Association of maternal vitamin B12 and folate levels in early pregnancy with gestational diabetes: a prospective UK cohort study (PRiDE study)
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Aims/hypothesis: The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide in all ethnic groups. Low vitamin B 12 and low/high folate levels may contribute to GDM risk, but there is conflicting evidence. Our aim is to assess the relationships of early pregnancy vitamin B 12 and folate levels with the risk of GDM status at 26–28 weeks of gestation. Methods: This was a prospective, multi-centre, multi-ethnic cohort study (n = 4746) in the UK. Participants who were eligible to be selectively screened as per the National Institute for Health and Care Excellence (NICE) criteria were included in the study. Results: GDM prevalence was 12.5% by NICE and 14.7% by International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Folate deficiency (1.3%) was rare but B 12 insufficiency (42.3% at <220 pmol/l) and folate excess (36.5%) were common in early pregnancy. Early pregnancy median B 12 levels were lower, and folate levels higher, in women who were diagnosed with GDM at 26–28 weeks. B 12 was negatively associated with fasting plasma glucose (1 SD: −0.06 mmol/l; 95% CI −0.04, −0.08; p < 0.0001) and 2 h plasma glucose levels (−0.07 mmol/l; 95% CI −0.02, −0.12; p = 0.004). Higher B 12 was associated with 14.4% lower RR of IADPSG-GDM (0.856; 95% CI 0.786, 0.933; p = 0.0004) after adjusting for key confounders (age, parity, smoking status, ethnicity, family history, household income and folate status). Approximately half of this association was mediated through BMI. Folate was positively associated with 2 h plasma glucose levels (0.08 mmol/l; 95% CI 0.04, 0.13; p = 0.0005) but its relationship with fasting plasma glucose was U-shaped (quadratic β: 0.011; p = 0.05). Higher folate was associated with 11% higher RR of IADPSG-GDM (adjusted RR 1.11; 95% CI 1.036, 1.182; p = 0.002) (age, parity, smoking status, ethnicity, family history, household income and B 12 status). Although no interactions were observed for B 12 and folate (as continuous variables) with glucose levels and GDM risk, a low B 12–high folate combination was associated with higher blood glucose level and risk of IADPSG-GDM (adjusted RR 1.742; 95% CI 1.226, 2.437; p = 0.003). Conclusions/interpretation: B 12 insufficiency and folate excess were common in early pregnancy. Low B 12 and high folate levels in early pregnancy were associated with small but statistically significant changes in maternal blood glucose level and higher RR of GDM. Our findings warrant additional studies on the role of unmetabolised folic acid in glucose metabolism and investigating the effect of optimising early pregnancy or pre-conception B 12 and folate levels on subsequent hyperglycaemia. Trial registration: ClinicalTrials.gov NCT03008824. Graphical abstract:
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Low pre-pregnancy vitamin B12 and high pre-pregnancy vitamin B9 (folate) levels are associated with a higher risk of GDM.
“Increasing research has suggested that low pre‐pregnancy vitamin B12 and high pre‐pregnancy vitamin B9 (folate) levels are associated with a higher risk of GDM [18].”
From Preconception Perceptions, Knowledge and Behaviours of Women With Gestational Diabetes Mellitus: A Qualitative Study (2026) · cites this paper as [18]
The Discussion and Abstract Conclusions report that low B12 and high folate measured in early pregnancy were associated with higher GDM risk. They do not establish the association for pre-pregnancy levels; the Discussion’s future-research section calls for studies before conception. Page numbers are not provided in our copy. (LLM, conf=0.90)
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- Authors
- Saravanan, P., Sukumar, N., Adaikalakoteswari, A., Goljan, I., Venkataraman, H., Gopinath, A., Bagias, C., Yajnik, C. S., Stallard, N., Ghebremichael-Weldeselassie, Y., & Fall, C. H. D.
- Affiliations
- George Eliot Hospital (GB)
- University of Warwick (GB)
- University Hospitals Birmingham NHS Foundation Trust (GB)
- MRC Lifecourse Epidemiology Unit (GB)
- Corresponding author
- Saravanan, Ponnusamy
- ORCID
- Venue
- Diabetologia
- Published
- 2021-07-22
- Volume
- 64
- Issue
- 10
- Pages
- 2170-2182
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC8423653
- OpenAlex
- W3171215392
- Cited by
- 91
- References
- 53
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 17 · 2023: 17 · 2022: 25 · 2021: 3
- FWCI
- 11.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Diabetologia (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Nottingham Trent University's Institutional Repository (Nottingham Trent Repository) (acceptedVersion)
- Open Research Online - ORO (The Open University) (acceptedVersion)
- Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Funders
- Medical Research Council (MR/J000094/1)
- Topics
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- gestational diabetes mellitus, vitamin B12, folic acid, early pregnancy, maternal micronutrient status, fasting blood glucose, 2-hour plasma glucose, body mass index, folate deficiency, GDM risk factors, PRIDE study, ethnic differences, U-shaped relationship
- MeSH terms
- Adolescent, Adult, Blood Glucose, Female, Folic Acid, Folic Acid Deficiency, Gestational Age, United Kingdom, Heart Diseases, Humans, Middle Aged, Pregnancy, Pregnancy in Diabetics, Prospective Studies, Vitamin B 12, Vitamin B 12 Deficiency, Prevalence, Diabetes, Gestational, Young Adult
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