L anémie ferriprive pendant la grossesse

Texte intégral

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L’anémie ferriprive pendant la grossesse

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• L’anémie ferriprive (AF) : La cause la plus fréquente d'anémie pendant la grossesse, affectant >

32 millions de grossesses par an dans le monde

• L'anémie pendant la grossesse est associée à un taux important de morbidité maternelle et néonatale, notamment une morbidité maternelle sévère (MMS), une septicémie, une

hémorragie post-partum et, chez la progéniture, à des problèmes cognitifs et comportementaux

• L'ACOG définit l'anémie pendant la grossesse comme un taux d'Hb inférieur à 11 g/dL au cours du 1 er trimestre et un taux d'Hb inférieur à 10,5 g/dL aux 2 ème et 3 ème trimestres ; les seuils varient selon les lignes directrices internationales.

• L'OMS définit l'anémie comme un taux d’Hb inférieur à 11 g/dL tout au long de la grossesse

• Anémie légère : Taux d’Hb inférieur à 9 - 10,9 g/dL

• Anémie modérée : Taux d’Hb entre 7 et 8,9 g/dL

• Anémie sévère : Taux d’Hb inférieur à 7 g/dL

• Les lignes directrices relatives à l'anémie post-partum varient entre des taux d'Hb inférieurs à 9 - 11 g/dL

• De nombreuses causes d'anémie : Physiologique, nutritionnelle, héréditaire, acquise, infectieuse - cependant, la carence en fer contribue à la majorité, > 70%, des cas d'anémie.

L’anémie ferriprive pendant la grossesse

Igbinosa I, et al. Curr Opin Obstet Gynecol. 2022; 34: 69-76. OMS : Organisation Mondiale de la Santé ; ACO : American College of Obstetricians and Gynecologists ; Hb : Hémoglobine ; g/dL : gramme par décilitre.

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L’anémie ferriprive pendant la grossesse : Prise en charge

Igbinosa I, et al. Curr Opin Obstet Gynecol. 2022; 34: 69-76. Hb : Hémoglobine.

• Les lignes directrices actuelles préconisent une supplémentation de 27 mg de fer élémentaire par jour pendant la grossesse, une équivalence couramment retrouvée dans les vitamines prénatales en vente libre

• Le fer oral, principalement sous forme de sels ferreux (fumarate ferreux, sulfate ferreux, gluconate ferreux), constitue le traitement de 1 ère intention de l'AF. Les sels ferreux étaient administrés en doses fractionnées de 100 à 200 mg de fer élémentaire par jour

• L'efficacité du fer oral augmente lorsqu'il est pris le matin après une nuit de jeûne. Plus récemment, une dose unique quotidienne ou tous les deux jours semble être aussi efficace

• Les préparations orales sont moins chères, mais elles sont associées à des effets indésirables gastro-intestinaux, à la non- observance du traitement et à une moindre augmentation du taux d'Hb au moment de l'accouchement que les

préparations intraveineuses (IV)

• Une méta-analyse a conclu que 40 à 70% des femmes enceintes prenant du fer oral ont présenté un effet indésirable, impliquant principalement le système gastro-intestinal, avec le fer oral et que la  moitié d'entre elles ont arrêté le traitement

• Les suppléments de fer à enrobage entérique améliorent la tolérance mais inhibent l'absorption

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L’anémie ferriprive pendant la grossesse : Fer intraveineux

Adapté de : Igbinosa I, et al. Curr Opin Obstet Gynecol. 2022; 34: 69-76. Hb : Hémoglobine.

Médicament Fer

élémentaire

Dosage Grossesse et allaitement

Sécurité

Fer-saccharose 20 minutes Doses multiples de 200 à 300 ng Le fer IV le plus étudié dans la grossesse

Aucun effet indésirable chez les nourrissons allaités Derisomaltose ferrique

(également connu sous le nom d'Isomaltoside de fer)

100 mg/ml 500 mg/dose, max. 3 doses à 7 jours d'intervalle

ou

Dose unique de 20 mg/kg

Données limitées

Excrété dans le lait maternel

Fer dextran à faible poids moléculaire

50 mg/ml - Doses multiples de 100 mg ou

- dose unique de 1000 mg (dans 250 ml de saline normale) sur 1 heure - dose d’essai requise

Essais publiés présentant des résultats maternels/fœtaux négatifs rares

Excrétion minime dans le lait

Férumoxytol 30 mg/ml 510 mg/dose, max. 2 doses administrées à 3 - 8 jours d'intervalle

Étude de 164 patientes enceintes ayant des résultats obstétriques dans la norme

Avantages > risques

Remarque : également un agent de contraste Aucune étude rapportée sur l’allaitement Carboxymaltose ferrique 50 mg/ml 750 mg/dose, max. 2 doses Surveiller pour une hypophosphatémie

Excrété dans le lait maternel

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L’anémie ferriprive pendant la grossesse : Conclusion

Igbinosa I, et al. Curr Opin Obstet Gynecol. 2022; 34: 69-76. AF : Anémie ferriprive ; IV : Intraveineux.

