The effects of oral ferrous bisglycinate supplementation on hemoglobin and ferritin concentrations in adults and children: a systematic review and meta-analysis of randomized controlled trials

Jordie A J Fischer; Arlin M Cherian; Jeffrey N Bone; Crystal D Karakochuk

doi:10.1093/nutrit/nuac106

. 2023 Feb 2;81(8):904–920. doi: 10.1093/nutrit/nuac106

The effects of oral ferrous bisglycinate supplementation on hemoglobin and ferritin concentrations in adults and children: a systematic review and meta-analysis of randomized controlled trials

Jordie A J Fischer ¹, Arlin M Cherian ², Jeffrey N Bone ³, Crystal D Karakochuk ^4,^✉

PMCID: PMC10331582 PMID: 36728680

Abstract

Context

Iron deficiency and anemia have serious consequences, especially for children and pregnant women. Iron salts are commonly provided as oral supplements to prevent and treat iron deficiency, despite poor bioavailability and frequently reported adverse side effects. Ferrous bisglycinate is a novel amino acid iron chelate that is thought to be more bioavailable and associated with fewer gastrointestinal (GI) adverse events as compared with iron salts.

Objective

A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the effects of ferrous bisglycinate supplementation compared with other iron supplements on hemoglobin and ferritin concentrations and GI adverse events.

Data sources

A systematic search of electronic databases and grey literature was performed up to July 17, 2020, yielding 17 RCTs that reported hemoglobin or ferritin concentrations following at least 4 weeks’ supplementation of ferrous bisglycinate compared with other iron supplements in any dose or frequency.

Data extraction

Random-effects meta-analyses were conducted among trials of pregnant women (n = 9) and children (n = 4); pooled estimates were expressed as standardized mean differences (SMDs). Incidence rate ratios (IRRs) were estimated for GI adverse events, using Poisson generalized linear mixed-effects models. The remaining trials in other populations (n = 4; men and nonpregnant women) were qualitatively evaluated.

Data analysis

Compared with other iron supplements, supplementation with ferrous bisglycinate for 4–20 weeks resulted in higher hemoglobin concentrations in pregnant women (SMD, 0.54 g/dL; 95% confidence interval [CI], 0.15–0.94; P < 0.01) and fewer reported GI adverse events (IRR, 0.36; 95%CI, 0.17–0.76; P < 0.01). We observed a non-significant trend for higher ferritin concentrations in pregnant women supplemented with ferrous bisglycinate. No significant differences in hemoglobin or ferritin concentrations were detected among children.

Conclusion

Ferrous bisglycinate shows some benefit over other iron supplements in increasing hemoglobin concentration and reducing GI adverse events among pregnant women. More trials are needed to assess the efficacy of ferrous bisglycinate against other iron supplements in other populations.

PROSPERO registration no

CRD42020196984.

Keywords: anemia, children, ferritin, ferrous bisglycinate, hemoglobin, iron, iron deficiency, pregnancy, systematic review

INTRODUCTION

Iron deficiency is one of the most prevalent nutritional disorders, affecting an estimated 2 billion people globally.¹ It has serious consequences on human health and development at all stages of life.² In infants and young children, iron deficiency may impair cognitive and psychomotor development and decrease physical activity levels.³ In adults, it can result in fatigue and reduce work capacity, burdening national economic growth.⁴ Women have higher dietary iron requirements due to monthly menstrual losses, and during pregnancy, women also need more iron to support the growing fetus.² Iron deficiency during pregnancy can cause anemia and is associated with an increased risk of maternal and fetal mortality and morbidity, premature birth, and low birth weight.⁵ For these reasons, there is a global consensus on the importance of alleviating and preventing iron deficiency in at-risk populations.⁶

Oral iron supplementation is a common approach to reduce, treat, and prevent this nutritional deficiency in individuals. However, the efficacy, safety, and tolerability of iron supplements are common issues that require study⁷^,⁸ because there is no global consensus on the optimal dose or form of elemental iron prescribed for iron deficiency treatment. Studies that have assessed iron bioavailability have shown that the form of iron supplementation is as important as the dose.⁹

Iron salts are a common form of iron supplements because they are inexpensive and readily accessible in the market. These conventional iron salts include ferrous sulfate, ferrous fumarate, ferrous gluconate, ferrous ascorbate, and ferrous glycine sulfate.^10–12 Iron bioavailability from inorganic salts is low; <20% is typically absorbed in the duodenum, and the remaining iron passes unabsorbed into the colon.¹³^,¹⁴ Ferrous iron often requires high therapeutic dosages (150–300 mg daily) for treatment,⁹ and phytates, commonly found in plant-based foods, further inhibit its absorption.¹⁵ Ferrous iron also irritates the stomach lining and can cause various adverse gastrointestinal (GI) side effects, such as heartburn, nausea, constipation, diarrhea, and abdominal pain. This poses a significant challenge to supplement compliance, potentially leading to decreased treatment efficacy.⁷^,¹⁶

Ferrous bisglycinate is an amino acid iron chelate that has at least 2-fold higher bioavailability than conventional iron salts and has been associated with fewer adverse GI side effects.^17–20 Ferrous bisglycinate chelate is a highly stable compound composed of 2 glycine molecules bound to a ferrous cation by covalent and coordinate covalent bonds.¹⁹ Owing to its chemical composition, ferrous bisglycinate chelate is not sequestered by iron absorption inhibitors, such as phytates, found in cereal-based foods,¹⁷^,¹⁸ which comprise a large portion of the diet in many countries. The amino acid iron chelate is thought to be better absorbed in the intestinal mucosal cells, thereby reducing adverse GI side effects and possibly increasing an individual’s adherence to the supplement.^20–22 Because of the superior bioavailability, smaller doses of ferrous bisglycinate may be warranted as compared with conventional iron salts. Because of inflammation and disease, a lower dose of iron may also be safer in individuals with iron overload or upregulated hepcidin expression.²³^,²⁴

The efficacy and tolerance of ferrous bisglycinate compared with other oral iron supplements has not yet been rigorously or systematically reviewed. These findings are key to informing nutrition policy on the most efficacious and well-tolerated forms of iron supplements to prevent, treat, and reduce iron deficiency and anemia globally. The aim was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effects of oral ferrous bisglycinate supplementation, as compared with other iron supplements, on hemoglobin and ferritin concentrations (primary outcomes) and GI adverse events (secondary outcome) in adults and children.

METHODS

This systematic review was conducted and reported following the Cochrane Collaboration Handbook of Systematic Reviews²⁵ and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.²⁶ The review protocol was registered in the PROSPERO database (registration no. CRD42020196984).

