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One-carbon metabolism, insulin resistance, and fecundability in a Singapore prospective preconception cohort study

One-carbon metabolism, insulin resistance, and fecundability in a Singapore prospective preconception cohort study
One-carbon metabolism, insulin resistance, and fecundability in a Singapore prospective preconception cohort study
Background: one-carbon metabolism, which consists of the folate cycle, methionine cycle, and trans-sulphuration pathway, is associated with nucleotide synthesis. However, the association between one-carbon metabolites, metabolic status, and reproductive health remains poorly understood.

Objectives: we examined the association between the one-carbon cycle plasma metabolites and fecundability and determined whether it is modified by metabolic health status, as assessed by insulin resistance (IR).

Methods: this prospective cohort study utilized data from the Singapore PREconception Study of long-Term maternal and child Outcomes. Fasting blood samples were collected, and one-carbon cycle metabolites were measured. Fecundability was measured by time to pregnancy in menstrual cycles within a year of enrollment. We identified patterns in plasma one-carbon cycle metabolites using principal component (PC) analysis. We estimated fecundability ratios (FRs) and confidence intervals (CIs), with confounder adjustment using discrete-time proportional hazards models. IR was determined using the Homeostatic Model Assessment 2 Insulin Resistance score, classified into lower IR (<0.65) and higher IR (≥0.65). The role of IR was examined through interaction tests and stratification.

Results: we identified 3 one-carbon cycle PCs. PC1, characterized by higher folate and lower homocysteine concentrations; PC2, characterized by higher concentrations of dimethylglycine, choline, methionine, and betaine; and PC3, characterized by higher concentrations of vitamins B2, B12, and B6. Each z-score increase in PC1 was associated with a 17% increase in fecundability (FR: 1.17; 95% CI: 1.03, 1.33). The association between PC1 and fecundability was more evident in women with lower IR (FR: 1.30; 95% CI: 1.08, 1.57) but was attenuated in those with higher IR (FR: 1.09; 95% CI: 0.92, 1.30), with a P-for-interaction of 0.127. PC2 and PC3 were not associated with fecundability.

Conclusions: our findings suggest that higher folate and lower homocysteine concentrations, which reflected the interlinked folate and methionine cycles, were associated with higher fecundability in preconception women with lower IR but less so in those with higher IR.

Clinical Trial Registration: this trial was registered at ClinicalTrials.gov as NCT03531658 (https://www.clinicaltrials.gov/study/NCT03531658).
serum folate, time to pregnancy, metabolic health, preconception, subfertility, plasma homocysteine, fecundability, insulin resistance, one-carbon metabolism
0002-9165
335-343
Ku, Chee Wai
dfc052e9-1c22-473f-b11d-ed82b15b9ca6
Chan, Hiu Gwan
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Sia, Alexandrea Lishan
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Huang, Christina
fb66b78f-acce-4f08-bf2d-f10a0d9bf9bc
Quek, Jessica
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Cheung, Yin Bun
c9beaf35-87d8-47f0-b41e-729e7820f991
Tan, Karen Mei Ling
f8c09297-2230-4125-80ca-409dbbe92d8e
Lai, Jun Shi
d23d8c38-bad8-4dfa-b5a6-82871897c01b
Godfrey, Keith M.
0931701e-fe2c-44b5-8f0d-ec5c7477a6fd
Chan, Jerry Kok Yen
42e59d61-c3d1-486b-b33a-22c4645acf12
Yap, Fabian
22f6b954-31fc-4696-a52b-e985a424b95b
Loy, See Ling
6fd10b64-1de2-419e-a5f4-b505be233e6e
Ku, Chee Wai
dfc052e9-1c22-473f-b11d-ed82b15b9ca6
Chan, Hiu Gwan
d430424a-2858-4dc3-96db-b95b0ec5cee3
Sia, Alexandrea Lishan
e78b5b8c-93c5-4354-a9d8-de7543416e33
Huang, Christina
fb66b78f-acce-4f08-bf2d-f10a0d9bf9bc
Quek, Jessica
051467a3-2d29-4954-9a7c-8db29f51cc48
Cheung, Yin Bun
c9beaf35-87d8-47f0-b41e-729e7820f991
Tan, Karen Mei Ling
f8c09297-2230-4125-80ca-409dbbe92d8e
Lai, Jun Shi
d23d8c38-bad8-4dfa-b5a6-82871897c01b
Godfrey, Keith M.
0931701e-fe2c-44b5-8f0d-ec5c7477a6fd
Chan, Jerry Kok Yen
42e59d61-c3d1-486b-b33a-22c4645acf12
Yap, Fabian
22f6b954-31fc-4696-a52b-e985a424b95b
Loy, See Ling
6fd10b64-1de2-419e-a5f4-b505be233e6e

