Global Folate Epidemiology

Folate Def iciency and Food Fortif ication | Brief ing Note 1
ABOUT THE FOLATE TASK TEAM
The Folate Task Team comprises a group of global experts and partners
under the leadership of Nutrition International (NI) through NTEAM
(Nutrition Technical Assistance Mechanism), all joined together to identify
priority actions to reduce folate-sensitive neural tube defects, build
laboratory capacity for the assessment of folate status, support research
in this critical area and to facilitate access to folate-related knowledge
products.
Through NTEAM, NI shares its expertise globally to support the scale-up of

nutrition for the most vulnerable. We believe that knowledge, rigorously
obtained and generously shared, is key to effective progress for nutrition.
NTEAM convenes global experts to tackle key nutrition issues and
encourage broad use of knowledge by translating technical information
and research into accessible guidance, tools and resources. We also
work with countries and agencies, sharing expertise through timely and
coordinated technical assistance.
FRAMING THE ISSUE
Neural Tube Defects (NTDs) are a group of congenital anomalies –
including anencephaly and spina bifida – which cause brain and spinal
malformations in a fetus. NTDs are formed within the first 28 days
of a pregnancy, often before a woman knows she is pregnant. While
anencephaly often results in early death, spina bifida has a varying degree
of outcomes. When no treatment is offered, spina bifida will most likely
result in premature death. Rehabilitation and surgery may allow affected
individuals to adjust to this life-long disability with different degrees of
success, but with considerable individual, economic, and social costs.
Folate insufficiency has been found to be the cause of a majority of

NTDs. To reduce the burden of NTDs globally, it is essential for women of
reproductive age (WRA) to have sufficient folate status throughout their
reproductive age. At minimum, it is critical to have sufficient folate status
for three months before they become pregnant and during the first month
of gestation. At a population level, the World Health Organization (WHO)
recommends WRA have a red blood cell (RBC) folate concentration greater
than 906 nmol/L to reduce the risk of having an NTD affected pregnancy.1
THE BURDEN
On average, 1.86 per 1,000 live births are affected by NTDs around the world.
However, there is wide variation in NTD incidence across the globe, and this
burden is disproportionately high in low- and middle-income countries in
Asia and Africa.
• Asia: 3.0-10.0 per 1,000 live births

• Africa: 1.0-2.5 per 1,000 live births
• Europe: 0.8-1.5 per 1,000 live births*
• Latin America and the Caribbean: 0.4-1.4 per 1,000 live births
• High-income countries with mandatory food fortification: 0.5-1.0 per
1,000 live births2
*Access to prenatal screenings and elective terminations of pregnancy for
fetal anomalies influence the prevalence of NTDs per live births in most
European countries.
According to web-based reviews of birth defect registry databases and

systematic literature reviews, and excluding miscarriages and elective
terminations of pregnancy, it has been estimated that in 2015:
• 260,100 pregnancies were affected by NTDs worldwide, which

resulted in 57,800 still-births and 117,900 under-five deaths; and
• Nearly half of the total NTDs were estimated to be cases of spina
bifida (128,000). While a majority of infants with spina bifida may
survive the newborn period, more than three-quarters of those born
in low- and middle-income countries will die before the age of 5.3
HOW MUCH FOLATE SHOULD BE CONSUMED
For many populations, it is very difficult to consume enough natural folate
in the regular diet to achieve sufficient levels to prevent NTDs.
• The WHO recommends WRA ingest 400 micrograms of folic acid

daily, in addition to any folate consumed in their regular diet. At a
population level, this intake helps to ensure that WRA have a red
blood cell (RBC) folate concentration greater than 906 nmol/L.
• Folate “insufficiency” in a population is defined by WHO as RBC
folate concentrations less than 906 nmol/L.
• Food fortification with folic acid has proven to be an effective
intervention to ensure WRA consume adequate amounts of folic acid
to prevent “insufficiency” before a pregnancy occurs, reducing the
risk of NTDs.
• Women who have given birth previously to a child with an NTD may
have to take much larger amounts of folate (4 – 5 mg daily) than may
be supplied via natural or fortified food, making it necessary to resort
to supplementation.
INSUFFICIENT VS. DEFICIENT FOLATE

