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Can I Take Folic Acid and Iron Tablets Together

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Effect of routine iron supplementation with or without folic acid on anemia during pregnancy

BMC Public Health book xi, Article number:S21 (2011) Cite this commodity

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Abstract

Introduction

Atomic number 26 deficiency is the most prevalent nutrient deficiency in the world, particularly during pregnancy. Co-ordinate to the literature, anemia, particularly astringent anemia, is associated with increased risk of maternal mortality. It too puts mothers at risk of multiple perinatal complications. Numerous studies in the past take evaluated the bear upon of supplementation with iron and atomic number 26-folate but data regarding the efficacy and quality of show of these interventions are lacking. This article aims to address the impact of fe with and without folate supplementation on maternal anemia and provides outcome specific quality co-ordinate to the Child Wellness Epidemiology Reference Group (CHERG) guidelines.

Methods

We conducted a systematic review of published randomized and quasi-randomized trials on PubMed and the Cochrane Library as per the CHERG guidelines. The studies selected employed daily supplementation of iron with or without folate compared with no intervention/placebo, and also compared intermittent supplementation with the daily regimen. The studies were abstracted and graded co-ordinate to study blueprint, limitations, intervention specifics and issue effects. CHERG rules were so practical to evaluate the impact of these interventions on iron deficiency anemia during pregnancy. Recommendations were made for the Lives Saved Tool (Listing).

Results

Later screening 3550 titles, 31 studies were selected for cess using CHERG criteria. Daily iron supplementation resulted in 73% reduction in the incidence of anemia at term (RR = 0.27; 95% CI: 0.17 – 0.42; random effects model) and 67% reduction in iron deficiency anemia at term (RR = 0.33; 95% CI: 0.16 – 0.69; random model) compared to no intervention/placebo. For this intervention, both these outcomes were graded as 'moderate' quality evidence. Daily supplementation with atomic number 26-folate was associated with 73% reduction in anemia at term (RR = 0.27; 95% CI: 0.12 – 0.56; random model) with a quality grade of 'moderate'. The effect of the aforementioned intervention on atomic number 26 deficiency anemia was non-significant (RR = 0.43; 95% CI: 0.17 – i.09; random model) and was graded as 'low' quality testify. There was no departure in rates of anemia at term with intermittent iron-folate vs. daily iron-folate supplementation (RR = ane.61; 95% CI: 0.82 –3.xiv; random model).

Conclusion

Applying the CHERG rules, we recommend a 73% reduction in anemia at term with daily iron (solitary) supplementation or iron/folate (combined) vs. no intervention or placebo; for inclusion in the LiST model. Given the paucity of studies of intermittent iron or iron-folate supplementation, specially in developing countries, we recommend further evaluation of this intervention in comparison with daily supplementation regimen.

Introduction

Effectually ii billion people, amounting to over 30% of the world's population are bloodless, mainly due to iron deficiency [one]. Iron deficiency is the most prevalent and also the most neglected nutrient deficiency in the globe, specially among meaning women and children, specially in developing countries [2]. It is likewise significantly prevalent in industrialized countries. Estimates say that globally, 50 half-dozen 1000000 pregnant women (41.8% of the full) are affected with anemia, again by and large due to fe deficiency [3]. In developing countries, this proportion tin exist as high every bit 80% like in Southern asia [4], making meaning mothers susceptible to increased adventure of mortality and decreased piece of work capacity. It may also lead to other perinatal complications like pre-eclampsia, low nascence weight, prematurity and perinatal mortality [5]. It is the poorest, virtually vulnerable and least educated who are unduly affected past fe deficiency, and it is this group that stands to proceeds the nearly by its reduction.

Anemia, equally divers past low hemoglobin or hematocrit, is unremarkably used to assess the severity of iron deficiency in populations without loftier rates of malaria. The high physiological requirement for iron in pregnancy is difficult to meet with most diets. Therefore, meaning women should routinely receive atomic number 26 supplementation, peculiarly in developing countries. Prenatal iron supplementation is non compulsory in many industrialized countries and the recommended dose is usually pocket-sized (30 mg ferrous iron daily) [half-dozen]. However, for developing countries, the recommendation is a daily dose of lx mg of iron for meaning, not-bloodless women for half-dozen months and an increased dose of 120 mg of fe daily if the elapsing of supplementation is shorter, if atomic number 26 deficiency prevalence in women of a given country is high, and if significant women are anemic. This supplement should include 400 µg of folic acid or lower doses if this amount is not available [7].

