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https://doi.org/10.1038/s41372-019-0320-2
REVIEW ARTICLE
Abstract
Objective To assess the effect of intravenous versus oral iron on hematologic indices and clinical outcomes for iron-
deficiency anemia (IDA) in pregnancy.
Study design Searches in Ovid Medline, Embase, SCOPUS, Cochrane Database, and ClinicalTrials.gov identified randomized-
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controlled trials comparing intravenous to oral iron for treating IDA in pregnancy. Primary outcomes were maternal hematologic
indices at delivery. Secondary outcomes were blood transfusion, cesarean delivery, neonatal outcomes, and medication reactions.
Results Of 15,637 studies, 20 randomized trials met inclusion criteria and were analyzed. Mean hemoglobin at delivery
(9 studies: WMD 0.66 g/dL (95% confidence Interval 0.31 –1.02 g/dL)) was significantly higher after intravenous iron
therapy. Intravenous iron was associated with higher birthweight (8 studies: WMD 58.25 g (95% CI: 5.57–110.94 g)) but no
significant differences in blood transfusion, cesarean delivery, or neonatal hemoglobin. There were fewer medication
reactions with intravenous iron (21 studies: RR 0.34% (95% CI: 0.20–0.57)).
Conclusion Intravenous iron therapy is associated with higher maternal hemoglobin at delivery with no difference in blood
transfusion and fewer mild medication reactions.
Introduction
The reason for the lack of consensus is twofold. First, created search strategies using a combination of keywords
both available treatment routes have shortcomings, with a and controlled vocabulary in Ovid Medline 1946-, Embase
low rate of systemic absorption and high rate of gastro- 1947-, Scopus 1823-, Cochrane Database of Systematic
intestinal side effects for oral iron [5] and more medical Reviews (CDSR), Cochrane Central Register of Controlled
resources and a risk of transfusion reaction for intravenous Trials (CENTRAL), and Clinicaltrials.gov 1997. All search
iron [6]. Notably, the risk of transfusion reaction is thought strategies were completed in February 2018 and executed
to be lower with the second- and third-generation intrave- again in October 2018. Reproducible search strategies for
nous iron formulations currently used in transfusions [6]. each database can be found in Appendix 1.
Second, current data on the risks and benefits of intravenous
iron in pregnancy are limited. The most recent Cochrane Study selection
review on treatment of iron-deficiency anemia in pregnancy
—published in 2011—concluded that intravenous iron may Titles and abstracts were screened independently by the co-
increase hematologic response compared to oral iron but first authors (A.K.L. and A.G.), and the full-text articles
that more good quality trial assessing clinical outcomes as were retrieved if they appeared relevant. The same two
well as adverse effects are needed [7]. More recent meta- authors independently reviewed all full-text articles, and
analyses either included a small sample size (six trials [8]) disagreements were resolved with discussion with a third
or both randomized controlled trials and observational stu- author (M.G.T.). Case reports, case series, review articles,
dies [9]. Both of these previous meta-analyses also focused studies without comparison groups, abstracts, and articles
on hematologic indices and adverse events with little on published in languages other than English were excluded,
obstetric and pediatric outcomes [8, 9]. while prospective randomized controlled trials comparing
Multiple randomized controlled trials have been pub- any formulation of intravenous iron to any formulation of
lished comparing intravenous iron to oral iron for the oral iron were included. We also searched the biblio-
treatment of iron-deficiency anemia in pregnancy since graphies of included studies to identify additional eligible
2011 [10–23]. Moreover, many of these reported clinical studies that were not identified in our literature search.
outcomes in addition to hematologic parameters and Studies were limited to having been published after 1980 to
adverse medication reactions [10, 13–16, 20, 23, 24]. Thus, ensure treatment algorithms analyzed were more relevant to
an updated meta-analysis is warranted. The primary aim of current clinical practice patterns.
this study is to assess the effect of intravenous iron com-
pared to oral iron on hematologic indices, maternal and Data extraction
neonatal outcomes, and medication reactions among women
with iron-deficiency anemia in pregnancy. Two authors (A.K.L. and A.G.) independently reviewed
eligible articles for data extraction; our data extraction tool
is included as Appendix 2. The primary outcomes were
Materials/subjects and methods mean maternal hemoglobin and ferritin at delivery. Sec-
ondary outcomes were mean maternal hemoglobin and
This study was registered on PROSPERO (#CRD42018090276) ferritin 2–6 weeks after treatment, rate blood transfusion,
and exempt from institutional board review as only deidentified cesarean delivery, neonatal outcomes, and medication
data available in the public domain through prior publications reactions. Study design and study location, inclusion criteria
were included. All search strategies and written methodology for including hemoglobin and ferritin threshold for iron-
this systematic review and meta-analysis were created using the deficiency anemia diagnosis, exclusion criteria, number of
standards and guidelines for conducting and reporting systematic patients, and pre and post-treatment mean hemoglobin and
reviews set forth by the Preferred Reporting Items for Systematic mean ferritin were abstracted. Extracted maternal outcomes
Reviews and Meta-Analyses (PRISMA) [25], the Institute for included the rate of blood transfusion and mode of delivery.