Eligibility criteria

Criteria for trial inclusion were (1) RCTs of parallel design among human participants of any age, regardless of iron status (deficient or replete) and reported comorbidities; (2) trials that included an intervention arm of oral ferrous bisglycinate as compared with other oral iron supplements; (3) trials of iron therapy of any dose, frequency, and duration of 4 weeks or longer (a minimum 4 weeks of supplementation is needed to assess a hemoglobin response); and (4) trial reports published in English or had translated English versions available.

Criteria for trial exclusion were (1) those that included iron plus other co-interventions (eg, folic acid or vitamin B₁₂ supplements in addition to iron) that did not include the same co-intervention in the comparator arm; (2) trials that administered either the ferrous bisglycinate or other iron interventions in a fortified food or drink.

Types of outcome measures

The following clinically relevant biomarkers commonly used to diagnose anemia and iron deficiency were selected as primary outcome measures: hemoglobin concentration (g/L) and plasma or serum ferritin concentration (μg/L). The secondary outcome was GI adverse events. Included studies reported on at least 1 of the 2 primary outcomes (Table 1).

Table 1.

PICOS criteria for inclusion of studies

Parameter	Description
Population	Human participants of any age, regardless of iron status
Intervention	Oral ferrous bisglycinate of any dose, frequency, and duration of ≥4 wk
Comparison	Another oral iron supplementation of any dose, frequency, and duration of ≥4 wk
Outcomes	Primary: hemoglobin concentration, plasma or serum ferritin concentration Secondary: Gastrointestinal adverse events
Study design	Randomized controlled trials of parallel design

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Search strategy

The following bibliographic online databases were searched for studies to include in this systematic review for all dates, from 1946 (when Ovid MEDLINE began indexing articles) up to and including July 17, 2020, following the PICO methodology²⁵: Ovid MEDLINE, Ovid Embase, Ovid CENTRAL, Cochrane Library, and Web of Science. Table S1 in the Supporting Information online contains the comprehensive search strategy performed on Ovid MEDLINE. Publications reporting RCTs with ferrous bisglycinate supplementation were identified in the Ovid MEDLINE search by using the following terms: iron bis(-)glycinate, ferrous bis(-) glycinate, iron chelate, iron amino acid chelate, Ferrochel, chelat* iron, iron deficiency, and iron deficient. No limits were set in terms of publication year.

A grey literature search was performed within the International Standard Randomized Controlled Trial Number Registry, World Health Organization International Clinical Trials Registry Platform, ProQuest Dissertations and Thesis, ClinicalTrials.gov, manual searches of journals via Google Scholar using keywords such as iron bisglycinate, ferrous bisglycinate, iron amino acid chelate, iron chelate, iron deficiency, and iron deficient. Additionally, reference lists of relevant articles were searched for more completed, ongoing, and unpublished trials, up to and including July 17, 2020.

Selection of studies

Search results from electronic databases were downloaded to a reference manager program (Mendeley, v1.19.4), and duplicate records were removed. Searches from other sources and studies with missing citation data were added manually. Next, references were imported to a systematic review screening software (Covidence) with screening guided in 2 phases: title and abstract screening and full-text screening.²⁷ Two independent reviewers (A.M.C. and J.A.J.F.) screened the titles and abstracts for potentially relevant published or unpublished studies on the basis of the study aim and inclusion and exclusion criteria to ensure inter-author agreement. The degree of agreement was measured using κ statistics. Discrepancies between the 2 reviewers for study inclusion were resolved by discussion and consensus. The 2 reviewers (A.M.C. and J.A.J.F.) then independently screened full texts of all identified trials to ensure they met the aforementioned inclusion criteria. Reasons for study exclusion were recorded at the full-text level.

Data extraction and management

Data were extracted using a form designed specifically for this review by 2 authors (A.M.C. and J.A.J.F.) and reviewed to reach a consensus. The following data were collected for each study: author identification, publication year, publication language, study setting, source of trial funding, study methods (patient selection, method of allocation, unit of randomization, masking of participants and outcomes, exclusion of participants after randomization, and proportion of losses at follow-up), sample size, participant characteristics (age, sex, weight, socioeconomic status, gastroenteric disease), experimental and comparator arms (iron formulation, dose, duration, frequency, length of follow-up, co-interventions), loss to follow-up, as well as results for the primary and secondary outcomes (definition and assessment methods and time) listed in Types of Outcome Measures section. In the event of repeated observations on participants, data from the time point closest to 3 months after baseline were chosen to be included in the meta-analysis. When information regarding any of the studies was unclear, the authors of the original reports were contacted for further details.

Assessment of risk of bias in included studies

Judgements of bias on individual studies were made by 2 independent review authors (A.M.C. and J.A.J.F.) using the Cochrane Collaboration Risk of Bias tool v2.0 for RCTs²⁸; disagreement between the 2 reviewers was resolved by discussion and input by a third author (C.D.K.). Each domain was categorized as having a low, high, or unclear risk of bias. When a study reported insufficient detail of what happened in the trial or the risk of bias is unknown, the judgement was an “unclear risk” of bias. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was used to assess the quality of the evidence for each outcome (A.M.C. and J.A.J.F.).²⁹

Measures of treatment effect

Study incidence rate ratio (IRR) was calculated for the dichotomous outcome of interest (GI adverse events).³⁰ A standardized mean difference (SMD) was calculated for continuous outcomes, such as hemoglobin (g/L) and ferritin concentrations (µg/L) across single studies.

Assessment of heterogeneity

Heterogeneity was assessed because the included trials varied widely in terms of iron doses, duration, populations, and methods. The methodological characteristics and risk of bias of included studies were examined to assess methodological heterogeneity. Heterogeneity was also statistically evaluated, as described in the next section. Heterogeneity was investigated to determine the causes by examining trial and subgroup characteristics. Reporting bias was assessed visually using funnel plots for asymmetry. Results were interpreted with caution in the event of high unexplained heterogeneity.

Data synthesis

It was decided a priori that a meta-analysis would only be conducted to provide an overall estimate of treatment effect if the populations, interventions, comparisons, and outcome measures were judged to be sufficiently similar to ensure clinically meaningful estimates. Thus, because population groups varied widely, meta-analyses were only conducted on trials of pregnant women (n = 9 trials) and children (n = 4 trials), because these population subgroups had the largest total sample sizes and number of comparable trials. The remaining trials of men and nonpregnant women (n = 4) were qualitatively evaluated. When a trial had more than 1 comparator arm, these arms were combined, because the primary interest was the comparison of ferrous bisglycinate vs other iron supplements.³¹

Data were pooled using meta-analytic random-effects models for the SMD between trial arms. To be conservative, confidence intervals (CIs) were calculated with the wider of the classic CI and the Hartung -Knapp CI.³² For count outcomes (namely, adverse events), IRRs were estimated using Poisson generalized linear mixed-effects models with log-link functions. The I² statistic was used to estimate the prediction intervals for each outcome to quantify the expected values for future studies and heterogeneity. Data were visualized with forest plots.

