Diagnosis and treatment of iron-deficiency anaemia in pregnancy and postpartum.

Iron deficiency occurs frequently in pregnancy and can be diagnosed by serum ferritin-level measurement (threshold value < 30 µg/L). Screening for iron-deficiency anemia is recommended in every pregnant women, and should be done by serum ferritin-level screening in the first trimester and regular hemoglobin checks at least once per trimester. In the case of iron deficiency with or without anaemia in pregnancy, oral iron therapy should be given as first-line treatment. In the case of severe iron-deficiency anemia, intolerance of oral iron, lack of response to oral iron, or in the case of a clinical need for rapid and efficient treatment of anaemia (e.g., advanced pregnancy), intravenous iron therapy should be administered. In the postpartum period, oral iron therapy should be administered for mild iron-deficiency anemia (haemorrhagic anemia), and intravenous iron therapy for moderately severe-to-severe anemia (Hb < 95 g/L). If there is an indication for intravenous iron therapy in pregnancy or postpartum, iron-containing drugs which have been studied in well-controlled clinical trials in pregnancy and postpartum such as ferric carboxymaltose must be preferred for safety reasons. While anaphylactic reactions are extremely are with non-dextrane products, close surveillance during administration is recommended for all intravenous iron products.

Treatment of Iron Deficiency in Women.

Iron deficiency with and without anaemia is a common cause of morbidity, particularly in women. Iron deficiency is generally the result of an imbalance between iron loss and iron absorption. In women with symptoms suspicious for iron deficiency, it is important to confirm or exclude the suspicion using proper tests. The use of serum ferritin levels is considered the gold standard for diagnosis. Although the ideal ferritin levels are not unknown the current consent is that levels < 40 ng/ml indicate iron deficiency, which needs to be treated in symptomatic patients. However, symptoms can already occur at ferritin levels of < 100 ng/ml and treatment must be adapted to the individual patient. Iron supplementation is only indicated in symptomatic patients diagnosed with iron deficiency whose quality of life is affected. It is important to treat iron deficiency together with its causes or risk factors. For example, blood loss from hypermenorrhea should be reduced. Women also need to receive information about the benefits of an iron-rich diet. If oral treatment with iron supplements is ineffective, parenteral iron administration is recommended.

Efficacy and safety of intravenous iron therapy as an alternative/adjunct to allogeneic blood transfusion.

Anaemia is a common condition among patients admitted to hospital medicosurgical departments, as well as in critically ill patients. Anaemia is more frequently due to absolute iron deficiency (e.g. chronic blood loss) or functional iron deficiency (e.g. chronic inflammatory states), with other causes being less frequent. In addition, preoperative anaemia is one of the major predictive factors for perioperative blood transfusion. In surgical patients, postoperative anaemia is mainly caused by perioperative blood loss, and it might be aggravated by inflammation-induced inhibition of erythropoietin and functional iron deficiency (a condition that cannot be corrected by the administration of oral iron). All these mechanisms may be involved in the anaemia of the critically ill. Intravenous iron administration seems to be safe, as very few severe side-effects were observed, and may result in hastened recovery from anaemia and lower transfusion requirements. However, it is noteworthy that many of the recommendations given for intravenous iron treatment are not supported by a high level of evidence and this must be borne in mind when making decisions regarding its application to a particular patient. Nonetheless, this also indicates the need for further large, randomized controlled trials on the safety and efficacy of intravenous iron for the treatment of anaemia in different clinical settings.

Effect of postpartum iron supplementation on red cell and iron parameters in non-anaemic iron-deficient women: a randomised placebo-controlled study.