Medicine Standards for Systematic Reviews [26], the Cochrane Extracted neonatal outcomes included gestational age at
Handbook of Systematic Reviews [27], and the Peer Review of delivery, birthweight, low-cord pH, total APGARS,
Systematic Search Strategies (PRESS) [28]. APGARS < 5 at 5 min, neonatal hemoglobin and ferritin,
and neonatal intensive care unit (NICU) admission. All
Eligibility criteria, information sources, and search reported adverse medical reactions were also abstracted. In
strategy studies in which both a composite of adverse medication
reactions and rates of individual adverse medication reac-
A medical librarian (L.E.S.) searched published literature tions were reported, we used the rates of individual adverse
for records discussing iron-deficiency anemia, intravenous reactions for our outcome to allow for individual patients to
iron, or oral iron therapies in pregnant women. The librarian have more than one adverse reaction.
Intravenous compared with oral iron for the treatment of iron-deficiency anemia in pregnancy: a. . .
reported initial mean hemoglobin ≤9.0 g/dL [10–13, 16, 17, hemoglobin or ferritin 2–6 weeks after treatment compared
19, 21, 23, 39, 40] and nine >9.0 g/dL [14, 18, 20, 22, 24, to baseline (n = 14), hemoglobin or ferritin at admission
36–38]. compared to baseline (n = 9).
Reporting of maternal or neonatal outcomes varied
Synthesis of results and risk of bias of included across studies (Table 1). Of the nine studies that reported
studies these outcomes, seven included blood transfusion, two
reported cesarean delivery, eight studies reported birth-
A total of 1359 women received intravenous iron and 1357 weight and neonatal hemoglobin, seven reported neonatal
women received oral iron across the 21 studies, with sample ferritin, four reported gestational age at delivery, and two
sizes ranging from 23 to 126 women per arm. Inclusion and included APGARs. No studies included extractable data on
exclusion criteria differed significantly across studies. cord blood pH, neonatal morbidity or NICU admission. All
Whereas the majority required women to have iron- studies reported rates of mild adverse medication reactions,
deficiency anemia, the hemoglobin and ferritin thresholds and ten reported rates of severe adverse medication
varied: the highest hemoglobin included was a range of 8.5– reactions.
11.5 g/dL while the lowest was ≤7 g/dL, and the highest fer- Compared to oral iron, intravenous iron was associated
ritin included was <100 µg/L and the lowest was <13 µg/L. In with a significantly higher hemoglobin (9 studies: WMD
addition, various formulations of iron were used, with fer- 0.66 g/dL (95% CI: 0.31–1.02 g/dL)) and ferritin (5 studies:
rous sulfate (n = 13) the most common oral and iron WMD 45.68 µg/L (95% CI: 26.21–65.16 µg/L)) on admis-
sucrose (n = 14) the most common intravenous formulation. sion to labor and delivery (Fig. 2). A high amount of inter-
The treatment effects assessed varied and included study heterogeneity was identified for both hemoglobin and
Table 1 Study Characteristics
Author Country (UN Inclusion criteria Exclusion criteria Iron formulation Quality BL mean Hgb and ferritin mean (SD) units: Hgb (g/ Maternal Neonatal outcomes: mean (SD) units:
(year) category) (sample size) Hgb dL), ferritin (mcg/L) outcomes GA (wks), BW (g), Hgb (g/dL),
ferritin (mcg/L)