Sensitivity analysis.

A sensitivity analysis was conducted to address the risk of bias, excluding studies with 2 or more domains identified as high risk or unclear risk of bias. The number of included trials was low; therefore, a sensitivity analysis was conducted using Bayesian meta-analyses with hierarchical random-effects models to pool trial estimates, which allows for uncertainty in estimates to be modelled explicitly and has been shown to be advantageous in situations such as these where the number of trials is small and, thus, the quantification of heterogeneity (statistically) is a challenge.³³ In these analyses, a noninformative normal prior with a mean of 0 and variance of 10 000 was used. For the heterogeneity parameter τ2, a half Cauchy distribution with a scaling parameter of 0.5 and 100 000 iterations of Markov Chain Monte Carlo resampling was used. Results were summarized as median estimates from these iterations and 95% credible intervals. All analyses were performed with R statistical software, version 4.0.3, using the meta, brms, and bmeta packages.³⁴^,³⁵

RESULTS

Study selection

There were 816 articles and abstracts initially identified from the literature search. After removing duplicates, 614 titles and abstracts were screened for eligibility, of which 565 were excluded. Forty-eight articles underwent the full-text screening phase, and 31 articles were excluded on the basis of eligibility criteria. Seventeen trials were selected for inclusion in the systematic review, with 13 of those included in meta-analyses. The PRISMA flow diagram (Figure 1) demonstrates the search flow for this systematic review and meta-analysis.

Characteristics of included studies

Seventeen trials (N = 2191 individuals) were included in this review. Characteristics of the eligible trials are presented in Table 2,⁸^,¹⁷^,¹⁹^,²⁰^,²²^,^36–47 The sample size of the eligible trials ranged from 18 to 270 individuals. Trials were conducted with children,¹⁷^,¹⁹^,²²^,³⁶ adolescents,³⁷ pregnant women,⁸^,²⁰^,^38–45 nonpregnant women,³⁹ and adult patients with cancer.⁴⁶^,⁴⁷ The iron intervention duration ranged between 28 days and 5 months. Reported doses of ferrous bisglycinate for children ranged from 3 mg of elemental iron per kg of body weight to 30 mg of elemental iron daily; elemental iron doses for adolescents and adults ranged from 15 mg once daily to 60 mg twice daily of ferrous bisglycinate. Some trial interventions included folic acid combined with iron,¹⁷^,¹⁹^,³⁷ and others comprised folic acid and vitamin B₁₂ in all intervention arms.⁸^,²⁰ The other forms of iron supplements (the comparator group) included ferrous sulfate,¹⁷^,¹⁹^,²⁰^,³⁶^,³⁷^,³⁹^,⁴¹^,⁴³^,⁴⁴^,⁴⁶^,⁴⁸ ferrous fumarate,⁸^,^38–40^,⁴² carbonyl iron,⁸ iron multi–amino acid chelate,³⁸ ferrous ascorbate,³⁹^,⁴⁵^,⁴⁶ sodium feredetate,³⁹ ferrous glycine sulfate,⁴¹ and polymaltose iron.²² Eight trials only included individuals diagnosed with iron deficiency anemia (defined as hemoglobin and serum ferritin concentration both below a specific threshold for that population),²²^,³⁶^,⁴⁰–42^,⁴⁵^,⁴⁷^,⁴⁸ 6 trials enrolled only individuals diagnosed with anemia,⁸^,¹⁹^,^37–39^,⁴³ and 1 trial included only iron-deficient individuals without anemia.¹⁷ In comparison, 1 trial enrolled only healthy participants,²⁰ and for another trial, hemoglobin and ferritin were not screening requirements for trial inclusion.⁴⁴ All trials included hemoglobin concentration and ferritin concentration measures at baseline and following the supplementation intervention period, except 1 trial in which participants’ hemoglobin concentration was measured at both time points.³⁶ In 11 studies GI adverse events also were studied. Trials were conducted in Brazil,²²^,⁴⁴^,⁴⁷ Denmark,²⁰ Egypt,³⁸^,^40–42 Guatemala,¹⁹^,³⁷ Italy,⁴⁶ India,⁸^,³⁹^,⁴⁵ Mexico,¹⁷ Pakistan,³⁶ and the Philippines,⁴³ and were published between 1994 and 2019.

Table 2.