Earlier studies have provided sufficient testify to testify that iron supplementation with or without folic acid results in a significant reduction in the incidence of anemia during pregnancy [2, 8]. There has besides been a express impact of iron supplementation in community settings owing to lack of compliance and poor infrastructure [ix]. Still, information regarding quality of evidence for the effectiveness of iron during pregnancy are lacking. Besides, the data on studies in developing countries accept not been presented separately. This commodity is i of the series of papers that aim to determine efficacy of interventions for recommendations into the Lives Saved Tool (List), particularly in developing countries and is, therefore, unlike from previously published systematic reviews. In Listing, increases in coverage of an intervention results in a reduction of risk factor or one or more than causes of mortality. In this review, the recommendations are made based on application of adapted Grading of Recommendations, Assessment, Evolution and Evaluation (GRADE) approach for the quality of bear witness and utilize of the Child Wellness Epidemiology Reference Grouping (CHERG) rules. For more details of the review methods, the adjusted Grade approach or the LiST model, see the methods newspaper for by CHERG group [x].

Methods

Searching

We systematically reviewed all published literature up to June 21, 2010 to identify studies of atomic number 26 supplementation with or without folic acid during pregnancy on maternal anemia. As per the Child Health Epidemiology Reference Group (CHERG) systematic review guidelines [ten], nosotros searched PubMed and the Cochrane Library, and included publications in any linguistic communication available in these databases. Every effort was made to gather unpublished information when reports were bachelor for total abstraction. Previous reviews on the topic were as well hand-searched to await for relevant studies [2, 8, 11]. We used the Medical Bailiwick Heading Terms (MeSH) and free text terms for the search strategy using a combination of terms for iron, folic acid and pregnancy, equally follows:

("Iron"[Mesh OR "Folic Acid"[Mesh] OR fe OR folic acid OR folate) AND ("Anemia"[Mesh] OR "Anemia, Fe-Deficiency"[Mesh] OR anemia) AND (pregnancy OR maternal)

Inclusion/exclusion criteria

Nosotros limited our search to randomized and quasi-randomized trials conducted in both adult and developing countries, comparing the effects of preventive prenatal oral iron or iron + folic acrid supplements among significant women versus no treatment/placebo. The developing countries were divers as countries with Gross National Income per capita (GNI) below US$11,905, according to World Banking company [12]. Pregnant mothers could be of any historic period or parity. Studies were included if fe or iron-folate was given lone to the intervention group. Those studies were excluded that assessed the effects of multiple combinations of vitamins and minerals except fifty-fifty if iron/iron-folate was the only difference amongst the study groups (arms). All included studies contained a placebo or a suitable control grouping that did not contain iron or iron-folate. There were no limits on gestational age at the time of enrolment in the study and the elapsing of supplementation. Studies of peri-conceptional or postpartum fe/iron-folate supplementation were excluded. Studies of fortification of iron/iron-folate in food or studies in which iron was given in forms other than oral supplements like pulverization were excluded. Similarly, studies where atomic number 26 or atomic number 26-folate was given in whatever parenteral conception were excluded. Other exclusion criteria included trials of supplementation with multiple micronutrients (MMN) containing iron or fe + folic acrid in comparison to supplementation with iron or fe + folic acid solitary as this has been reviewed in some other paper of this series [13]. Studies where atomic number 26/iron-folate was given to anemic pregnant women as a medical treatment were too excluded as the primary objective of this review was to assess the efficacy of preventive iron/folate supplementation for anemia during pregnancy. The therapeutic role of atomic number 26 for anemia during pregnancy had been reviewed elsewhere [14]. We conducted sub-group analyses with respect to study country setting i.e. developed or developing. However, we did not specifically evaluate minor adverse furnishings of the supplements such as nausea, vomiting, headache or constipation among the pregnant mothers.

Brainchild, analyses and summary measures

Studies were included if data from one of the following outcomes was provided: anemia at term, iron deficiency anemia at term, severe anemia at term and astringent anemia at any time during the second and third trimester. All outcome measures to be included were determined a priori. The interventions described in this review can be subdivided into four categories: i) daily atomic number 26 supplementation alone compared to placebo/command, 2) weekly iron supplementation alone compared to daily regimen, 3) daily supplementation of fe and folic acid versus placebo/control and 4) weekly supplementation of iron and folic acid versus daily supplementation.

