Recommendations of the AGG (Obstetrics Working Group, Section for Maternal Diseases) for the Management of Anemia in Pregnancy – Part 1 (Iron Deficiency Anemia)

Abstract

Objective

These recommendations by the AGG (Committee for Obstetrics, Department of Maternal Diseases) on how to treat iron-deficiency anemia during pregnancy aim to improve the diagnosis and management of iron-deficiency anemia in pregnancy.

Methods

The task force members developed the following recommendations and statements based on the current literature. Recommendations were adopted after the members of the working group achieved consensus.

Recommendations

This article gives an insight into the diagnosis and management of iron-deficiency anemia in pregnancy and provides recommendations on its treatment.

Introduction

Manifest anemia is present if the number of red blood cells (and therefore their capacity to transport oxygen) is insufficient to meet the body’s physiological needs 1 . The plasma volume during physiological pregnancy increases by 40–50%; however, the number of red blood cells only increases by around 20–50%. This leads to physiological dilutional anemia which is asymptomatic 2 . This also means that the standard values for pregnant and non-pregnant women differ considerably ( Table 1 ) 1 .

Table 1 Hemoglobin values for the diagnosis of anemia at sea level during pregnancy and puerperium (4–6 weeks postpartum), based on the WHO. Data from 1 3 4 .

			Anemia
Population	Hb value normal range g/dl (mmol/l)	Lowest normal value g/dl (mmol/l)	Mild g/dl (mmol/l)	Moderate g/dl (mmol/l)	Severe g/dl (mmol/l)
Non-pregnant women above 15 years of age	12–15 (7.4–9.4)	12 (7.4)	11–11.9 (6.9–7.4)	8–10.9 (5–6.8)	< 8 (< 5)
Pregnancy and puerperium
First trimester (< 14 weeks)	11–14 (6.9–8.7)	11 (6.9)	10–10.9 (6.3–6.8)	7–9.9 (4.4–4.9)	< 7 (4.4)
Second trimester (14–28 weeks)	10.5–14 (6.6–8.7)	(10.5)	10–10.4 (6.3–6.5)	7–9.9 (4.4–4.9)	< 7 (4.4)
Third trimester (> 28 weeks till delivery)	11–14 (6.9–8.7)	11 (6.9)	10–10.9 (6.3–6.8)	7–9.9 (4.4–4.9)	< 7 (4.4)
Puerperium	10–14 (6.3–8.7)	10 (6.3)		7–9.9 (4.4–4.9)	< 7 (4.4)

The lower threshold hemoglobin concentration decreases to around 11 g/dl in the first trimester of pregnancy, 10.5 g/dl in the second trimester and 11 g/dl again in the third trimester 3 . The international consensus defines the lower threshold for postpartum anemia as 10 g/dl 4 5 6 .

Method

We carried out a MEDLINE search of the literature using the search terms “pregnancy AND anemia,” “pregnancy AND iron deficiency,” “pregnancy AND iron deficiency anemia” and the filters “meta-analysis,” “systematic review” and “5 years.” Identified abstracts were assessed for relevance and appropriate studies were reviewed for this publication. Topic-related searches of the literature were additionally carried out for specific individual issues. Recommendations were formulated and agreed upon with the Section “Maternal Disease” of the Obstetrics and Prenatal Medicine Working Group (AGG) and the executive board of the AGG of the German Society for Gynecology and Obstetrics (DGGG).

Prevalence

Karami et al. carried out a meta-analysis of the global prevalence of anemia in pregnant women 7 . They identified 52 articles published between 1991 and 2021. According to their analysis, the overall prevalence of anemia in pregnant women was 37% (95% confidence interval: 32–42%). 71% of these cases (95% CI: 58–81%) could be categorized as mild. Anemia was found to be particularly common in the third trimester of pregnancy (49% [95% CI: 39–59%]). The prevalence of anemia in pregnant women was especially high in Africa where the mean was 42% (95% CI: 32–49%). However, the highest prevalence was recorded for Pakistan with 93% 8 and the lowest for Belgium with 7.7% 9 . The leading cause of anemia is iron deficiency, which was calculated to be 87% for women at the time of giving birth 10 .

