Mill scale (ferrous metal)

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

other: human data

Adequacy of study:

key study

Study period:

literature searches updated to 2012-05-31

Reliability:

other: Not rated acc. to Klimisch

Rationale for reliability incl. deficiencies:

other: Any kind of reliability rating is not considered to be applicable, since human studies/reports are not conducted/reported according to standardised guidelines.

Data source

Reference

Reference Type:

publication

Title:

Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis

Author:

Haider, B.A. et al.

Year:

2013

Bibliographic source:

BMJ 2013;346:f3443

Materials and methods

Study type:

other: meta-analysis

Endpoint addressed:

developmental toxicity / teratogenicity

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The purpose of the study was to summarise evidence on the associations of maternal anaemia and prenatal iron use with maternal haematological and adverse pregnancy outcomes; and to evaluate potential exposure-response relations of dose of iron, duration of use, and haemoglobin concentration in prenatal period with pregnancy outcomes.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Iron

EC Number:

231-096-4

EC Name:

Iron

Cas Number:

7439-89-6

Molecular formula:

Fe

IUPAC Name:

Iron

Test material form:

not specified

Details on test material:

not specified

Specific details on test material used for the study:

not specified

Method

Type of population:

general

Ethical approval:

not applicable

Remarks:

meta-analysis

Details on study design:

METHOD OF DATA COLLECTION
- Type: systematic review and meta-analysis
- Details: 48 randomised trials (17 793 women) and 44 cohort studies (1 851 682 women) were systematically reviewed and analysed

STUDY PERIOD: literature searches updated to 2012-05-31

SETTING: high middle- and low-income countries not mentioned by name

STUDY POPULATION
- Total number of potential references: 13668
- Selection criteria:
Randomised trials in pregnant women of daily oral iron or iron and folic acid use compared with placebo, no iron, or no iron and folic acid. trials of both supplementation and fortification examining maternal haematological, morbidity, and birth outcomes (see below `HEALTH EFFECTS STUDIED´). Individual and cluster randomised trials were included.
Prospective cohort studies that allowed examination of the association of baseline anaemia with the below specified birth outcomes, studies defining anaemia as haemoglobin <100 g/L to haemoglobin <115 g/L (when haemoglobin was not reported but haematocrit was available, haemoglobin concentrations (g/L) was estimated by dividing haematocrit by 3 and then multiplying by 10).
- Exclusion criteria:
Trails of multiple vitamins and minerals, except those that examined the additional effect of iron or iron with folic acid in which all treatment groups received similar vitamins and minerals (except for iron or iron and folic acid).
Cross sectional and case-control studies (as these do not allow assessment of the temporal association between exposure and an outcome), trials with a quasi-randomised design (owing to the high risk of bias) and studies in HIV infected women or those with haemoglobinopathies, trials evaluating different doses of iron (unless they presented comparison groups that met the eligibility criteria).
- Total number of subjects participating in study: 48 randomised trials: 17 793 pregnant women from high income countries (4861 women) and from low- or middle-income countries (12 932 women); 44 cohort studies: 1 851 682 women from high income countries (650 126 women) and from low- or middle-income countries (1 201 556 women).
- Sex/age/race & smoker/non-smoker: not specified

HEALTH EFFECTS STUDIED
- Maternal haematological outcomes included mean haemoglobin concentration (g/L), anaemia (defined as haemoglobin <110 g/L), iron deficiency (defined as serum ferritin <12 μg/L), and iron deficiency anaemia (defined as haemoglobin <110 g/L and serum ferritin <12 μg/L) in the second or third trimester or at delivery and in the postpartum period.
- Birth outcomes included mean duration of gestation (weeks), preterm birth (defined as birth of a neonate <37 weeks of gestation), mean birth weight (g), low birth weight (defined as birth weight <2500 g), mean birth length (cm), small for gestational age birth (defined as birth weight below the 10th centile of the gestational age and sex), stillbirth (defined as death of a foetus after 28 weeks of gestation), perinatal mortality (defined as deaths including stillbirths and neonatal deaths before 7 days of life), and neonatal mortality (defined as death of a neonate in the first month of life).
- Other maternal outcomes included gestational diabetes mellitus, infection during pregnancy and postpartum, maternal malaria and parasitaemia, and placental malaria. We placed no limits on gestational age at the time of starting iron or duration of iron use.