• Les lignes directrices nationales fournissent des recommandations variables sur le diagnostic et le traitement de l’AF pendant la grossesse

• Ferritine sérique : Un complément utile pour le diagnostic de l'AF

• Le fer, sous forme diététique, orale et intraveineuse, s'est révélé efficace pour résoudre l'anémie pendant la grossesse

• Le fer par voie orale reste une option thérapeutique ; l'absorption est améliorée avec une administration tous les deux jours et est efficace pour les patients capables de tolérer cette voie

• Il est raisonnable d'envisager les fers IV chez les patients présentant une anémie persistante, une intolérance au fer oral et une anémie grave pendant la grossesse

• Les nouvelles études sur les générations modernes de fer IV montrent des temps de perfusion plus courts et des profils de sécurité améliorés

• Les récentes lignes directrices britanniques envisagent une supplémentation universelle en fer IV pour le traitement de l'anémie au-delà de 34 semaines de grossesse

• Les femmes enceintes souffrant d'AF au cours du 3 ème trimestre sont plus susceptibles de bénéficier de fer IV

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C O

URRENTPINION

Iron deficiency anemia in pregnancy

Irogue Igbinosaa, Caroline Berubeb, and Deirdre J. Lyella

Purpose of review

Anemia in pregnancy is associated with increased maternal and neonatal morbidity. There is increasing awareness amongst obstetricians about the need to screen for iron deficiency anemia (IDA), as well as growing literature on diagnosis and treatment. This review aims to summarize causes, consequences, treatment, and evaluation of IDA in pregnancy.

Recent Findings

National guidelines provide varying guidance on diagnosis and treatment of IDA in pregnancy. Serum ferritin is a helpful adjunct for the diagnosis of IDA. Oral iron remains an option for treatment; absorption is improved with every other day dosing and is effective for patients able to tolerate. Emerging studies on modern generations of intravenous (IV) iron demonstrate shorter infusion times and improved safety profiles.

Notably, recent UK guidelines provide consideration for universal IV iron supplementation for treatment of anemia beyond 34 weeks of pregnancy.

Summary

Iron, in dietary, oral, and IV forms, has been found effective in resolving anemia in pregnancy. Pregnant people with IDA in the third trimester are more likely to benefit from IV iron. Future studies designed and powered to assess maternal and perinatal morbidity indicators and blood transfusion rates can strengthen recommendations.

Keywords

anemia, iron, iron deficiency, pregnancy

INTRODUCTION

Iron deficiency anemia (IDA) is the most common cause of anemia in pregnancy, affecting more than 32 million pregnancies annually worldwide [1&&]. Ane- mia in pregnancy is linked to significant maternal and neonatal morbidity, including severe maternal morbidity (SMM), sepsis, postpartum hemorrhage, and in offspring, cognitive and behavioral issues [2,3]. Although thresholds differ among guidelines, the American College of Obstetricians and Gynecol- ogists (ACOG) defines anemia in pregnancy as hemo- globin below 11 grams per deciliter (g/dL) in the first trimester and hemoglobin below 10.5 g/dL in the second and third trimester; thresholds vary among international guidelines [4&&]. There are many causes of anemia – physiological, nutritional, hereditary, acquired, infectious – yet, iron deficiency contributes to the majority, more than 70% of anemias [5&].

CAUSES OF ANEMIA

Iron, a critical component of oxygen-heme metab- olism, functions to support the demands of the maternal-fetal-placental triad [6]. Physiologically, increases in maternal blood volume (50%) and

red blood cell mass (35%) contribute to a tempo- rary dilutional effect on hemoglobin concentra- tions. As iron metabolism efforts grow, iron deficiency (a state of decreased iron) precedes IDA (low iron plus anemia) [7]. Iron utilization increases from 2 mg/day in early pregnancy to approximately 5–6 mg/day by the third trimester [8]. Over 1000 mg elemental iron is required for the average term singleton pregnancy, and iron requirements are amplified nearly two-fold in multifetal pregnancies [9]. The remaining causes of anemias in pregnancy range from nutritional (acquired B12 and folate deficiency) anemias, hemoglobinopathies (i.e.

sickle cell anemia and thalassemia), infection (HIV, malaria), and chronic diseases [10].

aStanford University, Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine and bStanford University, Department of Medicine, Division of Hematology, Stanford, California, USA

Correspondence to Irogue Igbinosa, MD, Stanford University, Depart- ment of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Stanford, California, USA. Tel: +650 725 5720;

e-mail: iiigbi@stanford.edu

Curr Opin Obstet Gynecol2022, 34:69–76 DOI:10.1097/GCO.0000000000000772

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DEFINITION OF ANEMIA

International variance exists on ideal cutoffs to define anemia in pregnancy. The Centers for Disease Control and Prevention and ACOG define anemia as hemoglobin/hematocrit below 11 g/dL/33% in the first and third trimester and below 10.5 g/dL/32.5%

in the second trimester [11]. Notably, the British Society of Hematology defines anemia as hemoglo- bin below 10.5 g/dL beyond 12 weeks and less than 10 g/dL postpartum [12&&]. The World Health Orga- nization (WHO) defines anemia as hemoglobin below 11.0 g/dL throughout pregnancy [1&&]. Mild anemiais defined by hemoglobin below 9–10.9,mod- erate anemiaby 7–8.9, andsevere anemiaby less than 7 g/dL [2]. Guidelines for postpartum anemia vary between hemoglobin levels less than 9.0–11.0 g/dL

[12&&,13]. Recent research challenges the applicability

of the hemoglobin cutoffs to more diverse popula- tions; a follow-up consensus statement from the WHO is pending at the time of this writing [14].

PREVALENCE AND CAUSES

Anemia in pregnancy affects more than 40 percent- age of pregnancies globally [1&&]. In the United States, underrepresented communities are particu- larly at risk for antenatal anemia, with the highest rates seen among Black women, 2–3-fold greater than White women even after excluding hereditary anemias (e.g., sickle cell anemia) [11,15].

Epidemiologic surveys underscore the impor- tant roles access to nutrition, socioeconomics, and social determinants of health play in addressing the public health challenge of anemia in pregnancy.

IDA risk factors include multiparity, interpregnancy interval less than one-year, adolescent pregnancy, and chronic medical illness [16]. Diets low in iron- rich/fortified foods (i.e. vegan, vegetarian) or high in foods diminishing iron absorption (i.e., coffee, tea) may contribute nutritional-related anemias [8,17].