The main causes of anemia in pregnancy worldwide are iron deficiency, folic acid deficiency, and vitamin B ₁₂ deficiency. The higher iron, folic acid, and vitamin B ₁₂ requirements during successive pregnancies may be additionally exacerbated by parasitic infections, e.g., hook worm or malaria. Other causes of anemia can include hemolytic disease, bone marrow suppression, or malignant disease 11 12 13 14 15 16 17 . Alongside medical factors, social factors such as work status, education, access to health care, and diet affect the prevalence of anemia in pregnant women 7 18 .

In Germany, the mean Hb concentration calculated for pregnant women in 2011 was 11.8 g/dl; 24% (95% CI: 12–45%) of pregnant women in Germany were found to have Hb levels of < 11 g/dl and 0.2% (95% CI: 0.0–1.0%) had Hb levels of < 7 g/dl 19 . According to the national perinatal survey in Germany, anemia was only recorded in 2% of pregnant women prepartum in Germany, but postpartum anemia was reported in 21% 20 . This discrepancy may be due to inadequate detection during prepartum care or inadequate taking of patients’ history or underreporting in maternity hospitals.

Screening

Article 2, section 6 of the German Maternity Protection Guideline 21 recommends monitoring hemoglobin levels as is also recommended in international guidelines 5 6 22 23 . If hemoglobin levels are within normal ranges at the first examination, repeat screening should be carried out from the 6th month of pregnancy at every prepartum examination and during the first weeks after giving birth (MuSchR Article 7, sections 1 and 3). Determination of Hb “if necessary” is suggested six to eight weeks after giving birth in the context of a general medical examination 21 . Regrettably no suggestions were proposed about further procedures if Hb levels fall below the threshold or anemia is incipient.

This policy document of the AGG Section for Maternal Disease provides a recommended course of action to deal with iron deficiency and iron deficiency in pregnancy and puerperium with the long-term aim of reducing the prevalence of anemia and improving women’s health.

Iron Deficiency Anemia

Definition

Iron deficiency anemia is microcytic, hypochromic, hyporegenerative anemia, known to be associated with significant anisocytosis 24 .

Iron deficiency in pregnancy

Iron requirements increase with the start of pregnancy but remain low in the first trimester of pregnancy due to the absence of menstruation-related iron loss. The daily iron requirement is about 0.8 mg in the first trimester, rising to 4 to 5 mg in the second trimester and more than 6 mg in the third trimester of pregnancy. To adjust for these changes, the physiology affecting iron resorption in the gut changes. It first decreases at the start of pregnancy. Later, the resorption capacity increases continuously over the further course of pregnancy 25 .

Prevalence, etiology, and risk factors

Malnutrition is the main cause of iron deficiency worldwide outside of pregnancy. In more economically stable regions such as Europe, iron deficiency can often be traced back to an unbalanced diet with reduced iron intake. However, even if nutritional iron is available in sufficient quantities, other factors such as reduced resorption in the duodenum, chronic blood loss, or chronic inflammatory disease may lead to iron deficiency 24 .

Reasons for iron deficiency anemia outside of pregnancy can be summarized as follows 26 :

1. Reduced iron intake: vegetarians, vegans with insufficient supplementation, or other types of diet with a low iron content

2. Reduced iron uptake:

   • medications which reduce gastric acidity

   • celiac disease

   • atrophic or autoimmune gastritis

   • bariatric surgery

   • genetic abnormality, e.g., iron refractory iron deficiency anemia (IRIDA)

3. Increased blood or iron loss:

   • Polymenorrhea/metrorrhagia/hypermenorrhea

   • frequent blood donations

   • chronic upper gastrointestinal bleeding due to reflux, gastritis, varices, and ulcers

   • chronic inflammatory bowel disease (ulcerative colitis/Crohn’s disease)

   • iatrogenic, e.g., frequent blood draw

   • blood loss during surgery

   • hemodialysis

   • intestinal parasites

   • clotting disorders, e.g., von Willebrand disease

   • small bowel hemorrhage from angioectasias and rare tumors

   • gastrointestinal or hereditary hemorrhagic telangiectasia (HHT)

   • colorectal carcinoma

Irrespective of the presence of anemia, around 27–58% of all women of childbearing age are already iron deficient prior to conception 27 28 29 30 . The reasons for this are often

1. low socioeconomic status and insufficient dietary iron intake,

2. blood loss during menstruation,

3. increased blood loss during previous pregnancies/birth,

4. short intervals between pregnancies, and

5. reduced iron uptake due to nausea, vomiting, chronic inflammatory bowel disease, bariatric surgery or other chronic diseases associated with iron loss or malabsorption.

