Ferric carboxymaltose in pregnancy maintains iron stores and reduces the need for repeat infusions: BJOG
Iron deficiency (ID) is the most common nutritional disorder worldwide, listed on the World Health Organization (WHO) top five mental and physical disabilities. ID is the leading underlying cause of anaemia, affecting approximately 45% of women of childbearing age in developed countries and up to 80% in lower resource settings. As iron is necessary for many biological functions, pregnant women with ID or iron deficiency anaemia (IDA) frequently suffer from cardiovascular problems, reduced physical activity, impaired cognitive performance, reduced immune function, fatigue and depressive episodes.
These women are at a higher risk of pregnancy complications, stillbirth, postpartum haemorrhage (PPH), peri-partum allogeneic red blood cell transfusion and death. Infants of mothers with ID are at increased risk of preterm birth, growth restriction, low birthweight, perinatal death, low Apgar scores, neonatal infection, postnatal ID and impaired cognitive development. In recognition of these adverse outcomes, WHO has targetted a 50% reduction of IDA in women of reproductive age by 2025.
Women with inadequate iron stores are ill-prepared for the increased iron demand of pregnancy. ID is detectable, preventable and treatable with oral iron considered the first-line treatment. Intravenous iron (IVI) is recommended when women are non-responsive, non-tolerant or noncompliant with oral iron, when ID/IDA is diagnosed late in pregnancy, or in women with severe anaemia or at risk of haemorrhage.
Clinicians lack high quality data on the optimal dose to improve and sustain iron status adequately, and to provide sufficient protection against adverse obstetric, neonatal or mental health sequelae. Froessler B and team conducted an RCT comparing two doses of IVI (500 and 1000mg) using an equivalence design.The outcomes of this trial suggest that successful treatment of ID can occur with a single 1000- mg dose, with no adverse outcomes for antenatal progression, neonatal or child outcomes.
This was a single centre, randomised, parallel, two-arm equivalence study. 278 pregnant women with iron deficiency. Participants received either 500 mg (n = 152) or 1000mg (n = 126) of intravenous ferric carboxymaltose in the second or third trimester. Primary outcome included the proportion of participants requiring additional intravenous iron (500mg) to achieve and maintain ferritin >30microg/L (diagnostic threshold for iron deficiency) at 4 weeks post-infusion, and at 6 weeks, and 3-, 6- and 12-months postpartum. Secondary endpoints included repeat infusion rate, iron status, birth and safety outcomes.
The two doses were not equivalent within a 5% margin at any time point. At 4 weeks post infusion, 26/73 (36%) participants required a repeat infusion in the 500- mg group compared with 5/67 (8%) in the 1000-mg group: difference in proportions, 0.283. Overall, participants in the 500-mg arm received twice the repeat infusion rate (0.81 [SD = 0.824] versus 0.40 [SD = 0.69], rate ratio 2.05).
This randomised controlled trial, comparing two pragmatic doses of intravenous iron for treating ID in pregnancy, demonstrated that 500 mg of intravenous FCM was not equivalent to the 1000-mg dose. To achieve initial and sustained correction of ID, participants in the lower dose arm received more than twice the rate of repeat infusions compared with the higher dose arm. Participants in the higher dose arm had significantly higher ferritin levels up to 6 months postpartum, coupled with a significantly greater increase in haemoglobin, reflecting favourable iron availability and utilisation.
Due to the close monitoring provided in this study, women with declining iron stores were able to receive subsequent IVI treatment. Given the higher rate of persistent ID observed in the low dose arm, authors suggested that continued monitoring after infusion of 500 g IVI is essential to ensure adequate iron stores are accomplished in pregnancy.
Iron deficiency and IDA are significant medical conditions with serious consequences for maternal and fetal outcomes. The study found no differences in pregnancy, birth- or infant-related outcomes between the 500- and 1000-mg IVI arms, with the exception of PPROM, which occurred only in participants receiving 1000mg. Although the pathways leading to PPROM are complex and multifaceted, increased oxidative stress appears to play a role. It is possible that first or second trimester IDA itself, or exposure to increased iron, or differences in ferritin levels after IVI, may have contributed to oxidative stress leading to PPROM in the current study. However, this must be interpreted with caution given the present study was not powered to examine this outcome.
The outcomes of this trial suggest that successful treatment of ID can occur with a single 1000- mg dose, with no adverse outcomes for antenatal progression, neonatal or child outcomes. This represents an effective treatment modality to shield from the detrimental short- and potential long-term impacts of ID and IDA. Further, adequate iron stores have the potential to have a positive impact on maternal mental health during pregnancy and postpartum; maternal mental health outcomes collected during this trial will be the subject of a subsequent article. Further studies will help to optimise IVI dose, which may be particularly relevant to those countries where 1000 mg is not currently routinely used.
"Low dose (500mg) intravenous FCM treatment was not equivalent to 1000mg within a 5% margin for successful correction of ID in pregnancy. A single 1000mg does represents an efficient and effective method to manage ID and IDA clinically in pregnancy. A lower dose approach requires ongoing monitoring to ensure adequate iron stores are reached and sustained. Neither doses had any adverse impact on neonatal or child outcomes."
Source: Froessler B, Schubert KO, Palm P, Church R, Aboustate N, Kelly T-L, et al. Testing equivalence of two doses of intravenous iron to treat iron deficiency in pregnancy: A randomised controlled trial. BJOG. 2022;00:1–9. https://doi. org/10.1111/1471-0528.17288