Khalafallah Australia Pregnancy, Age 18+, IDA, Hgb Anemia from causes other than IDA, known Oral: Ferrous Higher >9.0 g/dL Oral: BL Hgb: 10.93 (0.48) Delivery Hgb: None Oral: GA at delivery: 39.1 (−) BW:
(2010) (developed) 8.5–11.5 g/dL, Ferritin < 30 mcg/L malabsorptive syndromes, iron overload, sulfate (N = 91) 12.18 (0.87)BL ferritin: 17.7 (17.7) IV: BL 3420 (−) Neonatal Hgb: 16.5 (0.96)
multiple gestation, first Hgb after 28 wks, IV: Iron Hgb: 10.74 (0.54) Delivery Hgb: 12.66 (0.97) Neonatal ferritin: 142 (86) IV: GA at
severe iron deficiency polymaltose BL ferritin: 18.1 (16.3) delivery: 38.9 (−) BW: 3440 (−)
(N = 92) Neonatal Hgb: 15.7 (1.4) Neonatal
ferritin: 185 (101)
Kocchar India Singleton pregnancy, Age 18+, GA Anemia from causes other than IDA, severe Oral: Ferrous Higher ≤9.0 g/dL Oral: BL Hgb: 7.6 (0.8); 2 wk Hgb: 8.9 (0.6); Oral: Blood Oral: GA at delivery: 37 (2) BW:
(2013) (developing) 24–34 wks, Moderate IDA, Hgb 7– anemia (Hgb < 7.0 g/dL), asthma, viral sulfate (N = 50) 3 wk Hgb: 9.6 (0.9); 4 wk Hgb: 10.7 (0.7) transfusion (n): 1 2695 (765) Neonatal Hgb: 15.9 (2.2)
9 g/dL, Ferritin < 15 mcg/L, hepatitis, cirrhosis, cardiovascular disease, IV: Iron sucrose Delivery Hgb: 11.2 (0.9) BL ferritin: 16.5 IV: Blood Neonatal ferritin: 138 (98) IV: GA at
Negative naked eye single tube red autoimmune disease, suspected acute (N = 50) (5.9) 4 wk ferritin: 77.6 (13.7) Delivery transfusion (n): 0 delivery: 38 (1) BW: 2870 (680)
cell osmotic fragility test, no infection, intolerance to iron derivatives, ferritin: 94.6 (14.2) IV: BL Hgb: 7.7 (0.5) 2 Neonatal Hgb: 16.3 (2.1) Neonatal
associated obstetric or medical receipt of earlier parenteral iron treatment, wk Hgb: 9.7 (0.8) 3 wk Hgb: 10.9 (0.8) 4 wk ferritin: 141 (101)
complications those unwilling to participate Hgb: 12.8 (1.1) Delivery Hgb: 13.4 (0.9) BL
ferritin:18.1 (4.6) 4 wk ferritin: 104 (13.4)
Delivery ferritin: 128.8 (15.8)
Abhilashini India GA 30–34 wks, IDA, Hgb 6–8 g/dL, Anemia from causes other than IDA, iron Oral: Ferrous Higher ≤ 9.0 g/dL Oral: BL Hgb: 7.16 (0.6); 2 wk Hgb: 8.22 Oral: Cesarean None
(2014) (developing) peripheral smear suggestive of IDA hypersensitivity, history of blood transfusion sulfate (N = 50) (0.7); 4 wk Hgb: 9.15 (0.7) IV: BL Hgb: 6.89 delivery (n): 4 IV:
in current pregnancy, liver disease, anemia in IV: Iron sucrose (0.86) 2 wk Hgb: 8.15 (0.6) 4 wk Hgb: 9.48 Cesarean delivery
failure (N = 50) (0.7) (n): 3
Abhilashini India GA 30–34 wks, IDA, Hgb 6–8 g/dL, Anemia from causes other than IDA, iron Oral: Ferrous Higher ≤ 9.0 g/dL Oral: BL Hgb: 7.16 (0.6); 2 wk Hgb: 8.22 Oral: Cesarean None
(2014) (developing) peripheral smear suggestive of IDA hypersensitivity, history of blood transfusion sulfate (N = 50) (0.7); 4 wk Hgb: 9.15 (0.7) IV: BL Hgb: 6.89 delivery (n): 4 IV:
in current pregnancy, liver disease, anemia in IV: Iron sucrose (0.86) 2 wk Hgb: 8.15 (0.6) 4 wk Hgb: 9.48 Cesarean delivery
failure (N = 50) (0.7) (n): 3
Gupta India Singleton pregnancy, GA 24–34 Known iron hypersensitivity, thalassemia, Oral: Ferrous Higher ≤ 9.0 g/dL Oral: BL Hgb: 7.88 (0.42); 2 wk Hgb: 8.11 Oral: Blood Oral: GA at delivery: 38.31 (1.47)
(2014) (developing) wks, Hgb 7–9 g/dL, ferritin < 15 clinical evidence of inflammation or sulfate (N = 50) (0.45); 4 wk Hgb 9.18 (0.55) Delivery Hgb: transfusion (n): 0 BW: 2568 (244.19) Neonatal Hgb:
mcg/L autoimmune disease IV: Iron sucrose 10.84 (1.12) BL ferritin: 10.4 (1.89) 4 wk IV: Blood 15.9 (2.2) Neonatal ferritin: 147.68