Exposure assessment:

not specified

Details on exposure:

TYPE OF EXPOSURE: Iron exposure as a supplement or through food
TYPE OF EXPOSURE MEASUREMENT: Information from the test persons (iron as supplement) and measurement of haemoglobin concentration in blood.
EXPOSURE LEVELS: The dose of iron from supplements ranged from 10 mg to 240 mg daily; one trial used a daily dose of 900 mg; anaemia was defined differently, with definitions ranging from haemoglobin <100 g/L to haemoglobin <115 g/L.
EXPOSURE PERIOD: Duration of supplementation varied from seven to eight weeks up to 30 weeks during pregnancy.

Statistical methods:

please refer to the field `Any other information on materials and methods incl. tables´

Results and discussion

Results:

Evidence from RANDOMISED trials

Findings for overall effect of iron, with or without folic acid, on haematological outcomes
- Iron use increased maternal mean haemoglobin concentration by 4.59 g/L (3.72 - 5.46; 95 % CI, n = 36 trails; no heterogeneity: I²= 0 %, P>0.05)
- Iron use significantly reduced the relative risk of anaemia (0.50, 0.42 - 0.59, n= 19; heterogeneity: P<0.001; I²= 83 %)
- Iron use significantly reduced the relative risk of iron deficiency (0.59, 0.46 - 0.79; I²= 79 %; n= 8)
- Iron use significantly reduced the relative risk of iron deficiency anaemia (0.40, 0.26 - 0.60; I² = 33 %, n= 6)
- Iron use significantly reduced the risk of low birth weight (0.81, 0.71 - 0.93)
- Mean haemoglobin concentration (3rd trimester or at delivery) was significantly higher in the low- or middle-income country category than in the high-income category (test P= 0.003) and for initial mean haemoglobin concentrations <110 g/L vs. ≥110 g/L (test P= 0.005)
- Meta-regression analyses for maternal anaemia showed that the effects were significantly larger in the high-income country category (test P= 0.009), with initial mean haemoglobin concentration ≥110 g/L (test P= 0.008), and in malaria non-endemic regions (test P= 0.003), adjusting for covariates independently did not explain heterogeneity substantially.

Findings for overall effect of iron, with or without folic acid, on birth outcomes
- The use of iron lead to a significantly higher mean birth weight (mean difference 41.2 g (1.2 - 81.2); I²= 99 %; n= 19). The analysis of the high-quality trials alone also indicated a significant effect (mean difference 68.7 g (37.7 - 99.7); I²= 97 %; n= 12). Heterogeneity was high, but subgroup analysis and meta-regression showed that birth weights were not significantly different in subgroups (test P>0.05).
- Iron use led to a reduction of 19 % in relative risk of low birth weight (0.81, 0.71 - 0.93; I²= 1 %; n= 13, similar results in high-quality trials, no evidence of publication bias (all P>0.05), but funnel plot indicated some asymmetry).
- No significant effect from the use iron did on preterm birth, duration of gestation, small for gestational age births, and birth length (P>0.05, similar effects in high-quality trials, no publication bias).
- A small number of trials reported effects on stillbirths (n= 3), perinatal mortality (n= 4), neonatal mortality (n= 3), and maternal morbidity outcomes such as gestational diabetes (n= 1), infection during pregnancy (n= 2), puerperal sepsis (n= 2), and malaria indicators (n= 2), precluding further analyses for these outcomes.

Exposure-response relation of iron dose with haematological and birth outcomes
- Significant non-linear, inverse relation between dose of iron and risk of maternal anaemia (3rd trimester or at delivery: P<0.001; n= 18).
- For an increase of 10 mg iron/day, the relative risk of anaemia was 0.88 (0.84 - 0.92; P for linear trend<0.001; n= 11, only trials providing ≤ 66 mg iron/day. The duration of use, adjusted for dose of iron, was not associated with anaemia (P>0.05).
- The exposure-response relation found an increase in birth weight of 15.1 g (6.0 - 24.2) for an increase of 10 mg iron/day (P= 0.005).
- The relative risk of low birth weight decreased by 3 % for an increase of 10 mg iron/day (0.97, 0.95 - 0.98; P for linear trend<0.001; n= 13).
- No evidence of a non-linear association with either birth weight or low birth weight (both P>0.05, only trials using ≤ 66 mg iron/day), findings for low birth weight did not change, but evidence of non-linearity for birth weight (P<0.001; n= 14). The duration of iron use was not significantly associated with either outcome, after adjustment for dose.
- Iron dose was not associated with relative risk of preterm birth (0.99, 0.95 - 1.04; P for linear trend= 0.67; n= 12).

Exposure-response relation of haemoglobin concentration with birth outcomes

- A unit increase in mean haemoglobin concentration in 3rd trimester or at delivery linearly increased birth weight by 14.0 g (6.8 - 21.8) (P= 0.002; n= 16 trials, no evidence of a non-linear association (P>0.05)).
- The effect on relative risk of low birth weight (0.96, 0.84 - 1.09; P for linear trend= 0.21; n= 11) and on relative risk of preterm birth (0.99, 0.94 - 1.04; P for linear trend= 0.70; n= 8) were non-significant.