Hemoglobin concentrations are also affected by

high altitudes (1000m above sea level) and smoking, which reduce heme oxygen carrying capacity [18].

MATERNAL CONSEQUENCES OF ANEMIA Common pregnancy symptoms often overlap with IDA symptoms and can cloud recognition of ane- mia. IDA contributes to fatigue, malaise, insomnia, chest pain, shortness of breath, and restless legs [19].

Physical exam findings of the skin or conjunctival pallor, flow murmurs, tachycardia, and decreased blood pressure should prompt evaluation for ane- mia [20&,21]. Infection, preterm delivery, cesarean delivery, preeclampsia, and severe maternal mortal- ity are seen more frequently with IDA, as are post- partum depression and decreased breastfeeding at six and twelve months.

The severity of anemia correlates with out- comes. In one study, blood transfusion odds increased with moderate anemia (2.45 OR, 95% CI 12.2–37.3) and severe anemia (84.1 OR, 95% CI 26.4–267.9) [2]. A rare consequence of anemia, severe anemia was associated with 1.86 odds (95%

CI, 1.39–2.49) of maternal death [22].

FETAL AND CHILDHOOD CONSEQUENCES OF ANEMIA

Fetal well-being is also affected by maternal anemia.

Fetal growth restriction (1.9% vs. 0.3%, p 0.006), preterm delivery (10.2% vs. 6.1%, p 0.009), and rarely neonatal anemia are associated with maternal IDA [23,24]. Neurocognitive dysfunction, such as reduced recognition memory [25], difficulty processing [26], slower processing speed [27,28&], and autism spec- trum disorders [29], have been associated with severe IDA. The hippocampus is highly metabolically active and develops more extensively after28 weeks. It is critical for memory, spatial and fact learning and is vulnerable to the lack of critical substrates such as iron [28&]. Less complex dendritic structure has been associated with severe maternal anemia [28&]. New- borns absorb iron poorly, and IDA that is established during pregnancy, a time when fetal ’iron loading’ is critical, can be difficult to overcome.

DIAGNOSIS OF IRON DEFICIENCY ANEMIA IN PREGNANCY

Anemia in pregnancy

The historical gold standard diagnosis for IDA is bone marrow aspiration with hemosiderin staining, though its invasiveness precludes widespread practice [30]. IDA is often the late stage of iron deficiency, or depleted iron stores in the absence of

KEY POINTS

Serum ferritin is a helpful adjunct for the diagnosis of IDA.

Oral iron remains an option for treatment; absorption is improved with every other day dosing and is effective for patients able to tolerate.

Intravenous iron can be used in obstetric populations;

guidelines provide consideration for use in patients with oral iron intolerance and anemia(less than 10 g/dl) beyond 34 weeks of pregnancy.

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anemia [31,32].Iron deficiency anemiareflects hemo- globin less than 11 g/dl plus evidence of iron defi- ciency. A complete blood count is the most common initial screening tool, with hemoglobin and hematocrit indices less than 11 g/dL or 33%

frequently prompting additional workup.

Peripheral blood smear

Morphologically, IDA findings on microscopy of peripheral smears are microcytosis and hypochro- mia of red cells [30]. Reticulocytes are decreased, consistent with decreased erythropoiesis. Platelets can be increased in IDA and normalized after reple- tion [30,33].

Mean corpuscular volume

In nonpregnant populations, microcytosis (mean corpuscular volume (MCV) less than 80 femtoliters (fL) suggests IDA [30]. However, pregnancy is asso- ciated with higher MCV values [12&&]. Thus, a nor- mal MCV does not exclude IDA [34]. Microcytosis may also be seen with thalassemia minor or sickle beta thalassemia, and macrocytosis points toward folate or vitamin B12 deficiency.

Serum ferritin

Serum ferritin, an intracellular protein crucial for iron storage, is a marker of IDA. Thresholds for defining IDA vary in the literature from serum ferri- tin less than 12–15 micrograms per milliliter (mg/L) to less than 20–30mg/L [35]. The specificity for serum ferritin approaches 98% for both cutoffs [36,37]. Serum ferritin cutoffs at less than 30mg/L are more efficient at identifying IDA; sensitivity, meaning that patients with IDA will be identified, is 25% at serum ferritin of 12–15mg/L vs. 92% at less than 30mg/L [38]. Serum ferritin is also an acute- phase reactant that can be increased by inflamma- tion, infection, stress, liver disease, and neoplastic conditions. In the absence of confounders, serum ferritin can reliably diagnose IDA [37].

Serum iron

Serum iron is a nonspecific marker of IDA [6]. In studies comparing serum iron to serum ferritin as control, the sensitivity of serum iron was 63.5% and specificity, 38.6% [12&&,20&,39]. Normal serum iron level does not rule out IDA.

Total iron-binding capacity

Total iron-binding capacity (TIBC) reflects the avail- ability of the iron transport protein transferrin in serum [40]. Generally, low levels of TIBC correspond to an iron-rich state, and high levels, to an iron-poor environment. The sensitivity of TIBC is 64.5%, and

specificity is 42.85%, identifying it as a less helpful marker for IDA [41].

Serum transferrin saturation

Serum transferrin saturation (TSAT) is the ratio of serum iron to TIBC. TSAT cutoffs to diagnose IDA are less than 16% in absence of inflammation vs. 20%

with inflammation [42]. Given limitations in diag- nosing inflammation, some guidelines use the 20%

cutoff [34].

Hepcidin

Hepcidin is a small peptide that is the main regula- tor of intestinal iron absorption and the release of iron from the macrophages [43]. Secreted by the liver and cleared by the kidney, hepcidin is low in iron deficiency states. Hepcidin levels indicative of iron deficiency precede anemia. Studies are under- way to evaluate thresholds for hepcidin as a single marker of IDA in pregnant women [43,44].