Clinical Signs, Symptoms of Iron Deficiency with/without Anemia

Some of the symptoms of iron deficiency are specific but rare, for example, Plummer-Vinson syndrome, pica and koilonychia. Skin pallor, conjunctival and nail bed pallor are common. If the symptoms have only recently emerged, these signs may be useful for diagnosis. Other signs and symptoms are the result of hypoxic functions: tiredness, stress dyspnea, dizziness, headache, tachycardia, and systolic flow murmur 31 . In severe cases, patients may present with dyspnea at rest, angina pectoris, or hemodynamic instability 32 . A detailed list of symptoms and their incidence is given in Table 2 .

Table 2 List of symptoms associated with iron deficiency anemia, based on Lopez et al. Data from 31 .

Symptom	Incidence (%)
Skin pallor	very common (45–50)
Tiredness	very common (44)
Dyspnea	very common
Headache	very common (63)
Diffuse, moderately severe alopecia	common (30)
Atrophic glossitis	common (27)
Restless legs syndrome	common (24)
Rough dry skin	common
Dry and damaged hair	common
Cardiac murmur	common (10)
Tachycardia	common (9)
Neurocognitive dysfunction	common
Angina pectoris	common
Dizziness	common
Hemodynamic instability	rare (2)
Koilonychia	rare
Plummer-Vinson syndrome	rare (< 1)
Pica	rare (< 1)

Impact of Anemia on Pregnancy

Untreated anemia can have a negative impact on pregnancy. Anemic pregnant women have a higher risk of severe complications at the time of birth including higher rates of delivery by cesarean section, postpartum bleeding, thrombosis, intrapartum and postpartum transfusions, hysterectomy, transfer to an intensive care unit, infections, hypertensive disorders of pregnancy, and maternal mortality. The probability of feto-maternal complications correlates with the severity of anemia 33 34 . Table 3 presents feto-maternal morbidities which occur in association with anemia.

Table 3 Adjusted odds ratios for maternal and fetal complications correlated to the severity of anemia in pregnancy (data from 33 ).

	Mild anemia (Hb 10–10.9 g/dl) aOR (95% CI)	Moderate anemia (Hb 7.0–9.9 g/dl) aOR (95% CI)	Severe anemia (Hb < 7.0 g/dl) aOR (95% CI)
Abbreviations: aOR = adjusted odds ratio; FGR = fetal growth restriction; Hb = hemoglobin; ICU = intensive care unit; CI = confidence interval; N/S = not significant; PPH = postpartum bleeding; HDP = hypertensive disorders of pregnancy * These complications are listed irrespective of the severity of anemia.
Maternal complications
Placental detachment	1.36 (1.34–1.38)	1.98 (1.93–2.02)	3.35 (3.17–3.54)
Preterm birth	1.08 (1.07–1.08)	1.18 (1.17–1.19)	1.36 (1.32–1.41)
Severe PPH	1.45 (1.43–1.47)	3.53 (3.47–3.6)	15.65 (15.1–16.22)
Maternal shock	N/S	1.5 (1.41–1.6)	14.98 (13.91–16.13)
Transfer to ICU	N/S	1.08 (1.01–1.16)	2.88 (2.55–3.25)
Cesarean section	1.13 (1.13–1.14)	1.16 (1.15–1.17)	N/S
Thrombosis*	20.8 (1.94–2.24)
Blood transfusion*	1.84 (1.66–2.05)
Hysterectomy*	7.66 (4.57–12.85)
HDP*	1.33 (1.18–1.5)
Maternal mortality*	18.1 (2.48–131.61)
Fetal complications
FGR	N/S	N/S	1.08 (1.00–1.17)
Malformations	1.15 (1.14–1.17)	1.19 (1.16–1.21)	1.62 (1.52–1.73)
Stillbirth	N/S	N/S	1.86 (1.75–1.98)

The rates of placental abruption, preterm birth, and severe postpartum bleeding increase with the severity of anemia 33 34 . The increased risk of some complications including maternal shock, transfer to an intensive care unit and maternal mortality, FGR and stillbirth were determined for patients with moderate or severe anemia but not for patients with mild anemia 33 35 . Some authors therefore recommend only carrying out interventions in cases with moderate to severe anemia and only monitoring hemoglobin levels in cases with mild anemia 33 .

