CORRESPONDENCE IV Iron in pregnancy: An unmet clinical need To the editor: This is the second in a series of short commentaries on the clinical use of intravenous iron. The American Journal of Hematology welcomes comments and questions, which will be addressed in the subsequent issue. Approximately 58% of normal, nonanemic, menstruating college freshmen have no stainable iron in their marrow. A recent French survey [1] reported 25% of menstruating women were iron deficient [1]. Given these staggering numbers, it is not surprising that iron deficiency with or without anemia is common in pregnancy yet unless anemia is present at the initial visit, iron parameters are not routinely ordered. While oral iron remains front line standard for gravidas in the western world, bloating and constipation are common problems due to the high progesterone levels, which slow bowel transit and increasing pressure of the gravid uterus on the rectum. Oral iron, rife to gastrointestinal perturbation, is associated with reported adverse events in up to 70% to whom it is prescribed, resulting in poor adherence [2]. Whereas numerous publications report the safety and efficacy of intravenous iron in gravidas without reported serious adverse events when given in the second or third trimester, its use in pregnancy is sporadic at best. It is likely that this reluctance to use intravenous iron is fueled by antiquated data reporting serious adverse events, such as anaphylaxis, which were much more common with older preparations no longer available. The advent of new formulations allowing complete replacement doses in a single setting, with marginal to no toxicity in gravidas, should obviate such concerns. Unfortunately, that has not occurred. In 2011, a report published in this journal, demonstrated the safety and efficacy of 1,000 mg of low molecular weight (LMW) iron dextran administered in 1 hr to 888 patients receiving 1,266 infusions, 162 of whom were pregnant [3]. Similar safety and efficacy data have been published with multiple doses of iron sucrose and total dose infusions of the newly approved agent ferric carboxymaltose. In all studies, rapid elimination of fatigue, pagophagia (ice craving), and less recognized symptoms, such as restless legs, was observed. No clinically significant toxicity has been reported. These observations are especially poignant considering that Congdon et al. reported that not only do iron deficient neonates have delayed growth and development but also a statistically significant increment in cognitive and behavioral abnormalities can be detected up to 10 years after iron repletion [4]. In our practice, we routinely administer 1,000 mg of LMW iron dextran to iron deficient gravidas intolerant of or unresponsive to oral iron independent of anemia. Approximately 1,400 pregnant women have been treated since 1991 when LMW iron dextran was approved for use in iron deficient patients in the United States. No serious adverse events have been observed. Given the preponderance of published evidence on the safety and efficacy of intravenous iron in pregnancy, the failure to address its use is an unmet clinical need and a more liberal use of IV iron will minimize the likelihood that the neonate born to an iron deficient mother will be iron deficient at birth. These data also suggest that the current guidelines of the American College of Obstetrics and Gynecology, which do not recommend the routine screening for iron deficient at the initial prenatal visit, should be revisited. MICHAEL AUERBACH* Clinical Professor of Medicine Georgetown University School of Medicine Auerbach Hematology and Oncology, Baltimore, Maryland Conflict of interest: Nothing to report. *Correspondence to: Michael Auerbach; Clinical Professor of Medicine, Auerbach Hematology and Oncology, Georgetown University School of Medicine, 9110 Philadelphia Rd Suite 314, Baltimore, MD 21237. E-mail: [email protected] Received for publication: 20 April 2014; Accepted: 21 April 2014 Published online: 25 April 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ajh.23748

䊏 References 1. Alleyne M, Horne MK, Miller JL. Individualized treatment for iron-deficiency in adults. Am J Med 2008;121:943–948. 2. Reveiz L, Gyte GM, Cuervo LG, Casasbuenas A. Treatments for iron-deficiency anaemia in pregnancy. Cochrane Database Syst Rev 2011:CD003094. 3. Auerbach M, Pappadakis JA, Bahrain H, et al. Safety and efficacy of rapidly administered (one hour) one gram of low molecular weight iron dextran (INFeD) for the treatment of iron deficient anemia. Am J Hematol 2011; 86:860–862. 4. Congdon E, Westerlund B, Algarin M, et al. Iron deficiency in infancy is associated with altered neural correlates of recognition memory at 10 years. J Pediatr 2012;160:1027–1033.

Reduction in serum IL-10 levels is a surrogate marker for predicting vaso-occlusive crisis in sickle cell disease To the Editor: Altered inflammatory cytokine expression substantially impacts the development of sickle cell disease (SCD) vaso-occlusive crises (VOC) [1,2]. This was evidenced

Figure 1. Receiver operating characteristics (ROC) curve for the prediction of VOC, based on binary logistic regression and discriminant classification analysis for VOC patients/steady-state control groups. The area under the curve (SE) is 0.688 (0.036) for IL-10. The value of specificity is plotted as 1-specificity on the x axis. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

by the elevation in proinflammatory, and the reduction in anti-inflammatory cytokine levels in SCD patients compared to healthy individuals [1,2]. The anti-inflammatory cytokine interleukin-10 (IL-10) was described to mediate several SCD-associated events, and reduction in its expression was reported in unselected SCD patients compared to healthy subjects [3], and in SCD patients with VOC compared to VOC-free SCD patients [1,4]. Other studies reported contradictory findings on the contribution of IL-10 to SCD and its complications [5,6], which was likely attributed to the low number of subjects and selection criteria used in those studies. The present study examined the relationship between reduced IL-10 levels and the occurrence of VOC and VOC-related parameters in pediatric SCD patients. Study subjects comprised 148 SCD patients with VOC event (VOC Group) and 63 asymptomatic control SCD patients who reported no VOC events for the past 9 months (Steady-state Group). SCD diagnosis was according to hemoglobin profile. VOC was defined as acute events characterized by diffuse pain in different body sites related only to SCD. VOC management consisted mostly of nonsteroidal anti-inflammatory drugs (NSAID; 67.7%), along with narcotics (2.2%), and narcotics plus NSAID (20.7%). Comparable frequencies of hydroxyurea- (P 5 0.80) and folic acid- (P 5 0.32) treated patients were seen in both patient groups. Steady-state controls were matched with VOC patients according to gender, HbS and HbF profiles, and other hematological indices. Local research and ethics committees approved the study protocol, which was in agreement with the 2000 Helsinki declaration. Serum samples were tested for IL-10 using human IL-10 sandwich ELISA (R&D Systems, Minneapolis, MN). Assay sensitivity was 3.9 pg/ml, and interassay and intraassay precision (coefficient of variation%) ranged from 5.9 to 7.5% and 1.7 to 5.0%, respectively. Quantitative data are described as medians, and upper and lower quartiles. The differences between VOC cases and SCD control groups were determined by Mann–Whitney comparison by ranks, since IL-10 values showed a nonparametric distribution. Using SCD controls as the reference group, univariate followed by multivariate logistic regression analyses were performed to analyze IL-10 as risk factor for VOC; IL-10 levels were used as continuous, and then as categorized variables. Correlations among continuous variables were determined by Spearman correlation coefficient (r). Gender distribution and age at examination were comparable between VOC and steady-state SCD patients. Hematological and inflammatory indices, including HbS, HbF. total hemoglobin, hematocrit, while blood cell count, platelet count, Mean corpuscular volume, Mean Corpuscular Hemoglobin, mean corpuscular hemoglobin concentration, and reticulocyte counts were comparable between both SCD patients groups. VOC patients reported 4.6 6 2.2 episodes/year (mean duration: 4.6 6 2.5 days/episode). Most

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doi:10.1002/ajh.23748

American Journal of Hematology, Vol. 89, No. 7, July 2014

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IV iron in pregnancy: an unmet clinical need.

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