Screening for iron deficiency anemia

Universally, guidelines recommend screening for anemia in pregnancy with the initiation of prenatal care. WHO supports the evaluation of hemoglobin levels with each trimester [12&&]. ACOG recom- mends repeat screening at 24–28 weeks’ gestation;

UK guidelines recommend 28 weeks’ gestation

[4&&,12&&]. Patient signs/symptoms, risk factors,

and medical and surgical history may also warrant additional testing; for example, patients with inflammatory bowel disorders, chronic diseases, pri- mary micronutrient deficiencies, bariatric surgery, or prior surgery impairing gastrointestinal (GI) absorption should undergo interval hemoglobin screening in pregnancy [45,46].

Once anemia is confirmed, serum ferritin levels of less than 30 micrograms per milliliter diagnose IDA in the absence of concomitant inflammation

[12&&,35,48]. Transferrin saturation less than 20%

also diagnoses IDA. Guidelines do not support uni- versal screening for iron deficiency in the absence of anemia in pregnancy; this is a critical gap in the literature and warrants further exploration [47].

Empirical treatment of presumed IDA without definitive diagnosis is optional [4&&,12&&]. However, a workup is indicated if rising hemoglobin indices are not evident within 2–4 weeks of treatment. Ideally, confirmation of IDA with serum ferritintransferrin saturation is recommended prior to treatment [35].

Accurate IDA diagnosis is essential for patients with concomitant hemoglobinopathies, increased bleed- ing risk, and those who decline blood products

[4&&,12&&]. Inconclusive workups warrant referral to a

specialist (i.e., maternal-fetal medicine; hematology).

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Management of iron deficiency anemia in pregnancy

Current guidelines support supplementation with 27 mg of elemental iron daily in pregnancy, an equivalency commonly found in over-the-counter prenatal vitamins [48]. Dietary sources of iron are also encouraged (see Table 1). Counseling on diet optimization is important; nevertheless, for most patients presenting with anemia later in pregnancy –diet alone is insufficient.

Oral iron, primarily in the form of ferrous salts (ferrous fumarate, ferrous sulfate, ferrous gluco- nate), is the first-line treatment for IDA [49]. Ferrous salts used to be administered in fractionated dosing of 100–200 mg of elemental iron daily.

Oral iron efficacy increases when taken in the morning after an overnight fast. More recently, single dose daily or every other day appear to be as effective [50,51].

Oral preparations are cheaper, though associ- ated with adverse GI side effects, noncompliance, and less increase in hemoglobin at the time of delivery compared to intravenous (IV) preparations.

A meta-analysis concluded that 40–70% of pregnant people taking oral iron experienced an adverse side effect, largely GI, with oral iron and approximately half discontinued treatment [50]. Iron supplements with enteric coating improve tolerance but inhibit absorption [50].

Consequently, some women will require paren- teral iron. Newer preparations of IV iron have been well tolerated with low anaphylaxis-type reactions and fewer adverse side effects than older formula- tions [34]. IV iron sucrose in pregnancy is efficacious in addressing anemia in late pregnancy, yet draw- backs include dosing (max 200 mg/dose), frequency (average of 4–5 infusions), and duration (1-2 h each) [52–55]. Modern IV irons available include ferric carboxymaltose (FCM), ferric derisomaltose, feru- moxytol, iron polymaltose, and low molecular weight dextran (LMWD) [5&,56]; availability may

vary by country (see Table 1). Advantages include single- and two-dose administrations, shorter infu- sion times, and better safety profiles [56–58]. Nota- ble disadvantages include medication costs, ancillary procedures (peripheral IV placement, monitoring pre, and postinfusion), and evidence on best dosing regimens in pregnancy [59]. Current practices utilize the Ganzoni formula or modified weight-based regimens [60]. Most guidelines sup- port IV iron as a therapeutic option for IDA in patients intolerant of oral iron. UK guidelines sup- port IV iron administration for pregnant patients presenting beyond 34 weeks of pregnancy with hemoglobin below 10ug/L [12&&].

Summary of intravenous irons (Table 2)

Ferric carboxymaltose

FCM, a newer generation of IV iron, allows for rapid infusion [61–63]. FCM shows similar efficacy when compared to other IV iron formulations [64–66].

Adverse reactions such as pruritis, rash, urticaria, and hypotension occurred in less than 1.5%, and serious adverse events, i.e., severe anaphylaxis, occurred in 0.1% (2/1775) [59,67]. In the general population, FCM-induced hypophosphatemia lead- ing to musculoskeletal compromise in association with FCM transfusion is a rising concern [68,69].

Pregnant people may be at increased risk for severe hypophosphatemia after FCM transfusion [70];

there is limited understanding on maternal or fetal implications of hyperphosphatemia.

Ferumoxytol

Ferumoxytol is a ’superparamagnetic iron oxide’

that creates an iron-carbohydrate complex with ele- mental iron permitting rapid infusion [71]. Feru- moxytol is Food and Drug Administration (FDA) approved for adults with IDA [71]. Animal studies have not shown teratogenic effects at human doses, and a clinical trial of 131 pregnant patients had no serious adverse effects [72].

Low molecular weight dextran

LMWD has the advantage of being administered in a single dose. LMWD requires a test dose before infu- sion and has a lower rate of anaphylaxis than its predecessor, high molecular weight iron dextran (HMWD) [73,74]. HMWD is no longer on the market.

Ferric derisomaltose

Ferric derisomaltose, composed of iron hydroxide and derisomaltose, was approved by the FDA in 2020 [75,76]. In clinical trials conducted in nonpregnant Table 1. Common iron rich foods

Meat and eggs Starch Vegetables

-Beef -Lentils -Spinach

-Lamb -Beans -Sweet potatoes

-Ham - Iron fortified cereal (varies) -Peas

-Turkey - Tofu -String beans

-Chicken - Almonds -Collards

-Veal - Baked potato -Kale

-Eggs -Cashews -Chard

Source of Information: USDA National Nutrient Database.