OBJECTIVE: To investigate the effect of oral iron on postpartum red cell and iron parameters in non-anaemic women with iron deficiency. DESIGN: Randomised study of supplementation with oral iron sulphate 80 mg daily or placebo for 12 weeks starting 24-48 hours after delivery, with visits antepartum and 1, 4, 6 and 12 weeks postpartum. SETTING: Swiss university hospital obstetric unit. PARTICIPANTS: Fifty-two women with antenatal iron deficiency (serum ferritin <15 microg/L) and no antenatal or postnatal anaemia (haemoglobin >11 g/dL up to 48 hours before delivery, and >10 g/dL postpartum), divided into two groups comparable in antenatal iron status. METHODS: Supplementation was started 24-48 hours after delivery (visit 1:V1). Additional tablets were issued one week after V1 (V2), four weeks after V1 (V3) and six weeks after V1 (V4). The last visit took place 12 weeks after visit 1 and 6 weeks after visit 4 (V5). Patients were required to return blisters and boxes whether they were used and unused at each visit and compliance was assessed by counting the tablets. Blood samples for haematology and iron status testing were taken before delivery and at each visit. MAIN OUTCOME MEASURES: Iron status (serum ferritin, hypochromic red cells, iron, transferrin saturation, soluble transferrin receptor concentration); erythropoiesis (standard parameters, including reticulocyte indices); and inflammatory response (serum neopterin, C-reactive protein, white cell count) in five-datapoint profiles. RESULTS: Increased ferritin (P= 0.0004) and transferrin saturation (P= 0.03), decreased soluble transferrin receptors (P= 0.02); increased haemoglobin (P= 0.02) and decreased hypochromic red cells (P= 0.04) compared with placebo at 12 weeks, with no differences in other red cell or reticulocyte parameters. There was a positive correlation between C-reactive protein and postpartum ferritin. No correlation was observed in the puerperium between C-reactive protein and hypochromic red cells or soluble transferrin receptors. CONCLUSIONS: Haemoglobin levels and iron stores in women with term gestational iron deficiency benefit significantly from iron supplementation compared with placebo, even in an industrialised population.

Haemoglobinopathy in pregnancy: diagnosis and treatment.

Haemoglobinopathies differ in geographic prevalence but together are amongst the most common genetic disorders worldwide. Despite huge diagnostic progress, therapeutic options remain limited, with many treatments still at the experimental stage, no more so than in pregnancy: not only does the presence of a fetus subject treatments to greater limitations, but also any worsening of the anaemia as pregnancy progresses results in higher fetomaternal morbidity and mortality. Anaemia weakens the response to peripartum blood loss, with the risk of postpartum complications. Until recently the standard conventional therapy for severe anaemia was (repeated) blood transfusion, with its well-known risks. Recombinant human erythropoietin (rhEPO) can induce fetal haemoglobin and is a safer, if less immediately effective, alternative for the correction of anaemia in pregnant patients with haemoglobinopathy.

Oxygen-regulated expression of TGF-beta 3, a growth factor involved in trophoblast differentiation.

The transforming growth factor-beta 3 (TGF-beta 3) is involved in oxygen-dependent differentiation processes during placental development and pregnancy disorders. However, the importance of oxygen partial pressure for the regulation of TGF-beta 3 expression is presently unclear. We and others presented preliminary evidence that the hypoxia-inducible factor-1 (HIF-1) confers TGF-beta 3 transcription but it was unknown whether this occurred directly or indirectly. To analyze how HIF-1 regulates TGF-beta 3 gene transcription, we cloned and sequenced the mouse TGF-beta 3 promoter region. Multiple putative HIF-1 binding sites (HBSs) were identified, many of which co-localized with two G+C rich CpG islands 5' to the TGF-beta 3 transcription start site. A 6.8 kb fragment of the TGF-beta 3 promoter induced reporter gene expression under hypoxic conditions or when treated with an iron chelator known to stabilize and activate the HIF-1 alpha subunit. Deletion of a 2.4 kb fragment upstream of the distal CpG island abolished inducibility of reporter gene expression. Two HBSs (HBS1 and HBS6) that bound the HIF-1 protein could be identified within this 2.4 kb fragment. These results suggest that TGF-beta 3 gene expression is directly regulated by HIF-1.

Impact of parturition on iron status in nonanaemic iron deficiency.