Characteristics of included trials in the systematic review

Study	Country	Study population	Baseline anemia/iron deficiency/IDA status	Duration	FB intervention	Oral elemental iron comparator	Participants randomized	Outcomes^a
Children
Pineda et al 2001¹⁹	Guatemala	Children (aged 6–36 mo) admitted to the Nutritional Recovery Unit of the Pediatric Department for protein-energy malnutrition Boys: 55% Girls: 45%	Anemia (Hb <11 g/dL)	28 d	Syrup containing 5 mg iron/kg body weight + 250 µg folic acid once daily	FS: syrup containing 5 mg iron/kg of body weight + 250 µg folic acid once daily	N = 40 FB = 20 C = 20	Hb, plasma ferritin
Duque et al 2014¹⁷	Mexico	School children (aged 5–13 y) in public boarding schools	Iron deficiency without anemia (serum ferritin <12 μg/L and altitude-adjusted Hb >12 g/dL for children aged ≥12 y and Hb >11.5 for those aged <12 y	3 mo	30 mg elemental iron + 250 µg folic acid once daily	FS: 30 mg elemental iron + 250 µg folic acid once daily	N = 200 FB = 101 FS = 99	Hb, serum ferritin
Name et al 2018²²	Brazil	Children (aged 1–13 y) attending a nonprofit institution for low-income families	Iron deficiency anemia (Hb <11 g/dL for children aged 6–59 mo; <11.5 g/dL for those aged 5–11 y; <12 g/dL for those ≥12 y and alterations in at least 1 parameter [MCV, MCH, ferritin or transferrin])	45 d	3 mg of elemental iron/kg of body weight	PI: 3 mg of elemental iron/kg body weight	N= 20 FB = 9 PI = 11	Hb, serum ferritin
Parveen et al 2020³⁶	Pakistan	Children (aged 6–60 mo)	IDA (Hb 7–10.9 g/dL, MCV < 70 fL, MCHC <20 g/dL, and serum ferritin <10 μg/L)	12 wk	5 mg iron/kg body weight per day—divided into 2 daily doses	FS: 5 mg iron/kg body weight per day—divided into 2 daily doses	N = 136 FB = 68 FF = 68	Hb
Adolescents
Pineda et al 1994³⁷	Guatemala	Adolescents (aged 10–19 y) living on a sugar-mill plantation in the lowlands of Guatemala Men: 42% Women: 58%	Anemia (Hb <12 g/dL)	4 wk	30, 60, or 120 mg iron + 250 µg folic acid once daily	FS: 120 mg iron once daily	N = 100 30 FB = 26 60 FB = 21 120 FB = 26 FS = 27	Hb, plasma ferritin, GI adverse events
Pregnant women
Szarfarc et al 2001⁴⁴	Brazil	Pregnant women enrolled in a prenatal course at <20 wk of gestation	Not a screening requirement for inclusion	10–20 wk	15 mg elemental iron once daily	FS: 40 mg elemental iron once daily	N = 145 FB = 71 FS = 74	Hb, serum ferritin, GI adverse events
Patil et al 2013⁸	India	Pregnant women participating in a prenatal check-up program between 12 and 22 wk of gestation	Anemia (Hb 7–10 g/dL), iron status unknown	90 d	100 mg elemental iron + 1.5 mg folic acid + 10 μg vitamin B₁₂ once daily	FF and carbonyl iron: 100 mg elemental iron + 1.5 mg folic acid + 10 µg vitamin B₁₂ once daily	N = 60 FB = 20 FF = 20 C = 20	Hb, serum ferritin
Milman et al 2014²⁰	Denmark	Healthy White women (aged >18 y) with a normal single pregnancy at 15–19 wk of gestation	Healthy	17–22 wk	25 mg elemental iron + multivitamin/multimineral tablets containing folic acid and vitamin B₁₂	FS: 50 mg elemental iron + multivitamin/multimineral tablets containing folic acid and vitamin B₁₂ (no iron)	N = 80 FB = 40 FS = 40	Hb, serum ferritin, GI adverse events
Youssef et al 2014³⁸	Egypt	Pregnant women (aged 18–40 y) attending outpatient clinic that participated in a prenatal checkup program after 13 wk of gestation	Anemia (Hb 7–9 g/dL and with microcytic hypochromic anemia diagnosis)	4 wk	27 mg elemental iron once daily	IMAAC: 15 mg elemental iron twice daily FF: 66 mg elemental iron 3 times daily	N = 300 FB = 100 IMAAC = 100 FF = 100	Hb, serum ferritin, GI adverse events
Singhal et al 2015³⁹	India	Pregnant women attending the antenatal clinic at a tertiary care center between 16–28 wk of gestation	Anemia (Hb 7–10 g/dL)	60 d	30 mg elemental iron once daily	FS or FF or FA: 100 mg elemental iron once daily SF: 33 mg elemental iron once daily	N = 250 FB = 50 FS = 50 FF = 50 FA = 50 SF = 50	Hb, serum ferritin, GI adverse events
Abdel Moety et al 2017⁴⁰	Egypt	Pregnant women at 14–18 wk of gestation	IDA (Hb 7–10.9 g/dL and serum ferritin <12 μg/L)	12 wk	15 mg elemental iron once daily	FF: 115 mg elemental iron once daily	N = 150 FB = 75 FF = 75	Hb, serum ferritin, GI adverse events
Abbas et al 2018⁴¹	Egypt	Pregnant women between 14–18 wk of gestation	IDA (Hb 7–10.9 g/dL and serum ferritin <15 mg/L)	8 wk	27 mg elemental iron once daily	FGS: 100 mg elemental iron once daily	N = 200 FB = 100 FGS = 100	Hb, serum ferritin, GI adverse events
Santiago et al 2018⁴³	Philippines	Outpatient pregnant women (aged 18–36 y) with singleton pregnancies	Anemia (Hb 10–11 g/dL during the first and third trimester, or 9.6–11 g/dL during the second trimester)	3 mo	30 mg elemental iron twice per day	FS: 65 mg elemental iron twice per day	N = 48 FB = 24 FS = 24	Hb, serum ferritin, GI adverse events
Makled et al 2020⁴²	Egypt	Pregnant women attending the antenatal care outpatient clinic between 14 and 18 wk of gestation	IDA (Hb 8–10.5 g/dL and serum ferritin <15 μg/L)	12 wk	15 mg elemental iron once daily	FF: 115 mg elemental iron once daily	N = 150 FB = 75 FF = 75	Hb, serum ferritin, GI adverse events
Nonpregnant women
GlaxoSmithKline 2018⁴⁵	India	Nonpregnant women (aged 18–55 y) in an outpatient setting	IDA (Hb 6–9 g/dL and serum ferritin <15 μg/L)	8 wk	60 mg elemental iron once daily, 60 mg twice daily	FA: 100 mg elemental iron once daily	N = 270 FB = 89 FB = 91 FA = 90	Hb, GI adverse events
Patients with cancer
Mimura et al 2008⁴⁷	Brazil	Patients with gastric cancer who underwent gastrectomy Men: 55% Women: 45%	IDA (Hb <12 g/dL, transferrin saturation <16%, and serum ferritin <20 μg/L)	4 mo	50 mg elemental iron once daily	FS: 80 mg elemental iron once daily	N = 18 FB = 9 FS = 9	Hb, serum ferritin
Ferrari et al 2012⁴⁶	Italy	Adults (aged 45–75 y) operated on for solid cancers (breast, colorectal, gastric) Men: 42% Women: 58%	IDA (Hb 10 –12 g/dL and ferritin < 30 ng/mL)	60 d	28 mg elemental iron once daily for 20 d, then 14 mg iron once daily for 40 d	FS: 105 mg elemental iron once daily for 60 d	N = 24 FB = 12 FS = 12	Hb, serum ferritin, GI adverse events

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Outcomes reported in each of the trials relevant to the primary or secondary outcomes in this review.

Abbreviations: FA, ferrous ascorbate; FB, ferrous bisglycinate; FF, ferrous fumarate; FGS, ferrous glycine sulfate; FS, ferrous sulfate; GI, gastrointestinal; Hb, hemoglobin; IDA, iron deficiency anemia; IMAAC, iron multi–amino acid chelate; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PI, polymaltose iron; SF, sodium feredetate.

Effect of intervention

Pooled effects in pregnant women.

Nine studies (n = 1383 pregnant women) were identified and included in the meta-analysis comparing ferrous bisglycinate and other iron supplements in pregnant women.⁸^,²⁰^,^38–44 One study was excluded from the hemoglobin meta-analysis because it only included mean change and no endline values³⁹; another study was excluded from the ferritin meta-analysis because it reported geometric mean values.²⁰ Of these 9 studies in pregnant women, the forms and doses of elemental iron in the comparator interventions included ferrous sulfate (40–100 mg),²⁰^,³⁹^,⁴³^,⁴⁴ ferrous fumarate (66–115 mg),⁸^,^38–40^,⁴² ferrous ascorbate (100 mg),³⁹^,⁴⁵ ferrous glycine sulfate (100 mg),⁴¹ carbonyl iron (100 mg),⁸ sodium feredetate (33 mg),³⁹ and iron multi–amino acid chelate (15 mg).³⁸ Eight trials provided a ferrous bisglycinate dose of 15–30 mg daily, with 1 trial providing 100 mg.⁸

Primary outcomes.