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Table2.IntravenousIron DrugTrade nameElemental IronDosingAnimalstudies[62]Pregnancy&Lactation SafetySerioushypersensitivity reactions[42,59,63] Ironsucrose[53]Venofer20mg/mlMultipledosesof200300ngNoadverseeffectsMoststudiedIVironin pregnancy Noadversereactionsin nursinginfants

21per100,00 (95%CI,1526) Ferricderisomaltose [75] (alsoknownasiron Isomaltoside)

Monferric100mg/ml500mg/dose,max3doses 7daysapart Or Singledose20mg/kg Skeletalanomaliesat 0.10.3timeshuman dosing

Limiteddata Excretedintobreastmilk0.3%(6in2008)inonetrial Lowmolecularweight irondextran[73]INFeD50mg/ml-Multipledosesof100mgor -singledoseof1000mg(in 250mlnormalsaline)over 1h -testdoserequired

Teratogenicityat3times humandosingPublishedtrialswithrare adversematernal/fetal outcomes Minimallyexcretedinmilk

82per100,000(95%CI, 7193)includesHMWD 1.3per100,000[63] FerumoxytolFeraheme30mg/ml510mg/dose,max2doses given38daysapartNoeffectsathuman dosing;fetal malformationsat6times humandosing

Studyof164pregnant patientsobstetricoutcomes withinnormal Benefits>risks Note:alsoacontrastagent Noreportedstudieson lactation

34per100,000(95%CI, 2350) FerricCarboxymaltoseInjectafer50mg/ml750mg/dose,max2dosesTeratogenic0.1325times humandoseMonitorforhypophosphatemia Excretedinbreastmilk6per100,000[63] SeeBibliographyforcorrespondingreferences.

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adults, efficacy was comparable to iron sucrose.

Research on use in pregnancy is limited.

Pregnancy and lactation safety

As a precaution, IV irons are not recommended in the first trimester during organogenesis [34]. The FDA updated labeling for pregnancy and lactation list provides consideration for IV iron use in the second/third trimester [77].

Safety of intravenous irons

Anaphylactic allergic reactions to IV iron are extremely rare, with approximately 1 death per 5 million doses of IV iron [57,73]. Minor reactions of flushing, and chest/flank myalgias may occur sec- ondary to temporary complement activation [73].

Premedication with diphenhydramine is not recom- mended as it may precipitate a Fishbane reaction (transient flushing, chest pain or myalgias) [21,78].

Most minor reactions resolved with pausing and resuming the infusion at a slower rate. Patients with multiple medication allergies may benefit from methyl-prednisone prior to IV iron infusion [72,79]. Institutes/centers desiring to utilize IV iron should identify treatment algorithms to assess and manage reactions [80].

Blood transfusion

Blood transfusions are reserved for severely anemic pregnant patients with active bleeding, hemody- namically instability, and signs of cardiac decom- pensation [12&&,75]. Red cell alloimmunization, infection and allergic reactions, although minor, pose additional consequences for women of child- bearing age.

Postpartum anemia

Postpartum anemia cutoffs vary from 9 to 11 g/dL [13]. A meta-analysis of 15 randomized control trials on postpartum anemia found IV iron increased hemoglobin by 0.9 g/dL more than oral iron at six weeks postpartum (P<0.05) [81]. This rise is similar to the effect seen after transfusion of one unit of red blood cell., IV iron presents as an likely alternative in preventing blood transfusions [81,82].

LITERATURE GAPS/FUTURE DIRECTIONS We have identified several gaps in the literature from the lens of screening, management and out- comes reported. Guidelines and recommendations for anemia in pregnancy reflect a broad spectrum of practice. Several systematic reviews and meta-anal- yses have demonstrated that treatment of IDA can

improve the individual hemoglobin and hematocrit indices. However, it is assumed though not demon- strated if treatment of IDA decreases SMM and improves perinatal/neonatal outcomes. Future stud- ies designed and powered to assess maternal and perinatal morbidity indicators and blood trans- fusion rates can strengthen recommendations.

Research on patient-reported perspectives regarding response to iron therapy and quality of life is also limited. Longitudinal studies on mother–infant are also needed. Global differences in the prevalence of IDA and implications of social determinants of health imply that more understanding of the causes and risk factors for IDA are needed.

SUMMARY

IDA in pregnancy is a known risk factor for SMM and mortality. Screening, management, and treatment guidelines for IDA in pregnancy have the potential to improve adverse pregnancy outcomes. Oral iron with alternate dosing may produce the same effects as daily dosing with less adverse effects. IV irons are reasonable to consider for patients with persistent anemia, intolerance to oral iron, and severe anemia in pregnancy.

Acknowledgements None.

Financial support and sponsorship None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

& of special interest

&& of outstanding interest

1.

&&

Hasan M, Magalhaes R, Garnett S,et al. Anemia in women of reproductive age in low and middle income countries: progress towards the 2025 global nutrition target. Bulletin of the World health Organization. BLT20.

280180.

World Heatlh Organization global database on the prevalence of anemia in pregnancy.

2. Smith C, Teng F, Branch E,et al. Maternal and perinatal morbidity and mortality associated with anemia in pregnancy. Obstet Gynecol 2019;

134:1234–1244. Available from: http://insights.ovid.com/crossref?an=

00006250-201912000-00015.

3. Malinowski AK, D’Souza R, Khan KS,et al.Reported outcomes in perinatal iron deficiency anemia trials: a systematic review. Gynecol Obstet Investig 2019; 84:417–434.

4.

&&

Anemia in pregnancy. Obstet Gynecol 2021; 138:e55–e64. [cited 2021 Nov 14] Available from: https://pubmed.ncbi.nlm.nih.gov/34293767/.

