J. Perinat. Med. 40 (2012) 469–474 • Copyright by Walter de Gruyter • Berlin • Boston. DOI 10.1515/jpm-2011-0231 Intravenous iron treatment in pregnancy: comparison of
high-dose ferric carboxymaltose vs. iron sucrose *

Patricia Christoph 1 , Christine Schuller 1 ,
Keywords: Anemia; ferric carboxymaltose; hemoglobin;
Hanna Studer 1 , Olivier Irion 2 , Begoña Martinez
intravenous iron therapy; iron defi ciency; iron sucrose; preg- De Tejada 2 and Daniel Surbek 1, **
1 Department of Obstetrics and Gynecology , University Hospital Insel and University of Bern, Bern , Switzerland 2 Department of Obstetrics and Gynecology , University Introduction
Anemia in pregnancy is one of the most frequent problems in Obstetrics. The most common cause of anemia in pregnancy Abstract
is iron defi ciency. Iron-defi ciency anemia is a serious public health problem with signifi cant impact on physical develop- Objective: Oral iron substitution has shown to be insuffi cient
ment [23, 24] . Iron defi ciency in pregnancy has been defi ned for treatment of severe iron defi ciency anemia in pregnancy. as low ferritin levels [9] , and it is considered the gold stan- Ferric carboxymaltose is a new intravenous (i.v.) iron for- dard for the diagnosis of iron-defi ciency anemia in pregnancy, mulation promising to be more effective and as safe as iron sucrose. We aimed to assess side effects and tolerance of fer- The clinical manifestations of anemia include skin or ric carboxymaltose compared to i.v. iron sucrose in pregnant mucosal pallor, lack of energy and shortness of breath, fatigue, lack of concentration and decreased mental, physi- Methods: We performed a retrospective analysis of 206 preg-
cal, and cognitive performance all of which can present in nant women who were treated either with ferric carboxymaltose different grades depending on the severity of the anemia [2] . or iron sucrose for iron-defi ciency anemia with into lerability Consequences of moderate to severe anemia in pregnancy to oral iron substitution, or insuffi cient hemoglobin increase are susceptibility to infection and premature delivery, intra- after oral iron treatment, or need for rapid hemoglobin recon- uterine growth restriction, and the consequences of prema- stitution. Primary endpoint was to evaluate the maternal safety turity: increased perinatal morbidity and mortality [13, 21] . and tolerability. Secondary endpoint was to assess effi cacy of This also means that anemia at the time of the delivery results the treatment and exclude safety concerns for the fetus. more often in the need for blood transfusion, increased car- Results: The incidence of drug-related adverse events was
diovascular risks, longer hospital stay, and problems in the low and mostly mild in both groups. Mild adverse events postpartum period like reduced lactation or postpartum mood occurred in 7.8 % for ferric carboxymaltose and in 10.7 % for disorder [7] . For the neonate, there is a risk of reduced iron iron sucrose. The mean rise of hemoglobin value was 15.4 g/L stores with serious consequences for their development [11, for ferric carboxymaltose and 11.7 g/L for iron sucrose. Conclusion: Ferric carboxymaltose administration in pregnant
There are various possible forms of treatment for iron- women is well tolerated and is not associated with any relevant defi ciency anemia. Oral iron is the preferred route of admin- clinical safety concerns. Ferric carboxymaltose has a compa- istration for mild anemia. Treatment with iron preparations is rable safety profi le to iron sucrose but offers the advantage of a used routinely in pregnancy, if iron defi ciency with or without much higher iron dosage at a time reducing the need for repeated anemia develops. However, oral iron supplementation often applications and increasing patients ’ comfort. Ferric carboxy- leads to adverse effects, such as constipation, abdominal pain, maltose is the drug of choice, if i.v. iron treatment becomes or sickness. If these unwarranted gastrointestinal effects arise, necessary in the second or third trimester of pregnancy. Intravenous (i.v.) iron preparations are promising, especially in cases of severe anemia. They provide a greater and more This study was supported by an unrestricted grant from Vifor rapid iron supply than oral iron therapy without the gastroin- testinal side effects of oral substitution and make it possible to avoid blood transfusion with associated risks [16] . To date, few studies have focused on the use of i.v. iron and its side effects and safety in pregnant women. Iron sucrose has been University Hospital Insel and University of Bern used for years for i.v. treatment of iron defi ciency in pregnant women after the fi rst trimester. However, its use is limited to low dose due to local and systemic side effects in higher doses. Recently, ferric carboxymaltose has been introduced. This iron Angemeldet | 470 Christoph et al., i.v. iron treatment in pregnancy preparation can be used intravenously in high doses with up and 103 received iron sucrose between 2005 and 2007. to 1000 mg infused in 15 min and low risk of side effects. Demographic characteristics and basic data are summarized We have previously shown that ferric carboxymaltose does not in Table 1 . While demographic data did not show any sig- cross the placental barrier in an in vitro dual perfusion model nifi cant difference between groups, there was a statistically (15), and its use is approved in the second and third trimesters highly signifi cant difference regarding the administered iron of pregnancy. However, no published data are available con- dose and the repeated application. Patients in the ferric car- cerning the clinical use of ferric carboxymaltose use in preg- boxymaltose group received, in average, the double dose of nant women. The aim of our study was, therefore, to compare iron weekly (Table 1). More patients in the iron sucrose group i.v. ferric carboxymaltose with i.v. iron sucrose during preg- received repetitive doses of iron intravenously. These differ- nancy regarding the tolerability and safety profi le. ences correspond to the recommended treatment schemes of ferric carboxymaltose and iron sucrose, respectively; ferric carboxymaltose can be administered in much higher single We performed a retrospective observational study to analyze the Side effects, tolerance