BACKGROUND: Iron-deficient nonanaemic parturients risk underdiagnosis as a result of the reliance on postpartum ferritin and haemoglobin as markers of iron status. Ferritin is an acute-phase protein whose levels increase during the inflammatory response, as occurs after delivery. Our aims were to evaluate the impact of parturition on iron status, erythropoiesis and the inflammatory response, and identify the optimal parameters and timing for diagnosing iron deficiency in the presence of postpartum inflammation. MATERIALS AND METHODS: Conventional parameters of iron status, erythropoiesis and the inflammatory response (serum ferritin, serum iron, transferrin saturation, C-reactive protein) were compared with more recent parameters [soluble transferrin receptors (sTfR), hypochromic red cells, reticulocyte indices] within 48 h either side of delivery in 64 iron-deficient nonanaemic women (defined by a prepartum serum ferritin < or =15 microg L(-1), and a pre- and postpartum haemoglobin of > or =11.0 g dL(-1) and > or =10.0 g dL(-1), respectively). RESULTS: Mean sTfR decreased pre to postpartum from 7.3 to 5.8 microg mL(-1) (P<0.01), while mean serum ferritin increased from 9.7 to 16.9 microg L(-1) (P<0.01). Serum ferritin did not correlate with haemoglobin pre or postpartum (r=0.04, P=0.7; r=0.2, P=0.09), but a correlation persisted postpartum between hypochromic red blood cells and haemoglobin (r=-0.26; P<0.05). The percentage of hypochromic red cells remained virtually unchanged pre- and postpartum (4.0% vs. 3.8%; NS). Postpartum mean reticulocyte haemoglobin content (CHr) was 27.1 +/- 1.6 pg. CONCLUSION: Iron status should be tested prepartum, in the absence of an inflammatory response, rather than in the early postpartum. A valuable additional parameter, where available, might be the hypochromic red cell percentage, which is virtually uninfluenced by the inflammatory response. Furthermore, hypochromic red cell percentage, CHr and sTfR can be helpful to differentiate between functional iron deficiency and depleted iron stores.

Hypertension in a pregnancy with renal anemia after recombinant human erythropoietin (rhEPO) therapy.

Management of renal anemia in pregnancy remains a major issue. We report the use of human recombinant erythropoietin (rhEPO) combined with parenteral iron sucrose in a pregnancy with chronic glomerulonephritis, progressive anemia and initially normal blood pressure. Therapy from 32 weeks gestation increased the hematocrit by 0.4% daily and the hemoglobin from 8.6 to 10.3 g/dL within 2 weeks. Despite the improvement of anemia, Cesarean section had to be performed at 34 weeks due to acute hypertension, preeclampsia and worsening renal function. Blood pressure remained elevated postpartum. Because of symptomatic postpartum anemia with a hemoglobin of 7.5 g/dL on the 5th postoperative day rhEPO in combination with parenteral iron sucrose was readministered over 3 following days. Blood pressure reached a maximum of 210/130 mm Hg 3 weeks later. Possible causes include advancing preeclampsia and renal disease, but also rhEPO (due to its intrinsic vascular effects and/or the rapid response of the hematocrit), and a combination of both.

Parenteral iron therapy in obstetrics: 8 years experience with iron-sucrose complex.

Fe is an essential component of haem in myoglobin and accounts for 70 % of haemoglobin. The balance of Fe, unlike that of other metals such as Na or Ca, is regulated solely by gastrointestinal absorption, which itself depends on the bioavailability of Fe in food, i.e. the chemical Fe species. Factors that maintain Fe homeostasis by modulating Fe transfer through the intestinal mucosa are found at the luminal, mucosal and systemic levels. Fe deficiency and its consequence, Fe-deficiency anaemia, form the commonest nutritional pathology in pregnant women. The current gold standard to detect Fe deficiency remains the serum ferritin value. Previously there was general consensus against parenteral Fe administration, i.e. parenteral Fe was only recommended for special conditions such as unresponsiveness to oral Fe, intolerance to oral Fe, severe anaemia, lack of time for therapy etc. However, especially in hospital settings, clinicians regularly face these conditions but are still worried about reactions that were described using Fe preparations such as Fe-dextrans. A widely used and safe alternative is the Fe-sucrose complex, which has become of major interest to prevent functional Fe deficiency after use of recombinant erythropoietin Numerous reports show the effectiveness and safety of the Fe-sucrose complex. Good tolerance to this Fe formulation is partly due to the low allergenic effect of the sucrose complex, partly due to slow release of elementary Fe from the complex. Accumulation of Fe-sucrose in parenchyma of organs is low compared with Fe-dextrans or Fe-gluconate, while incorporation into the bone marrow for erythropoiesis is considerably faster. Oral Fe is only started if haemoglobin levels are below 110 g/l. If levels fall below 100 g/l or are below 100 g/l at time of diagnosis, parenteral Fe-sucrose is used primarily. In cases of severe anaemia (haemoglobin <90 g/l) or non-response to parenteral Fe after 2 weeks, recombinant erythropoietin is considered in combination. By using parenteral Fe-sucrose in cases of severe Fe deficiency, anaemia during pregnancy is treated efficiently and safely according to our results and rate of blood transfusion could be reduced considerably to below 1 % of patients per year.

[Two-stage delivery after spontaneous rupture of fetal membranes and delayed abortion of the first twin in conservative management]. / Zweizeitige Geburt nach spontanem Blasensprung und Spätabort des ersten Mehrlings bei konservativem Management.

