Introduction
In Mexico, specific data on the prevalence of anemia and iron deficiency (ID) exclusively in pregnant women is unavailable. However, globally, the World Health Organization estimates that approximately 25-37% of pregnant women suffer from anemia, and 40% experience ID, which is the leading cause of anemia during pregnancy1–4.
A general idea can be drawn based on the 2022 national health and nutrition survey, which, while excluding pregnant women, provides significant data on the national state of anemia and ID, showing that the prevalence of anemia by age group is predominantly in women of reproductive age5,6. Shamah-Levy et al.6, in their analysis of the 2022 survey, observed that 15.7% of women presented with anemia and 41.9% with ID. It was also noted that 12.3% of Mexican women had both anemia and ID, which were significantly associated (p < 0.05). In this sense, the coexistence of anemia and ID (12%) represents 77.9% of the total number of women with anemia in Mexico.
In Mexico, 1 in 6 women aged 12-49 presented anemia, while a higher proportion (39.1%) showed ID. As a result, ID anemia affects 12% of the total non-pregnant Mexican women population.
The current prevalence of ID shows an increase compared to 2018-2019 (29.6%)6.
This condition can have negative effects on both the mother and the fetus3–9.
Anemia presents significant challenges, so hemoglobin (Hb) levels are routinely monitored to detect it preventively. However, a large percentage of pregnant women with ID without anemia are neither diagnosed nor monitored in daily clinical practice since serum ferritin (SF) is not routinely measured3,4,10,11. In Europe, 10-33% of pregnant women have ID,3 and we could estimate that the figures in Mexico may be similar, based on the ID and anemia rates in non-pregnant women4,5.
Therefore, this review article seeks to highlight the importance of detecting and treating ID in pregnant women before anemia develops. While anemia is systematically checked for in pregnancy, ID is often not documented, which can affect maternal and perinatal health. This article aims to educate on the difference between ID and anemia, emphasize the consequences of not adequately treating ID, and present ferric carboxymaltose (FCM) as an effective and safe option for addressing this issue, offering better outcomes in less time with fewer doses required.
Material and methods
Review study. An electronic search was conducted for articles published in English and Spanish, primarily using PubMed and Google Scholar, as well as databases such as the INSP Library and national clinical practice guidelines, in both Spanish and English, published within the last 5 years.
Health science descriptors (Decs or MeSH) used were: pregnancy anemia; ID and iron carboxymaltose; pregnancy; anemia; ID; FCM.
Results
Thirty-five articles were found, of which 31 were selected for being consistent with the review’s objectives. Two were excluded due to methodological validity issues or lack of relevance to the study’s objectives. The included sources are listed in the references section. Based on data from the reviewed articles and the author’s experience, conclusive recommendations are made.
ID versus anemia in pregnancy
Anemia is common during pregnancy, and while most anemias are physiological, the most common pathological cause is ID, affecting maternal health and fetal development12. ID and anemia in pregnancy are related but not the same. ID is the initial stage, where iron levels decrease without a significant reduction in Hb. It is characterized by a reduction in iron stores (low ferritin) before noticeable signs of anemia, such as decreased Hb and hematocrit (Hct), appear.
In a normal pregnancy, iron requirements include 300-350 mg for the fetus and placenta, 500 mg for the expansion of maternal red blood cell mass, and 250 mg associated with blood loss during labor and delivery. These requirements increase depending on the trimester: 0.8 mg/day in the first, up to 7.5 mg/day in the third13.
Pregnancy increases maternal iron demand for three reasons: Maternal plasma and blood volumes increase during pregnancy1,2,14, each additional gram of Hb synthesized by the mother requires 3.46 mg of elemental iron. Furthermore, the fetus needs iron for its metabolic and oxygen transport needs, as well as to form its relatively large endogenous iron stores, which will be used during the first 6 months of post-natal life, and the placenta is a highly metabolically active organ with significant iron requirements14.
Iron sufficiency is essential for oxygen supply to the maternal-placental-fetal unit to meet the increased oxygen consumption during pregnancy1. Maintaining adequate maternal Hb concentrations supports the oxygen demands of all three components. Beyond oxygen supply, iron in cytochromes catalyzes ATP generation, at a time when fetal oxygen consumption is high, driven primarily by the structural development of fetal organs2. Among these organs, the brain is particularly “voracious,” accounting for an astonishing 60% of total fetal oxygen consumption2.
However, in fetal iron metabolism, red blood cells are prioritized over all other tissues, including the brain. Therefore, in cases of ID and chronic anemia, the brain and other essential structures will not be prioritized by the body, potentially causing deleterious effects on the infant’s development.