The pooled SMD (95%CI) for postintervention hemoglobin concentrations by random-effects model was greater in those receiving ferrous bisglycinate as compared with those receiving other iron supplements (0.54 [0.15, 0.94] g/dL; heterogeneity: I² = 90%; P < 0.01) (Figure 2).⁸^,²⁰^,³⁸^,^40–44 The pooled effect size for ferritin concentrations (SMD [95%CI]) was 0.31 (–0.11, 0.73) µg/L; heterogeneity, I² = 91%; P < 0.01 (Figure 3),⁸^,^38–44 showing minimal differences. The results are uncertain but showed potential for a trend consistent with a slight decrease (–0.11) to moderate increases (0.73) in ferritin concentrations in those supplemented with ferrous bisglycinate. Significant heterogeneity was found among the trials of both hemoglobin and ferritin analyses, and evidence of significant publication bias was observed (Figures S1 and S2, Funnel plots in the Supporting Information online).

Forest plot of trials (n = 8) comparing the effects of ferrous bisglycinate supplementation and other iron supplements on hemoglobin concentrations in pregnant women (>0 favors ferrous bisglycinate, <0 favors other iron supplements). CI, confidence interval; SD, standard deviation; SMD, standardized mean difference.

Forest plot of trials (n = 8) comparing the effects of ferrous bisglycinate supplementation and other iron supplements on ferritin concentrations in pregnant women (>0 favors ferrous bisglycinate, <0 favors other iron supplements). CI, confidence interval; SD, standard deviation; SMD, standardized mean difference.

Secondary outcome.

Supplementation with ferrous bisglycinate resulted in fewer reported adverse GI side effects (IRR, 0.36 [95%CI, 0.17–0.76]; heterogeneity, I² = 90%; P < 0.01) as compared with other iron supplements (Figure 4).^38–44

Forest plot of trials (n = 7) comparing the effects of ferrous bisglycinate supplementation and other iron supplements on risk of adverse gastrointestinal side events in pregnant women (>1 favors other iron supplements, <1 favors ferrous bisglycinate). CI, confidence interval; IRR, incidence rate ratio.

Pooled effects in children.

Four trials (n = 456 children) evaluating the effects of ferrous bisglycinate on hemoglobin and ferritin concentrations compared with other iron supplements in children were included in this pooled analysis.¹⁷^,¹⁹^,²²^,³⁶ Three trials provided ferrous sulfate as the iron comparator, and 1 trial provided polymaltose iron. In these trials, the doses of elemental iron were 3–5 mg iron per kg body weight or 30 mg iron daily in both the ferrous bisglycinate and iron comparator arms.

Primary outcomes.

The pooled SMD and 95%CI for postintervention hemoglobin concentrations in children by random-effects model were not significantly different between children receiving ferrous bisglycinate supplementation and other iron supplements (0.10 (–0.10, 0.30) g/dL; heterogeneity, I² = 0%, P = 0.80) (Figure 5).¹⁷^,¹⁹^,²²^,³⁶ Similarly, the pooled effect size for ferritin concentrations (SMD [95%CI]) was 0.42 (–0.14, 0.98) µg/L; heterogeneity, I² = 64%, P = 0.06) (Figure 6).¹⁷^,¹⁹^,²² For both outcomes, the data were compatible with favorable outcomes for ferrous bisglycinate or small decreases compared with the control. Evidence of significant publication bias was observed via visual inspection of funnel plot asymmetry (Figures S3 and S4 in the Supporting Information online).

Forest plot of trials (n = 4) comparing the effects of ferrous bisglycinate supplementation and other iron supplements on hemoglobin concentrations in children (>0 favors ferrous bisglycinate, <0 favors other iron supplements). ¹⁹ CI, confidence interval; SD, standard deviation; SMD, standardized mean difference.

Forest plot of trials (n = 3) comparing the effects of ferrous bisglycinate supplementation and other iron supplements on ferritin concentrations in children (>0 favors ferrous bisglycinate, <0 favors other iron supplements). ¹⁹ CI, confidence interval; SD, standard deviation; SMD, standardized mean difference.

Effect of interventions in all populations.

The measurable outcome of each included study is found in Supplementary Table 2. Subgroup meta-analysis was only deemed appropriate for 2 population groups (pregnant women [n = 9 trials] and children [n = 6 trials]) on the basis of the degree of heterogeneity in the trials and the inherent biological variation in iron metabolism across sex,⁴⁹ life stage,⁴⁹ pregnancy status,⁵⁰ and inflammation status²⁴ across the population groups in these trials. Furthermore, there was an insufficient number of trials for the certain population subgroups of interest (adolescents [n = 1], nonpregnant women [n = 1], and patients with cancer [n = 2]).

The 4 trials³⁷^,^45–47 not included in the meta-analysis are narratively synthesized below. One trial included 100 Guatemalan adolescents (aged 10–19 years) with anemia who were randomly assigned to receive 30, 60, or 120 mg iron as ferrous bisglycinate or 120 mg iron as ferrous sulfate plus 250 µg folic acid for 4 weeks.³⁷ Hemoglobin concentrations significantly increased in all intervention groups after 4 weeks of intervention, but the authors found no significant differences in hemoglobin concentration between groups at 4 weeks. Adolescents in the 30-mg ferrous bisglycinate group had a significantly lower mean ferritin concentration following the 4-week intervention (P = 0.01) than the 120-mg ferrous sulfate, and 120- and 60-mg ferrous bisglycinate groups. Yet, the remaining 3 iron intervention groups (120 mg ferrous sulfate and 120 and 60 mg ferrous bisglycinate) were not significantly different from one another (no P values stated). Finally, adolescents in the 120-mg ferrous sulfate group were twice as likely to report gastric complaints than those in the 120-mg ferrous bisglycinate group (33.3% vs 15.4%). Only 9.5% of adolescents in the 60 mg ferrous bisglycinate group reported GI adverse events, and no adolescents reported gastric complaints in the 30-mg ferrous bisglycinate group. Study outcomes may be biased because the trial was evaluated to have a high risk of bias arising from the randomization process due to a lack of reported randomization information.

A trial among 270 nonpregnant women (aged 18–65 years) with iron deficiency anemia (IDA) in India were randomized to the following interventions: 100 mg ferrous bisglycinate once daily, 100 mg ferrous bisglycinate twice daily, or 100 mg ferrous ascorbate once daily for 8 weeks (unpublished data).⁴⁵ Hemoglobin concentrations significantly increased in all 3 groups (P < 0.001) after 8 weeks of intervention, but no differences were found between groups at 8 weeks (P > 0.05). Prevalence of reported GI adverse events (namely, abdominal pain, gastritis, nausea, dyspepsia, change in bowel habit, constipation, discolored feces, diarrhea, and flatulence) was ∼13% among women in the 100-mg ferrous ascorbate once daily group, ∼13% among women in the twice daily ferrous bisglycinate group, and 9% among women in the once daily ferrous bisglycinate group (statistical test comparisons were not reported).

