Recommendation

Intermittent oral iron and folic acid supplementation with 120 mg of elemental irone and 2800 µg (2.8 mg) of folic acid once weekly is recommended for pregnant women to improve maternal and neonatal outcomes if daily iron is not acceptable due to side-effects, and in populations with anaemia prevalence among pregnant women of less than 20%.

(Context-specific recommendation)

 

Publication history

First published: November 2016

Updated: No update planned

Assessed as up-to-date: November 2016

 

Remarks

• This recommendation supersedes the previous WHO recommendation found in the 2012 Guideline: daily iron and folic acid supplementation in pregnant women (1) and should be considered alongside Recommendation on daily iron.
• In general, anaemia prevalence of less than 20% is classified as a mild public health problem (2).
• Before commencing intermittent iron supplementation, accurate measurement of maternal blood Hb concentrations is needed to confirm the absence of anaemia. Therefore, this recommendation may require a strong health system to facilitate accurate Hb measurement and to monitor anaemia status throughout pregnancy.
• If a woman is diagnosed with anaemia (Hb < 110 g/L) during ANC, she should be given 120 mg of elemental iron and 400 µg (0.4 mg) of folic acid daily until her Hb concentration rises to normal (Hb 110 g/L or higher) (3, 4). Thereafter, she can continue with the standard daily antenatal iron and folic acid dose (or the intermittent regimen if daily iron is not acceptable due to side-effects) to prevent recurrence of anaemia.
• Stakeholders may need to consider ways of reminding pregnant women to take their supplements on an intermittent basis and of assisting them to manage associated side-effects.
• The equivalent of 120 mg of elemental iron is 600 mg of ferrous sulfate hepahydrate, 360 mg of ferrous fumarate or 1000 mg of ferrous gluconate

 

 

Background

Anaemia is associated with iron, folate and vitamin A deficiencies. It is estimated to affect 38.2% of pregnant women globally, with the highest prevalence in the WHO regions of South-East Asia (48.7%) and Africa (46.3%), medium prevalence in the Eastern Mediterranean Region (38.9%) and the lowest prevalence in the WHO regions of the Western Pacific (24.3%), the Americas (24.9%) and Europe (25.8%) (2).

Major contributory factors to anaemia include parasitic infections such as malaria, hookworm and schistosomiasis, in areas where these infections are endemic. In addition, chronic infections such as tuberculosis (TB) and HIV, and haemoglobinopathies such as sickle-cell disease, contribute to the prevalence of anaemia. It is estimated that 0.8 million pregnant women globally have severe anaemia (defined as a blood haemoglobin concentration < 70 g/L) (2). In pregnancy, severe anaemia is associated with an increased risk of maternal and infant mortality (3). It is estimated that about half of the anaemia found in pregnant women is amenable to iron supplementation (5); however, this may be quite variable and is likely to be much lower in malaria-endemic areas.

In addition to causing anaemia, iron deficiency adversely affects the use of energy sources by muscles and, thus, physical capacity and work performance, and also adversely affects immune status and morbidity from infections (5). Folate (vitamin B9) deficiency, in addition to anaemia it is also linked to fetal neural tube defects (6). Vitamin A deficiency affects about 19 million pregnant women, mostly in Africa and South-East Asia, causing night blindness (7).

 

Methods

The ANC recommendations are intended to inform the development of relevant health-care policies and clinical protocols. These recommendations were developed in accordance with the methods described in the WHO handbook for guideline development (8). In summary, the process included: identification of priority questions and outcomes, retrieval of evidence, assessment and synthesis of the evidence, formulation of recommendations, and planning for the implementation, dissemination, impact evaluation and updating of the guideline.

The quality of the scientific evidence underpinning the recommendations was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) (9) and Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) (10) approaches, for quantitative and qualitative evidence, respectively. Up-to-date systematic reviews were used to prepare evidence profiles for priority questions. The DECIDE (Developing and Evaluating Communication Strategies to support Informed Decisions and Practice based on Evidence) (11) framework, an evidence-to-decision tool that includes intervention effects, values, resources, equity, acceptability and feasibility criteria, was used to guide the formulation and approval of recommendations by the Guideline Development Group (GDG) – an international group of experts assembled for the purpose of developing this guideline – at three Technical Consultations between October 2015 and March 2016.

To ensure that each recommendation is correctly understood and applied in practice, the context of all context-specific recommendations is clearly stated within each recommendation, and the contributing experts provided additional remarks where needed.

In accordance with WHO guideline development standards, these recommendations will be reviewed and updated following the identification of new evidence, with major reviews and updates at least every five years.

 

Further information on procedures for developing this recommendation are available here.