Postnatal effects have also been observed in children born after an anemic pregnancy, including neonatal hypoferritinemia (< 20 µg/dl) in 87% and anemia (< 13 d/dl) in 5.6% of infants 36 . Neonates born to anemic mothers had higher rates of respiratory distress syndrome (aOR 1.15; 95% CI: 1.02–1.3) and required transfer to a neonatal intensive care unit more often (aOR 1.16; 95% CI: 1.07–1.25) 35 . Some recent studies have posited an association between long-term cognitive child development and maternal anemia 37 38 . But these are observational studies which cannot confirm a definitive cause-and-effect relationship between iron deficiency and the above-listed complications.

Laboratory Diagnostics in Pregnancy

Screening is usually done after a pregnancy has been confirmed including the determination of hemoglobin, carried out for practical reasons in the context of a small blood count. Regular clinical controls and laboratory tests as mandated in the German Maternity Protection Guidelines are carried out during the further course of pregnancy 21 . International guidelines also recommend determining serum ferritin levels because of the high prevalence of iron deficiency in pregnancy and the efficacy of early treatment of iron deficiency. But because this has not been included in the German Maternity Protection Guidelines and could therefore involve additional costs for patients and as ferritin values can deteriorate over the course of pregnancy, patients in Germany should be informed about this 26 .

Laboratory tests may show microcytic (low MCV), hypochromic (low MCH) anemia (low hemoglobin, depending on the week of gestation, see Table 4 ) with signs of depleted iron stores (serum ferritin concentrations < 15–30 µg/dl) 5 6 . The current gold standard is based on the determination of serum ferritin to identify iron deficiency anemia in pregnancy 39 . But as ferritin is an acute phase reactant, high ferritin values may also be a sign of inflammation and ferritin levels may be slightly elevated even in normal pregnancies 40 41 . This means that normal ferritin values cannot absolutely preclude iron deficiency during pregnancy 5 6 39 . American and British guidelines have defined 30 µg/l as the lower threshold for ferritin 5 6 24 42 while the WHO and CDC consider 15 µg/l to be the lower threshold 43 44 . The recently published literature which includes guidelines and primary studies on iron interventions shows differences in the definition of the ferritin threshold for iron deficiency in pregnancy, with the lower threshold ranging from 6–60 μg/l 45 .

Table 4 Laboratory classification of iron deficiency according to the AWMF guideline. Data from 24 .

Phase	Latent iron deficiency	Clinically manifest iron deficiency with reduced total body iron stores	Clinically manifest iron deficiency with normal or elevated total body iron stores
CRP = C-reactive protein; MCV = mean corpuscular volume; MCH = mean corpuscular hemoglobin; sTfR = soluble transferrin receptor
Hemoglobin	normal	reduced	reduced
MCV	normal	reduced	reduced
MCH	normal	reduced	reduced
Reticulocytes	normal	reduced	reduced
Ferritin	reduced	reduced	normal or elevated
sTfR	normal	elevated	not elevated
CRP	normal	normal	elevated

Further investigation may show low serum iron levels, high total iron-binding capacity (soluble transferrin receptor, sTfR), and elevated free erythrocyte protoporphyrin levels 6 24 42 . The differential diagnoses based on blood count results are shown in Table 4 . The latter parameters are not routinely assessed in pregnancy 5 .

Patients should be informed that health insurance companies may not cover the costs of testing.

Iron deficiency can be divided into three phases depending on the results of the laboratory tests (see Table 4 ) 24 . Microcytosis may be present with iron deficiency anemia but tends to be a late finding of iron deficiency and may also be caused by thalassemia. An absence of microcytosis does not preclude the possibility of iron deficiency and the presence of microcytosis is not a confirmation 26 .