All studies that met concluding inclusion and exclusion criteria were double-information abstracted into a standardized form for each consequence of interest. Nosotros abstracted key variables with regard to the written report identifiers and context, study design and limitations, intervention specifics, and event effects. Each study was assessed and graded according to the CHERG adaptation of the Class technique [15]. Studies received an initial score of high if they were RCTs or cluster-RCTs (cRCTs). The grade was decreased by 0.5 - 1 point for each study design limitation like inadequate methods of sequence generation, allocation concealment and compunction > 20% etc. In addition, studies reporting an intent-to-care for analysis or with statistically significant potent levels of association (> 80% reduction) received 0.v – 1.0 grade increase. Whatever written report with a final grade of very low was excluded on the basis of inadequate written report quality.

For whatsoever outcome with more than ane report, we conducted a meta-analysis and reported the Mantel-Haenszel pooled relative risk and respective 95% confidence interval (CI). In case of heterogeneity (P < 0.1 and I2 > fifty%), the random effect model (DerSimonian-Laird) pooled relative risk and corresponding 95% CI was used, especially where in that location was unexplained heterogeneity such equally major differences in report design [ten]. All analyses were conducted using RevMan v statistical software.

We summarized the evidence based on outcome by including cess of the study quality and quantitative measures co-ordinate to standard guidelines [ten] for each outcome. For the outcomes of interest, namely the consequence of iron/atomic number 26-folate on maternal anemia, we practical the CHERG Rules for Testify Review [10] to recommend final estimates for reduction in anemia with atomic number 26 or iron-folate supplementation. Additional file one contains a list of studies from the search that were excluded from the meta-analyses with a brief explanation for why the study was excluded.

Definitions

Anemia was defined every bit hemoglobin (Hb) level of less than 110g/Fifty and severe anemia was defined every bit hemoglobin level of less than 70g/L. Iron deficiency anemia was defined every bit Hb less than 110 g/L and at least one additional laboratory indicator (mean cell volume, haemoglobin concentration, serum ferritin, erythrocyte protoporphyrin concentrations etc) of fe deficiency .

Results

The search generated 3550 hits on PubMed and 290 in Cochrane Library that were screened and afterward removing duplicates, 81 abstracts were preliminarily selected. These were reviewed in particular, including full texts and finally 31 [16–47] studies were selected for inclusion in this paper. A detailed account of the number of abstracts and titles scanned is given every bit a menstruum chart (Figure i). Table i gives the summary of the quality of bear witness and the touch estimates of different interventions.

Figure 1
figure 1

Flow chart of the literature search

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Table ane Quality assessment of trials of fe and/or folate on the incidence of anemia during pregnancy

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Anemia at term

This outcome was reported past 18 studies [16, 17, 19–21, 23, 24, 27, 29, 30, 32–34, 37–39, 41, 47]. Daily supplementation with atomic number 26 merely versus no intervention/placebo was evaluated past 14 studies [17, xix, 21, 23, 24, 27, 29, xxx, 33, 34, 37–39, 41]. There was a statistically significant 73% reduction in the incidence of anemia at term (RR = 0.27; 95% CI: 0.17 – 0.42; random model) (Figure ii). There were three studies [16, 17, 21] that evaluated daily supplementation with iron and folic acid both versus no intervention/placebo and pooled data as well showed a significant 73% reduction in anemia at term (RR = 0.27; 95% CI: 0.12 – 0.56; random model) (Figure three). There was, still, no divergence between intermittent iron-folic acid supplementation vs. daily iron-folate on this outcome based on three studies [20, 32, 47] (RR = 1.61; 95% CI: 0.82 –iii.xiv; random model) (Figure 4).

Figure ii
figure 2

Affect of daily iron supplementation compared with no supplementation on anemia at term (hemoglobin less than 110g/L)

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Figure three
figure 3

Affect of daily supplementation with iron and folate compared with no supplementation on anemia at term (hemoglobin less than 110g/L)

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Figure four
figure 4

Affect of intermittent supplementation with fe and folic acid compared with daily supplementation on anemia at term (hemoglobin less than 110g/L)

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Iron deficiency anemia at term

