Which of these combinations would provide the recommended amount of iron per day during pregnancy?

Recommendation

Daily oral iron and folic acid supplementation with 30 mg to 60 mg of elemental iron and 400 g (0.4 mg) of folic acid is recommended for pregnant women to prevent maternal anaemia, puerperal sepsis, low birth weight, and preterm birth.

(Recommended)

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 intermittent iron.
• The equivalent of 60 mg of elemental iron is 300 mg of ferrous sulfate hepahydrate, 180 mg of ferrous fumarate or 500 mg of ferrous gluconate.
• Folic acid should be commenced as early as possible (ideally before conception) to prevent neural tube defects.
• In settings where anaemia in pregnant women is a severe public health problem (i.e. where at least 40% of pregnant women have a blood haemoglobin [Hb] concentration < 110 g/L), a daily dose of 60 mg of elemental iron is preferred over a lower dose.
• In the first and third trimesters, the Hb threshold for diagnosing anaemia is 110 g/L; in the second trimester, the threshold is 105 g/L (2).
• If a woman is diagnosed with anaemia during pregnancy, her daily elemental iron should be increased to 120 mg until her Hb concentration rises to normal (Hb 110 g/L or higher) (3, 4). Thereafter, she can resume the standard daily antenatal iron dose to prevent recurrence of anaemia.
• Effective communication with pregnant women about diet and healthy eating – including providing information about food sources of vitamins and minerals, and dietary diversity – is an integral part of preventing anaemia and providing quality ANC.
• Effective communication strategies are vital for improving the acceptability of, and adherence to, supplementation schemes.
• Stakeholders may need to consider ways of reminding pregnant women to take their supplements and of assisting them to manage associated side-effects.
• In areas with endemic infections that may cause anaemia through blood loss, increased red cell destruction or decreased red cell production, such as malaria and hookworm, measures to prevent, diagnose and treat these infections should be implemented.
• Oral supplements are available as capsules or tablets (including soluble tablets, and dissolvable and modified-release tablets) (5). Establishment of a quality assurance process is important to guarantee that supplements are manufactured, packaged and stored in a controlled and uncontaminated environment (6).
• A better understanding of the etiology of anaemia (e.g. malaria endemnicity, haemoglobinopathies) and the prevalence of risk factors is needed at the country level, to inform context-specific adaptations of this recommendation.
• Standardized definitions of side-effects are needed to facilitate monitoring and evaluation.
• Development and improvement of integrated surveillance systems are needed to link the assessment of anaemia and iron status at the country level to national and global surveillance systems.
• To reach the most vulnerable populations and ensure a timely and continuous supply of supplements, stakeholders may wish to consider task shifting the provision of iron supplementation in community settings with poor access to health-care professionals (see Recommendation: Health systems interventions to improve the utilization and quality of ANC).

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%) (7).

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) (7). In pregnancy, severe anaemia is associated with an increased risk of maternal and infant mortality (8). It is estimated that about half of the anaemia found in pregnant women is amenable to iron supplementation (7); 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 (9). Folate (vitamin B9) deficiency, in addition to anaemia it is also linked to fetal neural tube defects (10). Vitamin A deficiency affects about 19 million pregnant women, mostly in Africa and South-East Asia, causing night blindness (11).

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 (12). 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) (13) and Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) (14) 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) (15) 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 daily iron supplementation (I) (with or without folic acid) compared with no iron supplementation or placebo (C), improve maternal and perinatal outcomes (O)?

Evidence summary

The evidence on the effects of daily iron and/or folic acid was derived from a Cochrane review of 61 trials conducted in low-, middle- and high-income countries (16). Twenty-three trials were conducted in countries with some malaria risk, of which two reported malaria outcomes.  Overall, 44 trials involving 43274 women contributed data to the review’s meta-analyses. The trials compared daily oral iron supplementation, with or without folic acid or other vitamin and mineral supplements, with various control groups (folic acid only, placebo, no intervention, other vitamin and mineral supplements without iron or folic acid). Most of the evidence was derived from studies comparing iron supplementation with no iron supplementation. In most trials, women began taking supplements before 20 weeks of gestation and continued taking supplements until delivery. The most commonly used dose of elemental iron was 60 mg daily (range: 30–240 mg) and that of folic acid was 400 µg daily.

Maternal outcomes

Anaemia was reported in many different ways and at different time points during pregnancy and the puerperium. Low-certainty evidence shows that daily iron supplementation may reduce the risk of anaemia at term (defined as blood Hb concentration 130 g/L at 34 weeks of gestation or later) (8 trials, 2156 women; RR: 3.07, 95% CI: 1.18–8.02). Regarding maternal morbidity, moderate-certainty evidence shows that daily iron supplementation probably reduces the risk of maternal puerperal infections (4 trials, 4374 women; RR: 0.68, 95% CI: 0.5–0.92).

Low-certainty evidence shows that daily iron supplementation may have little or no effect on pre-eclampsia (4 trials, 1704 women; RR: 1.63, 95% CI: 0.87–3.07) and antepartum haemorrhage (2 trials, 1157 women; RR: 1.48, 95% CI: 0.51–4.31), and moderate-certainty evidence shows that it probably has little or no effect on postpartum haemorrhage (4 trials, 1488 women; RR: 0.93, 95% CI: 0.59–1.49). Evidence on other morbidity outcomes, including placental abruption and blood transfusions, is of very low certainty.