INTRODUCTION: 1-2% of all twin pregnancies are complicated by premature contractions, leading to premature rupture of membranes before 26 weeks of pregnancy. In this situation, a decision is required to either actively induce premature delivery or to initiate expectant management. Maternal and fetal risks regarding perinatal mortality and morbidity and the benefits of pregnancy prolongation have to be weighted against each other. CASE REPORT: We present delayed deliveries of two I-Parae with dichorionic twin pregnancies, achieved by in vitro fertilisation. In both cases, spontaneous membrane rupture and miscarriage of the leading fetus occurred prior to 20 gestational weeks. As signs of infection were missing initially, we adopted a conservative, expectant management. In both cases, the pregnancies could be prolonged to more than 30 weeks' gestation. DISCUSSION: In the absence of additional risk factors, expectant, conservative management of multiple pregnancies after loss of one fetus can lead to pregnancy prolongation of 91 and 96 days, respectively. The gained gestational age of the remaining fetus and the healthy mother-child pairs are discussed under perinatal, economical and psychological aspects.

[Current aspects of diagnosis and therapy of iron deficiency anemia in pregnancy]. / Aktuelle Aspekte der Diagnostik und Therapie der Eisenmangelanämie in der Schwangerschaft.

Anaemia is one of the most common risk factors in the area of obstetrics and perinatal medicine. During pregnancy and in the puerperium it is associated with an increased incidence of both maternal and fetal morbidity and mortality, the extent of which is dependent upon the severity of anaemia and the resulting complications. In order to correctly diagnose the type and degree of anaemia, a prerequisite for selection of the proper therapy, one must first of all correctly differentiate between the relative, i.e., the physiological anaemia of pregnancy due to the normal plasma volume increase during pregnancy, and "real anaemias" with various different pathophysiological causes. When defining the Hb cutoff value for anaemia in pregnancy, the extent of the plasma volume changes with respect to the gestational age must be taken into consideration. It has been found that haemoglobin values < 11.0 g/dl in the first and third trimesters, and < 10.5 g/dl in the second trimester may point to an anaemic situation which should be further clarified. The first important steps for diagnosing anaemia in a pregnant patient include a thorough check of her medical history and a medical examination. This procedure often lays the basis for a correct diagnosis. The current gold standard to detect iron deficiency remains the serum ferritin value. To be reliable, this requires the ruling out of an infection (chronic or acute) as a cause of the anaemia. We recommend a complete laboratory test for the exact haematological status as well as the assessment of specific chemical laboratory parameters. These should include a palette of additional, promising new parameters such as hypochromic red cells and transferrin receptors which allow more accurate detection of iron deficiency and differential diagnosis of iron deficiency anaemia. After correct diagnosis, major emphasis should be put on safe and effective treatment of anaemia which again depends on severity of anaemia, time for restoration and patients characteristics. Today effective alternatives to oral iron only or blood transfusion such as parenteral iron sucrose complex and in selected cases also recombinant erythropoietin have been investigated and show promising results concerning effective treatment of anaemia during pregnancy and postpartum.

Efficacy and safety of intravenously administered iron sucrose with and without adjuvant recombinant human erythropoietin for the treatment of resistant iron-deficiency anemia during pregnancy.

OBJECTIVE: This study was undertaken to determine the efficacy and safety of intravenously administered iron sucrose with versus without adjuvant recombinant human erythropoietin in the treatment of gestational iron-deficiency anemia resistant to therapy with orally administered iron alone. STUDY DESIGN: Forty patients with gestational iron-deficiency anemia were randomly assigned to receive intravenously iron sucrose plus recombinant human erythropoietin or iron sucrose alone twice weekly. Target hemoglobin value was 11.0 g/dL. Efficacy measures were reticulocyte count, increase in hematocrit, and time to target hemoglobin level (treatment duration in weeks and need for continued therapy after 4 weeks). RESULTS: Both regimens were effective, but with adjuvant recombinant human erythropoietin the reticulocyte counts were higher from day 4 (P<.01), increases in hematocrit were greater from day 11 (P <.01), and the median duration of therapy was shorter (18 vs 25 days), with more patients reaching the target hemoglobin level by 4 weeks of treatment (n = 19 vs. n = 15). The groups did not differ with respect to maternal-fetal safety parameters. CONCLUSION: Adjuvant recombinant human erythropoietin safely enhanced the efficacy of iron sucrose in the treatment of gestational iron-deficiency anemia resistant to orally administered iron alone.