(N = 50) ferritin: 13.96 (1.88) IV: BL Hgb: 7.81 (0.43) transfusion (n): 0 (39.05) IV: GA at delivery: 38.48
2 wk Hgb: 8.39 (0.43) 4 wk Hgb: 9.8 (0.46) (1.36) BW: 2607 (253.28) Neonatal
Delivery Hgb: 11.5 (0.78) BL ferritin: 10.7 Hgb: 15.8 (0.7) Neonatal
(1.47) 4 wk ferritin: 37.45 (5.73) ferritin:155.77 (46.34)
Darwish Egypt GA 14–28 wks, Age 18+, IDA Anemia from causes other than IDA, iron Oral: Ferrous Higher ≤9.0 g/dL Oral: BL Hgb: 8.58 (0.73) 4 wk Hgb: 9.51 None None
(2017) (developing) (confirmed with clinical and overload or disturbances in utilization of iron fumarate (N = (0.77) BL ferritin: 2.76 (1.03) 4 wk ferritin:
laboratory evidence), Hgb 7–10 g/ (e.g., hemochromatosis, hemosiderosis), 33) IV: Iron 58.79 (18.5) IV: BL Hgb: 8.22 (0.87) 4 wk
dL, consideration of MCV, MCH, decompensated liver cirrhosis, active dextran (N = Hgb: 10.29 (0.86) BL ferritin: 8.22 (0.87) 4
MCHC, serum iron, serum ferritin, hepatitis, active acute or chronic infections, 33) wk ferritin: 78.59 (27.4)
and TIBC rheumatoid arthritis w sx or signs of active
inflammation, hx of multiple allergies, GI
tract disorders or known hypersensitivity to
parenteral iron, recipients of investigational
drug product, Hgb < 7 g/dL, EPO within 8
wks prior to screening visit, other iron tx or
Intravenous compared with oral iron for the treatment of iron-deficiency anemia in pregnancy: a. . .
multiple pregnancy, previous blood (N = 45) IV: BL ferritin: 5 (2.2) 4 wk ferritin: 11 (11) Cesarean delivery Oral: GA at delivery: 39.1 (1.2) BW:
transfusion, history of hematological disease, Iron sucrose (N Delivery ferritin: 18.1 (11) IV: BL Hgb: 9.9 (n): 27 IV: Blood 3439 (451) IV: GA at delivery: 39.2
risk of preterm labor, intolerance to iron = 45) (0.5) 2 wk Hgb: 10.5 (0.6) 4 wk Hgb: 11.1 transfusion (n): 0 (1.5) BW: 3498 (452)
derivatives, recent administration of iron for (0.6) Delivery Hgb: 12 (0.8) BL ferritin: 4.1 Cesarean delivery
treatment of IDA, current usage of iron (2.5) 4 wk ferritin: 28 (26) Delivery ferritin: (n): 20
supplement 23.7 (13.8)
Bayoumeu France GA 24 wks, Age 18+, Hgb 8–10 g/ Anemia from causes other than IDA, asthma, Oral: Ferrous Higher >9.0 g/dL Oral: BL Hgb: 9.7 (0.5) 4 wk Hgb: 11 (1.25) Oral: Blood Oral: GA at delivery: 37.1 (−) BW:
(2002) (developed) dL, MCV < 100 fl, ferritin < 50 mcg/ cirrhosis, viral hepatitis, multiple pregnancy, sulfate (N = 23) Delivery Hgb: 11.5 (1.2) IV: BL Hgb: 9.6 transfusion (n): 1 3220 (570) Neonatal Hgb: 15.3 (2.17)
L risk of premature birth, suspected acute IV: Iron sucrose (0.79) 4 wk Hgb: 11.11 (1.3) Delivery Hgb: IV: Blood Neonatal ferritin: 134 (107) IV: GA at
infection, parenteral iron treatment before (N = 24) 12 (1.1) transfusion (n): 0 delivery: 37.2 (−) BW: 3595 (785)
inclusion, intolerance to iron derivatives, Neonatal Hgb:15.15 (2.1) Neonatal
transport difficulties, difficulties in ferritin: 132 (104)
comprehension of study guidelines, no
consent, participation in clinical trial in
previous month
Abdelazim Kuwait GA 24–30 wks, Age 18+, Hgb 8– Anemia from causes other than IDA, receipt Oral: Proferrin- Lower (Not >9.0 g/dL Oral: BL Hgb: 8.5 (3.5) BL ferritin: 19.4 (4.9) None None
(2017) (developing) 10 g/dL of blood transfusion in current pregnancy ES (N = 124) inten-tion to IV: BL Hgb: 8.7 (2.5) BL ferritin: 15.3 (5.6)
IV: Iron treat)
saccharate (N =
126)
Neeru India GA 14–36 wks, Hgb 6.5–10.9 g/dL, Severe anemia requiring blood transfusion, Oral: Ferrous Lower (11% >9.0 g/dL Oral: BL Hgb: 9.75 (0.415) 4 wk Hgb: 11.06 Oral: Blood None