STATUS
Insufficient folate levels are related to an increased risk of NTDs, while
deficient folate levels are related to an increased risk of megaloblastic
anemia.
Low folate intake gradually leads to folate depletion, which has functional
consequences for the body. The initial stages of inadequate folate intake
are reflected in low serum folate, followed by a depletion in red blood cell
folate, which if continued will then cause changes in the bone marrow
(where the red blood cells are produced).
Evidence has shown that insufficient folate intake by WRA increases the
risk of NTDs. The WHO recommends that WRA ingest 400 micrograms of
folic acid daily from fortified foods or supplements, in addition to any folate
consumed in their regular diet. This recommendation is based on evidence
that this level of consumption leads to an optimal folate concentration that
reduces the risk of NTDs to a minimum.4
If inadequate folate intake persists, this insufficiency turns into a folate
deficiency. Folate deficiency is defined by the Institute of Medicine in the
United States on the basis of the amount of folate required to maintain
physiological folate levels in red blood cells.5 Megaloblastic anemia is
caused by these low levels of folate which affect the formation of red
blood cells and hemoglobin concentration in them. This is the basis for
the estimated average requirement, on which the recommended dietary
allowance (RDA) is based.
FOOD FORTIFICATION WITH FOLIC ACID
Large-scale food fortification with folic acid has proven to be an
effective intervention to reduce the risk of NTDs in countries which have
implemented mandatory fortification programs, such as Canada, the
United States, Costa Rica, South Africa, Oman and others.
• In all of these countries, the incidence of NTDs have been

consistently reduced to 0.5-0.6 per 1,000 live births after fortification
and effective monitoring programs were implemented.
For countries with a relatively low prevalence of NTDs, it is feasible to

reach an NTD threshold of 0.5 per 1,000 live births through mandatory
folic acid fortification of appropriately selected foods. Food fortification
has the potential to reach the majority of the target population when
implemented following the right practices; i.e., when it is mandatory;
regulated; conducted through large-scale food-processing facilities;
effectively monitored; and utilizes staple foods that are already consumed
by a majority of the target population.
THE INVESTMENT CASE

Food fortification with folic acid has proven to be a rewarding economic
investment. This investment includes two groups of costs -upfront and
on-going- which include purchasing folic acid, updating milling machinery,
training, marketing, monitoring and evaluation, testing, and compliance.
Further costs may be required for advocacy and education activities.
The benefits of mandatory folic acid food fortification largely outweigh the
costs.6 Investing in food fortification with folic acid also compares favorably
to other lifesaving interventions:
• Average cost per NTD-death averted: US $957

• Average cost per death averted through insecticide-treated bed nets:
US $2,770
• Average cost per death averted by rotavirus vaccine: US $3,0156
SAFETY OF FOLIC ACID

Concerns related to the safety of folic acid often include questions related
to the potential increased risk of cancer and the risk of “masking” an
underlying vitamin B12 deficiency.
There is no evidence that folic acid consumed in fortified foods increases

