Review investigates increased folate supplementation for high-risk pregnancies

By Olivia Haslam

- Last updated on GMT

Review investigates increased folate supplementation for high-risk pregnancies

Related tags Diabetes Folate deficiency Folate intake Pregnancy Folic acid Neural tube defects maternal nutrition hyperglycemia

A narrative review investigating the benefits and risks of high-dose folic acid for women with pre-existing diabetes in periconception concludes doses of 4mg folate a day or 5mg every second day are warranted, taking individualised needs into consideration.

The review from researchers in Australia concluded that while low-dose folic acid supplementation is widely recommended for all women during the periconceptual period, some guidelines suggest high-dose folic acid for women with pre-existing diabetes due to their increased risk of neural tube defects (NTDs).

The authors state: “The most pragmatic approach for women with pre-existing diabetes​ may be to use folate supplementation with an upper dose of 5 mg/day from 2–3 months preconception until the end of the 12th week of pregnancy.

“However, this advice should form part of a preconception plan that is tailored to the individual woman.”

NTD and Diabetes

Evidence shows that folate deficiency in early pregnancy increases the likelihood of NTDs​, which result from the failure of the neural tube to fuse between days 21 and 27 of embryonic life, leading to varying levels of disability.

In women with pre-existing diabetes (around 1–2%​ of all women who pursue pregnancy), the risk of an NTD is 2.2% ​compared with 0.57%​ in the general population. 

The additional risk of NTDs in diabetic women is largely attributable to maternal hyperglycemia​. 

It has been hypothesised that this is because high glucose modifies epigenetic mechanisms which subsequently alter expression of genes involved in cell fate specification of neural stem cells, thereby resulting in NTD​s.

In a previous study​, major congenital malformations were assessed among the offspring of mothers with pre-existing diabetes who had received preconception care and the offspring of women who had not, finding that the rate of major anomalies was over 4% lower among folate supplement recipients (2.1%) than non-recipients (6.5%).

Folate supplementation

Folate, the general term for various forms of vitamin B9, functions metabolically​ as an enzyme cofactor in the synthesis of nucleic acids and amino acids. 

It has a recognised tolerable upper intake​ level of 1 mg/day and the lowest observed adverse effect level​ of 5 mg/day. 

There is uncertainty about which groups of women benefit from high-dose folic acid supplementation​ (4–5 mg folate per day) , which has led to variations in international guidelines.

High-dose folate is recommended for women with pre-existing diabetes by the Royal College of Obstetricians and Gynaecologists ​(RCOG), World Health Organisation​ (WHO), and The Royal Australian and New Zealand College of Obstetricians and Gynaecologists​ (RANZCOG). 

Although National Institute for Health and Care Excellence​ (NICE) recommends high-dose folate in women with Type 1 diabetes and Type 2 diabetes, it acknowledges that there is little evidence to support this larger dose. 

Society of Obstetrics and Gynaecology Canada​ (SOGC) recommends medium-dose folate (1 mg/day) for women with pre-existing diabetes. 

The American College of Obstetrics and Gynaecology​ (ACOG) only advises high-dose folate in the setting of a previous offspring with an NTD or seizure disorder.

The review

Exploring the potential benefits of high-dose supplemental folate beyond the prevention of NTDs, the authors of the review searched the Medline (Ovid) online database, Cochrane Database, and the registry to identify relevant studies.

Human and animal studies published in English before 1 February 2023 were included based on relevance, originality, and impact (e.g., number of citations). Reference lists of relevant articles were also screened.

The authors reported that no trials have compared high-dose versus low-dose folic acid for the prevention of NTDs in the general population, and none that have compared the dose-response in a population of women with pre-existing diabetes. 

They note a Cochrane Review​ in 2015 found that while there is high-quality evidence that periconception folic acid supplementation prevents NTDs, subgroup analysis showed no additional protection with higher doses of folate in the general population. 

Additionally, a previous study​ conducted in 2013, found that in women with pre-existing diabetes, lower folic acid intake (<0.4 mg/day) resulted in a lower rate of spina bifida than higher folic acid intake (>0.4 mg/day). 

Yet in a subsequent case-control study,​ a subgroup of women with pre-existing diabetes was examined, where folic acid supplementation was associated with a lower rate of NTD. The study suggested the possible benefit was from the higher periconceptual folate doses (>1 mg/day) but the study numbers were small, so further research was required. 

Limited data are available on the use of folate to prevent NTDs in women with pre-existing diabetes, and the authors note: “In studies that included participants with pre-existing diabetes, the data are difficult to interpret due to the infrequent reporting of folate dose and failure to adjust for variables such as glycaemic control and body weight.”


Given the heterogeneity of data, the review's authors recommend that the dose should be tailored with consideration to all health factors. 

They conclude: “Women with pre-existing diabetes could be advised to take a 4 mg folate tablet or half of a 5 mg tablet per day (or 5 mg taken every second day), with dosing individualised based on the risk factors of the woman. 

“This advice would result in a total intake of 3–5 mg/day without exceeding the recommended 5 mg/day dose.”

However, they note: “This advice should form part of a preconception plan that is tailored to the individual woman.”

Journal: Nutrients

“Folate Supplementation in Women with Pre-Existing Diabetes”

Authors: Nayomi Perera, Victoria L. Rudland, David Simmons, and Sarah A. L. Price.

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