1. Objectives

To evaluate the effects of intermittent oral supplementation with iron alone or in combination with folic acid or other micronutrients on neonatal and pregnancy outcomes in pregnant women

2. How studies were identified

The Cochrane Pregnancy and Childbirth Group’s Trials Register was searched to July 2015, which included trials identified from:

• CENTRAL
• MEDLINE
• EMBASE
• CINAHL
• handsearches of 30 journals and proceedings of major conferences
• weekly current awareness alerts for a further 44 journals
• monthly BioMed Central email alerts

Reference lists were also searched and relevant organizations were contacted to identify any further trials

3. Criteria for including studies in the review

3.1 Study type

Randomised and quasi-randomised trials, including cluster-randomized trials

3.2 Study participants

Pregnant women of any gestational age or parity

(Studies that targeted women with specific diseases, such as HIV or tuberculosis, were excluded, as were studies specifically targeting anaemic women)

3.3 Interventions

Intermittent oral supplementation with iron, iron and folic acid, or iron with vitamins and minerals, in comparison to placebo or no supplementation, or compared with the same supplements provided daily

(Intermittent supplementation is defined as the provision of iron supplements one, two or three times a week on non-consecutive days)

(Supplementation was to be provided as a public health strategy as opposed to a treatment for anaemia)

3.4 Primary outcomes

Infant

• Low birth weight (<2500g)
• Birth weight (g)
• Premature birth (<37 weeks’ gestation)
• Neonatal death (within 28 days after delivery)
• Congenital anomalies, such as neural tube defects

Maternal

• Maternal anaemia at term (haemoglobin <110g/L at ≥37 weeks’ gestation)
• Maternal iron deficiency at term (as defined by study authors)
• Maternal iron-deficiency anaemia at term (haemoglobin <110g/L and at least one additional laboratory indicator at ≥37 weeks’ gestation)
• Maternal death (death while pregnant or within 42 days of termination of pregnancy)
• Adverse effects
• Severe anaemia during second or third trimesters (haemoglobin <70g/L)
• Clinical malaria (as defined by study authors)
• Infection during pregnancy

Secondary outcomes for infants included very low birth weight <1500 g, very premature birth <34 weeks’ gestation, haemoglobin and ferritin concentrations in the first six months of life, development and motor skills, and admission to an intensive care unit. For mothers, secondary outcomes included: anaemia at or near term; iron deficiency at or near term; iron-deficiency anaemia at or near term; haemoglobin concentrations at or near term or within one month postpartum; high haemoglobin concentrations during the second or third trimester (haemoglobin >130 g/L); moderate anaemia at postpartum (haemoglobin between 80 and 109 g/L); severe anaemia at or near term (haemoglobin <70 g/L); severe anaemia postpartum (haemoglobin <80 g/L); puerperal infection; antepartum haemorrhage; postpartum haemorrhage; blood transfusion given; diarrhoea or constipation; nausea or vomiting; heatburn; well being/satisfaction; placental abruption; premature rupture of membranes; and pre-eclampsia

4. Main results

4.1 Included studies

Twenty-one trials enrolling 5490 women contributed data to this review (six further trials that did not contribute data were also included)

• All studies excluded women with severe anaemia at baseline; nine studies included no anaemic women; one study included women who were anaemic at baseline; the remaining studies likely had samples including some women with mild or moderate anaemia at baseline
• Three studies provided iron alone; 14 provided iron plus folic acid; and four provide iron plus other vitamins and minerals
• In nine studies women were recruited and supplementation was initiated before 20 weeks’ gestation, whilst gestational age at the initiation of supplementation in the remaining studies was either mixed or unclear
• Total weekly doses of elemental iron in the intermittent arms ranged between 80 mg and 300 mg; and in the trials also including folic acid, total doses of folic acid ranged from 0.4 mg to 3.5 mg per week
• Intermittent dosing regimens ranged from once a week to every second day

4.2 Study settings

• Argentina, Bangladesh, China, Guatemala (2 trials), India (4 trials), Indonesia (2 trials), Iran (5 trials), Malawi, Mexico (3 trials), Pakistan (2 trials), Republic of Korea, Sri Lanka, and Thailand
• The study was conducted at antenatal clinics in most trails; in three studies the iron supplements were delivered by lay workers; in two studies they were delivered by midwives; in one they were delivered by traditional birth attendants; whilst in the remainder of studies they were supplied by physicians, obstetricians or haematologists
• All included studies took place in countries where risk of malaria is present to a varying degree, and one study in Indonesia specifically reported being in a malaria-endemic area

