Iron deficiency is the most common micronutrient deficiency worldwide, contributing significantly to the global burden of disease.¹ Iron deficiency is poorly defined in the O&G setting, with variations in diagnostic thresholds, investigative frameworks and management strategies.^{2 3} Iron deficiency can occur with or without anaemia, and remains the most common cause of anaemia in pregnancy worldwide.⁴ Anaemia in pregnancy is defined by the World Health Organization as a haemoglobin (Hb) of <110g/L in the first 20 weeks, and <105g/L in the second 20 weeks of pregnancy.⁵ In this article, we aim to cover the essentials of iron deficiency for students and clinicians alike, with a focus on providing a framework for the investigation and management of iron deficiency in pregnancy and the early postpartum period.

Iron deficiency (ID) has important implications for both maternal and fetal health. For women of reproductive age, 14–22% have ID.⁶ Women with ID can experience impairment to muscle, immune and neurological function, and have lower reported quality of life.^{7 8} In Australia, 18% of pregnant people have iron deficiency anaemia (IDA), associated with a two- to threefold increase in iron requirements during pregnancy.^{9 10} This occurs largely due to an increase in maternal red cell volume and fetal erythropoiesis (see Figure 1).¹¹ Inadequate iron stores are associated with immediate neonatal complications including preterm birth, low birth weight, and reduced iron stores in the newborn.^{12 13} In the longer term, ID in pregnancy has been associated with neurodevelopmental concerns, including cognitive and behavioural difficulties.¹⁴ Anaemia additionally has an impact on lactation, including reduced milk supply and lower rates of breastfeeding at six months.^{15 16}

Figure 1. Iron requirements of pregnancy. Adapted from tables provided in reference 11.

Outside of pregnancy, heavy menstrual bleeding (HMB) is a common, under-recognised cause of ID in the O&G setting. It affects 25% of menstruating people, increasing in prevalence in the perimenopausal period.^{17 18}ID in patients with HMB may go untreated as clinicians are focused on managing the HMB in isolation.¹⁹ Typically women experience >400 menstruations in their lifetime, depending on contraceptive and family choices, which can have a significant impact on blood loss and iron requirements.²⁰ Historically, women experienced 100–150 menstruations over a lifetime due to increased parity; hence establishing amenorrhea to reduce overall iron losses may be a more physiological treatment option for those not wishing to conceive. It is important to recognise that neither HMB or pregnancy in isolation are likely to cause significant or refractory IDA, and further investigation is required in most cases.²¹ Guidance on the management of HMB can be found in the Australian Heavy Menstrual Bleeding Clinical Care Standard (2017).²²

Interpretation of the full blood examination (FBE) and ferritin in pregnancy are challenging due to the normal reduction in some parameters due to physiological haemodilution. These changes are most significant from 28–36 weeks, which is similar to the timeframe of greatest iron requirement.²³ It is important to recognise the difference between ID that has onset in later stages of pregnancy, where pregnancy factors are the likely cause, versus ID identified in the first trimester or non-pregnant state. We suggest checking ferritin levels as part of routine prenatal care. During preconception counselling, clinicians have an opportunity to discuss optimisation of iron status prior to pregnancy, and additionally identify and manage potential causes of ID. Of note, patients with ferritin levels >80ug/L in the first trimester are likely to have adequate iron stores for the remainder of their pregnancy.²⁴

ID can be confirmed in pregnancy on the basis of a serum ferritin level <30ug/L. Complete iron studies are not typically required and are significantly more expensive (see Table 1). Serum iron levels have significant diurnal variation and can reflect recent iron intake. The FBE will confirm anaemia, and the red cell indices (MCV and MCH) and blood film can help confirm ID (ie. microcytic, hypochromic red cells), and distinguish from thalassaemia trait.²⁵ Haemoglobinopathies, including thalassaemia and abnormal haemoglobins (eg. sickle cell disease), are increasing in prevalence in the Australian context due to immigration patterns.²⁶ Occasionally, IDA is confused with thalassaemia trait as both conditions present with microcytic, hypochromic red cells, and it is possible for these conditions to co-occur. Individuals with anaemia in pregnancy due to thalassaemia trait do not require iron supplementation, unless they have proven co-existing iron deficiency.²⁷

Table 1. Cost of pathological investigations as per MBS schedule.

Where ID is identified, particularly where refractory to iron replacement, potential causes should be carefully considered. A diet history is essential as approximately 40% of Australian women of reproductive age do not have adequate dietary iron intake.²⁸ In premenopausal women with ID, British guidelines (endorsed by the gastroenterological society of Australia) recommend screening for Coeliac disease (CD), as this cohort of patients represent 4% of ID cases and are typically refractory to oral iron supplementation.^{29 30 31} In Australia, the prevalence of CD is approximately 1.4%, with a significant portion undiagnosed. Dietary gluten must remain for accurate testing via serology.³² HLA gene testing on gluten-free patients may assist as 99.6% of the CD population have genes coding HLA-DQ2 or HLA-DQ8; thus, a negative test largely excludes the possibility of CD.³³ Identifying CD as a cause of ID in patients is important, as it has implications for fertility including recurrent miscarriage.³⁴ Those at risk of mixed nutritional deficiency should have B12 and folate levels assessed. This includes patients with restrictive intake, malabsorption or refugee background where there is emerging B12 and folate deficiency.^{35 36}