Hemoglobin concentration in multiple versus singleton pregnancies--retrospective evidence for physiology not pathology.

OBJECTIVE: To describe hemoglobin (Hb) levels and percentiles for multiple pregnancies and to compare them with reference ranges of singleton pregnancies as published by the Center for Disease Control. STUDY DESIGN: Maternal hemoglobin and red cell indices were compared: (a) between multiple and singleton pregnancies of our hospital and (b) with trimester-specific cut-offs for singleton pregnancies obtained from literature. RESULTS: While early pregnancy hemoglobin values were similar in multiple and singleton pregnancies, second trimester values decreased much faster in multiple pregnancies. Nadir in multiple pregnancies was reached in weeks 24-28 of gestation. In the third trimester mean hemoglobin values were higher in multiple pregnancies, while 5th and 10th percentile were still lower compared to singleton pregnancies at term. The mean whole-pregnancy hemoglobin exceeded the Center for Disease Control (CDC) cut-off for anemia in singleton pregnancies (fifth percentile) and red cell indices remained constant. CONCLUSION: We conclude that with a significantly lower fifth percentile than introduced by the CDC in all trimesters, there should be different cut-offs for anemia in multiple pregnancies considered. A more pronounced decrease in multiple pregnancy hemoglobin levels seems to be physiological.

Intravenous versus oral iron supplementation for preoperative stimulation of hemoglobin synthesis using recombinant human erythropoietin.

To compare two modalities of iron supplementation for the preoperative stimulation of erythropoiesis using recombinant human erythropoietin (rhEPO), 12 adults in normal hemoglobin and iron status due for elective surgery were randomized to rhEPO 200 U/kg body weight subcutaneously twice weekly combined with either iron sucrose 200 mg intravenously twice weekly or iron sulfate 160 mg/day orally, for 3 weeks preoperatively. Efficacy was measured by the increases over baseline in hemoglobin, reticulocyte count, and ferritin determined 3 days before surgery; preoperative reticulocyte count and ferritin were significantly higher with intravenous iron, whereas the only significant intragroup increases in hemoglobin between time points also occurred in this group. Intravenous iron significantly boosts the hematopoietic response to rhEPO and prevents iatrogenic iron depletion in otherwise healthy candidates for elective surgery.

Erythropoietin test methods.

Recombinant human erythropoietin (rhEPO), which increases red cell mass, is one of the most abused substances in sport. Abuse is currently undetectable by the only direct routine method, immunoassay, since blood and urine rhEPO are immunologically indistinguishable from endogenous EPO. Elevated EPO levels are only detectable several days after rhEPO administration. Indirect parameters have therefore been introduced, primarily the haematocrit level, but also markers of functional iron deficiency during or after rhEPO administration (hypochromic red cells and reticulocytes, serum transferrin receptors, ferritin levels) and, in the urine, fibrin degradation products. Although iron status indices have yielded promising results, athletes are currently banned solely on the basis of their haematocrit. Yet various factors can cause false positive haematocrit results with potentially fatal consequences to athletes' careers. Until new direct assays such as liquid chromatography-mass spectrometry have been evaluated and introduced, efforts must be directed at using a battery of tests to increase the sensitivity and specificity and reduce the number of false positives and false negatives.

Intraoperative endogenous erythropoietin levels and changes in intravascular blood volume in healthy humans.

There is accumulating evidence of a relationship between changes in intravascular blood volume and endogenous erythropoietin (EPO) levels. In this study, eight healthy adult American Society of Anesthesiologists class-I patients due for prolonged elective surgery were randomised either to preoperative hypervolaemic haemodilution using hydroxyethyl starch, followed by intraoperative crystalloid infusion, or to standard intraoperative normovolaemic fluid balance management using crystalloids (control group). Electrolytes, creatinine, urea, osmolality, urine output and blood gases were monitored pre- and intraoperatively for 6 h, Comparable cardiopulmonary and renal homeostasis were maintained in both groups. We found that central venous pressure increased and EPO levels decreased, both significantly, in the hypervolaemic haemodilution group relative to controls. There were no significant intergroup changes in any other parameters. By controlling for other known determinants of EPO levels, our data indicate a relationship between EPO levels and changes in intravascular blood volume in humans, supporting the notion of EPO as a volume-regulated, and possibly volume-regulating, hormone.