Recent data show that a complete blood count is insufficient to diagnose iron deficiency in pregnancy. It is important to identify iron deficiency in pregnancy because of the associated obstetric and pediatric disorders. Two new studies have illustrated the important role of ferritin in screening for iron deficiency, as anemia is only detected at a late stage. In a study of 345 women who had both a complete blood count (CBC) and a ferritin test in the first trimester of pregnancy, hemoglobin levels of < 11 g/dl or a mean corpuscular volume of < 80 fL only had a sensitivity of 30% for the identification of iron deficiency 46 . In another study of 629 pregnant women who were not anemic at their first prepartum appointment, 21% had a ferritin level of < 30 µg/l by the 15th week of gestation and 84% had a ferritin level of < 30 µg/l in week 33 of gestation 47 . These studies support our standard practice of screening for iron deficiency and using ferritin values in addition to blood count findings.

Prophylaxis Against Iron Deficiency in Pregnancy

Most guidelines recommend increasing iron intake by around 15 mg/day, i.e., to about 27–30 mg/d, an amount that can be achieved without difficulty with most food supplements 6 39 . The aim is to reduce feto-maternal morbidity/mortality 32 34 35 . Although taking regular prepartum iron supplements reduces the risk of maternal anemia, it is still not clear whether and to what extent feto-maternal complications can be avoided 48 49 . Iron supplementation is therefore recommended in American guidelines 6 22 , while British guidelines advise against it because of the lack of evidence 5 . The AWMF guideline (025/021, Iron Deficiency Anemia) recommends “ensuring sufficient iron status in the pregnant woman with iron deficiency to prevent iron deficiency in the infant” 24 . Iron supplementation, e.g., from dietary supplements, is a good compromise as the side effects are low. If a pregnant woman has oral iron intolerance, dietary supplements which do not contain iron can be prescribed. Parenteral administration (see below) may be suitable for such cases with iron deficiency.

Iron requirements increase in pregnancy due to the increase in maternal erythropoiesis, fetal growth, and the expected blood loss during the birth 26 . Pregnant women should therefore be advised at the start of pregnancy about the importance of a balanced diet.

Patients should be informed about the bioavailability of iron in different foods as well as inhibiting factors. Data on this are available in German on the website of the German Federal Institute for Risk Assessment ( Bundesinstitut für Risikobewertung ) and have been summarized here in Table 5 50 .

Table 5 Summary of the most important questions and answers on iron in foodstuffs by the German Federal Institute for Risk Assessment. Data from 50 .

Question	Answer
Plant-based or animal-based iron?	Heme iron (from animal source foods) is absorbed better than non-heme iron (from plant-based foods).
Factors which inhibit iron uptake	Plant-based foods: Chyle, such as phytates (in grains, nuts, pulses), polyphenols (in vegetables, tea, pulses), galactans, and calcium (in milk, cheese) Tannins in black tea, coffee or red wine, calcium salts and some medications. Animal source foods: the uptake of heme iron is not affected by other food components.
Factors which promote iron uptake	Plant-based foods: Vitamin C, organic acids, e.g., citric or lactic acid and the amino acids methionine and cysteine. Animal source foods: the uptake of heme iron is not affected by other nutritional components.
Iron-rich foodstuffs	Meat is the best source of iron. Plant-based foods: beetroot, pulses, whole-meal grain products, vegetables, fruits, as well as nuts, seeds, and soya.
Special requirements for vegetarians	High intake of vitamin C and organic acids (citric acid, lactic acid) with their food. As many grain products made from whole grain as possible (bread should be sourdough where possible) Soak or germinate grains and pulses. This reduces iron-inhibiting substances.

Treatment of Iron Deficiency

The standard treatment for uncomplicated iron deficiency consists of administering iron in higher doses than the usual substitution preparations for pregnant women or the amount of iron usually absorbed from a balanced diet. The choice between oral and intravenous iron administration depends on a number of factors 26 . The treatment plan is summarized in Fig. 1 .

Fig. 1.

Diagnosis of iron deficiency and iron deficiency therapy in pregnancy. If there are signs of infection (e.g., elevated CRP), reticulocytes and transferrin saturation must be determined (iron deficiency is present if TSAT < 20%). Algorithm for the diagnosis and treatment of iron deficiency. * This is subject to the proviso that CRP is normal and there is no acute phase reaction. TSAT/Ret Hb may be additionally determined to ensure that there is no inflammatory process. Substitution should be initiated if values are low (< 20–30%).