Ku, Chee Wai, Chan, Hiu Gwan, Sia, Alexandrea Lishan, Huang, Christina, Quek, Jessica, Cheung, Yin Bun, Tan, Karen Mei Ling, Lai, Jun Shi, Godfrey, Keith M., Chan, Jerry Kok Yen, Yap, Fabian and Loy, See Ling (2025) One-carbon metabolism, insulin resistance, and fecundability in a Singapore prospective preconception cohort study. American Journal of Clinical Nutrition, 122 (1), 335-343. (doi:10.1016/j.ajcnut.2025.04.035).

Record type: Article

Abstract

Background: one-carbon metabolism, which consists of the folate cycle, methionine cycle, and trans-sulphuration pathway, is associated with nucleotide synthesis. However, the association between one-carbon metabolites, metabolic status, and reproductive health remains poorly understood.

Objectives: we examined the association between the one-carbon cycle plasma metabolites and fecundability and determined whether it is modified by metabolic health status, as assessed by insulin resistance (IR).

Methods: this prospective cohort study utilized data from the Singapore PREconception Study of long-Term maternal and child Outcomes. Fasting blood samples were collected, and one-carbon cycle metabolites were measured. Fecundability was measured by time to pregnancy in menstrual cycles within a year of enrollment. We identified patterns in plasma one-carbon cycle metabolites using principal component (PC) analysis. We estimated fecundability ratios (FRs) and confidence intervals (CIs), with confounder adjustment using discrete-time proportional hazards models. IR was determined using the Homeostatic Model Assessment 2 Insulin Resistance score, classified into lower IR (<0.65) and higher IR (≥0.65). The role of IR was examined through interaction tests and stratification.

Results: we identified 3 one-carbon cycle PCs. PC1, characterized by higher folate and lower homocysteine concentrations; PC2, characterized by higher concentrations of dimethylglycine, choline, methionine, and betaine; and PC3, characterized by higher concentrations of vitamins B2, B12, and B6. Each z-score increase in PC1 was associated with a 17% increase in fecundability (FR: 1.17; 95% CI: 1.03, 1.33). The association between PC1 and fecundability was more evident in women with lower IR (FR: 1.30; 95% CI: 1.08, 1.57) but was attenuated in those with higher IR (FR: 1.09; 95% CI: 0.92, 1.30), with a P-for-interaction of 0.127. PC2 and PC3 were not associated with fecundability.

Conclusions: our findings suggest that higher folate and lower homocysteine concentrations, which reflected the interlinked folate and methionine cycles, were associated with higher fecundability in preconception women with lower IR but less so in those with higher IR.

Clinical Trial Registration: this trial was registered at ClinicalTrials.gov as NCT03531658 (https://www.clinicaltrials.gov/study/NCT03531658).

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Accepted/In Press date: 30 April 2025
e-pub ahead of print date: 5 May 2025
Published date: 1 July 2025
Additional Information: For the purpose of Open Access, the author has applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising from this submission.
Keywords: serum folate, time to pregnancy, metabolic health, preconception, subfertility, plasma homocysteine, fecundability, insulin resistance, one-carbon metabolism

Identifiers

Local EPrints ID: 501933
URI: http://eprints.soton.ac.uk/id/eprint/501933
ISSN: 0002-9165
PURE UUID: d28e715e-610a-4b06-9c8a-ea6a9cb003bc
ORCID for Keith M. Godfrey: ORCID iD orcid.org/0000-0002-4643-0618

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Date deposited: 12 Jun 2025 16:44
Last modified: 04 Sep 2025 02:01

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Contributors

Author: Chee Wai Ku
Author: Hiu Gwan Chan
Author: Alexandrea Lishan Sia
Author: Christina Huang
Author: Jessica Quek
Author: Yin Bun Cheung
Author: Karen Mei Ling Tan
Author: Jun Shi Lai
Author: Jerry Kok Yen Chan
Author: Fabian Yap
Author: See Ling Loy

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