Low-certainty evidence shows that daily iron supplementation may have little or no effect on maternal mortality (2 trials, 12 560 women; RR: 0.33, 95% CI: 0.01–8.19). Women’s satisfaction was evaluated in one small trial (49 women), which found little difference between daily iron and control groups.

Side-effects: Moderate-certainty evidence indicates that daily iron supplementation probably has little or no effect on the risk of experiencing any side-effect (11 trials, 2425 women; RR: 1.29, 95% CI: 0.83–2.02), and that it may have little or no effect on constipation (4 trials, 1495 women; RR: 0.95, 95% CI: 0.62–1.43), heartburn (3 trials, 1323 women; RR: 1.19, 95% CI: 0.86–1.66) and vomiting (4 trials, 1392 women; RR: 0.88, 95% CI: 0.59–1.30). Evidence that daily iron has little or no effect on nausea is of low certainty (4 trials, 1377 women; RR: 1.21, 95% CI: 0.72–2.03). High-certainty evidence shows that diarrhoea is less common with daily iron supplements (3 trials, 1088 women; RR: 0.55, 95% CI: 0.32–0.93).

Fetal and neonatal outcomes

Low-certainty evidence shows that daily iron may reduce the risk of low-birth-weight neonates (< 2500 g) (11 trials, 17 613 neonates; RR: 0.84, 95% CI: 0.69–1.03). High-certainty evidence shows that it does not reduce the risk of preterm birth before 37 weeks of gestation (13 trials, 19 286 women; RR: 0.93, 95% CI: 0.84–1.03), but it does reduce the risk of very preterm birth (i.e. less than 34 weeks of gestation) (5 trials, 3749 women; RR: 0.51, 95% CI: 0.29–0.91).

Low-certainty evidence suggests that daily iron may have little or no effect on congenital anomalies (4 trials, 14 636 neonates; RR: 0.88, 95% CI: 0.58–1.33).

Moderate-certainty evidence indicates that daily iron probably has little or no effect on neonatal deaths (4 trials, 16 603 neonates; RR: 0.91, 95% CI: 0.71–1.18).

Neonatal infections and SGA were not reviewed as outcomes.

Additional considerations

Evidence from subgroups tended to be consistent with the overall findings for the main outcomes.

Resources

Daily iron and folic acid supplements are relatively low cost, at less than 1 United States dollar (US$ 1) per pregnant woman (17).

Equity

Iron deficiency and parasitic infections are more common in LMICs and disadvantaged populations. Poor, rural and least-educated populations also experience the highest maternal, infant and child mortality (18). Increasing coverage of effective nutritional interventions to prevent anaemia, particularly among disadvantaged populations, might help to address maternal and newborn health inequalities.

Acceptability

Qualitative evidence suggests that the availability of iron supplements may actively encourage women to engage with ANC providers (low confidence in the evidence) (19). 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). Lower doses of iron may be associated with fewer side-effects and therefore may be more acceptable to women than higher doses.

Feasibility

Qualitative evidence about the views of health-care providers suggests that resource constraints, both in terms of the availability of the supplements and the lack of suitably trained staff to deliver them, may limit implementation (high confidence in the evidence) (20).

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: 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).
2. The clinical use of blood in general medicine, obstetrics, paediatrics, surgery & anaesthesia, trauma & burns. Geneva: World Health Organization; 1998 (http://www.who.int/ bloodsafety/clinical_use/en/Manual_EN.pdf, accessed 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_health/ iron_folate_supplementation.pdf, accessed 29 September 2016).
5. The international pharmacopoeia, 5th edition, volumes 1 and 2. Geneva: World Health Organization; 2015 (http://apps.who.int/phint/ en/p/about, accessed 4 October 2016).
6. The global prevalence of anaemia in 2011. Geneva: World Health Organization; 2015 (http://apps.who.int/iris/bitstream/ 10665/177094/1/9789241564960_eng.pdf, accessed 29 September 2016).
7. 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).
8. The WHO Expert Committee on Specifications for Pharmaceutical Preparations. Quality assurance of pharmaceuticals: meeting a major public health challenge. Geneva: World Health Organization; 2007 (WHO/PSM/QSM/2007.5; http://www.who.int/medicines/publications/ brochure_pharma.pdf, accessed 4 October 2016).
9. 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).
10. 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).
11. 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).
12. 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).
13. GRADE [website]. The GRADE Working Group; 2016 (http://gradeworkinggroup.org/, accessed 27 October 2016).
14. GRADE-CERQual [website]. The GRADECERQual Project Group; 2016 (https://cerqual. org/, accessed 27 October 2016).
15. The DECIDE Project; 2016 (http://www.decide-collaboration.eu/, accessed 27 October 2016).
16. Peña-Rosas JP, De-Regil LM, Garcia-Casal MN, Dowswell T. Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev. 2015;(7):CD004736.
17. OneHealth Model: intervention treatment assumptions (draft 28 September). Geneva and Glastonbury (CT): United Nations InterAgency Working Group on Costing and the Futures Institute; 2013 (http://avenirhealth. org/Download/Spectrum/Manuals/ Intervention%20Assumptions%202013%20 9%2028.pdf, accessed 4 October 2016).
18. State of inequality: reproductive, maternal, newborn and child health. Geneva: World Health Organization; 2015 (http://www.who.int/gho/ health_equity/report_2015/en/, accessed 29 September 2016).
19. 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
20. Downe S, Finlayson K, Tunçalp Ö, Gülmezoglu AM. Factors that influence the provision of good quality routine antenatal care services by health staff: a qualitative evidence synthesis. Cochrane Database Syst Rev. 2016

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

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