Oral iron substitution

The cost-effective treatment for pregnant women with iron deficiency, especially in the first trimester of pregnancy, is oral iron administration. Oral iron is safe, easily available and effective, if tolerated 5 6 24 31 39 .

Preparation

Preferred preparations are 6 24 :

• Iron (II) salts:

  • Iron (II) sulfate (ferrous sulfate)

  • Iron (II) fumarate (ferrous fumarate)

  • Ferrous (II) gluconate (ferrous gluconate)

• Iron (III) salts: are tolerated better and have fewer gastrointestinal side effects. Iron (III) preparations such as iron (III) hydroxide polymaltose may be used alternatively, especially when patients cannot tolerate iron (II) preparations.

The advantages of iron (III) salts are the better side-effects profile compared to iron (II) salts due to the slower iron release properties and the fact that preparations can be taken at mealtimes 39 51 .

Dosages

The recommended dosage of elemental iron to treat iron deficiency is currently 100–200 mg per day 5 42 .

Side effects

Some side effects have been reported in connection with oral iron intake 26 52 53 :

1. Gastrointestinal side effects are common (metallic taste, stomach irritation, nausea, diarrhea, and/or constipation).

2. These side effects may compromise adherence. There are reports that only 36–42% of patients take oral iron preparations regularly 39 .

Oral iron preparations could therefore be inadequate to treat cases with severe or persistent blood loss as they require regular intake over several months which may lead to higher overall costs compared to more expensive intravenous preparations.

The following conditions are associated with a poor or limited response to oral iron preparations 39 :

• Insufficient adherence

• Severe gastrointestinal side effects

• Limited resorption, (e.g., in cases with chronic inflammatory bowel disease)

• Postoperative phase (days or weeks)

• Increased release of hepcidin for a limited time, e.g., in cases with renal insufficiency

• Chronic inflammation (e.g., rheumatoid arthritis)

• Severe iron deficiency anemia or long-term iron deficiency

• Iron preparations with limited pharmacological properties

Review of the therapeutic effect

When pregnant women with moderate iron deficiency anemia receive appropriate iron therapy, reticulocytosis is observed 7–10 days after iron therapy, followed by an increase in hemoglobin in subsequent weeks 24 . A non-response to iron therapy should prompt further examinations and may be an indication for a wrong diagnosis, a coexisting disorder, malabsorption (sometimes caused by the use of gastro-resistant tablets or the simultaneous intake of antacids) or blood loss 6 .

Parenteral iron substitution

Intravenous iron substitution can be an alternative to oral iron substitution 5 6 24 .

Advantages of parenteral compared to oral iron substitution

Table 6 shows the advantages of parenteral therapy compared to oral iron therapy.

Table 6 Benefits of iron infusion compared to oral iron substitution based on 3 meta-analyses. Data from 54 55 56 .

Benefit
CI = confidence interval; MD = mean difference; pOR = pooled odds ratio; RR = relative risk; WMD = weighted mean difference
Higher hemoglobin levels at the time of giving birth (data from 54 )	WMD 0.66 g/dl (95% CI: 0.31–1.02 g/dl)
Fewer interactions with other medications (data from 54 )	RR 0.34% (95% CI: 0.20–0.57)
Higher birth weight (data from 54 )	WMD 58.25 g (95% CI: 5.57–110.94 g)
Higher probability of therapeutic success as evidenced by reaching the target hemoglobin value (data from 55 )	pOR 2.66 (95% CI: 1.71–4.15), p < 0.001
Higher hemoglobin level after 4 weeks (data from 55 )	pWMD 0.84 g/dl (95% CI: 0.59–1.09), p < 0.001;
Lower side-effects profile (data from 55 )	pooled OR 0.35 (95% CI: 0.18–0.67), p = 0.001
Higher hemoglobin levels 6 weeks postpartum (data from 56 )	MD 0.9 g/dl (95% CI: 0.4–1.3), p = 0.0003
Fewer gastrointestinal side effects (data from 56 )
Obstipation	OR 0.08 (95% CI: 0.03–0.21), p < 0.00001, I 2  = 27%
Dyspepsia	OR 0.07 (95% CI: 0.01–0.42), p < 0.004, I 2  = 0%