(2012) (developing) Ferritin < 27 ng/dL bronchial asthma, suspected acute infection fumarate (N = loss to follow- (0.315) Delivery Hgb: 11.65 (0.455) BL transfusion (n): 0
44) IV: Iron up) ferritin: 14.74 (3.775) 4 wk ferritin: 27.33 IV: Blood
sucrose (N = (7.48) IV: BL Hgb: 9.18 (0.47) 4 wk Hgb: transfusion (n): 4
45) 11.24 (0.35) Delivery Hgb: 11.76 (0.4) BL
ferritin: 8.6 (2.585) 4 wk ferritin: 139.93
(61.065)
Deeba India GA 28–37 wks, established IDA, Anemia from causes other than IDA, multiple Oral: Ferrous Higher >9.0 g/dL Oral: BL Hgb: 7.925 (0.862) 2 wk Hgb: 8.5 None None
(2012) (developing) Hgb 6–10 g/dL, ferritin < 15 ng/mL pregnancy, previous blood transfusion, ascorbate (N = (0.862) 4 wk Hgb: 9.32 (0.8707) 6 wk Hgb:
history of hematologic disease, risk of 100) IV: Iron 9.903 (0.8848) BL ferritin: 8.13 (1.45) 2 wk
preterm labor, iron derivative intolerance, sucrose (N = ferritin: 16.65 (4.87) 4 wk ferritin: 23.36
recent administration of iron, current use of 100) (8.57) 6 wk ferritin: 34.78 (8.793) IV: BL
iron supplements Hgb: 7.9 (0.8741) 2 wk Hgb: 9.63 (0.885) 4
wk Hgb: 10.09 (0.8072) 6 wk Hgb: 10.79
(0.8432) BL ferritin: 8.44 (1.35) 2 wk ferritin:
48.46 (16.66) 4 wk ferritin: 61.05 (19.662) 6
wk ferritin: 86.98 (19.939)
Singh (1998) Singapore GA 20–28 wks, Age 16+, Hgb < 9 Anemia from causes other than IDA, acute Oral: Ferrous Lower (Rand- ≤9.0 g/dL Oral: BL Hgb: 8.6 (0.01) BL ferritin: 8.1 (0.5) None None
(developed) g/dL, Ferritin < 20 mcg/L, serum infections, parasitosis, severe liver, kidney, or fumarate (N = omiz-ation not IV: BL Hgb: 8.1 (0.01) BL ferritin: 7.1 (0.4)
iron < 10 mmol/L, MCH < 27 pg, cardiovascular disease, severe psychiatric 50) IV: Iron described)
MCV < 80 fL disorders, any form of parenteral iron therapy dextran (N =
for anemia within 20 days prior to intended 50)
recruitment, history of allergy or abnormal
reaction to iron therapy, history of alcohol
and drug abuse, inability to comply with
therapy
Bhavi India Singleton pregnancy, Age 18–45, Hemoglobinopathy or other red blood cell Oral: Ferrous Lower >9.0 g/dL Oral: BL Hgb: 9.14 (1.1) 4 wk Hgb: 10.65 None None
(2017) (developing) Hgb 7–11 g/dL, ferritin < 15 mcg/L disorders, history of bleeding tendency, fumarate (N = (Randomization (1.03) BL ferritin: 9.1 (3.42) 4 wk ferritin:
history of blood transfusion within prior 56) IV: Iron not described) 30.62 (9.88) IV: BL Hgb: 8.9 (1.07) 4 wk
120 days, allergy, asthma, acute inflammatory sucrose (N = Hgb: 10.64 (1.3) BL ferritin: 8.84 (3.47) 4 wk
state 56) ferritin: 120.85 (87.91)
Aggarwal India GA > 24 wks, Age 18+, Hgb ≤ 7 g/ Placenta previa, placental abruption, Oral: Ferrous Lower ≤9.0 g/dL Oral: BL Hgb: 5.94 (0.62) 2 wk Hgb: 7.64 Oral: Blood None
(2012) (developing) dL, transferrin saturation ≤ 10%, preeclampsia, clotting disorder, patients who sulfate (N = 25) (Randomization (1.21) 3 wk Hgb: 8.6 (0.79) 4 wk Hgb: 10.26 transfusion (n): 0
ferritin ≤ 15 mcg/L participated in another clinical study within IV: Iron sucrose not described) (1.077) BL ferritin: 10 (1.9) 4 wk ferritin: IV: Blood
the previous 3 months, iron intolerance or (N = 25) 160.8 (33.1) IV: BL Hgb: 6.27 (0.48) 2 wk transfusion (n): 0
hypersensitivity, hemolytic anemia, Hgb: 8.62 (0.6) 3 wk Hgb: 9.9 (0.66) 4 wk
hemoglobinopathies (thalassemia, sickle Hgb: 11.3 (0.7) BL ferritin: 9.44 (3.01) 4 wk
cell), bleeding tendency, hypersplenism, ferritin: 295.5 (45.1)
