotide polymorphism rs1801133 on blood homocysteine: a systematic review and meta-Analysis. Am J Clin Nutr 107, 817825.10.1093/ajcn/nqy035
40.Shere, M, Nguyen, P, Tam, Cet al. (2015) Pregnancy-induced changes in the long-term pharmacokinetics of 1.1 mg vs. 5 mg folic acid: a randomized clinical trial. J Clin Pharmacol 55, 159167.10.1002/jcph.387
41.Lassi, ZS, Salam, RA, Haider, BAet al. (2013) Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes. Cochrane Database Syst Rev 3, CD006896.
42.Wen, SW, White, RR, Rybak, Net al. (2018) Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial. BMJ 362, k3478.10.1136/bmj.k3478
43.Nygård, O, Refsum, H, Ueland, PMet al. (1998) Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study. Am J Clin Nutr 67, 263270.10.1093/ajcn/67.2.263
44.Bakker, R, Timmermans, S, Steegers, EAPet al. (2011) Folic acid supplements modify the adverse effects of maternal smoking on fetal growth and neonatal complications 1–3. J Nutr 141, 21722179.10.3945/jn.111.142976
45.Joelson, DW, Fiebig, EW & Wu, AHB (2007) Diminished need for folate measurements among indigent populations in the post folic acid supplementation era. Arch Pathol Lab Med 131, 477480.
46.CDC: National Center for Health Statistics; National Center for Chronic Disease Prevention and Health Promotion; and National Center for Environmental Health (2000) Folate status in women of childbearing age--United States, 1999. Morb Mortal Wkly Rep 49, 962965.
47.Caudill, MA, Le, T, Moonie, SAet al. (2001) Folate status in women of childbearing age residing in Southern California after folic acid fortification. J Am Coll Nutr 20, 129134.10.1080/07315724.2001.10719024
48.WHO (2015) Guideline: Optimal Serum and Red Blood Cell Folate Concentrations in Women of Reproductive Age for Prevention of Neural Tube Defects. Geneva: World Health Organization.
49.Colapinto, CK, O’Connor, DL & Tremblay, MS (2011) Folate status of the population in the Canadian Health Measures survey. Can Med Assoc J 183, E100E106.10.1503/cmaj.100568
50.Crider, KS, Zhu, J, Hao, Let al. (2011) MTHFR 677C>T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation. Am J Clin Nutr 93, 13651372.10.3945/ajcn.110.004671
51.Shere, M, Bapat, P, Nickel, Cet al. (2015) Association between use of oral contraceptives and folate status: a systematic review and meta-analysis. J Obstet Gynaecol Canada 37, 430438.10.1016/S1701-2163(15)30258-9
52.Nurk, E, Tell, GS, Vollset, SEet al. (2004) Changes in lifestyle and plasma total homocysteine: the Hordaland Homocysteine Study. Am J Clin Nutr 79, 812819.10.1093/ajcn/79.5.812
53.Visser, S, Hermes, W, Ket, JCFet al. (2014) Systematic review and metaanalysis on nonclassic cardiovascular biomarkers after hypertensive pregnancy disorders. Am J Obstet Gynecol 211, 373.e1373.e9.10.1016/j.ajog.2014.03.032
54.Bakker, DJ, de Jong-van den Berg, LTW & Fokkema, MR (2009) Controlled study on folate status following folic acid supplementation and discontinuation in women of child-bearing age. Ann Clin Biochem 46, 231234.10.1258/acb.2009.008207
55.Shiraishi, M, Haruna, M, Matsuzaki, Met al. (2014) Relationship between plasma total homocysteine level and dietary caffeine and vitamin B6 intakes in pregnant women. Nurs Health Sci 16, 164170.10.1111/nhs.12080
56.Ray, J, Singh, G & Burrows, S (2004) Evidence for suboptimal use of periconceptual folic acid supplements globally. BJOG 111, 399408.10.1111/j.1471-0528.2004.00115.x
57.Tam, LE, McDonald, SD, Wen, SWet al. (2005) A survey of periconceptional folic acid use in a group of Canadian women. J Obstet Gynaecol Canada 27, 232236.10.1016/S1701-2163(16)30515-1
58.McNulty, B, Pentieva, K, Marshall, Bet al. (2011) Women’s compliance with current folic acid recommendations and achievement of optimal vitamin status for preventing neural tube defects. Hum Reprod 26, 15301536.10.1093/humrep/der078
59.Richard-Tremblay, AA, Sheehy, O, Audibert, Fet al. (2012) Concordance between periconceptional folic acid supplementation and Canadian clinical guidelines. J Popul Ther Clin Pharmacol 19, 150159.
60.Nelson, CRM, Leon, JA & Evans, J (2014) The relationship between awareness and supplementation: which Canadian women know about folic acid and how does that translate into use? Can J Public Heal 105, e40e46.10.17269/cjph.105.4155
61.Nilsen, RM, Leoncini, E, Gastaldi, Pet al. (2016) Prevalence and determinants of preconception folic acid use: an Italian multicenter survey. Ital J Pediatr 42, 110.10.1186/s13052-016-0278-z
62.Yamamoto, S & Wada, Y (2018) Awareness, use and information sources of folic acid supplementation to prevent neural tube defects in pregnant Japanese women. Public Health Nutr 21, 732739.10.1017/S1368980017003172
63.Cawley, S, Mullaney, L, Kennedy, Ret al. (2017) Duration of periconceptional folic acid supplementation in women booking for antenatal care. Public Health Nutr 20, 371379.10.1017/S1368980016002585
64.MacFarlane, AJ, Greene-finestone, LS & Shi, Y (2011) Vitamin B-12 and homocysteine status in a folate-replete population: results from the Canadian Health Measures Survey. Am J Clin Nutr 94, 10791087.10.3945/ajcn.111.020230

Keywords

Type Description Title
WORD
Supplementary materials

Chaudhry et al. Supplementary Materials
Chaudhry et al. Supplementary Materials

 Word (49 KB)
49 KB

The determinants of maternal homocysteine in pregnancy: findings from the Ottawa and Kingston Birth Cohort

  • Shazia H Chaudhry (a1) (a2) (a3), Monica Taljaard (a1) (a3), Amanda J MacFarlane (a4) (a5), Laura M Gaudet (a1) (a2) (a3), Graeme N Smith (a6) (a7), Marc Rodger (a1) (a3), Ruth Rennicks White (a1) (a2), Mark C Walker (a1) (a2) (a3) and Shi Wu Wen (a1) (a2) (a3)...

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.