Recommended approach to managing iron deficiency in obstetric patients

Dietary sources are inadequate to replace iron stores for pregnant people with established ID, hence first-line therapy is oral iron supplementation. The Australian recommendations are to commence treatment where ferritin levels are <30ug/L.³⁷ Recent data indicates that second daily iron dosing may be superior to daily dosing, with fewer side effects, and a higher total and fractional iron absorption.³⁸  Whilst 100mg iron supplementation has a greater fractional absorption compared to 200mg, the total absorption is greater with 200mg, and as such would be advisable in IDA. Consideration should be given to lower doses (minimum 60mg elemental iron) for patients that are not anaemic.³⁹ We suggest a trial of iron for four weeks, followed by repeat FBE and ferritin level. An earlier FBE at two weeks may be prudent in the setting of significant anaemia in early pregnancy, concerns regarding ongoing blood loss and/or uncertainty about the diagnosis. Treatment compliance should be reviewed on an ongoing basis, with consideration being given to missed doses and optimising tolerability (see Table 2). In anaemic patients, failure of oral therapy should be demonstrated by a lack of Hb response after four weeks of therapy. Pregnant people with Hb <70g/L or those who are hemodynamically unstable require prompt review and urgent referral to a Haematologist. Lifeblood’s flowchart ‘Hb assessment and optimisation in pregnancy’ is a useful management guideline.⁴⁰

Table 2. Management options for side effects of oral iron therapy.

In later stages of pregnancy, where there are significant bleeding risks or where oral iron has been inadequate/not tolerated, intravenous (IV) iron replacement may be more appropriate. IV iron and its indications have been previously discussed in O&G Magazine along with potential side effects.⁴¹ Hypophosphatemia is a potential serious side effect of treatment with ferric carboxymaltose; however, is less well recognised compared to anaphylaxis, extravasation, and delayed serum sickness.⁴² Clinicians should be familiar with all potential side effects, and refer to their local guidelines prior to administering IV iron. The need for a blood transfusion should be considered based on clinical symptoms and a patient’s Hb level, and is generally appropriate in the postpartum setting where the Hb is <70g/L. When transfusion is indicated, a single red cell unit should be transfused with re-evaluation of the Hb and clinical status, unless clinically significant haemorrhage. The risk of transfusion and the potential for red cell alloimmunisation should be balanced against the potential of minimal benefit. Iron infusions may be given in addition to blood transfusion where additional iron is needed to support post pregnancy recovery, including for lactation. Of note, a single unit of red cells typically contains 250mg of iron. Lifeblood guidelines recommend oral iron therapy in the postpartum setting if Hb >80g/L in the non-transfused population for a minimum of six weeks.⁴³

For all pregnant people, and those trying to conceive, it is essential to discuss dietary contributions to iron deficiency. Early identification of patients at risk of ID is important to facilitate a preventative rather than curative strategy. Key risk factors for ID are outlined in Table 3, and particular attention should be paid to patients with multiple risk factors. These patients should be considered for referral to an accredited practising dietitian. Dietary iron is differentiated as haem and non-haem, with haem iron having the greatest bioavailability (see examples of each in Table 4). Consider dietary intake of substances that inhibit or promote iron absorption. Phytates, including unprocessed bran, polyphenols including tea and coffee, and calcium decrease the absorption of non-haem iron particularly and should be spaced apart.⁴⁴ In contrast, ascorbic acid found in foods such as citrus fruits, berries, broccoli, tomato and capsicum increases non-haem iron absorption, as does co-ingestion of haem iron foods. The possibility that an individual’s microbiome may lead to variations in iron absorption is the subject of ongoing research.

Table 3. Key factors to consider when screening patients at risk of iron deficiency.

Table 4. Examples of dietary sources of haem and non-haem iron.

Table 5. The dos and don’ts of iron deficiency in pregnancy.

Conclusions

ID is a treatable cause of anaemia in pregnancy. We suggest clinicians focus on optimising iron stores prenatally where possible by providing clear dietary advice, and commencing oral iron supplementation where serum ferritin levels are low. For those who are already pregnant, second daily oral iron should be considered to improve both absorption and tolerability. In cases where there is refractory iron deficiency, or perceived higher risks of anaemia, IV iron replacement may be more appropriate. In all cases, ongoing review for treatment compliance and monitoring for the common side effects of oral iron replacement should be undertaken. Screening for common causes of ID in premenopausal people, including HMB and CD, may help to improve not only a patient’s iron status, but also their pregnancy outcome and overall quality of life.

Our feature articles represent the views of our authors and do not necessarily represent the views of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG), who publish O&G Magazine. While we make every effort to ensure that the information we share is accurate, we welcome any comments, suggestions or correction of errors in our comments section below, or by emailing the editor at [email protected].

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