This review provides updated guidance for management of anemia in pregnancy in the United States. Notable changes include removal of race-based hemoglobin cutoffs for the diagnosis of anemia in pregnancy.

Maternal fetal medicine

74 www.co-obgyn.com Volume 34 Number 2 April 2022

(12)

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

5.

&

James AH. Iron deficiency anemia in pregnancy. Obstet Gynecol 2021;

138:663–674.

Comprehensive clinical expert gudiance on anemia in pregnancy and current gaps in literature

6. Van Den Broek NR, Letsky EA, White SA,et al.Iron status in pregnant women:

which measurements are valid? Br J Haematol 1998; 103:817–824.

7. Horowitz KM, Ingardia CJ, Borgida AF. Anemia in pregnancy. Clin Lab Med 2013; 33:281–291.

8. Bothwell TH. Iron requirements in pregnancy and strategies to meet them. Am J Clin Nutr 2000; 72((1 Suppl)):257S–264S.

9. Shinar S, Skornick-Rapaport A, Maslovitz S. Iron supplementation in twin pregnancythe benefit of doubling the iron dose in iron deficient pregnant women: a randomized controlled trial. Twin Res Hum Genet 2017;

20:419–424. [cited 2021 Oct 31] Available from: https://www.cambridge.

org/core/journals/twin-research-and-human-genetics/article/iron-supplementa tion-in-twin-pregnancy-the-benefit-of-doubling-the-iron-dose-in-iron-deficient- pregnant-women-a-randomized-controlled-trial/3B43C78C153CCEB8BAC 074E73D53C4BF.

10. Hemoglobinopathies in pregnancy. Int J Gynecol Obstet [Internet]. 1996 May 1 [cited 2021 Nov 23];53(2):184-94. Available from: https://onlineli- brary.wiley.com/doi/full/10.1016/S0020-7292%2896%2990113-7 11. Mei Z, Cogswell ME, Looker AC,et al.Assessment of iron status in US

pregnant women from the national health and nutrition examination survey (NHANES), 1999–2006. Am J Clin Nutr 2011; 93:1312–1320.

12.

&&

Pavord S, Daru J, Prasannan N,et al.UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol 2020; 188:819–830.

This recent guidance by the UK provides structured recommendations for an approach to iron deficinecy anemia in pregnancy, including guidelines for interval follow up of CBCs and iron indices recommended from the initiation of iron therapy. Guidelines also support IV iron for pregnant patients with hemoglobin less than 10 grams per deciliter based on expert opinion.

13. Milman N. Postpartum anemia I: definition, prevalence, causes, and conse- quences. Ann Hematol 2011; 90:1247–1253.

14. Addo OY, Yu EX, Williams AM,et al.Evaluation of hemoglobin cutoff levels to define anemia among healthy individuals. JAMA Netw Open 2021;

4:e2119123–e12119123.

15. Le CH. The prevalence of anemia and moderate-severe anemia in the US population (NHANES 2003–2012). PLoS One 2016; 11:e0166635.

16. Mohamed MA, Ahmad T, Macri C, et al. Racial disparities in maternal hemoglobin concentrations and pregnancy outcomes. J Perinat Med 2012;

40:141–149.

17. Sekhar DL, Murray-Kolb LE, Kunselman AR,et al.Differences in risk factors for anemia between adolescent and adult women. J Women’s Heal 2016;

25:505–513.

18. Nahum G, Stanislaw H. Hemoglobin, altitude and birth weight: does maternal anemia during pregnancy influence fetal growth? J Reprod Med 2004;

49:297–305.

19. Staibano P, Perelman I, Lombardi J,et al.Patient-centered outcomes in the management of anemia: a scoping review. Transfus Med Rev 2019; 33:7–11.

20.

&

Means RT. Iron deficiency and iron deficiency anemia: implications and impact in pregnancy, fetal development, and early childhood parameters. Nutrients 2020; 12:447. doi: 10.3390/nu12020447.

This paper answers key questions on the potential linkages between maternal anemia and neontal/fetal growth.

21. Breymann C, Auerbach M. Iron deficiency in gynecology and obstetrics:

clinical implications and management. Hematology 2017; 2017:152–159.

22. Daru J, Zamora J, Ferna´ndez-Fe´lix BM,et al.Risk of maternal mortality in women with severe anaemia during pregnancy and post partum: a multilevel analysis. Lancet Glob Heal 2018; 6:e548–e554.

23. Kemppinen L, Mattila M, Ekholm E,et al.Gestational iron deficiency anemia is associated with preterm birth, fetal growth restriction, and postpartum infec- tions. J Perinat Med 2020; 49:431–438.

24. Leslie MS, Park J, Briggs LA,et al.Is anemia in low income pregnant women related to their infants’ having anemia? a cohort study of pregnant women- infant Pairs in the United States. Matern Child Health J 2020; 24:768–776.

25. Riggins T, Miller NC, Bauer PJ,et al.Consequences of low neonatal iron status due to maternal diabetes mellitus on explicit memory performance in childhood. Dev Neuropsychol 2009; 34:762–779.

26. Siddappa AM, Georgieff MK, Wewerka S,et al.Iron deficiency alters auditory recognition memory in newborn infants of diabetic mothers. Pediatr Res 2004; 55:1034–1041.

27. Amin SB, Orlando M, Eddins A,et al.In utero iron status and auditory neural maturation in premature infants as evaluated by auditory brainstem response.

J Pediatr 2010; 156:377–381.

28.

&

Georgieff MK. Iron deficiency in pregnancy. Am J Obstet Gynecol 2020;

223:516–524.

This paper highlights key physiologic pathways of iron homeostasis in pregnancy and its correlation to fetal development.