chronic heart failure, class II–IV heart
disease, uncontrolled arterial hypertension
(DBP ≥ 115 mmHg), DVT, thrombocytosis,
chronic renal disease, severe renal failure
(2.5× or higher plasma creatinine level than
high limit of normal state), severe liver
A. K. Lewkowitz et al.
Table 1 (continued)
Author Country (UN Inclusion criteria Exclusion criteria Iron formulation Quality BL mean Hgb and ferritin mean (SD) units: Hgb (g/ Maternal Neonatal outcomes: mean (SD) units:
(year) category) (sample size) Hgb dL), ferritin (mcg/L) outcomes GA (wks), BW (g), Hgb (g/dL),
ferritin (mcg/L)
IDA iron deficiency anemia, Hgb hemoglobin, Hct hematocrit, GA gestational age, wks weeks, ferritin serum ferritin, ULN upper limit of normal, BL baseline, BW birthweight, Sx symptoms, Tx
therapy, Hx history, mcg micrograms, EPO erythropoietin
A. K. Lewkowitz et al.
ferritin (I2 was 92.8% and 97.7%, respectively). In stratified Forest plots for stratified analyses for primary outcomes
analyses the treatment effect of intravenous iron on and for all secondary outcomes and pooled or stratified
admission was higher among higher-quality studies, studies WMD for maternal and neonatal outcomes are included in
from developing countries, and studies with mean pre- Appendix 3 and Appendix 4, respectively. Of note, all
treatment hemoglobin of ≤9.0 g/dL, with high amount of stratified analyses and analyses for secondary outcomes
heterogeneity identified in each analysis (Table 2). The demonstrated high amount of inter-study heterogeneity
funnel plot for the primary outcome of hemoglobin at (Table 2). In terms of hematologic indices, intravenous iron
delivery did not show asymmetry, and the Egger test con- was also associated with increased hemoglobin and ferritin
firmed there was no evidence of publication bias (p = 2–6 weeks after treatment (14 studies: WMD 0.67 g/dL
0.294) (Fig. 3). (95% CI: 0.44–0.90 g/dL) and 11 studies: WMD 58.95 µg/L
Intravenous compared with oral iron for the treatment of iron-deficiency anemia in pregnancy: a. . .
Table 2 Pooled and stratified analyses of the effect of intravenous iron versus oral iron for the treatment of iron deficiency anemia in pregnancy
Outcome No. of Intravenous iron Oral Measure of effect Effect size (95% confidence I2 P
studies (n) iron (n) intervaI)
Hematologic indices
Hemoglobin (Hgb) at 9 571 565 Weighted mean 0.66 (0.31–1.02) 92.8 <0.001
admission for delivery (g/dL) difference (WMD)
Higher quality 8 526 521 WMD 0.74 (0.37–1.11) 91.4 <0.001
Lower quality 1 45 44 WMD 0.11 (−0.07 to 0.29) – –
Developing countries 5 290 289 WMD 0.84 (0.24–1.44) 96.3 <0.001
Developed countries 4 281 276 WMD 0.43 (0.27–0.60) 0 0.956
Mean pretreatment 3 200 200 WMD 1.14 (0.16–2.12) 97 <0.001
hemoglobin ≤ 9.0 g/dL
Mean pretreatment 6 371 365 WMD 0.39 (0.20–0.58) 56.4 0.04
hemoglobin > 9.0 g/dL
Ferritin at admission for 5 360 357 WMD 45.68 (26.21–65.16) 97.7 <0.001
deliverya (µ/L)
Mean Pretreatment 2 150 150 WMD 28.83 (18.88–38.79) 88.1 0.004
hemoglobin ≤ 9.0 g/dL
Mean Pretreatment 3 210 207 WMD 59.95 (−5.29 to 125.19) 98.7 <0.001
hemoglobin > 9.0 g/dL
Hgb at 2–6 weeks after 14 829 827 WMD 0.67 (0.44–0.90) 92.1 <0.001
treatment (g/dL)
Feritin at 2–6 weeks after 11 669 665 WMD 58.95 (50.08–67.82) 98.0 <0.001