 

Recommendation question

For this recommendation, we aimed to answer the following question:

• For pregnant women (P), does intermittent iron supplementation (I) (with or without folic acid) compared with daily iron supplementation (with or without folic acid) (C), improve maternal and perinatal outcomes (O)?

 

Evidence summary

The evidence on the effects of intermittent iron and folic acid was derived from a Cochrane review that included 27 trials from 15 countries; however, only 21 trials (involving 5490 women) contributed data to the review’s meta-analyses (12). All trials were conducted in LMICs with some degree of malaria risk (Argentina, Bangladesh, China, Guatemala, India, Indonesia, the Islamic Republic of Iran, Malawi, Malaysia, Mexico, Pakistan, Republic of Korea, Sri Lanka, Thailand and Viet Nam); however, only one trial specifically reported that it was conducted in a malaria-endemic area. Most of the intermittent iron regimens involved women taking weekly supplements, most commonly 120 mg elemental iron per week (range: 80–200 mg weekly), which was compared with daily regimens, most commonly 60 mg elemental iron daily (range: 40–120 mg daily). Where folic acid was also provided in the trials, it was administered weekly in the intermittent supplement groups (range: 400–3500 μg weekly) compared with the usual standard daily dose for control groups.

Maternal outcomes

Anaemia was reported in different ways across trials. Low-certainty evidence suggests there may be little or no difference between intermittent and daily iron supplementation in the effect on anaemia at term (4 trials, 676 women; RR: 1.22, 95% CI: 0.84–1.80). Moderate-certainty evidence shows that anaemia at or near term (defined as a Hb of < 110 g/L at 34 weeks of gestation or later) probably occurs more frequently with intermittent than daily iron supplementation (8 trials, 1385 women; RR: 1.66, 95% CI: 1.09–2.53), and that intermittent iron supplementation is probably less likely to be associated with a Hb concentration of more than 130 g/L than daily iron (15 trials, 2616 women; RR: 0.53, 95% CI: 0.38–0.74). No events of severe anaemia occurred in either group in six trials reporting this outcome (1240 women). The evidence on mean Hb concentrations at or near term and severe postpartum anaemia is of very low certainty. Limited evidence on maternal morbidity from one small trial (110 women) was assessed as very uncertain. Maternal infections and maternal satisfaction were not evaluated in the review.

Side-effects: Moderate-certainty evidence shows that intermittent iron supplementation is probably less commonly associated with nausea than daily iron supplementation (7 trials, 1034 women; RR: 0.60, 95% CI: 0.37–0.97). However, the evidence on other specific side-effects (constipation, diarrhoea, heartburn or vomiting) or any side-effect is of very low certainty.

Fetal and neonatal outcomes

Low-certainty evidence suggests that intermittent iron supplementation may have a similar effect to daily iron supplementation on low birth weight (< 2500 g) (8 trials, 1898 neonates; RR: 0.82, 95% CI: 0.50–1.22). However, the evidence on preterm birth and very preterm birth was assessed as very uncertain. Evidence on the relative effects of intermittent versus daily iron supplementation on neonatal mortality is also very uncertain. Neonatal infections and SGA outcomes were not included in the review.

 

Additional considerations

Resources

Intermittent iron and folic acid supplementation might cost a little less than daily iron and folic acid supplementation due to the lower total weekly dose of iron.

Equity

Intermittent iron and folic acid supplementation may have less impact on health inequalities than daily iron and folic acid supplementation, as anaemia is more common in disadvantaged populations.

Acceptability

Qualitative evidence suggests that the availability of iron supplements may actively encourage women to engage with ANC providers (low confidence in the evidence) (13). However, where there are additional costs associated with supplementation or where the supplements may be unavailable (because of resource constraints) women are less likely to engage with ANC services (high confidence in the evidence). Women may find intermittent iron supplementation more acceptable than daily iron supplementation, particularly if they experience side-effects with daily iron supplements.

Feasibility

Intermittent iron may be more feasible in some low-resource settings if it costs less than daily iron.

 

Further information and considerations related to this recommendation can be found in the WHO guidelines, available at:

http://apps.who.int/iris/bitstream/10665/250796/8/9789241549912-websupplement-eng.pdf?ua=1

 

Implementation considerations

• The successful introduction of evidence-based policies related to antenatal care into national programmes and health care services depends on well-planned and participatory consensus-driven processes of adaptation and implementation. These processes may include the development or revision of national guidelines or protocols based on this recommendation.
• The recommendation should be adapted into locally-appropriate documents and tools that are able to meet the specific needs of each country and health service. Modifications to the recommendation, where necessary, should be justified in an explicit and transparent manner.
• An enabling environment should be created for the use of this recommendation, including changes in the behaviour of health care practitioners to enable the use of evidence-based practices.
• Local professional societies may play important roles in this process and an all-inclusive and participatory process should be encouraged.
• Antenatal care models with a minimum of eight contacts are recommended to reduce perinatal mortality and improve women’s experience of care. Taking this as a foundation, the GDG reviewed how ANC should be delivered in terms of both the timing and content of each of the ANC contacts, and arrived at a new model – the 2016 WHO ANC model – which replaces the previous four-visit focused ANC (FANC) model. For the purpose of developing this new ANC model, the ANC recommendations were mapped to the eight contacts based on the evidence supporting each recommendation and the optimal timing of delivery of the recommended interventions to achieve maximal impact.