29. Wiegersma AM, Dalman C, Lee BK,et al.Association of prenatal maternal anemia with neurodevelopmental disorders. JAMA Psychiatry 2019;

76:1294–1304.

30. Lopez A, Cacoub P, Macdougall IC,et al.Iron deficiency anaemia. Lancet 2016; 387:907–916.

31. Scholl TO, Hediger ML, Fischer RL,et al.Anemia vs iron deficiency: increased risk of preterm delivery in a prospective study. Am J Clin Nutr 1992;

55:985–988.

32. Rasmussen KM. Is there a causal relationship between iron deficiency or iron- deficiency anemia and weight at birth, length of gestation and perinatal mortality? J Nutr 2001; 131:590S –603S.

33. Kadikoylu G, Yavasoglu I, Bolaman ZST. Platelet parameters in women with iron deficiency anemia. J Natl Med Assoc 2006; 98:398–402.

34. Auerbach M, Landy H. Anemia in pregnancy – UpToDate [Internet]. [cited 2020 Nov 19]. Available from: https://www.uptodate.com/contents/anemia- in-pregnancy

35. Auerbach M, Adamson JW. How we diagnose and treat iron deficiency anemia. Am J Hematol 2016; 91:31–38.

36. Breymann C, Milman N, Pharma V,et al.Patient Blood Management and Life Cycle Management Open Access Ferric carboxymaltose vs. oral iron in the treatment of pregnant women with iron deficiency anemia: an international, open-label, randomized controlled trial (FER-ASAP). J Perinat Med 2017;

45:443–453.

37. Byg KE, Milman N, Hansen SAA. Serum ferritin is a reliable, noninvasive test for iron status in pregnancy: comparison of ferritin with other iron status markers in a longitudinal study on healthy pregnant women; erythropoiesis.

Hematology 2000; 5:319–325.

38. Daru J, Allotey J, Pen˜a-Rosas JP,et al.Serum ferritin thresholds for the diagnosis of iron deficiency in pregnancy: a systematic review. Transfus Med 2017; 27:167–174.

39. Fisher AL, Nemeth E. Iron homeostasis during pregnancy. Am J Clin Nutr 2017; 106(Suppl 6):1567S –1574S.

40. Huang R, McEvoy DS, Baron JMDA. Iron studies and transferrin, a source of test ordering confusion highly amenable to clinical decision support. Clin Chim Acta 2020; 510:337–343.

41. Asif N, Ijaz A, Rafi T,et al.Diagnostic accuracy of serum iron and total iron binding capacity (TIBC) in iron deficiency state. J Coll Physicians Surg Pak 2016; 26:958–961.

42. Achebe MM, Gafter-Gvili A. How I treat anemia in pregnancy: iron, cobalamin, and folate. Blood 2017; 129:940–949.

43. Bah A, Pasricha S-R, Jallow MW,et al.Serum hepcidin concentrations decline during pregnancy and may identify iron deficiency: analysis of a longitudinal pregnancy cohort in The Gambia. J Nutr 2017; 147:1131–1137.

44. Lewkowitz AK, Tuuli MG. Iron-deficiency anaemia in pregnancy: the role of hepcidin. Lancet Glob Heal 2019; 7:e1476–e1477.

45. Mahadevan U, Robinson C, Bernasko N,et al.Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenter- ological Association IBD Parenthood Project Working Group. Gastroenter- ology 2019; 156:1508–1524.

46. Pavord S, Daru J, Prasannan N,et al.UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol 2019; 188:819.

47. Kemper AR, Fan T, Grossman DC,et al.Gaps in evidence regarding iron deficiency anemia in pregnant women and young children: summary of US Preventive Services Task Force recommendations. Am J Clin Nutr 2017;

106:1555S–1558S.

48. Cantor AG, Bougatsos C, Dana T,et al.Routine iron supplementation and screening for iron deficiency anemia in pregnancy: A systematic review for the U.S. preventive services task force. Ann Intern Med 2015; 162:

566 – 576.

49. Pen˜a-Rosas JP, De-Regil LM, Dowswell T,et al.Daily oral iron supplementa- tion during pregnancy. In: Pen˜a-Rosas JP, editor. Cochrane Database of Systematic Reviews [Internet]. Chichester: John Wiley & Sons, Ltd; 2012.

50. Pen˜a-Rosas JP, De-Regil LM, Gomez Malave H,et al.Intermittent oral iron supplementation during pregnancy. Cochrane database Syst Rev 2012;

7:CD009997.

51. Yakoob M, Bhutta Z. Effect of routine iron supplementation with or without folic acid on anemia during pregnancy. BMC Public Health 2011; 11:S21.

https://doi.org/10.1186/1471-2458-11-S3-S21.

52. Kochhar PK, Kaundal A, Ghosh P. Intravenous iron sucrose versus oral iron in treatment of iron deficiency anemia in pregnancy: a randomized clinical trial. J Obstet Gynaecol Res 2013; 39:504–510.

53. Shi Q, Li J, Yao Q,et al.Intravenous iron sucrose: an alternative for oral iron in pregnancy with iron deficiency anemia. Ann Hematol 2015; 94:

523 – 525.

54. Froessler B, Cocchiaro C, Saadat-Gilani K,et al.Intravenous iron sucrose versus oral iron ferrous sulfate for antenatal and postpartum iron deficiency anemia: a randomized trial. J Matern Fetal Neonatal Med 2013; 26:

654 – 659.

55. [Venofer] (iron sucrose) Vifor Switzerland. 2000. PremierProRx, Federal Drug Administration [package insert]. Reference ID: 4187126 accessdata.fda.gov.

56. Govindappagari S, Burwick RM. Treatment of iron deficiency anemia in pregnancy with intravenous versus oral iron: systematic review and meta- analysis. Am J Perinatol 2019; 36:366–376.