treatment (µ/L)
Maternal outcomes
Blood transfusion 8 404 399 Relative Risk 1.02 (0.99–1.04) 7.5 0.37
Cesarean delivery rate 2 95 95 Relative Risk 1.03 (0.94–1.13) 0 0.39
Neonatal outcomes
Gestational age at delivery 4 245 245 WMD 0.29 (−0.12 to 0.71) 57 0.073
(wks)
Neonatal birthweight (g) 8 534 521 WMD 58.25 (5.57–110.94) 0 0.663
Neonatal Hgb (g/dL) 8 582 567 WMD −0.12 (−0.43 to 0.18) 72.2 0.001
Neonatal ferritin (µ/L) 8 582 567 WMD 21.38 (5.50–37.25) 63.8 0.007
Adverse medication reactions
Mild side effects: overall 21 1359 1357 Relative Risk 0.34 (0.20–0.57) 88.0 <0.001
Mild gastrointestinal side 13 960 957 Relative Risk 0.06 (0.02–0.16) 89 <0.001
effects
Mild nongastrointestinal side 21 1359 1357 Relative Risk 2.65 (1.42–4.92) 57.6 0.001
effects
a
All included studies were high-quality in developing countries
(95% CI: 50.08–67.82 µg/L), respectively) (Table 2). Stra- (Appendix 4). Intravenous iron was also associated with
tified analyses suggested this impact persisted regardless of increased neonatal ferritin (8 studies: WMD 21.38 µg/L
study quality, setting of the study, and initial hemoglobin (95% CI: 5.50–37.25 µg/L)). There were no significant
(Appendix 4). differences in gestational age at delivery or neonatal
Few studies reported maternal or neonatal outcomes hemoglobin (Table 2).
(Table 1). There were no significant differences in rates of The majority of studies reported severe (10 studies) or
blood transfusion at delivery and cesarean delivery among mild (21 studies) medication reactions (Table 2). Within the
women receiving intravenous and oral iron (Table 2). studies reporting severe medication reactions, 624 women
Intravenous iron was associated with a higher neonatal received intravenous iron and 622 women received oral
birthweight overall (8 studies: WMD 58.25 g (95% CI: iron, and no severe medication reactions or anaphylaxis
5.57–110.94 g)), and, in particular, among higher-quality occurred. Table 3 describes the specific medication reac-
studies (n = 7: WMD 69.32 g (11.85–126.79 g)) tions reported in each study. When pooled, the rate of all
A. K. Lewkowitz et al.
Oral iron
Nonsevere 0 12 21 23 57 26 18 17 1 2 11 27 0 14 15 23 32 28 153 153 19 652 1357 40.0%
medication
reaction
GI AE 25 12 16 21 57 23 18 17 1 2 10 27 0 14 12 23 29 24 142 142 19 624 1163 38.0%
composite
Nausea 3 4 0 11 6 0 0 0 2 0 0 18 18 4 66 791
Vomiting 3 1 13 2 0 0 0 8 16 4 12 12 3 74 891
Heartburn 2 6 10 13 8 0 4 3 16 41 41 6 150 796
Constipation 4 1 9 20 3 2 23 13 0 45 45 3 168 889
Diarrhea 2 2 1 4 4 1 5 2 5 4 26 26 82 787
Non GI AE 0 1 5 2 0 3 0 0 0 0 1 0 0 0 3 0 6 4 11 11 0 47 1357 2.0%
composite
Headache 1 1 0 0 0 0 2 398
Chest 0 2 0 0 2 323
tightness
Faintness/ 0 0 0 0 0 1 0 1 512
lethargy
Fever 0 0 0 0 0 0 0 0 0 432
Itching 0 0 0 0 0 0 0 0 0 365
Urticaria 0 0 0 0 0 0 8 8 16 528
Flushing 0 0 0 145
Arthralgia/ 0 0 0 0 0 0 0 0 0 517
myalgia
Tachycardia 0 0 0 0 0 197
Hypertension 0 0 0 25
Hypotension 0 0 0 0 0 0 0 0 497
Metallic taste 5 2 0 0 0 0 0 0 3 0 6 4 3 3 26 901
IV site 0 0 0 0 0 0 0 0 0 488
irritation
Discontinuation 4 0 4 0 0 8 371 2.0%
from AE
Severe 0 0 0 0 0 0 0 0 0 0 0 0 759
Intravenous compared with oral iron for the treatment of iron-deficiency anemia in pregnancy: a. . .