Considering that anemia represents the final stage of ID, it is important to highlight that anemia is not a sensitive marker for tissue ID, including cerebral ID14. For this reason, the iron status of these tissues should be inferred from SF3. While anemia presents significant problems for maternal and child health2–4, and Hb levels should be routinely monitored to detect it preventively, it should not be overlooked that a large percentage of pregnant women present with ID without anemia. They are neither diagnosed nor monitored in daily clinical practice, as SF is not routinely measured3.
ID is therefore a precursor to anemia, and preventing or treating it is beneficial both for the mother and for the proper development of the newborn.
ID occurs when the body uses its iron stores (reflected in low ferritin levels) to meet the growing demand caused by fetal development and the dilution caused by the increased maternal plasma volume. If the deficiency is not corrected in time, Hb production is affected, which can eventually lead to anemia and complications for both mother and baby. These complications include preeclampsia, premature birth, low birth weight, impaired neurological development in the child, and an increased rate of cesarean sections3,14,15. Moreover, women with ID have a higher risk of developing postpartum anemia, which can prolong maternal recovery and affect the mother’s mental health15.
Diagnosis of ID during pregnancy
The American College of Obstetricians and Gynecologists recommends confirming ID anemia through specific iron studies when anemia is diagnosed during pregnancy. However, it acknowledges that in clinical practice, treatment is often initiated presumptively based on suspicion of ID anemia1,2,4,12,15.
The Hb values used to detect the presence of anemia are levels < 11 g/dL12,15,16. However, a diagnosis approach limited to anemia may overlook cases of ID without anemia, highlighting the need for comprehensive iron screening during pregnancy16,17.
The criteria for diagnosing anemia in pregnancy are as follows: Hb < 11 g/dL or Hct < 33% in the first and third trimesters, and Hb < 10.5 g/dL or Hct < 32% for the second trimester1,2,4,12,18.
In the absence of inflammation, SF levels below 30 ng/dL will indicate ID (Table 1)12,16–19.
Table 1. Ferritin normal level
| Normal | 100-200 ng/mL |
|---|---|
| Absolute deficiency without inflammation | < 30 ng/mL |
| absolute deficiency with inflammation* | > 100 ng/mL |
| Functional deficiency | 100-300 ng/mL (0 >) + TSAT < 20% |
|
Modified from Capellini et al.19 |
|
Pavord et al.12 recommend a proactive approach to the detection and treatment of anemia with oral iron administration as the first line of treatment, and intravenous iron for women who do not respond to or cannot tolerate oral iron, or for those with severe anemia. Administration should be done cautiously, considering the patient’s safety and tolerance. An adequate diagnosis and treatment can improve health outcomes for both mother and baby.
Treatment of ID: limitations of oral iron
The conventional treatment for ID is based on the administration of oral iron, such as ferrous sulfate. However, oral treatment has significant limitations, including low gastrointestinal absorption, side effects (primarily gastrointestinal), and poor adherence due to the need for prolonged administration of at least 6 months20. Oral iron replacement is economical but requires fasting for maximum effect and good adherence over an extended period, which can be complicated due to common side effects such as constipation, diarrhea, and abdominal pain.
Moreover, in cases of severe anemia or when a rapid correction of iron levels is needed, oral iron is insufficient21,22.
In a large population study conducted across 22 sub-Saharan African countries, only 22.9% of Nigerian women received more than 90 days of iron supplementation during pregnancy for their most recent childbirth22,23.
Considering that correction should occur in the embryonic and fetal stages to see the appropriate outcomes in the newborn, as demonstrated in the study by Oskovi-Kaplan et al.1, in which anemia correction in the third trimester only impacted maternal factors, maintaining adequate maternal iron reserves for the third trimester ensures that women can face the requirements of childbirth.
FCM: An Effective Therapeutic Approach FCM has emerged as an effective and rapid option for correcting ID and anemia during pregnancy15,21. It offers an alternative to traditional oral treatments. Compared to other oral and intravenous preparations, it has demonstrated superiority.
A randomized controlled trial found that FCM was more effective than oral iron (ferrous sulfate) in increasing Hb levels in pregnant women with ID anemia, with fewer side effects and greater efficacy in achieving anemia correction within 6 weeks24.
A meta-analysis compared the efficacy of FCM with other intravenous preparations in pregnant women. The results showed that FCM is more effective than other intravenous treatments in increasing Hb and ferritin levels in women with ID anemia during pregnancy25.
Various studies have demonstrated that a single infusion of 1000 mg of FCM can significantly increase Hb and ferritin levels, achieving a faster and more lasting correction compared to oral treatment20.
In a study conducted in Japan, women with postpartum anemia treated with FCM experienced a significant increase in Hb levels at 8 weeks, with minimal adverse effects15. Other clinical trials have confirmed that FCM has a favorable safety profile, with a low incidence of adverse events and greater tolerability compared to other intravenous and oral preparations26.
Efficacy and safety of FCM in different populations
In a study conducted on pregnant women between 14 and 26 weeks of gestation, FCM was shown to be effective in raising Hb levels from 7.99 g/dL to 14.04 g/dL within 6 weeks27. This significant increase persisted even at 12 weeks post-treatment, suggesting a durable correction of ID.