57. Wang C, Graham DJ, Kane RC,et al.Comparative risk of anaphylactic reactions associated with intravenous iron products. JAMA 2015; 314:

2062–2068.

58. Auerbach M, Deloughery T. Single-dose intravenous iron for iron deficiency: a new paradigm. Hematology 2016; 2016:57–66.

Iron deficiency anemia in pregnancyIgbinosaet al.

1040-872X Copyrightß2022 Wolters Kluwer Health, Inc. All rights reserved. www.co-obgyn.com 75

(13)

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

59. Koch TA, Myers J, Goodnough LT. Intravenous iron therapy in patients with iron deficiency anemia: dosing considerations. Anemia 2015; 2015:763576.

doi:10.1155/2015/763576.

60. Dignass AU, Gasche C, Bettenworth D,et al.European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory Bowel Diseases. J Crohn’s Colitis 2015; 9:211–222.

61. Khalafallah AA, Hyppa A, Chuang A,et al. A prospective randomised controlled trial of a single intravenous infusion of ferric carboxymaltose vs single intravenous iron polymaltose or daily oral ferrous sulphate in the treatment of iron deficiency anaemia in pregnancy. Semin Hematol 2018;

55:223 – 234.

62. [Injectafer (Ferric Carboxymaltose)] Vifor (International), Switzerland. 2013.

American Regent, INC. Shirley, NY Federal Drug Administration [package insert]. Reference ID: 4212697 accessdata.fda.gov

63. Durup D, Schaffalitzky de Muckadell P, Strom CC. Evaluation of the reported rates of hypersensitivity reactions associated with iron dextran and ferric carboxymaltose based on global data from VigiBaseTMand IQVIATMMIDAS1 over a ten-year period from 2008 to 2017. Expert Rev Hematol 2020;

13:557–564.

64. Jose A, Mahey R, Sharma JB,et al.Comparison of ferric Carboxymaltose and iron sucrose complex for treatment of iron deficiency anemia in pregnancy- randomised controlled trial. BMC Pregnancy Childbirth 2019; 19:54. https://

doi.org/10.1186/s12884-019-2200-3.

65. Shim JY, Kim MY, Kim YJ,et al.Efficacy and safety of ferric carboxymaltose versus ferrous sulfate for iron deficiency anemia during pregnancy: subgroup analysis of Korean women. BMC Pregnancy Childbirth 2018; 18:349. doi:

10.1186/s12884-018-1817-y.

66. Qassim A, Gergis RG, Jeffries B,et al.Use of intravenous iron polymaltose in the management of iron deficiency in pregnancy: a retrospective cohort study.

Aust New Zeal J Obstet Gynaecol 2018.

67. Ehlken B, Nathell L, Gohlke A,et al.Evaluation of the reported rates of severe hypersensitivity reactions associated with ferric carboxymaltose and iron (III) isomaltoside 1000 in Europe based on data from Eudra- Vigilance and VigiBaseTMbetween 2014 and 2017. Drug Saf 2019; 42:463–

471.

68. Wolf M, Chertow GM, Macdougall IC,et al.Randomized trial of intravenous iron-induced hypophosphatemia. JCI Insight 2018; 3:e124486.

69. Zoller H, Schaefer B, Glodny B. Iron-induced hypophosphatemia: an emer- ging complication. Curr Opin Nephrol Hypertens 2017; 26:266–275.

70. Huang LL, Lee D, Troster SM,et al.A controlled study of the effects of ferric carboxymaltose on bone and haematinic biomarkers in chronic kidney disease and pregnancy. Nephrol Dial Transplant 2018; 33:1628–1635.

71. [Feraheme]. AMAG Pharmaceuticals. 2015. Patheon Manufacturing Ser- vices, Federal Drug Administration [package insert]. Reference ID:

3716604 accessdata.fda.gov.

72. Gerb J, Strauss W, Derman R,et al.Ferumoxytol for the treatment of iron deficiency and iron-deficiency anemia of pregnancy. Ther Adv Hematol 2021;

12:1–8.

73. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlme´n J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant 2006;

21:378–382.

74. [INFeD] (low molecular weight iron dextrose). Watson Pharmeceuticals, Inc, revised 2009. Patheon Italia, Federal Drug Administration [package insert].

Reference ID: 4782273 accessdata.fda.gov.

75. Markova V, Hansen R, Thomsen LL,et al.Intravenous iron isomaltoside versus oral iron supplementation for treatment of iron deficiency in pregnancy: protocol for a randomised, comparative, open-label trial. Trials 2020; 21:. [cited 2021 Nov 24] Available from: https://pubmed.ncbi.nlm.nih.gov/32843079/.

76. [Monoferrric (ferric derisomaltose). Pharmacosomos A/S. 2020. Pharmaco- somos Denmakr., Federal Drug Administration [package insert]. Reference ID: 4547577 accessdata.fda.gov.

77. Breymann C, von Seefried B, Stahel M,et al.Milk iron content in breast- feeding mothers after administration of intravenous iron sucrose complex. J Perinat Med 2007; 35:115–118.

78. 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.

79. Rampton D, Folkersen J, Fishbane S,et al.Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haemato- logica 2014; 99:1671–1676.

80. Patterson JA, Roberts CL, Bowen JR,et al.Blood transfusion during preg- nancy, birth, and the postnatal period. Obstet Gynecol 2014; 123:126–133.

81. Sultan P, Bampoe S, Shah R,et al.Oral vs intravenous iron therapy for postpartum anemia: a systematic review and meta-analysis. Am J Obstet Gynecol 2019; 221:19–29.e3.

82. Giannoulis C, Daniilidis A, Tantanasis T,et al.Intravenous administration of iron sucrose for treating anemia in postpartum women. Hippokratia 2009;

13:38–40.

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