tolerability and effi cacy of i.v. iron therapy in pregnancy. Data were obtained from the maternity units in the University Hospitals of As summarized in Table 2 , patients treated with ferric car- Berne and Geneva in Switzerland. The study was approved by the boxymaltose had fewer side effects than those receiving iron local ethics committees of the respective institutions. sucrose, but the difference did not reach statistical signifi - All pregnant women who received i.v. ferric carboxymaltose since the approval of this new drug in Switzerland in February 2008 were cance. Mild local reactions at the injection site were reported eligible for entry into the study. The comparison group was formed by three patients after receiving ferric carboxymaltose. One by a group of equal number of pregnant women who were treated reported local pain and swelling at the injection site, the two with i.v. iron sucrose, before ferric carboxymaltose was introduced other patients reported a rush on the arms and legs. Mild sys- on the market (i.e., before February 2008). temic reactions were reported by fi ve patients, three patients Laboratory testing, indication, and prescription of the iron sub- had a transient hypotension (systolic blood pressure < 100 stitution treatment were determined by the attending medical team. mm Hg), one of them also described dizziness, and another Inclusion criteria for i.v. iron treatment at both centers were accord- one had headache. Concerning the hypotension, no medical ing to specifi c local maternity guidelines on diagnosis and treatment intervention was required, and their blood pressures normali- of anemia in pregnancy as well as to specifi c national guidance [7] . zed spontaneously. In the group receiving iron sucrose, a total These included the following: pregnancy, clinically relevant severe iron-defi ciency anemia, intolerance to oral iron substitution, failure of 11 adverse events were reported, 8 mild systemic reactions of hemoglobin increase after oral iron treatment, or need for rapid and 3 local reactions. The systemic reactions consisted in fi ve hemoglobin- reconstitution. Patients with early pregnancy (before cases of mild hypotension with dizziness and headache, two cases of heart palpitation during/after the infusion, and one Patients were identifi ed by searching digital records of the hospi- case of nausea. Figure 1 graphically depicts the differences tals. Baseline data were collected on maternal age and weight, ges- tational age, results from peripheral blood counts before and after treatment, serum ferritin prior to treatment, adverse events during i.v. Fetal safety and neonatal outcome
iron treatment, and pregnancy outcomes. i.v. iron was administered by nurses or midwives, and they were instructed to document the Among women treated with ferric carboxymaltose, 60.2 % procedure and any side effects during and after i.v. administration. The primary endpoint of this study was to evaluate the maternal were hospitalized due to high-risk pregnancy, such as preterm tolerability and side effects of ferric carboxymaltose compared to labor, intrauterine growth restriction, or abnormal placenta- iron sucrose being used for treatment of iron-defi ciency anemia in tion. They were closely monitored with daily CTG, Doppler the second and third trimesters of pregnancy. Secondary endpoints ultrasound twice a week, and biophysical profi le every included effi cacy of the treatment and signs for concern regarding the 2 weeks. No signs of negative effects of the i.v. iron treatment fetal safety. For the effi cacy analysis, only women with ferritin lev- els ≤ 30 μ g/L were included as a ferritin level ≤ 30 μ g/L is required Of all women treated with ferric carboxymaltose, 77 for the diagnosis of iron-defi ciency anemia. delivered healthy babies at term. Twenty-three percent of the Statistical analysis was performed using Windows Excel women delivered preterm babies due to complications, which Calculation and Graphpad InStat (GraphPad Software, Inc., La Jolla, were present before ferric carboxymaltose administration, CA, USA). Continuous variables were compared using Student ’ s t - test; categorical variables were compared using χ 2 -test or Fisher ’ s exact test where applicable. For all analyses, P-values < 0.05 were Among the women treated with i.v. iron sucrose, fewer had high-risk pregnancies, and fewer had inpatient treatment. This explains the difference in neonatal outcome: in this group, 91, 8 % delivered healthy babies at term, 8, 2 % had preterm deli- very, all of them due to high-risk pregnancy situations other than anemia. Among the women treated with i.v. iron sucrose, A total of 206 pregnant women were included in the study; 16.5 % had been treated as inpatients due to their high-risk 103 received ferric carboxymaltose since February 2008, Angemeldet | Christoph et al., i.v. iron treatment in pregnancy 471 Demographic characteristics and base data. applications ( > 1 × )Follow-up interval (days) *Statistically signifi cant.