This outcome was reported by 7 studies [23, 27, 31, 33, 34, 43, 45]. Daily supplementation with atomic number 26 lone versus no intervention/placebo had a significant 67% reduction in incidence of iron deficiency anemia at term based on six studies [23, 27, 33, 34, 43, 45] (RR = 0.33; 95% CI: 0.16 – 0.69; random model). There was one study [31] on daily fe-folic acid versus no intervention/placebo and the upshot was big but non-significant (RR = 0.43; 95% CI: 0.17 – ane.09; random model)

Severe anemia at term

This outcome was estimated by 13 studies [16, eighteen, 20, 23, 27, 30–35, 41, 45]. Daily iron supplementation versus no intervention/placebo, as seen in viii studies [18, 23, 27, 30, 33, 34, 41, 45], had a non significant adverse impact on astringent anemia at term (RR = 4.83; 95% CI: 0.23 - 99.88; random model). This event was primarily based on one study [33] every bit all the other studies had zero events in both groups. Three studies evaluated the impact of daily supplementation with iron and folate both on severe anemia at term [16, 18, 31], merely the number of events in these studies in both groups was aught. Intermittent supplementation with iron and folate vs. daily supplementation of aforementioned micronutrients also yielded no severely anemic patients in the intervention and command groups in the three studies that looked at this event [twenty, 32, 35].

Severe anemia at any time during 2d and third trimester

Severe anemia during second and tertiary trimester was reported by 19 studies [sixteen, 18, 22, 23, 25, 27, 28, xxx–36, 40, 42, 44–46]. Daily iron alone compared to no supplementation had no impact on severe anemia in second and 3rd trimester based on ix studies [xviii, 22, 23, 27, 28, 30, 33, 34, 45], (RR = 0.48; 95% CI: 0.01 – 34.52; random model), with only two studies [22, 33] having events greater than zero in the intervention and control groups. For intermittent iron alone vs. daily atomic number 26 alone, there were two studies [36, 44] that looked at this outcome and both had zero events in the two groups. Daily iron-folic acid versus no intervention/placebo too had no result on severe anemia at whatsoever time during second and third trimester based on four studies [16, 18, 22, 31] (RR = 0.11; 95% CI: 0.01 – 0.83), with zero events in three of these studies in both groups, except i [22]. Intermittent fe-folate vs. daily iron-folate outcome included half dozen studies [25, 32, 35, twoscore, 42, 46] and events were nil in both groups in all these six studies.

Discussion

Iron supplementation alone or in combination with folic acid has been associated with the well being of the mother and fetus. Information technology leads to a significant reduction in anemia incidence during pregnancy and, thus, plays a vital office in reducing maternal morbidity and mortality. The results of our review were consistent with those of an before Cochrane review past Pena Rosas and Viteri [ii] that also showed a significant reduction in incidence of anemia and iron deficiency anemia at term with daily iron supplementation and that of anemia at term due to daily fe-folate supplementation versus no intervention/placebo.

The pooled assay of outcome of daily fe supplementation vs. control had a loftier heterogeneity (fig two). The well-nigh likely explanation of this substantial statistical heterogeneity (I2 =73 %) is the variable effect size of the studies which in turn depend on the baseline anemia status of the study population. An important observation to brand is that the direction effect in all the studies was in the same direction. We can expect that biologic result of iron supplementation would differ based on prevalence of anemia in the report population. To farther elaborate on this ascertainment, we conducted a mail service hoc subgroup analysis based on baseline anemia condition of the written report population (information not shown). There were seven studies that included only non-anemic pregnant women based on laboratory bear witness of absence of anemia (hemoglobin < 110 chiliad/L) [21, 23, 24, 27, 29, 33, 39] and in other 7 studies, population was that of mixed status [17, 19, 30, 34, 37, 38, 41]. Pooled estimates for non-anemic women were less heterogeneous (I2 =47%) and size of summary approximate was less prominent (RR 0.31, 95 % CI 0.19-0.52) compared to that of mixed population that had more heterogeneous (I2=83%) and more prominent results (RR 0.22, 95 % CI 0.xi-0.47). This shows a strong biologic effect in favor of the intervention and also indicates that result of Iron supplementation would depend on degree of baseline anemia in the written report population.