medication
reaction
Intravenous iron
Nonsevere 2 3 2 5 2 13 4 27 11 1 0 8 5 6 5 17 35 12 5 10 6 179 1359 13.0%
medication
reaction
GI AE 0 3 0 0 0 0 0 6 0 0 0 4 0 0 0 17 0 4 0 0 1 35 1170 1.0%
composite
Nausea 0 0 0 0 0 5 4 0 0 17 0 4 1 31 805
Vomiting 0 0 0 0 1 0 0 0 0 0 1 685
Heartburn 1 0 0 0 0 0 0 0 0 0 1 640
Constipation 2 0 0 0 0 0 0 0 0 0 2 685
Diarrhea 0 0 0 0 0 0 0 0 0 0 0 0 626
Non GI AE 2 0 2 5 2 13 4 21 11 1 0 4 5 6 5 0 35 8 5 10 5 144 1359 9.0%
composite
Headache 0 4 0 0 0 0 3 7 446
Chest 0 0 0 0 0 326
tightness
A. K. Lewkowitz et al.
AEa (%)
Rate of
Pooled
0.02%
allergic reactions reported. This difference may be
0%
Total
Oral
because we included only randomized controlled trials
561
471
326
350
145
685
200
500
735
534
368
966
(N) while Qassim et al. [9] included observational studies.
25
Indeed, Qassim et al. [9] noted that serious medication
AE (N)
Total
Oral
13
11
14
20
28
42
5
4
0
0
0
0
reactions were higher in observation trials compared to
randomized controlled trials.
Shim
(44)
0
Our study offers several strengths. We used a prede-
Khalafallah
10
0
ducted by an expert research librarian, and two researchers
independently screened all articles for eligibility before
Khalafallah
PM (81)
0
recent meta-analyses [9], all studies included were rando-
mized controlled trials published after 1980, further redu-
Rudra
(100)
2
1
0
0
4
0
cing bias. We also updated our search during the review
process, which identified another three eligible randomized
Mehta
(75)
21
5
0
9
0
0
0
1
2
1
0
1
11
0
0
0
0
12
Al
1
0
0
1
1
1
0
0
3
0
1
0
0
0
0
(91)
Discontinuation
Hypotension
Tachycardia
Medication
Urticaria
Flushing
Author (N)
irritation
lethargy
myalgia
Itching
IV site
Reaction
Fever
Severe
Acknowledgments Dr. Lewkowitz is supported in part by a National 14. Khalafallah AA, Hyppa A, Chuang A, Hanna F, Wilson E, Kwok C,
Institutes of Health training grant T32-HD-55172-9. Dr. Tuuli is et al. A prospective randomised controlled trial of a single intra-
supported by National Institutes of Health U01 (U01HD077384-03) venous infusion of ferric carboxymaltose vs. single intravenous
and R01 (1Ro1HD0867001-01) grants. The contents of this publica- iron polymaltose or daily oral ferrous sulphate in the treatment of
tion are solely the responsibility of the authors and do not necessarily iron deficiency anaemia in pregnancy. Semin Hematol.
represent the official view of the NIH. 2018;55:223–34.
15. Shim JY, Kim MY, Kim YJ, Lee Y, Lee JJ, Jun JK, et al. Efficacy
Author contributions AKL, AG, BAS, EC, RR, and MGT designed and safety of ferric carboxymaltose versus ferrous sulfate for iron
the work that led to the submission. AKL, AG, LS, CS, and MGT deficiency anemia during pregnancy: subgroup analysis of Korean
acquired data and conducted the analyses. AKL and AG drafted the women. BMC Pregnancy Childbirth. 2018;18:1–8.
manuscript. All authors revised the manuscript and approved its final 16. Gupta A, Manaktala U, Rathore AM. A randomised controlled
submission. trial to compare intravenous iron sucrose and oral iron in treatment
of iron deficiency anemia in pregnancy. Indian J Hematol Blood
Transfus. 2014;30:120–5.
Compliance with ethical standards 17. Darwish AM, Khalifa EE, Rashad E, Farghally E. Total dose iron
dextran infusion versus oral iron for treating iron deficiency
Conflict of interest The authors declare that they have no conflict of anemia in pregnant women: a randomized controlled trial. J
interest. Matern Neonatal Med. 2017;7058:1–6.
18. Breymann C, Milman N, Mezzacasa A, Bernard R, Dudenhausen J.
Publisher’s note: Springer Nature remains neutral with regard to Ferric carboxymaltose vs. oral iron in the treatment of pregnant
jurisdictional claims in published maps and institutional affiliations. women with iron deficiency anemia: an international, open-label,
randomized controlled trial (FER-ASAP). J Perinat Med.
2017;45:443–53.
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