Findings for effect of iron only versus no iron/placebo on haematological and birth outcomes

- Use of iron was associated with significantly increased mean haemoglobin concentration in 3rd trimester or at delivery (mean difference 4.50 g/L (3.62 - 5.39); I²= 0 %; n= 31 trails) and in the postpartum period (7.01 g/L (0.36 - 13.66); I²= 0 %; n= 8) compared with no iron or placebo.
- Significant reductions in the relative risk of anaemia (0.56, 0.48 - 0.65; I²= 75 %; n= 17), iron deficiency (0.59, 0.44 - 0.79; I²= 79 %; n= 8), and iron deficiency anaemia (0.37, 0.23 - 0.60; I²= 47 %; n= 5). Heterogeneity was significant, visual inspection of the forest plots indicated that it seemed to be due to the variation in effects sizes, rather than the direction of the effect.
- Use of iron was associated with a significant increase in birth weight (mean difference 40.8 g (0.97 - 80.6); I²= 99 %; n= 1) and reduction in relative risk of low birth weight (0.81, 0.71 - 0.91; I²= 9 %; n= 10).
- Effects from the use of iron on duration of gestation (mean difference 0.11 weeks (−0.35 - 0.57); n= 9), relative risk of preterm birth (0.92, 0.80 - 1.07; n= 10), relative risk of small for gestational age births (0.84, 0.66 - 1.07; n= 6), and birth length (mean difference −0.93 cm (−4.76 - 2.90); n = 7) were not significant.

Findings for effect of iron with folic acid versus no iron and folic acid/placebo on haematological and birth outcomes

- Iron with folic acid was associated with a significant increase in mean haemoglobin concentration (mean difference 10.41 g/L (5.36 - 15.46); I²= 0 %; n= 9) and reduction in relative risk of anaemia in the 3rd trimester or at delivery (0.44, 0.37 - 0.53; I²= 44 %; n= 5). Effects on other haematological and pregnancy outcomes could not be evaluated owing to the small number of available trials (n < 5).

Evidence from COHORT STUDIES

Association between anaemia and birth outcomes

- Prenatal anaemia significantly increased the risk of low birth weight compared with no anaemia (crude odds ratio (OR) 1.25, 1.08 - 1.45; I²= 90 %; n= 25 studies); the association was non-significant when adjusted estimates extracted from the included studies were pooled (adjusted OR 1.13, 0.94 - 1.35; I²= 86 %; n= 9).
- A significantly higher risk of preterm birth in the anaemic group (crude OR 1.28, 1.12 - 1.47; I²= 89 %; n= 26) was noted, even after pooled adjusted estimates (adjusted OR 1.28, 1.11 - 1.48; I²= 83 %; n= 13).
- Significantly higher risk of stillbirth in the anaemic group (crude OR 1.19, 1.09 - 1.29; I²= 24 %; n= 12); adjusted estimates could not be pooled because only two studies presented them.
- Anaemia was marginally associated with the duration of gestation (P= 0.05) but not with birth weight; associations with small for gestational age births and perinatal mortality were not significant (P>0.05). Associations with birth length and neonatal mortality could not be evaluated owing to paucity of data.
- Significant heterogeneity in the preterm birth and low birth weight analyses was found.
- Subgroup analysis found a significantly higher risk of preterm birth with 1st or 2nd trimester anaemia (adjusted OR 1.21, 1.13 - 1.30; I²= 0 %; n= 7) but not with 3rd trimester anaemia (adjusted OR 1.20, 0.80 - 1.79; I²= 90 %; n= 6) (test P= 0.71).
- No significant difference for subgroups of country category (high- (adjusted OR 1.26, 1.02 - 1.57; I²= 87 %; n= 9) versus low- or middle-income countries (adjusted OR 1.30, 1.05 - 1.61; I²= 77 %; n= 5) (test P= 0.83). Subgroup analysis for malaria endemicity could not be done owing to the small number of studies in one of the subgroups.
- The low birth weight subgroup analysis showed significantly higher risk with 1st or 2nd trimester anaemia (adjusted OR 1.29, 1.09 - 1.53; I²= 82 %; n= 6) and no significant associations in subgroups of high income countries (adjusted OR 1.21, 0.95 - 1.53; I²= 90 %; n= 6) or malaria non-endemic countries (adjusted OR 1.13, 0.94 - 1.35; I²= 86 %; n= 9)
- P values could not be calculated for subgroup differences owing to the small number of studies in one of the subgroups. Funnel plots and Harbord tests for low birth weight and preterm birth (both P>0.05) did not suggest any evidence of publication bias.