CHERG rules were applied to the collective outcomes of anemia for recommendation of iron deficiency anemia into the LiST model. Daily supplementation with iron led to 73% reduction in incidence of anemia at term as compared to no supplementation. This intervention had a 'moderate' quality prove owing to some limitations in included studies like unclear [17, 21, 24, 30, 34, 38, 39, 41] or inadequate sequence generation [19], and high loss to follow upwardly [17, 23, 27]. Another limitation was that all the studies in the pooled analysis were non conducted in developing countries. In any instance, based on strong biologic plausibility and consequent direction of consequence beyond the studies, nosotros recommend a 73 % reduction in anemia at term with atomic number 26 supplementation during pregnancy, for inclusion in the Listing model. Daily supplementation with iron and folate led to 73% reduction in incidence of anemia at term when compared with no supplementation. We recommend this estimate for reduction in anemia at term for inclusion in the Listing model. The quality of evidence regarding this intervention had to be down-graded from 'high' to moderate due to some limitations like high loss to follow up [17] and unclear sequence generation [21] and as well the fact that all the studies were not conducted in developing countries.

Our results prove that there was not much difference in effect between fe lonely and iron-folate combined. The upshot sizes were like for both the analyses but CIs were wider for that of fe/folate, mainly due to less number of studies in the pooled analysis. This shows that nosotros can expect a similar biological effect when the iron is supplemented alone or in combination with folate. Nosotros did a subgroup for developing and developed countries. At that place were non sufficient studies from developing countries for all the analyses. An important observation to make in figure 2 is that fifty-fifty though there were two studies from developing countries, the results were very consistent (Itwo=0%). Fifty-fifty though there are not a lot of randomized trials conducted in developing countries but we can advise that iron supplementation would be much effective in developing world by looking at biological plausibility of the intervention. The populations that are well-nigh at adventure for iron deficiency and IDA are young children and women of reproductive age, peculiarly during pregnancy. The global estimates on prevalence of anemia showed that more than half the pregnant women and young children are anemic in Southeast Asia, Westward Pacific and Africa [48]. This shows that amount of effect would be substantially loftier in developing countries even so more efficacy trials are required to determine the behave of the intervention.

Weekly iron and folic acid supplementation (WIFS) is a relatively new miracle, and there is very little data at the moment comparison weekly supplementation with daily dosage. Weekly iron and folic acid supplementation, in synchrony with the turnover of mucosal cells, may be a promising substitute for daily iron supplementation and has been proposed as a more efficient preventive arroyo in public health programs [49, fifty]. The WHO says that WIFS should exist considered a strategy for prevention of iron deficiency in population groups where the prevalence of anemia is above 20% amidst women of reproductive historic period and mass fortification programs of staple foods with iron and folic acrid are unlikely to be implemented within 1-2 years. However, conclusive information regarding its efficacy equally compared to the daily regimen are non however available. Weekly dosage may have benefits of reduced side furnishings and increased compliance, but more than field randomized controlled trials are needed to establish the efficacy of weekly supplementation compared to daily regimen.

Conclusions

Iron supplementation has a significant benefit in reducing anemia and iron deficiency anemia at term. Fe in combination with folic acrid also has a beneficial bear on on anemia at term and should be routinely used in pregnant women at least in developing countries to reduce the incidence of anemia due to increased demands during pregnancy.

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Acknowledgment

This work was supported in part past a grant to the US Fund for UNICEF from the Neb & Melinda Gates Foundation (grant 43386) to "Promote evidence-based decision making in designing maternal, neonatal and child health interventions in low- and eye-income countries".

This article has been published as office of BMC Public Wellness Volume xi Supplement 3, 2011: Technical inputs, enhancements and applications of the Lives Saved Tool (Listing). The full contents of the supplement are available online at http://www.biomedcentral.com/1471-2458/eleven?consequence=S3.

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  1. Division of Women & Child Health, The Aga Khan Academy, Karachi, Pakistan

    Mohammad Yawar Yakoob & Zulfiqar A Bhutta

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Correspondence to Zulfiqar A Bhutta.

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Competing interests

We practice not accept any fiscal or non-financial competing interests for this review.

Authors' contributions

Professor Zulfiqar A Bhutta developed the parameters and scope for the review and secured back up. Dr Mohammad Yawar Yakoob undertook the literature search, data extraction and wrote the manuscript along under the supervision of Professor Bhutta.

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Yakoob, G.Y., Bhutta, Z.A. Effect of routine iron supplementation with or without folic acid on anemia during pregnancy. BMC Public Health 11, S21 (2011). https://doi.org/x.1186/1471-2458-11-S3-S21

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Keywords

  • Folic Acid
  • Iron Deficiency
  • Iron Deficiency Anemia
  • Severe Anemia
  • Iron Supplementation

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