Aims/hypothesis

The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide in all ethnic groups. Low vitamin B₁₂ 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 B₁₂ 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 B₁₂ insufficiency (42.3% at <220 pmol/l) and folate excess (36.5%) were common in early pregnancy. Early pregnancy median B₁₂ levels were lower, and folate levels higher, in women who were diagnosed with GDM at 26–28 weeks. B₁₂ 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 B₁₂ 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 B₁₂ status). Although no interactions were observed for B₁₂ and folate (as continuous variables) with glucose levels and GDM risk, a low B₁₂–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

B₁₂ insufficiency and folate excess were common in early pregnancy. Low B₁₂ 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 B₁₂ and folate levels on subsequent hyperglycaemia.

Trial registration:

ClinicalTrials.gov NCT03008824.

Graphical abstract

中文翻译：

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孕早期母亲维生素 B12 和叶酸水平与妊娠糖尿病的关联：一项前瞻性英国队列研究（PRiDE 研究）

目标/假设

妊娠期糖尿病 (GDM) 的患病率在世界范围内所有种族群体中都在增加。低维生素 B ₁₂和低/高叶酸水平可能会增加 GDM 风险，但证据相互矛盾。我们的目的是评估妊娠早期维生素 B ₁₂和叶酸水平与妊娠 26-28 周时 GDM 状态风险的关系。

方法

这是一项在英国进行的前瞻性、多中心、多种族队列研究 ( n  = 4746)。根据国家健康与护理卓越研究所 (NICE) 标准有资格接受选择性筛选的参与者被纳入研究。

结果

根据 NICE 标准，GDM 患病率为 12.5%，根据国际糖尿病和妊娠研究组协会 (IADPSG) 标准，GDM 患病率为 14.7%。叶酸缺乏症 (1.3%) 很少见，但 B ₁₂不足 (42.3% at <220 pmol/l) 和叶酸过量 (36.5%) 在妊娠早期很常见。在 26-28 周时被诊断患有 GDM 的女性中，早孕 B ₁₂水平中位数较低，而叶酸水平较高。B ₁₂与空腹血糖（1 SD：−0.06 mmol/l；95% CI −0.04、−0.08；p  < 0.0001）和 2 小时血糖水平（−0.07 mmol/l；95% CI −0.02）呈负相关, -0.12; p  = 0.004)。较高的 B ₁₂与 IADPSG-GDM 的 RR 降低 14.4% 相关（0.856；95% CI 0.786，0.933；p = 0.0004) 在针对关键混杂因素（年龄、胎次、吸烟状况、种族、家族史、家庭收入和叶酸状况）进行调整后。大约一半的关联是通过 BMI 介导的。叶酸与 2 小时血糖水平呈正相关（0.08 mmol/l；95% CI 0.04，0.13；p  = 0.0005），但其与空腹血糖的关系呈 U 形（二次 β：0.011；p  = 0.05）。更高的叶酸与 IADPSG-GDM 的 11% 更高的 RR 相关（调整后的 RR 1.11；95% CI 1.036，1.182；p  = 0.002）（年龄、产次、吸烟状况、种族、家族史、家庭收入和 B ₁₂状态）。尽管没有观察到 B _{12的相互作用}和叶酸（作为连续变量）与葡萄糖水平和 GDM 风险，低 B ₁₂ -高叶酸组合与较高的血糖水平和 IADPSG-GDM 风险相关（调整后的 RR 1.742；95% CI 1.226、2.437；p  = 0.003 ).

结论/解释

B ₁₂不足和叶酸过量在早孕期很常见。早孕期低 B ₁₂和高叶酸水平与母体血糖水平的微小但具有统计学意义的变化和 GDM 的高 RR 相关。我们的研究结果需要进一步研究未代谢的叶酸在葡萄糖代谢中的作用，并调查优化早孕或孕前 B ₁₂和叶酸水平对随后高血糖的影响。

试用注册：

ClinicalTrials.gov NCT03008824。

图形概要