Indications

Various guidelines and citations have listed the following indications for parenteral iron infusion in pregnant women with iron deficiency or iron deficiency anemia 5 6 :

1. moderate to severe anemia

2. long established iron deficiency

3. side effects of oral iron substitution

4. limited adherence to oral treatment

5. ineffective oral iron substitution

6. iron deficiency anemia in the third trimester of pregnancy

7. anatomical anomalies such as a prior history of bariatric surgery, chronic bowel disease or other disorders which impair oral iron absorption

Contraindications

Most statement letters from medical societies, guidelines and scientific studies currently advise against parenteral iron infusion in the first trimester of pregnancy 5 6 39 .

Other contraindications include bacteremia, decompensated liver disease, and anaphylaxis or severe reactions to parenteral iron infusion 5 6 . A Red Hand Letter on this issue was published in Germany in 2013 but the Letter mainly focuses on older iron dextran preparations 57 . The conclusions of the Letter cannot be simply transferred to modern preparations.

An increased risk of anaphylaxis is present in the following cases 57 :

• Patients with a known allergy including a drug allergy

• Patients with immunological or inflammatory diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis)

• Patients with known severe asthma, eczema, or other atopic allergies

Ferric carboxymaltose and iron (III) isomaltose are currently preferred because they are associated with lower immunogenic reactions, although more recent studies have found that iron dextran preparations have similar safety profiles with respect to anaphylactic reactions. Ferric carboxymaltose appears to be less immunoreactive than iron (III) isomaltose 58 . Administration of a test dose is mandatory, especially before administering dextran-containing preparations.

Administration

Intravenous iron is administered without premedication in a monitored environment. The dosages and administration of specific products are summarized in Table 7 26 . According to the Red Hand Letter, selected patients with a prior history of allergic reactions and/or chronic inflammatory disease can be given a dose of a glucocorticoid or of prednisolone equivalents and histamine receptor blockers (H1 and H2) in addition to the iron infusion to reduce the probability of developing a reaction to the infusion.

Table 7 Properties of different IV iron formulations. Data from 26 59 . Pediatric data are only available for iron carboxymaltose and iron sucrose. Data from 39 .

Medication	Trade name	Iron concentration (mg/ml)	Maximum permitted dose per administration per week (mg)	Number of doses	Duration of administration (min)	Benefits	Side effects
* The total iron requirement can be calculated using the Ganzoni formula.
Iron (III) derisomaltose	Monofer	100	1500	1	15	Total dose administered in one infusion; no test dose required	Similar to other often used products
Ferric carboxymaltose	Ferinject or Injectafer	50	1000	2	15	Several clinical studies carried out in pregnant women	Rare. Possibly higher rates of of hypophosphatemia compared to other products.
Low molecular weight iron dextran	INFeD	50	1000	1	60	Total dose administered in one infusion; cost-effective	Rare. Similar safety profile to profiles of other standard products.
Ferric gluconate	Ferrlecit	12.5	125	8	60	Safe for persons with a prior history of dextran-induced anaphylaxis	Rare. Hypotension, hot flushes, headache
Iron sucrose	Venofer	20	200–300, 1000 in total	3–5	15	Safe for persons with a prior history of dextran-induced anaphylaxis	Rare. Diarrhea, headache, nausea, dizziness, hypotension
Ferumoxytol	Feraheme	30	510	2	15	Total dose is administered in 2 infusions	Diarrhea, headache, nausea, dizziness, hypotension

Procedure in the event of allergic reactions

Swift and appropriate action is essential if the patient suffers a reaction to the iron infusion. The steps to be followed in the event of an allergic reaction or side effects from the iron infusion are listed below 57 :

1. The following symptoms are among the most common side effects and must be watched for during administration of the infusion: headache, nausea, erythema, chest pain, dizziness or fainting, breathing difficulties and allergic reactions such as skin rash, itchiness, or swelling.

2. The infusion must be stopped immediately of any of the above-listed symptoms occur.

3. Medical approach:

   1. Administration of antihistamines, corticosteroids, or other medications to treat an allergic reaction.

   2. Monitor blood pressure, pulse, and other vital signs.

   3. Emergency treatment such as the administration of epinephrine (adrenalin) may be required for severely affected cases.

