Numerous meta-analyses show possible greater haematological benefit of intravenous (or injectable) iron compared with oral iron, which is the more common therapy for treatment of iron deficiency but which exacerbate or cause common gastrointestinal symptoms of pregnancy.
Anaemia, usually due to iron deficiency, is a common problem in pregnant women worldwide, affecting nearly 50% of pregnancies globally, and associated with problems like maternal morbidity, including impaired quality of life, a need for blood transfusions, post-partum haemorrhage, and maternal mortality.
Additionally, it is linked to adverse foetal outcomes such as preterm birth, small for gestational age, and perinatal death, while impaired neurodevelopmental outcomes of the child have also been reported in some studies.
In a comment in The Lancet, in reference to an earlier study – Ferric carboxymaltose versus standard-of-care oral iron to treat second-trimester anaemia in Malawian pregnant women: a randomised controlled trial – Antonia Shand and Giselle Kidson-Gerber write that while oral iron is the main therapy for prevention and treatment of iron deficiency and iron deficiency anaemia, being cheap and readily available, it might, however, exacerbate or cause common gastrointestinal symptoms of pregnancy like nausea, vomiting, and constipation.
This can lead to poor tolerance and adherence to treatment, they wrote.
Numerous meta-analyses show possible greater haematological benefit of intravenous (or injectable) iron compared with oral iron, with use of more expensive intravenous iron increasing.
Guidelines have been developed to improve care of pregnant women with iron deficiency and iron deficiency anaemia, however, these aren’t based on high-quality evidence.
There is little evidence on the role of universal oral iron supplementation and, for oral iron, the optimal iron salt, dose, timing of the dose (i.e. morning vs evening), and frequency of dosing (i.e. twice daily, daily, or alternate daily) is not known. For intravenous iron, the optimal preparation, dose and gestation are unknown.
In the study in The Lancet, Sant-Rayn Pasricha and colleagues presented a large open-label randomised controlled trial including pregnant women with predominantly moderate to severe anaemia (haemoglobin 7–10 g/dL) in Malawi, in which 430 women were randomly assigned to receive intravenous iron (ferrous carboxymaltose up to 1000 mg) and 432 to receive oral iron (ferrous sulphate 60 mg twice daily).
The mean age was 22·4 years and women were at a median of 22 weeks’ gestation.
A total of 366 (43%) of 844 women had baseline iron deficiency and all had malaria excluded. The primary maternal outcome was anaemia at 36 weeks’ gestation. The primary neonatal outcome was birthweight.
There was no significant reduction in anaemia prevalence at 36 weeks’ gestation in the women randomly assigned to ferrous carboxymaltose compared with those assigned to oral iron (ferrous carboxymaltose 179 [52%] of 341 vs oral iron 189 [57%] of 333; prevalence ratio [PR] 0·92 [95% CI 0·81 to 1·06]).
There was no significant change in birthweight (mean difference –3·1 g [95% CI –75 to 69]).
The only significant reduction in anaemia in women randomly assigned to ferrous carboxymaltose was at four weeks’ post-treatment (ferrous carboxymaltose 306 [77%] of 399 vs oral iron 329 [84%] of 390; PR 0·91 [95% CI 0·85 to 0·97]). There was no change in any infection (ferrous carboxymaltose 103 [24%] of 430 vs oral iron 87 [20%] of 432; risk ratio [RR] 1·19 [95% CI 0·92 to 1·52]).
There was no difference in the composite adverse birth outcome (ferrous carboxymaltose 158 [40%] of 398 vs oral iron 155 [38%] of 407; RR 1·04 [95% CI 0·88 to 1·24]), nor any of its components, including pregnancy loss or stillbirth.
Women who received intravenous iron were less likely to have iron deficiency anaemia at delivery than those who received oral iron (ferrous carboxymaltose 29 [9%] of 324 vs oral iron 93 [29%] of 321; PR 0·30 [95% CI 0·20 to 0·44]).
The strength of the study is the pragmatic randomised trial design including women with moderate to severe anaemia.
A weakness is that the cause of anaemia was not determined. There was high prevalence of recently treated malaria (61%), and most participants (57%) did not have iron deficiency, while 55% (368/674) of the women remained anaemic at 36 weeks’ gestation, rising to 75% (37/50) for those with severe baseline anaemia.