4.3 Study settings

How the data were analysed
Eight comparisons were made, with the first being the main comparison: i) any intermittent iron regimen (with or without other vitamins and minerals) compared with a daily regimen (of the same vitamins and minerals); ii) any intermittent iron regimen (with or without other vitamins and minerals) compared with no supplementation or placebo; iii) intermittent iron alone in comparison to no supplementation or placebo; iv) intermittent iron and folic acid supplementation compared with no supplementation or placebo; v) intermittent iron with vitamins and minerals compared with no supplementation or placebo; vi) intermittent iron alone compared with daily iron supplementation; vii) intermittent iron and folic acid supplementation compared with daily iron and folic acid supplementation; and viii) intermittent iron with vitamins and minerals compared to daily iron with vitamins and minerals. Random effects models were employed to produce pooled estimates of dichotomous data (risk ratios, RR) and continuous data (mean differences, MD) with 95% confidence intervals (CI). To explore potential sources of variation, the following subgroup analyses were planned:

• By gestational age (before 20 weeks’, ≥20 weeks’, mixed/unspecified)
• By anaemia status at baseline (anaemic, non-anaemic mixed/unspecified)
• By weekly iron dose in the group receiving intermittent supplementation (≤120 mg/week, >120 mg/week)
• By speed of release of iron supplement (slow release, normal release, unspecified)
• By bioavailability of the iron compound relative to ferrous sulphate (higher: NaFeEDTA; equivalent or lower: ferrous fumarate, ferrous gluconate; unspecified/unknown)
• By type of intermittent iron supplementation regimen (once per week, other)
• By malaria endemicity (malaria risk free, malaria risk area, unspecified/unknown)

Results
Any intermittent iron regimen (with or without other vitamins and minerals) compared with daily regimen (of the same vitamins and minerals)
Infant outcomes
Low birth weight (<2500 g)
The risk of giving birth to a baby weighing <2500 g was similar between the two treatment groups (RR 0.82, 95% CI [0.55 to 1.22], p=0.33; 8 studies/1898 women). No subgroup differences were identified.

Birth weight (g)
Overall, no statistically significant difference in birth weight was observed between the two groups (MD 5.13 g, 95% CI [-29.46 to 39.72], p=0.77; 9 studies/1939 participants), and no differences were revealed in subgroup analyses.

Premature birth (<37 weeks’ gestation)
The risk of premature birth was not different between treatment groups overall (RR 1.03, 95% CI [0.76 to 1.39], p=0.85; 5 studies/1177 women), or in subgroup analyses.

Neonatal death (within 28 days of delivery)
The risk of neonatal death in one study of 795 mother-infant pairs was not different between treatment groups (RR 0.49, 95% CI [0.04 to 5.42], p=0.56).

No data was reported on the risk of congenital anomalies.

Maternal outcomes
Maternal anaemia at term (haemoglobin <110 g/L at ≥37 weeks’ gestation)
In pooled analysis, no significant difference in maternal anaemia at term was observed between the two treatment groups (RR 1.22, 95% CI [0.84 to 1.80], p=0.3; 4 studies/676 women). No subgroup differences were identified.

Maternal iron-deficiency anaemia at term (haemoglobin <110 g/L and at least one additional laboratory indicator at ≥37 weeks’ gestation)
In one study of 156 women, no significant difference in maternal iron-deficiency anaemia at term was observed between the two groups (average RR 0.71, 95% CI [0.08 to 6.63], p=0.76).

Adverse effects
Women receiving intermittent supplements were 44% less likely to report adverse effects in comparison to the daily dosing group (RR 0.56, 95% CI [0.37 to 0.84], p=0.0057; 11 studies/1777 women). This finding became non-statistically significant in the following subgroup analyses: gestational age >20 weeks’ at initiation of supplementation; unspecified/mixed anaemia status at baseline; <120 mg of iron provided per week; and in regimens where iron was provided more than once per week.

For all other primary outcomes, either none of the trials reported data or no estimable data were available.

Additional outcomes: infant
Infant ferritin concentrations in the first six months postpartum were greater in the intermittent iron group in one study of 88 mother-infant dyads (MD 0.09 μg/L, 95% CI [0.05 to 0.13]), and in one study of 713 mother-infant pairs cognitive score at six months of age was greater in the intermittent iron group (MD 1.90, 95% CI [0.26 to 3.54]).

Additional outcomes: maternal
Women receiving intermittent supplements were 66% more likely to have maternal anaemia at or near term (haemoglobin <110 g/L at ≥34 weeks’ gestation) compared to the daily dosing group (RR 1.66, 95% CI [1.09 to 2.53], 8 studies/1385 women). In addition, women receiving intermittent supplements were at greater risk of having iron deficiency at or near term (based on one or more indicators of iron status) (RR 2.38, 95% CI [1.30 to 4.36], 3 studies/587 women), but at lower risk of having high haemoglobin concentrations (>130 g/L) during the second or third trimester (RR 0.53, 95% CI [0.38 to 0.74], 15 studies/2616 women). Nausea was also reported less frequently among women receiving intermittent dosing (RR 0.60, 95% CI [0.37 to 0.97], 7 studies/1034 women).

For all other secondary outcomes, no significant findings were observed or no data were available.