Two trials that compared ferrous bisglycinate and ferrous sulfate have been conducted with patients with cancer who had IDA. Mimura et al⁴⁷ led a trial of 18 men and women with gastrectomized gastric cancer and IDA in Brazil who were randomly assigned to receive 50 mg ferrous bisglycinate or 80 mg ferrous sulfate once daily for 4 months. The authors found a nonsignificant trend of higher hemoglobin concentrations in the ferrous sulfate groups after 4 months, as compared with the ferrous bisglycinate group (P < 0.09). Adults in the ferrous sulfate group had higher mean ferritin concentrations than adults in the 50-mg ferrous bisglycinate group (P < 0.04) after 4 months in this specialized population of patients with cancer who had undergone gastrectomy and who had IDA. There were no differences in reported side effects between intervention groups, but these findings are limited by the small sample size (n = 18).

In another study, 24 Italian adult patients with cancer who had undergone surgery for solid cancerous tumors (including breast, colorectal, and gastric tumors) with IDA (aged 45–75 years) were randomly assigned to receive 28 mg ferrous bisglycinate daily for 20 days followed by 14 mg for 40 days or 105 mg ferrous sulfate for 60 days.⁴⁶ Authors found that hemoglobin concentrations significantly increased in both groups after the intervention (ferrous bisglycinate, P = 0.0003; ferrous sulfate, P < 0.0001), but no difference in hemoglobin concentrations was detected between groups after 60 days (P = 0.924). Similarly, ferritin concentrations increased in both groups after the intervention (ferrous bisglycinate, P = 0.020; ferrous sulfate, P = 0.017), but no difference in ferritin concentration was detected between groups at 60 days (P = 0.685). Finally, adverse GI adverse events (ie, stomach pain, nausea, diarrhea, or constipation) were reported among 17% of adults in the ferrous bisglycinate group and 33% in the ferrous sulfate group (statistical test comparisons were not reported, possibly because total adverse events only numbered 7 in the combined groups).

Sensitivity analysis.

Studies of pregnant women assessed with a high or unclear risk of bias in 2 or more domains were removed from the meta-analyses in a sensitivity analysis on the basis of the risk of bias assessments. With the removal of 5 studies,⁸^,³⁸^,³⁹^,⁴³^,⁴⁴ the pooled effect size for hemoglobin concentrations (SMD [95%CI]) was 0.53 (–0.04, 1.11) g/dL (heterogeneity, I² = 91%; P < 0.01). Contrary to the primary outcome analysis, this sensitivity analysis showed a nonsignificant difference in postintervention hemoglobin concentration in pregnant women receiving ferrous bisglycinate compared with other iron supplements but is limited by a small number of studies (n = 4). The sensitivity analysis results for the ferritin concentration outcome in pregnant women were consistent with those of the primary analysis.

One study of children assessed with a high or unclear risk of bias in 2 or more domains was removed from the meta-analyses in a sensitivity analysis³⁶ but did not change the overall result. No sensitivity analysis was conducted for ferritin concentration in children, because all the studies in the primary analysis had a low risk of bias.

Results using Bayesian methods were broadly consistent with the frequentist random-effects models, with credible intervals being slightly wider than CIs (see Table S3 in the Supporting Information online).

Quality of evidence

The GRADE approach was used to assess the quality of evidence on outcomes across studies and rated for levels of evidence quality (high, moderate, low, or very low). The overall certainty of evidence for the effect of ferrous bisglycinate on primary outcomes (hemoglobin and ferritin) was rated very low (Table 3).

Table 3.

Quality of evidence included in the systematic review and meta-analysis of the effect of ferrous bisglycinate on hemoglobin, ferritin, and adverse gastrointestinal side effects, based on the GRADE approach

Population	No. of participants (no. of studies)	Relative (95%CI)	Absolute (95%CI)	Certainty	Importance
Hemoglobin
Pregnant women	1120 (8)	–	SMD 0.54 SD higher (0.15 higher to 0.94 higher)	⊕○○○ Very low^a^,^b^,^c Due to risk of bias and imprecision	Critical
Children	394 (4)	–	SMD 0.10 SD higher (0.10 lower to 0.30 higher)		Critical
Ferritin
Pregnant women	1170 (7)	–	SMD 0.31 SD higher (0.11 lower to 0.73 higher)	⊕○○○ Very low^a,c,d due to risk of bias and imprecision	Critical
Children	260 (3)	–	SMD 0.42 SD higher (0.14 lower to 0.98 higher)	⊕○○○ Very low^a,c,d due to risk of bias and imprecision	Critical
Gastrointestinal adverse effects^e
Pregnant women	1243 (7)	IRR 0.36 (0.17–0.76)	255 fewer per 1000 (from 331 fewer to 96 fewer)	⊕◯◯◯ Very low^a^,^c due to risk of bias	Important

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Only 4 out of 17 trials included showed an overall low risk of bias. Seven trials showed an unclear risk of bias for reasons including little to no information bias on randomization process and deviations from intended interventions and bias in measurements of outcomes. Six trials showed a high risk of bias due to bias arising from the randomization process. Some trials were not double-blinded or did not analyze data according to a prespecified plan or had missing outcomes and issues with data measurements.

Ten trials showed no differences in hemoglobin concentrations between iron groups after the intervention.

Evidence of publication bias was detected with the visual inspection of funnel plots for both hemoglobin and ferritin concentration outcome measures in pregnant and children.

Three trials showed no statistical significance in serum ferritin concentration between iron groups after the intervention.

Adverse gastrointestinal side effects: heartburn, nausea, diarrhea and abdominal pain, vomiting, constipation, and black stool.

Abbreviations: CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; IRR, incidence rate ratio; SD, standard deviation; SMD, standardized mean difference.

The outcomes evaluated in meta-analyses for population subgroups (pregnant women and children) were downgraded for certainty, mainly due to the high risk of bias for the studies (inability in blinding treatments, inadequate information about allocation concealment) and imprecision (no statistical significance in hemoglobin or ferritin concentrations postintervention). A summary of the risk-of-bias domains in each trial is detailed in Figure 7 and Figure S5 in the Supporting Information online. The trials were judged to be at varying levels of risk of bias, with 6 having an overall high risk of bias, 7 with an overall unclear risk of bias, and 4 with an overall low risk of bias. The studies with a high or unclear risk of bias commonly lacked information about the randomization process, because they did not specify the methods used to generate a random sequence, had people delivering the intervention who were aware of the intervention groups (ie, not double-blinded), or did not analyze the data according to a prespecified analysis plan. There was also some evidence to suggest publication bias as detected with the visual inspection of funnel plot asymmetry (see Figures 2–5 in the Supporting Information online). Owing to funnel plot asymmetry and heterogeneity, there is little confidence in the pooled effect estimate of ferrous bisglycinate on adverse GI side effects (Table 3).

