WHO Guideline (April 2015): Optimal Serum and RBC Folate Concentrations to prevent Neural Tube Defects

The World Health Organization (WHO) has recently (April 2015) released a guideline document on the optimal serum and RBC folate concentrations in women of reproductive age group to prevent Neural Tube Defects (NTDs).

Key Messages:


In 2012, an estimated 270, 358 deaths globally were attributable to congenital anomalies during the first 28 days of life (3.3 deaths per 1000 live births). NTDs were one of the most serious and most common anomalies.

Multiple factors influence folate status, including diet, a woman’s physiological status (age, pregnancy/lactation) and contextual factors such as comorbidities and low socioeconomic status.

Folate requirements are increased during pregnancy and lactation, and may be influenced by drugs, etc.

Severe Folate deficiency may cause megaloblastic anaemia.


1. At the population level, red blood cell folate concentrations should be above 400 ng/mL (906 nmol/L) in women of reproductive age, to achieve the greatest reduction of NTDs (strong recommendation, low quality evidence).

2. The above red blood cell folate threshold can be used as an indicator of folate insufficiency in women of reproductive age (strong recommendation, low quality evidence).

3. No serum folate threshold is recommended for prevention of NTDs in women of reproductive age at the population level (strong recommendation, low quality evidence).

4. Microbiological assay is recommended as the most reliable choice to obtain comparable results for red blood cell folate across countries (strong recommendation, moderate quality evidence).

Remarks (by the authors):

• Values indicative of folate deficiency, based on the concentrations at which megaloblastic anaemia is more likely to appear, are❤ ng/mL (<6.8 nmol/L) in serum and <100 ng/mL (<226.5 nmol/L) in red blood cells.

• Although both serum and red blood cell folate concentrations are useful for monitoring interventions aimed at improving folate status, red blood cell folate is preferred, given that there is less biological variation.

• High folic acid intake has not reliably been shown to be associated with negative health effects.

• A threshold for public health concern on the prevalence of folate insufficiency (i.e. red blood cell folate below 400 ng/mL [906 nmol/L] in women of reproductive age) is difficult to establish at this time.

Also note:

One study reported a threshold for red blood cell folate at concentrations of 400 ng/mL (906 nmol/L; mean 1292 nmol/L), above which the risk of NTDs was lowest (8.0 NTDs per 10 000 live births). Red blood cell folate concentrations <340 nmol/L were associated with a NTD risk of 66 per 10 000 live births.

Using modelled results, it was estimated that a folate intake from natural food of 450 µg dietary folate equivalents (DFE) per day or higher could achieve the lower bound of a red blood cell folate concentration (~1050 nmol/L) associated with the lowest risk of NTDs (~6 NTDs per 10 000 live births).

Useful Links:

Link to the Guideline page:


Link to the Guideline document:


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