**Value prior to fi rst drug administration. The gestational age at birth between both groups was sta- Women treated with ferric carboxymaltose received up to tistically different: ferric carboxymaltose group (38.4 ± 3.26) 1300 mg iron per week. On average, 13 mg/kg body weight per week was given. This corresponds to more than double more babies in the ferric carboxymaltose group were trans- the amount of iron that was administered with iron sucrose. ferred to NICU due to prematurity. There were no differences Only 13 patients had one more repetitive application. Most between both groups in the APGAR scores and umbilical patients just got 1000 mg ferric carboxymaltose i.v. In two cord pH values. There was no statistically signifi cant differ- women with body weights below 60 kg, the recommended ence between both groups regarding intrauterine deaths and maximal ferric carboxymaltose dose of 15 mg/kg body weight was exceeded with no associated noticeable negative effect. Effi cacy of i.v. iron treatment
The mean hemoglobin rise in the group receiving ferric car- boxymaltose was 15.4 g/L and 11.7 g/L in the group receiving In the group treated with ferric carboxymaltose, 85 % had iron sucrose. The mean follow-up time was different in both a ferritin level ≤ 30 μ g/L. In the group treated with iron groups after i.v. iron administration. The mean follow-up for sucrose, 77 % had a ferritin level ≤ 30 μ g/L. Table 3 shows the group treated with ferric carboxymaltose was 28.4 days mean hemoglobin values in both groups before and after i.v. and 41.2 days for the group treated with iron sucrose. This iron treatment. Women treated with iron sucrose received difference is statistically signifi cant. 400 mg iron per week in two infusions, 48 h apart. Forty-seven patients received repeated applications up to eight times. The maximum dose of 500 mg/week was never exceeded. For the mean, every woman treated with iron sucrose was given 6 mg iron sucrose/kg body weight per Ferric carboxymaltose Iron sucrose P-value Angemeldet | 472 Christoph et al., i.v. iron treatment in pregnancy Hemoglobin values before and after treatment. iron substitution in this low-resource setting seems to be a very good and safe alternative. Side effects and tolerance
The tolerance and effi cacy of ferric carboxymaltose has been demonstrated previously in several studies for differ- ent groups of patients with iron-defi ciency anemia [3, 4, 7, 8, 14, 19, 21] with similar results. Bailie GR [3] showed in a review paper, including nine randomized studies with more than 3000 patients, that ferric carboxymaltose had a good tol- erability and effi ciency profi le. The use of ferric carboxymalt-ose for treatment of postpartum anemia has been extensively Discussion
investigated [7, 19, 21] . No safety concerns have been identi-fi ed in breastfed infants of mothers receiving ferric carboxy- Screening for iron-defi ciency anemia in pregnancy has been based on the association with increased risk of preterm deli- Ferric carboxymaltose is approved for use in pregnancy in very and low birth weight, and maternal signs and symptoms the second and third trimesters. However, up to now, no pub- of anemia. While the consequences of mild to moderate iron- lished data from clinical studies investigating the use of ferric defi ciency anemia for the fetus may be overestimated [2] , carboxymaltose in pregnancy are available. severe iron-defi ciency anemia leads to increase in morbidity Our study shows that ferric carboxymaltose is well toler- of pregnant women and their children in developing as well ated in pregnant women and has fewer or equal number of side effects compared to the previously used iron sucrose In the majority of cases, anemia can be treated effectively when administered in a dose double as high. The incidence of with oral iron preparations. Many patients tolerate oral drug-related adverse events was low and comparable to those intake of iron supplements well; however, up to 40 % have described for ferric carboxymaltose and iron sucrose in other side effects related to oral iron treatment. The incidence studies. Registered adverse events were all classifi ed as mild of adverse reactions is dose dependent. The main adverse and quickly reversible and mostly restricted to local reactions effects are of gastrointestinal nature [1, 5, 7] , the most com- at the infusion site. There were no treatment-related serious mon being constipation, diarrhea, epigastric discomfort, adverse events. No anaphylactic or anaphylactoid reaction nausea, severe abdominal pain, or vomiting. These second- was detected. No venous thrombosis was registered. None of ary effects can be lessened by the intake of tablets after the adverse events required further medical intervention. meals, although this leads to a concomitant reduction of iron absorption. Typically, these adverse effects lead to poor Fetal safety and neonatal outcome