Traffic-light plots presenting the risk of bias by 5 domains and overall for included studies.

DISCUSSION

Oral iron supplementation has been a longstanding intervention to prevent and treat iron deficiency in both clinical and public health settings. Many intervention trials have evaluated the change in hemoglobin concentrations and iron status in various populations receiving oral iron supplementation. However, the iron salts (eg, ferrous sulfate, fumarate) that are routinely used in most of these interventions are often provided in large doses (due to low bioavailability) and have noticeable adverse GI side effects. Ferrous bisglycinate is a relatively novel form of iron supplementation used to prevent or treat iron deficiency. Ferrous bisglycinate is often administered with a lower dose of elemental iron than most other iron salts because it is thought to have higher bioavailability.

In this systematic review, we compiled evidence from RCTs evaluating the effects of ferrous bisglycinate against other commonly used forms of oral iron supplements. The purpose of this review was to evaluate the effects of oral iron supplementation as ferrous bisglycinate against other forms of iron supplements on hemoglobin and ferritin concentrations and adverse GI events. Compared with other iron supplements, supplementation with ferrous bisglycinate for 4–20 weeks resulted in greater hemoglobin concentrations in pregnant women and a similar but nonsignificant increase in serum ferritin. Additionally, supplementation with ferrous bisglycinate resulted in significantly fewer reported GI adverse events as compared with other forms of iron supplements. In contrast, pooled estimates of hemoglobin and ferritin concentrations in children displayed increases, albeit nonsignificant, following ferrous bisglycinate supplementation, compared with other forms of iron supplementation. The prediction intervals of these analyses were wide, indicating that, based on the data thus far, future studies may present a variety of possible effect sizes. The overall findings of this review suggest that ferrous bisglycinate supplementation improves biomarkers of anemia and is better tolerated by the gut in pregnant women, supporting the use of ferrous bisglycinate in iron and/or iron and folic acid supplementation during pregnancy.

Evidence of publication bias was suspected upon visual inspection of funnel plots. A high level of heterogeneity was observed for the outcomes in pregnant women (I² > 50%), which may likely be due to 2 trials reporting divergent results.³⁸^,⁴¹ These trials were investigated to determine the causes of heterogeneity; although baseline characteristics were not different across groups, bias may have arisen from the use of different control-group iron formulations (ferrous glycine sulfate and iron multi–amino acid chelate) than in other trials (ferrous fumarate was commonly used as a comparison with ferrous bisglycinate). For the hemoglobin outcome in children, the I² statistic was 0%, but this estimate of heterogeneity is likely an underestimation due to the small number of studies (n = 4).⁵⁰

In pregnancy, iron requirements increase considerably throughout gestation despite the absence of iron losses through menses. Iron needs increase from 0.8 mg/day in the first trimester to 7.5 mg/day during the third trimester.⁵^,⁴⁹ During the second half of pregnancy, these heightened needs are due to the expansion of blood cell mass and necessary iron to support placental and fetal growth.⁴⁹ Iron status during pregnancy is likely reflective of a woman’s iron stores at the start of pregnancy and the bioavailability and quantity of both dietary and supplemental iron consumed throughout pregnancy.⁵ Because pregnant women already experience pregnancy-related symptoms of nausea, it is vital to provide tolerable iron supplements to ensure compliance and efficacy to improve biomarkers of anemia and iron deficiency in this critical life stage. This review shows that ferrous bisglycinate conveys some benefit over other iron supplements in increasing hemoglobin concentration and reducing GI adverse events among pregnant women.

Children are also at risk of developing iron deficiency, particularly young children (younger than 5 years). Iron requirements change dramatically during stages of cell growth and maturation and, consequently, are high to meet the physical growth demands of children.²³^,⁵¹ Iron deficiency can have detrimental impacts on neurocognitive development and the immune system and is associated with increased morbidity.² A systematic review of RCTs of daily iron supplementation (any daily iron dose, including studies in which other micronutrients were simultaneously administered, excluding iron fortificants or multiple micronutrient powders) in children revealed supplementation reduced the risk of anemia by 50% (n = 7 trials; n = 1763 children; IRR [95%CI], 0.50 [0.39–0.64]; P < 0.001) and the risk of iron deficiency by 79% (n = 4 trials, n = 1020 children; IRR [95%CI], 0.21 [0.07–0.63]; P = 0.006).⁵² Another systematic review of RCTs assessed the impact of oral or parenteral iron supplementation or fortified formula or cereal on the incidence of infections (including respiratory tract infection, diarrhea, malaria, and other infections) in 7892 children (n = 28 trials).⁵³ Stratified analyses showed oral iron supplementation was associated with a small yet significant increase in diarrhea risk (n = 9 trials; IRR [95%CI], 1.15 [1.01–1.32], P = 0.04; incidence rate difference [95%CI], 0.18 –0.01, 0.37] episodes per child year; P = 0.07), a major cause of death in children younger than 5 years.⁵³^,⁵⁴ Excess iron in the gut may favor the growth of pathogenic bacteria and modify the gut microbiota; thus, the provision of iron must be monitored appropriately.⁵⁵ To reduce the amount of unabsorbed iron passing into the colon, the dose of iron in supplements and multiple micronutrient powders should be as low as possible while remaining effective against iron deficiency. Ferrous bisglycinate has higher bioavailability in the intestinal mucosal cells, thus a higher proportion is thought to be absorbed as compared with iron salts; it may be a safer source of iron, allowing for lower doses of elemental iron.

Strengths of this review include following best-practice systematic review methodology and thoroughly searching numerous databases and the grey literature. The authors acknowledge several limitations. First, studies evaluating ferrous bisglycinate fortification were omitted, which may be important when evaluating the formulation's effectiveness. Trials comparing ferrous bisglycinate vs placebo (no other iron intervention arm) were excluded (n = 2). However, the efficacy of ferrous bisglycinate in treating iron deficiency has been previously established,^17–20 and the inclusion of these studies would not have aided in answering the research question. Second, the review was not positioned to evaluate the optimal dose, frequency, or duration of ferrous bisglycinate supplementation; therefore, research is necessary to inform best-practice ferrous bisglycinate dosing. Last, the measured outcomes (hemoglobin and ferritin concentrations) are commonly measured anemia and iron status biomarkers in nutrition research. Other biomarkers of iron status were not included (eg, soluble transferrin receptor), which may have resulted in different outcomes in this review. On a similar note, ferritin is an acute-phase protein known to be affected by inflammation status; thus, best practices adjust ferritin values for inflammation using 2 acute-phase proteins, α-1-acid glycoprotein and C-reactive protein.⁵⁶^,⁵⁷ Not all trials included in this review used inflammation-adjusted ferritin concentrations, which potentially presents bias to the effect estimates reported in this review.