 

Research implications

The GDG identified these priority questions related to this recommendation

• What is the most effective, acceptable and feasible regimen of recommended supplements (iron, calcium and folic acid)? Could micronutrients be combined into a single, or slow-release, formulation? To what extent do iron and calcium (or zinc) supplements compete for absorption?
• What is the most cost-effective iron compound and formulation (coated versus not) in terms of benefits and side effects?
• Can a rapid, portable, less invasive, and field-friendly test for iron deficiency anaemia be developed?
• Are there haemoconcentration risks associated with haemoglobin concentrations of more than 130 g/L in pregnancy?

 

 

Related links

WHO recommendations on antenatal care for a positive pregnancy experience

(2016) - full document and evidence tables

Managing Complications in Pregnancy and Childbirth: A guide for midwives and doctors

Pregnancy, Childbirth, Postpartum and Newborn Care: A guide for essential practice

WHO Programmes: Sexual and Reproductive health

WHO Programmes: Department of Nutrition for Health and Development

Maternal Health

 

 

References

1. Guideline: intermittent iron and folic acid supplementation in non-anaemic pregnant women. Geneva: World Health Organization; 2012 http://apps.who.int/iris/bitstream/10665/75335/1/9789241502016_eng.pdf, accessed 28 September 2016).
2. The global prevalence of anaemia in 2011.Geneva: World Health Organization; (http://apps.who.int/iris/bitstream/10665/177094/1/9789241564960_eng.pdf,... 29 September 2016).
3. WHO; de Benoist B, McLean E, Egli I, Cogswell M, editors. Worldwide prevalence of anaemia 1993–2005. WHO global database on anaemia. Geneva: World Health Organization (WHO); 2008 (http://apps.who.int/iris/bitstream/10665/43894/1/9789241596657_eng.pdf, accessed 26 September 2016).
4. Iron and folate supplementation: integrated management of pregnancy and childbirth (IMPAC). Standards for maternal and neonatal care 1.8. Geneva: Department of Making Pregnancy Safer, World Health Organization; 2006 (http://www.who.int/reproductivehealth/publications/maternal_perinatal_he..., accessed 29 September 2016).
5. United Nations Children’s Fund, United Nations University, WHO. Iron deficiency anaemia: assessment, prevention, and control: a guide for programme managers. Geneva: World Health Organization (WHO); 2001 (WHO/NHD/01.3; http://www.who.int/nutrition/publications/ en/ida_assessment_prevention_control.pdf, accessed 29 September 2016).
6. Guideline: daily iron and folic acid supplementation in pregnant women. Geneva: World Health Organization; 2012 (http://www. who.int/nutrition/publications/micronutrients/ guidelines/daily_ifa_supp_pregnant_women/ en/, accessed 28 September 2016).
7. Global prevalence of vitamin A deficiency in populations at risk 1995–2005. WHO Global Database on vitamin A deficiency. Geneva: World Health Organization; 2009 (http://www. who.int/nutrition/publications/micronutrients/ vitamin_a_deficiency/9789241598019/en/, accessed 29 September 2016).
8. WHO handbook for guideline development, 2nd edition. Geneva: World Health Organization; 2014 (http://www.who.int/kms/handbook_2nd_ ed.pdf, accessed 6 October 2016).
9. GRADE [website]. The GRADE Working Group; 2016 (http://gradeworkinggroup.org/, accessed 27 October 2016).
10. GRADE-CERQual [website]. The GRADECERQual Project Group; 2016 (https://cerqual. org/, accessed 27 October 2016).
11. The DECIDE Project; 2016 (http://www.decide-collaboration.eu/, accessed 27 October 2016).
12. Peña-Rosas JP, De-Regil LM, Garcia-Casal MN, Dowswell T. Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev. 2015;(7):CD004736.
13. Downe S, Finlayson K, Tunçalp Ö, Gülmezoglu AM. Factors that influence the use of routine antenatal services by pregnant women: a qualitative evidence synthesis. Cochrane Database Syst Rev. 2016;(10):CD012392

 

Citation: WHO Reproductive Health Library. WHO recommendation on intermittent oral iron and folic acid supplementation (November 2016). The WHO Reproductive Health Library; Geneva: World Health Organization.