Another limitation was that the trial was open label, however, blinding to brown intravenous iron might be difficult. Adherence was also unable to be measured, partly due to Covid-19 pandemic disruption.
Pasricha and colleagues used standard doses and preparations of iron, although studies suggest other preparations might be more effective than ferrous sulphate.
Once daily or alternate day dosing with 60 mg might be just as effective;
however, these regimens have not been tested in randomised trials in pregnant women.
Despite being a negative trial in terms of anaemia, foetal growth, and perinatal death outcomes, this trial gives important information about the relative safety of intravenous iron treatment of anaemia predominantly in the second trimester, in a setting with high prevalence of infections including malaria and HIV.
Improvements in testing for iron deficiency (e.g. point-of-care ferritin testing) are required, so that women with anaemia in low-resource settings can receive targeted therapy. In addition, it is to be hoped long-term infant outcomes will be reported.
Further high-quality studies in pregnant women with iron deficiency and iron deficiency anaemia in various settings are urgently needed.
Short-term maternal and foetal outcomes, patient-reported outcomes, long-term childhood outcomes, and cost effectiveness need to be measured.
Study details
Ferric carboxymaltose versus standard-of-care oral iron to treat second-trimester anaemia in Malawian pregnant women: a randomised controlled trial
Sant-Rayn Pasricha, Martin Mwangi, Ernest Moya, Ricardo Ataide, Glory Mzembe, Rebecca Harding, et al.
Published in The Lancet on 20 April 2023
Summary
Background
Anaemia affects 46% of pregnancies in Africa; oral iron is recommended by WHO but uptake and adherence are suboptimal. We tested a single dose of a modern intravenous iron formulation, ferric carboxymaltose, for anaemia treatment in Malawian pregnant women.
Methods
In this open-label, individually randomised controlled trial, we enrolled women with a singleton pregnancy of 13-26 weeks’ gestation in primary care and outpatient settings across two regions in southern Malawi. Women were eligible if they had capillary haemoglobin of less than 10·0 g/dL and negative malaria rapid diagnostic test. Participants were randomised by sealed envelope 1:1. Assessors for efficacy outcomes (laboratory parameters and birthweight) were masked to intervention; participants and study nurses were not masked. Participants were given ferric carboxymaltose up to 1000 mg (given once at enrolment in an outpatient primary care setting), or standard of care (60 mg elemental iron twice daily for 90 days), along with intermittent preventive malaria treatment. The primary maternal outcome was anaemia at 36 weeks’ gestation. The primary neonatal outcome was birthweight. Analyses were performed in the intention-to-treat population for mothers and liveborn neonates, according to their randomisation group. Safety outcomes included incidence of adverse events during infusion and all adverse events from randomisation to four weeks’ post partum. The trial is registered with ANZCTR, ACTRN12618001268235. The trial has completed follow-up.
Findings
Between Nov 12, 2018, and March 2, 2021, 21 258 women were screened, and 862 randomly assigned to ferric carboxymaltose (n=430) or standard of care (n=432). Ferric carboxymaltose did not reduce anaemia prevalence at 36 weeks' gestation compared with standard of care (179 [52%] of 341 in the ferric carboxymaltose group vs 189 [57%] of 333 in the standard of care group; prevalence ratio [PR] 0·92, 95% CI 0·81 to 1·06; p=0·27). Anaemia prevalence was numerically lower in mothers randomly assigned to ferric carboxymaltose compared with standard of care at all timepoints, although significance was only observed at four weeks’ post-treatment (PR 0·91 [0·85 to 0·97]). Birthweight did not differ between groups (mean difference –3·1 g [–75·0 to 68·9, p=0·93). There were no infusion-related serious adverse events or differences in adverse events by any organ class (including malaria; ≥1 adverse event: ferric carboxymaltose 183 [43%] of 430 vs standard of care 170 [39%] of 432; risk ratio 1·08 [0·92 to 1·27]; p=0·34).
Interpretation
In this malaria-endemic sub-Saharan African setting, treatment of anaemic pregnant women with ferric carboxymaltose was safe but did not reduce anaemia prevalence at 36 weeks’ gestation or increase birthweight.
Antonia Shand, Children's Hospital Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Australia.
Giselle Kidson-Gerber, Prince of Wales Hospital, NSW Health Pathology, Sydney, Australia.
The Lancet article – Anaemia in pregnancy: a major global health problem (Open access)
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