Any intermittent iron regimen (with or without other vitamins and minerals) compared with no supplementation or placebo
No studies were included in this comparison

Intermittent iron alone supplementation compared with no supplementation or placebo
No studies were included in this comparison

Intermittent iron and folic acid supplementation compared with no supplementation or placebo
No studies were included in this comparison

Intermittent iron and vitamins and minerals supplementation compared with no supplementation or placebo
No studies were included in this comparison

Intermittent iron alone supplementation compared with daily iron alone supplementation
The risk of maternal high haemoglobin concentrations (>130 g/L) during the second or third trimester was reduced with intermittent iron supplementation in comparison to daily supplementation (RR 0.50, 95% CI [0.26 to 0.96]). No statistically significant results were observed for the following analyzed outcomes: low birth weight, birth weight, premature birth, maternal anaemia at term, maternal anaemia at or near term, or maternal haemoglobin concentrations at or near term.

Intermittent iron and folic acid supplementation compared with daily iron and folic acid supplementation
Infant outcomes
Infant ferritin concentrations in the first six months of life were greater in the intermittent supplementation group in one study of 88 mother-infant pairs (MD 0.09 μg/L, 95% CI [0.05 to 0.13]), and in one study of 713 mother-infant dyads, infant cognitive score at six months of age was greater in the intermittent iron group (MD 1.90, 95% CI [0.26 to 3.54]) (as reported above). No statistically significant results were observed for the following analyzed primary outcomes: low birth weight, birth weight, and premature birth. For all other infant outcomes, no significant findings were observed or no data were available.

Maternal outcomes
The risk of adverse effects was lower among women receiving intermittent iron and folic acid supplementation in comparison to daily supplementation (RR 0.60, 95% CI [0.40 to 0.91], 9 trials/1487 women). This finding became non-significant when restricted to women beginning supplementation after 20 weeks’ gestation, or with mixed gestational ages; among those with unspecified anaemia status at baseline; in women receiving <120 mg iron per week; and when iron was given more than once per week. Women in the intermittent group were at lower risk of high haemoglobin concentrations (>130 g/L) during the second or third trimester (RR 0.56, 95% CI [0.37 to 0.84], 10 trials/1942 women), and at lower risk of experiencing nausea (RR 0.60, 95% CI [0.37 to 0.97], 7 studies/1034 women). No statistically significant result was found in analysis of the outcome maternal anaemia at term. For all other maternal outcomes, no significant findings were observed or no data were available.

Intermittent iron and vitamins and minerals supplementation compared with daily iron and vitamins and minerals supplementation
The risk of maternal anaemia at term (haemoglobin <110 g/L, ≥37 week’s gestation) was increased among women receiving intermittent supplementation in comparison to those receiving daily supplementation (RR 4.62, 95% CI [2.18 to 9.76]), as was the risk of maternal anaemia at or near term (haemoglobin <110 g/L, ≥34 week’s gestation) (RR 4.62, 95% CI [2.18 to 9.76]). This was mirrored in the MD in haemoglobin between the groups at ≥34 week’s gestation (MD -9.50 g/L, 95% CI [-13.19 to -5.81]). Adverse effects were less frequent in the intermittent group (RR 0.28, 95% CI [0.12 to 0.70]). No statistically significant results were observed in analyses of maternal iron deficiency at or near term or maternal high haemoglobin concentrations during the second or third trimester.

5. Additional author observations*

In general, the methodological quality of the trials included in this review was low, with the majority of the studies being at some risk of bias. High levels of attrition were also identified as being problematic. Assessment of the quality of the evidence using GRADE criteria found primary infant outcomes to be low quality and maternal outcomes to be very low quality. The included studies were conducted in a variety of settings and there was little difference detected between the supplementation regimens for the majority of outcomes investigated, including anaemia at term, haemoglobin concentrations at term, risk of premature birth, and risk of low birth weight; and women experienced fewer side effects and a reduced risk of high haemoglobin concentrations. However, the applicability and generalizability of the findings may be limited due to the small number of studies reporting on primary outcomes and the small sample size of the studies. As a result, the authors recommend limiting the implementation of intermittent dosing to those women at low risk of developing anaemia until further supporting evidence accumulates. Furthermore, whilst it is clear that those receiving intermittent supplementation suffered from fewer adverse effects compared to those receiving daily dosing, the authors suggest that those on intermittent supplementation may have only suffered from side effects once or twice a week following supplement ingestion as opposed to everyday in the daily dosing group.

Though intermittent supplementation with iron could be considered as a viable strategy to avert gestational anaemia, further investigation is needed to establish safe and effective and doses and regimens of intermittent iron plus folic acid supplementation; to assess the safety of intermittent iron supplementation in pregnant women with malaria; to determine the effects of varying maternal haemoconcentration during pregnancy; to investigate factors associated with non-compliance and the causes of attrition among women receiving iron supplementation; to monitor longer-term maternal and infant outcomes following intermittent iron supplementation; and to establish acceptable iron doses, preparations and dosing regimens.