CONCLUSION

In conclusion, ferrous bisglycinate shows some benefit over other iron supplements in increasing hemoglobin concentration and reducing GI adverse events among pregnant women. More trials are needed to assess the efficacy of ferrous bisglycinate against other forms and doses of iron supplements in pregnant women as well as in other populations, such as nonpregnant women, men, children, and athletes.

Supplementary Material

nuac106_Supplementary_Data

Click here for additional data file.^{(413.4KB, docx)}

Acknowledgments

The authors thank Ursula Ellis, reference librarian, The University of British Columbia, for her assistance with the literature search strategy and Lorri Puil, editor, Cochrane Hypertension Therapeutics Initiative Drug Assessment Working Group, for her teaching on systematic review methods in health research during the graduate coursework of J.A.J.F. and A.M.C.

Author contributions. J.A.J.F., A.M.C., and C.D.K. contributed to the conception and design of the systematic review and meta-analysis; J.A.J.F. and A.M.C. conducted the literature search, extracted the data, conducted the risk of bias assessment, performed the GRADE assessment, and drafted the manuscript; J.N.B. analyzed the data; J.A.J.F., J.N.B., and C.D.K. interpreted the data; CDK had primary responsibility for the content; and all authors contributed to writing, manuscript revisions, and read and approved the final manuscript.

Funding. This research was funded by the Faculty of Land and Food Systems at The University of British Columbia. C.D.K. received financial support as a Michael Smith Foundation for Health Research Scholar and a Canada Research Chair Tier 2 in Micronutrients and Human Health, and J.A.J.F. received graduate student funding from the Canadian Institutes of Health Research.

Declarations of interest. The authors declare no relevant interests to declare.

Contributor Information

Jordie A J Fischer, Department of Food, Nutrition, and Health, The University of British Columbia, Vancouver, British Columbia, Canada. Healthy Starts, BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada.

Arlin M Cherian, Department of Family Practice, The University of British Columbia, Vancouver, British Columbia, Canada.

Jeffrey N Bone, BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada.

Crystal D Karakochuk, Department of Food, Nutrition, and Health, The University of British Columbia, Vancouver, British Columbia, Canada. Healthy Starts, BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada.

Supporting information

The following Supporting Information is available through the online version of this article at the publisher’s website.

Figure S1 Funnel plot for random effects meta-analysis of mean difference in hemoglobin concentration with ferrous bisglycinate compared with other forms of iron supplementation in pregnant women

Figure S2 Funnel plot for random effects meta-analysis of mean difference in ferritin concentration with ferrous bisglycinate compared with other forms of iron supplementation in pregnant women

Figure S3 Funnel plot for random effects meta-analysis of mean difference in hemoglobin concentration with ferrous bisglycinate compared with other forms of iron supplementation in children

Figure S4 Funnel plot for random effects meta-analysis of mean difference in ferritin concentration with ferrous bisglycinate compared with other forms of iron supplementation in children

Figure S5 Summary of risk-of-bias domains in the included studies

Table S1 Ovid Medline search strategy: Ovid MEDLINE and Epub from 1956 to July 17, 2020

Table S2 Summaries of trials evaluating the effect of ferrous bisglycinate compared with other iron supplements by population group

Table S3 Comparison of Bayesian and frequentist approaches to pooled estimates of hemoglobin and ferritin concentrations in pregnant women and children in response to ferrous bisglycinate supplementation compared with other iron supplements

Table S4 PRISMA 2020 checklist

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50. Von Hippel PT. The heterogeneity statistic I² can be biased in small meta-analyses. BMC Med Res Methodol. 2015;15:35. [DOI] [PMC free article] [PubMed] [Google Scholar]
51. Lopez A, Cacoub P, Macdougall IC, et al. Iron deficiency anaemia. Lancet. 2016;387:907–916. [DOI] [PubMed] [Google Scholar]
52. Low M, Farrell A, Biggs BA, et al. Effects of daily iron supplementation in primary-school-aged children: systematic review and meta-analysis of randomized controlled trials. CMAJ. 2013;185:E791–E802. [DOI] [PMC free article] [PubMed] [Google Scholar]
53. Zimmermann MB, Chassard C, Rohner F, et al. The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Côte d’Ivoire. Am J Clin Nutr. 2010;92:1406–1415. [DOI] [PubMed] [Google Scholar]
54. Gera T, Sachdev HPS. Effect of iron supplementation on incidence of infectious illness in children: systematic review. BMJ. 2002;325:1142–1142. [DOI] [PMC free article] [PubMed] [Google Scholar]
55. Paganini D, Zimmermann MB. The effects of iron fortification and supplementation on the gut microbiome and diarrhea in infants and children: a review. Am J Clin Nutr. 2017;106:1688S–1693S. [DOI] [PMC free article] [PubMed] [Google Scholar]
56. Karakochuk CD, Whitfield KC, Barr SI, et al. Genetic hemoglobin disorders rather than iron deficiency are a major predictor of hemoglobin concentration in women of reproductive age in rural Prey Veng, Cambodia. J Nutr. 2015;145:134–142. [DOI] [PubMed] [Google Scholar]
57. Namaste SM, Rohner F, Huang J, et al. Adjusting ferritin concentrations for inflammation: biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. Am J Clin Nutr 2017;106:S359–71. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

nuac106_Supplementary_Data

Click here for additional data file.^{(413.4KB, docx)}

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PERMALINK

The effects of oral ferrous bisglycinate supplementation on hemoglobin and ferritin concentrations in adults and children: a systematic review and meta-analysis of randomized controlled trials

Jordie A J Fischer

Arlin M Cherian

Jeffrey N Bone

Crystal D Karakochuk

Abstract

Context

Objective

Data sources

Data extraction

Data analysis

Conclusion

PROSPERO registration no

INTRODUCTION

METHODS

Eligibility criteria

Types of outcome measures

Table 1.

Search strategy

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Assessment of heterogeneity

Data synthesis

Sensitivity analysis.

RESULTS

Study selection

Figure 1.

Characteristics of included studies

Table 2.

Effect of intervention

Pooled effects in pregnant women.

Primary outcomes.

Figure 2.

Figure 3.

Secondary outcome.

Figure 4.

Pooled effects in children.

Primary outcomes.

Figure 5.

Figure 6.

Effect of interventions in all populations.

Sensitivity analysis.

Quality of evidence

Table 3.

Figure 7.

DISCUSSION

CONCLUSION

Supplementary Material

Acknowledgments

Contributor Information

Supporting information

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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