4. Subsequent monitoring: the patient should continue to be monitored even if the reactions were not severe to ensure that no further complications occur.

It is advisable to report all symptoms prior to the infusion to the treating physician, especially if the patient has known allergies or intolerances. If the patient experiences a reaction to the infusion, the physician will adjust any further procedures accordingly, for example, by prescribing a different form of iron treatment.

Preparations, dosages, mode of administration

Several studies in pregnant women have reported that parenteral iron substitution is safe and effective 59 60 61 62 . Dosages are similar to those for non-pregnant persons and the drugs appear to be well tolerated in pregnancy and are associated with higher levels of satisfaction 26 59 . The Ganzoni formula can be used to calculate iron requirements. This formula takes the patient’s actual hemoglobin level and calculates how much iron is needed to compensate for the existing iron deficit and to return hemoglobin levels to normal ranges 63 .

The Ganzoni formula:

Iron need (mg) = (target Hb – actual Hb) × body weight (kg) × 2.4 + storage iron

Explanation of variables:

• Target Hb: intended hemoglobin level in normal ranges (in g/dl). The target Hb is usually 15 g/dl.

• Actual Hb: the patient’s actual hemoglobin level.

• 2.4: conversion factor showing the amount of iron required per gram of hemoglobin.

• Storage iron: this figure represents the amount of iron additionally required to fill the body’s iron stores as iron is not just needed for hematopoiesis but also for iron stores. Iron stores in pregnant women are usually 500 mg.

A summary of well-known iron preparations is given in Table 7 .

AGG statement 1.

An Hb concentration of < 11 g/dl in the first trimester, < 10.5 g/dl in the second and third trimesters of pregnancy and < 10 g/dl postpartum is defined as prepartum and postpartum anemia.

AGG recommendation 1.

(Analogous to the German Maternity Protection Guideline)

The Hb level must be determined during the initial examination in pregnancy. If the concentration is normal at the initial examination, the Hb level must be determined at least every 4 weeks until the birth from week 20+0 of gestation (6th month), irrespective of the treatment of any complaints or symptoms of disease.

AGG recommendation 2.

(Analogous to the German Maternity Protection Guideline)

In principle, the Hb level must be determined in the first week after giving birth and “if necessary” six to eight weeks after giving birth during a general medical examination.

AGG statement 2.

Iron deficiency anemia is characterized by reduced hemoglobin levels due to depletion of the body’s iron reserves.

AGG recommendation 3.

Every iron deficiency (ferritin < 30 µg/l) must be treated, irrespective of the Hb value.

AGG recommendation 4.

Iron deficiency indicators (ferritin, poss. CRP, transferrin saturation) should be assessed at the same time as hemoglobin levels at the start and during pregnancy. This should ensure that iron deficiency is identified at an early stage and therapeutic measures can be initiated before iron deficiency anemia develops.

AGG recommendation 5.

At the start of pregnancy, the patient should be informed about an iron-rich diet as part of the general advice provided to her.

AGG statement 3.

According to current studies, prophylactic administration of oral iron when laboratory tests have not provided evidence of iron deficiency has no significant benefits.

AGG statement 4.

Iron salts are currently the preferred preparations for oral iron substitution.

AGG recommendation 6.

Women should be advised on the correct way to take oral iron preparations. Iron (II) preparations should be taken on an empty stomach together with water or a vitamin C source.

AGG recommendation 7.

No other medications, dietary supplements, or antacids should be taken at the same time.

AGG recommendation 8.

Anemia treatment should be initiated without delay by the treating medical specialist.

AGG statement 5.

An iron infusion should be prescribed without delay when required and the indication must be based on ferritin values, the severity of anemia, the success of oral iron therapy, maternal symptoms, and the interval till delivery.

AGG statement 6.

Iron (intravenous or oral) may be administered irrespective of any prior RBC transfusion.

AGG recommendation 9.

Oral iron substitution after a previous iron infusion should only be initiated after Hb and ferritin values have been determined.

AGG recommendation 10.

Every administered iron infusion must be entered in the patient’s Mutterpass (= maternity booklet issued to every pregnant woman in Germany).