The group led by Oskovi-Kaplan et al.1 evaluated maternal and neonatal outcomes in pregnant women treated with FCM in the third trimester. They demonstrated that anemia correction in the third trimester did not significantly impact neonatal outcomes but did benefit maternal health, reducing maternal mortality, decreasing morbidity, and lowering the need for cesarean sections and postpartum transfusions.
These findings suggest that correcting anemia during pregnancy will not radically affect the neonate since neurodevelopment has already progressed past its critical stages, but it will benefit the mother.
Another systematic review and meta-analysis found that FCM is more effective and has fewer side effects compared to iron sucrose, confirming its superiority in correcting ID in obstetrics and gynecology26.
The team of Vanobberghen et al.21 noted in their publication that intravenous FCM is more effective than oral iron in correcting ID anemia in postpartum women, providing a quicker and more sustained normalization of Hb and ferritin levels. These results support the use of FCM as a safe and effective intervention in low-resource settings. These data suggest that FCM is an effective and safe option for treating ID during pregnancy, with potential benefits for both mother and baby.
Challenges for implementation in low-resource countries
Despite the proven efficacy of FCM, its implementation in low- and middle-income countries presents challenges due to associated costs and limited access to diagnostic tests such as ferritin level measurements28. It is essential to consider the limitations of local health systems when promoting the adoption of this treatment, especially in settings with limited resources.
The preferred treatment is the administration of oral iron salts, with a suggested dose of 40-80 mg of elemental iron daily. In cases of intolerance, malabsorption, or the need for a rapid response, intravenous iron is recommended, especially from the second trimester onward. It is advised for women who do not respond to or tolerate oral iron or for those with severe anemia in the third trimester. The administration should be done cautiously, considering patient safety and tolerance12.
Oral iron treatment typically shows results in about 2-3 weeks. However, it may require a treatment period of 2-3 months to fully correct anemia and replenish the body’s iron stores.
Hb usually increases by around 1-2 g/dL/month. The response may vary depending on the severity of the ID, the underlying cause, the dosage of the supplement, intestinal iron absorption, and adherence to the treatment. It is recommended to continue supplementation for several months even after Hb levels normalize, to restore iron reserves and prevent relapse.
On the other hand, intravenous FCM is more effective and better tolerated than oral ferrous sulfate in treating ID anemia during pregnancy. FCM showed a more significant, rapid, and sustained increase in Hb and ferritin levels with fewer side effects24,25.
Casellas-Caro et al.29 noted that although the acquisition cost of FCM is higher than that of ferrous sulfate, the clinical benefits of FCM may justify its use in certain circumstances.
A comparative study of different doses of FCM during pregnancy showed that administering 1000 mg was more effective in maintaining iron reserves and reducing the need for additional infusions compared to a 500 mg dose, which required more monitoring30.
Evstatiev et al.31 suggest determining anemia status by Hb levels and calculating the dose based on the patient’s weight to determine the FCM dosage, noting that the maximum dose is 1000 mg/week. However, this table is not calculated for a pregnant population but can serve as a guide for preconceptionally and postpartum patients (Table 2).
Table 2. Determination of iron requirements (must be individualized per patient)
| Hemoglobin (g/dL) | Body weight | ||
|---|---|---|---|
| < 35 kg | 35-70 kg | > 70 kg | |
| < 10 | 500 mg | 1500 mg | 2000 mg |
| 10-14 | 500 mg | 1000 mg | 1500 mg |
| > 14 | 500 mg | 500 mg | 500 mg |
|
No more than 1000 mg of FCM should be administered per week. Modified from Evstatiev et al.31 |
|||
Conclusion
Early detection and treatment of ID during pregnancy are essential to prevent the development of anemia and its associated complications for both the mother and the fetus. Although ID anemia is routinely monitored, ID without anemia is often undetected, highlighting the importance of assessing SF as an additional marker. FCM presents itself as an effective and safe therapeutic option that offers a quicker and more sustained correction of ID compared to traditional oral treatments. Its use can improve maternal and neonatal outcomes, particularly in women who cannot tolerate oral iron or who require a rapid response. However, the implementation of this treatment in low-resource countries may face challenges due to its cost and lack of access to timely diagnostics, underscoring the need for solutions tailored to each context.
Funding
The authors declare that they have not received funding.
Conflicts of interest
The authors declare no conflicts of interest.
Ethical considerations
Protection of humans and animals. The author declares that no experiments involving humans or animals were conducted for this research.
Confidentiality, informed consent, and ethical approval. The study does not involve patient personal data nor requires ethical approval. The SAGER guidelines do not apply.
Declaration on the use of artificial intelligence. The author declares that no generative artificial intelligence was used in the writing of this manuscript.