Exposure- response relation of haemoglobin concentration with birth outcomes
- Non-significance of the exposure-response relation between mean haemoglobin concentration and birth weight (mean difference 3.2 (−17.9 - 24.3) g; P= 0.77; n= 9 studies)
- A small significant exposure-response relation of mean haemoglobin concentration with relative risk of low birth weight (0.99, 0.98 - 0.99; P for linear trend<0.001; n= 2)
- A significant association of mean haemoglobin concentration in the 1st or 2nd trimester with the relative risk of preterm birth (0.98, 0.98 - 0.99; P for linear trend<0.001; n=12)

For further details please refer to the tables in the `Attached background material´.

Confounding factors:

Analysis of confounders:
- low-, middle- or high- income country
- malaria endemicity
- baseline anaemia
- start of iron use: early (≤ 21 weeks’ gestation), late (>22 weeks’ gestation)

Further confounders were not stated

Strengths and weaknesses:

Strengths:

This meta-analysis is a comprehensive evaluation of the evidence, incorporating randomised trials and cohort studies, with examination of associations with haematological, morbidity, and birth outcomes in one report. This meta-analysis examined the exposure-response relation of dose of iron, duration of use, and haemoglobin concentration on birth weight and risk of low birth weight and preterm birth. Various comparisons were made evaluating the overall effect of iron, iron only, and iron with folic acid. An effort was made to extract all available data from trials, especially those with multiple comparison groups. Effects in various predefined subgroups were assessed and meta-regression was performed to identify sources of heterogeneity. Furthermore, sensitivity analysis was conducted to assess the impact of the methodological quality of trials on effect estimates.

Weakness:

Although adjusted estimates from randomised trails and cohort studies were used, these data were of observational nature. These associations still could have been biased owing to residual confounding, in either direction, depending on the nature of the residual confounding.
Associations with several outcomes could not be evaluated owing to the paucity of data (stillbirths, neonatal and perinatal mortality in iron use meta-analyses; birth length, neonatal mortality in the cohort studies analysis).
A small number of trials had evaluated the effect of iron fortification in pregnant women, so a separate meta-analysis for fortification trials could not be done.
Significant heterogeneity existed for several outcomes that could not be explained substantially by pre-specified subgroups. This limits the understanding of the association in various settings and restricts the generalisability of the findings.
For the exposure-response analysis of cohort studies, mean haemoglobin concentrations for most studies were missing. An assumption was made, that countries within the same category (low-, middle-, or high-income) would have similar mean haemoglobin concentrations. These mean values were used for analysis, which may have introduced bias towards the null due to random measurement error.

Applicant's summary and conclusion

Conclusions:

48 randomised trials (17 793 women) and 44 cohort studies (1 851 682 women) were included.
Iron use increased maternal mean haemoglobin concentration by 4.59 (95% confidence interval 3.72 to 5.46) g/L compared with controls and significantly reduced the risk of anaemia (relative risk 0.50, 0.42 to 0.59), iron deficiency (0.59, 0.46 to 0.79), iron deficiency anaemia (0.40, 0.26 to 0.60), and low birth weight
(0.81, 0.71 to 0.93).
The effect of iron on preterm birth was not significant (relative risk 0.84, 0.68 to 1.03).
Analysis of cohort studies showed a significantly higher risk of low birth weight (adjusted odds ratio 1.29, 1.09 to 1.53) and preterm birth (1.21, 1.13 to 1.30) with anaemia in the first or second trimester.
Exposure-response analysis indicated that for every 10 mg increase in iron dose/day, up to 66 mg/day, the relative risk of maternal anaemia was 0.88 (0.84 to 0.92) (P for linear trend<0.001).
Birth weight increased by 15.1 (6.0 to 24.2) g (P for linear trend=0.005) and risk of low birth weight decreased by 3% (relative risk 0.97, 0.95 to 0.98) for every 10 mg increase in dose/day (P for linear trend<0.001).
Duration of use was not significantly associated with the outcomes after adjustment for dose. Furthermore, for each 1 g/L increase in mean haemoglobin, birth weight increased by 14.0 (6.8 to 21.8) g (P for linear trend=0.002); however, mean haemoglobin was not associated with the risk of low birth weight and preterm birth. No evidence of a significant effect on duration of gestation, small for gestational age births, and birth length was noted.
The analysis was restricted to trails with up to 66 mg iron/day supplementation, no information on effects of higher iron supplementation were provided.