Erythropoietin Powerful Therapy For Anemia In Pregnant Patients
Overview
Treatment options for severe, refractory iron deficiency anemia during pregnancy are quite limited. This review aimed to examine the available literature on the use of recombinant erythropoietin for treating this condition in pregnant women. A thorough search was conducted across seven databases, covering studies from their inception up to March 2022, using a combination of relevant keywords. The review included both randomized controlled trials and observational studies that involved pregnant patients with iron deficiency anemia who were treated with recombinant erythropoietin or a control. The main focus was on the change in hemoglobin or hematocrit levels after treatment. The studies were evaluated using criteria from the Cochrane Handbook for Systematic Reviews of Interventions. Data from these studies were summarized narratively and analyzed with descriptive statistics where appropriate. The review was registered with PROSPERO to ensure that it followed established systematic review guidelines.
Introduction
Anemia, a widespread hematologic disorder, affects approximately one-third of pregnant women in the United States, posing significant health challenges for both the mother and the developing fetus. Anemia is categorized based on its underlying cause, the mechanism of red blood cell dysfunction (such as reduced production or increased destruction), and the size of the red blood cells involved, which can be microcytic, macrocytic, or normocytic. Among these, iron deficiency anemia (IDA) is the most common type encountered during pregnancy. IDA is a microcytic anemia, primarily resulting from insufficient red blood cell production due to iron deficiency. This condition is associated with a range of adverse outcomes, including increased risks of pre-eclampsia, postpartum hemorrhage, cesarean delivery, infections, postpartum depression, and complications for the fetus, such as low birth weight, preterm birth, fetal growth restriction, and impaired neurodevelopment.
The cornerstone of IDA management during pregnancy is iron supplementation, which can be administered either orally or intravenously. However, in cases of severe or refractory IDA, where conventional iron therapy proves inadequate, treatment options are significantly constrained, often leaving blood transfusions as the only viable intervention. Blood transfusions, while effective, present several drawbacks, including the risk of transfusion-related infections, the possibility of refusal by patients due to religious or cultural reasons, and the broader issue of national blood supply shortages. These challenges underscore the urgent need for alternative therapeutic approaches for managing severe or unresponsive IDA in pregnancy.
Erythropoietin (EPO), a naturally occurring glycoprotein hormone produced by the kidneys in response to hypoxia and anemia, plays an essential role in stimulating red blood cell production. During pregnancy, there is a physiological increase in erythropoietin levels to accommodate the growing oxygen demands of the mother and fetus. Recombinant erythropoietin (rEPO), a synthetic analog produced using Chinese hamster ovary cells, has been primarily utilized in pregnant women with anemia related to end-stage renal disease. Despite its established use in this specific context, there has been limited investigation into the broader application of recombinant erythropoietin for treating refractory IDA in pregnancy. The objective of this study was to systematically review the current literature on the use of rEPO as a potential treatment for IDA in pregnant women, exploring its efficacy and safety in this critical population.
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Methods
Inclusion Criteria:
– Study Design: The review included both randomized controlled trials (RCTs) and observational studies.
– Population: Pregnant patients diagnosed with iron deficiency anemia (IDA).
– Intervention: Studies that evaluated the use of recombinant erythropoietin (rEPO) as a treatment for IDA during pregnancy.
– Outcome Measures: Primary outcomes were changes in hematologic parameters, specifically hemoglobin and/or hematocrit levels, following erythropoietin treatment.
– Language and Geography: No restrictions were placed on the language of publication or geographical location of the study.
Exclusion Criteria:
– Study Design: Non-controlled studies, case reports, case series, and review articles were excluded.
– Population: Studies involving non-pregnant populations or those with anemia not specifically classified as iron deficiency anemia were excluded.
– Intervention: Studies that did not involve the use of recombinant erythropoietin as the primary intervention for IDA in pregnancy were excluded.
– Outcome Measures: Studies that did not report changes in hematologic parameters post-treatment or that lacked sufficient data to evaluate these outcomes were excluded.