treatment adherence especially in pregnancy when similar gastrointestinal complaints are often a problem prior to iron Previously, an in vitro study using a dual-placenta perfusion treatment due to the physiological changes in pregnancy. model has shown that ferric carboxymaltose does not cross Intolerance to oral iron intake leads to a greater percentage the placental barrier to the fetal side [15] . Though there is no of failure in the treatment. In addition, even with strict oral previous published clinical data available on the use of ferric iron treatment adherence, there are still quite a number of carboxymaltose in pregnancy and its effects on the fetus, fer- patients who do not respond with an appropriate hemoglo- ric carboxymaltose is approved for use in the second and third bin increase (i.e., hemoglobin increase below 10 g/L within trimesters of pregnancy. We, therefore, have chosen to give ferric carboxymaltose initially in an inpatient setting to be Other possible indications for i.v. iron treatment include able to closely monitor the pregnant women and the fetus for the necessity of rapid increase of hemoglobin, for example, adverse reactions and negative effects. The pregnant women pregnancies in the third trimester with high-risk of peripar- being treated as inpatients were mainly high-risk pregnancies tum hemorrhage (e.g., placenta previa or placenta increta), or due to other complications than IDA. This explains why the gestational age was signifi cantly higher in the iron sucrose In these clinical situations described above, i.v. iron group compared to the group receiving ferric carboxymaltose, administration is indicated. A faster increase in hemoglobin, and therefore, birth weight at delivery was also higher in the ferritin, and iron stores by i.v. iron therapy has been reported group of iron sucrose. Newborn intensive care unit (NICU) by different authors [5, 6, 8, 10, 15, 17, 20 – 22] . admission rate was higher in the group of newborns from Severe anemia mainly occurs in developing countries women receiving ferric carboxymaltose due to a lower gesta- where it has been attributed to poor nutrition and concurrent tional age at delivery in this group with no correlation to i.v. conditions, especially infectious diseases, such as malaria. iron treatment. There was no statistically signifi cant differ- These women particularly benefi t from high-dose i.v. iron ence between both groups regarding intrauterine deaths and substitution because availability of blood transfusions is very neonatal deaths. Both groups of pregnant women were het- limited, and blood transfusions still bare certain risks. I.V. erogeneous, and therefore not really comparable, regarding Angemeldet | Christoph et al., i.v. iron treatment in pregnancy 473 pregnancy complications. Nevertheless, no sign for negative carboxymaltose regarding either mother or fetus could be effect on the fetus of iron infusion could be detected, although levels of ferritin were not determined in newborns. In view of the limited evidence from prospective randomi- zed trials of i.v. iron treatment in pregnancy, full consider- Effi cacy
ation must be given to possible benefi ts and risks. Indications for the use of parenteral iron should be limited to specifi c I.V. iron treatment indications were heterogeneous and did conditions, in which oral iron supplementation is not possible not always correspond to national recommendations. Owing to heterogeneity in indications for i.v. iron treatment and in While further research including randomized trials is dosage of the drugs and also regarding follow-up intervals in needed [18] , ferric carboxymaltose seems to be the drug of our study population, comparability of effi cacy of ferric car- choice if i.v. iron treatment during pregnancy becomes neces- boxymaltose vs. iron sucrose is limited. Both i.v. iron prepa- rations are effective in treating anemia in pregnancy. The differences between the administered amounts of iron were statistically signifi cant when giving ferric carboxymaltose References
and iron sucrose as well as the repetitions of the treatment (Table 1). These facts suggest that the larger the amount of [1] Al RA, Unlubilgin E, Kandemir O, Yalvac S, Cakir L, Haberal iron that can be administered in the form of ferric carboxy- A. Intravenous versus oral iron for treatment of anemia in maltose, the more effective the replenishment of the iron pregnancy: a randomized trial. Obstet Gynaecol. 2005;106: stores is and the more effective the correction of the anemia is. This, however, needs to be confi rmed in appropriately Al-Momen AK, Al-Meshari A, Al-Nuaim L, Saddique A, Abotalib Z, Khashogji T, et al. Intravenous iron sucrose complex in the treatment of iron defi ciency anemia during Whether ferric carboxymaltose provides a faster and higher pregnancy. Eur J Obstet Gynecol Reprod Biol. 1996;69:121 – 4. increase in hemoglobin level than iron sucrose cannot be con- [3] Bailie GR. Effi cacy and safety of ferric carboxymaltose in cor- cluded from these data due to the possibility of administering recting iron-defi ciency anemia: a review of randomized con- a higher dose of iron within a shorter time period. trolled trials across different indications. Arzneimittelforschung. 2010;60:386 – 98. Strength of the study
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