the risk of any type of cancer. In fact, there is strong evidence that low
folate status promotes development of cancer, and in the US, where
food fortification with folate acid has been mandatory for two decades,
it has actually been found that the risk of different types of cancer has
progressively declined post-fortification.7
Since both vitamin B12 and folate are required to make DNA, a deficiency
of either impairs the division of RBCs. This leads to megaloblastic anemia,
which is characterized by larger and fewer cells. This type of anemia will
respond to therapeutic doses of either B12 or folic acid. The term “masking”
refers to a potential delay in diagnosis and treatment of a vitamin B12
deficiency due to the initial reversal of anemia when therapeutic doses
of supplemental folic acid are given to a vitamin B12-deficient patient. A
differential diagnosis depends on evaluations of blood folate and vitamin
B12 prior to treatment, a routine clinical practice. There is no evidence that
consumption of folic acid in fortified foods has resulted in any cases of
misdiagnosed or “masking” of a vitamin B12 deficiency in the US.7 However,
given that the metabolism of folic acid and vitamin B12 are closely linked,
for populations at high-risk of vitamin B12 deficiency, such as vegetarians
or the elderly, relatively high intakes of folic acid may mask signs of B12
deficiency, like anemia. In these cases, it is necessary to increase vitamin B12
intake, which can be achieved by direct supplementation or by adding this
vitamin to the fortified food.8
KEY MESSAGES
• It is estimated that in 2015 there were 260,100 pregnancies affected
by NTDs, worldwide.
• Folate insufficiency is associated with increased risk of NTD. Folate
deficiency is associated with megaloblastic anemia.
• NTDs form within the first 28 days of a pregnancy, often before a
women knows she is pregnant.
• In order to reduce the risk of folate-sensitive NTDs, women of
reproductive age must have sufficient folate status at least three
months prior to conception and throughout the first month of
pregnancy.
• In most settings it may be almost impossible for women to ingest
enough natural folate from dietary sources to effectively reduce the
risk of NTDs.
• Mandatory fortification with folic acid can significantly reduce the
prevalence of NTDs, and it is a low-cost, high impact, lifesaving
nutrition intervention.
• Published literature has shown no adverse public health
consequences from large-scale mandatory folic acid fortification
programs.7
ENDNOTES
1. World Health Organization. Optimal serum and red blood cell folate
concentrations in women of reproductive age for prevention of neural
tube defects (2015). Retrieved from https://www.who.int/nutrition/
publications/guidelines/optimalserum_rbc_womenrep_tubedefects/en/
2. Kancherla, V. & R.E. Black. 2018. Historical perspective on folic acid and
challenges in estimating global prevalence of neural tube defects. Ann.
N.Y. Acad. Sci. 1414: 20 – 30.
3. Blencowe, H., V. Kancherla, S. Moorthie, et al. 2018. Estimates of global
and regional prevalence of neural tube defects for 2015: a systematic
analysis. Ann. N.Y. Acad. Sci. 1414: 31 – 46.
4. Bailey, L.B. & D.B. Hausman. 2018. Folate status in women of
reproductive age as basis of neural tube defect risk assessment. Ann.
N.Y. Acad. Sci. 1414: 82 – 95.
5. Institute of Medicine (US) Standing Committee on the Scientific
Evaluation of Dietary Reference Intakes and its Panel on Folate, Other
B Vitamins, and Choline. 1998. Dietary Reference Intakes for Thiamin,
Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid,
Biotin, and Choline. National Academies Press (US).
6. Hoddinott, J. 2018. The investment case for folic acid fortification in
developing countries. Ann. N.Y. Acad. Sci. 1414: 72 – 81.
7. Field, M.S. & P.J. Stover. 2018. Safety of folic acid. Ann. N.Y. Acad. Sci. 1414:
59 – 71.
8. Molloy, A.M. 2018. Should vitamin B12 be considered in assessing risk of
neural tube defects. Ann. N.Y. Acad. Sci. 1414: 109 – 125.
WWW.NUTRITIONINTL .ORG
Contact
Homero Martinez
Senior Technical Advisor
[email protected]

Global Folate Epidemiology

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Folate Def iciency and Food Fortif ication | Brief ing Note 1

ABOUT THE FOLATE TASK TEAM

Through NTEAM, NI shares its expertise globally to support the scale-up of

Folate insufficiency has been found to be the cause of a majority of

• Asia: 3.0-10.0 per 1,000 live births

According to web-based reviews of birth defect registry databases and

• 260,100 pregnancies were affected by NTDs worldwide, which

• The WHO recommends WRA ingest 400 micrograms of folic acid

INSUFFICIENT VS. DEFICIENT FOLATE

• In all of these countries, the incidence of NTDs have been

For countries with a relatively low prevalence of NTDs, it is feasible to

THE INVESTMENT CASE

• Average cost per NTD-death averted: US $957

SAFETY OF FOLIC ACID

There is no evidence that folic acid consumed in fortified foods increases

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