These criteria were carefully selected to ensure the inclusion of relevant and high-quality studies while excluding those that would not contribute meaningfully to the analysis of rEPO’s effectiveness in treating IDA during pregnancy.
Results
A comprehensive search identified 234 studies, of which 10 were found to be relevant and underwent full-text review. Five studies were excluded due to either a non-controlled design or incomplete outcome data, leaving five studies with a total of 207 pregnant patients with iron deficiency anemia (IDA). These patients were divided into treatment and control groups, with 103 in the treatment group and 104 in the control group.
The included studies focused on patients in the second or third trimester of pregnancy. In three of these studies, patients were required to take oral iron supplements before enrollment. The treatment groups received either intravenous or subcutaneous recombinant erythropoietin (rEPO) combined with iron supplementation, while the control groups received only iron supplementation in various forms (intravenous, intramuscular, or oral). Laboratory assessments were conducted at different intervals across the studies, and the criteria for group allocation as well as the study endpoints varied.
Baseline hematologic parameters, including gestational age at the start of treatment, were similar between the groups. However, in two studies, patients with lower baseline hemoglobin levels were assigned to the intervention group, which resulted in a significant difference in baseline hemoglobin levels between the treatment and control groups.
Three studies reported that the combination of erythropoietin and iron supplementation was more effective in raising hemoglobin or hematocrit levels than iron alone. Notably, one study found that patients in the intervention group achieved target hemoglobin levels faster than those in the control group. Another study suggested that the benefits of rEPO persisted even after discontinuation of the treatment.
However, two studies found no significant difference in hemoglobin levels by the end of the study period, although in one of these studies, patients in the intervention group exhibited a more rapid increase in hemoglobin levels early in the treatment course. None of the included studies reported adverse events related to erythropoietin or iron supplementation.
Overall, the risk of bias in the included studies was generally low, although two studies were identified as having a high risk of bias due to deviations from the intended intervention, and two others had moderate risk due to selection bias. While outcome assessments were not blinded, the reliance on laboratory evaluations minimized detection bias, resulting in a moderate risk of bias for these assessments. Reporting bias was deemed low across all studies.
Discussion
Our review provides evidence indicating that recombinant erythropoietin (rEPO) combined with iron supplementation may be more effective in increasing hemoglobin and/or hematocrit levels than iron supplementation alone. Notably, one study did not find significant differences in these parameters by day 28, but it is important to highlight that this study involved only a single dose of rEPO, whereas other studies utilized serial dosing.
The administration of rEPO does not seem to elevate the risk of maternal or fetal adverse events, aligning with existing literature that supports rEPO as an effective treatment for improving hematologic parameters. Previous research has also demonstrated that rEPO does not cross the placenta and is not associated with negative fetal outcomes. While our review cannot conclusively rule out the possibility of rare adverse events associated with rEPO use during pregnancy, the available evidence supports its safety in this population.
Most studies on rEPO use in pregnancy have focused on patients with end-stage renal disease. One such study suggested that subcutaneous administration of rEPO is preferable to intravenous administration due to its lower required dosage. However, due to the limitations in available data, our study could not assess the impact of different administration routes on the efficacy of rEPO.
The strength of our study lies in its comprehensive literature review and detailed data extraction, which summarize the available evidence and emphasize the potential benefits of rEPO in treating a condition with few therapeutic options. Nevertheless, the study’s limitations include a relatively small number of participants and included studies. Furthermore, a significant limitation was our inability to perform a meta-analysis due to variations in study design and incomplete data reporting. Attempts to contact the original authors for missing data to facilitate pooling and analysis were unsuccessful.
Conclusion
In conclusion, our study indicates that when iron deficiency anemia (IDA) does not respond to iron supplementation alone, the combination of serial recombinant erythropoietin (rEPO) administration with iron supplementation may offer a safe and effective treatment alternative. To establish strong evidence supporting the use of rEPO in pregnancy, further randomized controlled trials are necessary.
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