Anaemia in Pregnancy

The normal physiological change of an increase in plasma volume causes haemodilution in a pregnant woman. Although the red cell mass increases, plasma volume increases disproportionately, resulting in a lowering of the haemoglobin (Hb) to approximately 11.5 g/dL.¹

The National Institute for Health and Clinical Excellence (NICE) advises that women should be offered screening for anaemia at booking and at 28 weeks' gestation.² They define anaemia at booking as an Hb level <11.0 g/dL at booking; haemodilution will result in further drops during pregnancy and subsequent reduction in oxygen-carrying capacity. At 28 weeks the diagnostic level for anaemia is an Hb level of <10.5 g/dL.

Iron deficiency anaemia accounts for 85% of all cases of anaemia that are identified and is characterised by low mean cell volume. It is usually caused by nutritional deficiency or low iron stores resulting from previous pregnancy or previous heavy menstrual blood loss.¹

Less common causes

• Folic acid deficiency
• Sickle cell disease
• Haemoglobin SC
• Beta thalassaemia (more common in patients from South East Asia, Southern Europe and Africa)
• Vitamin B12 deficiency
• Chronic haemolysis (hereditary spherocytosis)
• Paroxysmal nocturnal haemoglobinuria
• Leukaemia
• Gastrointestinal bleeding
• Occult coeliac disease in pregnancy (recent evidence suggests a strong association with anaemia)³

Incidence: this is a common problem. It occurs in about a third of women in the third trimester.¹

Risk factors

The body of a healthy adult woman contains 3,500-4,500 mg iron.

• 75% is in red blood cells as haemoglobin (Hb).
• 20% is as ferritin in bone marrow and the reticulo-endothelial system.
• 5% is in muscles and enzyme systems.

Nearly all of the iron in red blood cells is recycled as they are replaced every 100-120 days. Normal loss in a nonpregnant woman is 1 mg iron daily from the death of epithelial cells plus an average of 1 mg loss for each day of menstruation.

• The average woman's diet in the developed world provides 12 mg iron daily, of which 14-20% is absorbed so a balance is maintained. However, in developing countries with a mainly vegetarian diet, iron levels are low because of the relative lack of iron in the diet and the ability of phytates in cereals to interfere with iron absorption. Also, in many countries, there is a very high level of infestation with hookworm, which causes considerable faecal blood loss.

This is often asymptomatic. However the following are most common:

• Fatigue
• Dyspnoea

The patient may also appear pale.

• Haemoglobin (Hb) ≤11.0 g/dL.
• Mean cell volume (MCV): if ≤76 fl then the probable cause is iron deficiency but, if lower than concomitant with other signs of anaemia and a raised red blood cell (RBC) count, then this suggests possible B2-thalassaemia (estimate HbA2 and use Hb electrophoresis).
• Normal MCV (76-96 fl) with low Hb is typical of pregnancy.
• Serum ferritin 10-50 μg/L needs monitoring and <10 μg/L requires treatment.

A Cochrane review in 2000 found twenty trials. Iron supplementation raised or maintained the serum ferritin above 10 μg/L. It resulted in a substantial reduction of women with a haemoglobin (Hb) level below 10 or 10.5 g/dL in late pregnancy. Iron supplementation, however, had no detectable effect on any substantive measures of either maternal or fetal outcome.⁴ One study, identified by the review, with the largest number of participants of selective versus routine supplementation, showed an increased likelihood of Caesarean section and postpartum blood transfusion but a lower perinatal mortality rate (up to 7 days after birth).

A further Cochrane review in 2009 confirmed that prenatal supplementation with iron or iron plus folic acid was effective in preventing anaemia and iron deficiency but again found no evidence of significant reduction in maternal or neonatal adverse clinical outcomes. Associated side-effects and particularly haemoconcentration (Hb>13 g/dL) were higher than patients on intermittent prophylaxis and the authors suggested a review of dosage regimes.⁵

One study did, however, find that iron supplementation during pregnancy was associated with significantly higher birthweight, independent of other pregnancy care factors, a mother's nutritional status, smoke exposure and a number of demographic and socioeconomic factors.⁶ Similar benefits were found in a randomised clinical trial (RCT) in the USA amongst women on low income.⁷

Iron deficiency

There is a lack of good quality trials.⁸

• Healthy patients on a normal mixed diet do not normally require iron supplements during the first half of pregnancy. Indeed there is some evidence that iron loading in women with normal initial iron levels may be associated with pre-eclampsia and gestational diabetes.¹¹
• However, women on a restricted diet (e.g. vegetarians, vegans) and women in developing countries need iron supplementation.
• One study found that there was no difference in clinical outcome between regular oral iron prophylaxis and intermittent intravenous treatment.¹²

• Inherited blood disorders with reduced or absent production of alpha or beta chains of the globin content of haemoglobin (Hb).
• Women who are carriers of thalassaemia, may be asymptomatic when not pregnant but more anaemic than usual during pregnancy.
• MCV ≤ 80 fl requires investigation, with an HbA2 ≥ 3.5% being positive for B2-thalassaemia.
• In these cases, the father of the child should be tested and the couple offered genetic counselling.
• Chorionic villus sampling in the first quarter of pregnancy and fetal cord blood sampling under ultrasound guidance in the second quarter can be used to detect B2-thalassaemia major, and termination of pregnancy offered.

• Genetic defect causes production of abnormal haemoglobin (Hb) with a red blood cell (RBC) life of ≤15 days.
  In a sickle cell crisis, RBC destruction causes severe haemolytic anaemia and bone pain. The most common form is haemoglobin S but this mainly affects people from East and West Africa. Where suspected, women should receive folate of 15 mg per day with frequent Hb counts.
• If Hb falls below 6 g/dL, a transfusion is needed.
• Use of regular prophylactic transfusions reduced the number of transfusions required but was associated with more pain crises.¹³
• Erythrocytapheresis transfusions may be beneficial in women who are in the third trimester of pregnancy.¹⁴
• May give prophylactic antibiotics during childbirth and afterwards.
  If a crisis occurs, give heparin, measure Hb every 2 hours and, if it falls ≥2 g, give exchange transfusion. One study reported significant adverse effects of transfusion in pregnancy patients with multiple red cell antibodies and advised using such treatment with caution.¹⁵ Other measures tried in sickle crisis include steroids, fluid replacement therapy and oxygen but there is a lack of RCTs.¹⁶

Complications of sickle cell anaemia in pregnancy

• Spontaneous abortion can occur in up to 25% of women affected by sickle cell anaemia with 15% approximate perinatal mortality also often associated with preterm delivery and low birth weight (30% ≤2500 g).
• Stillbirth rates of 8-10% have been seen and thorough antenatal fetal testing is required to assess growth, including ultrasound of the umbilical artery for systolic/diastolic ratio. Frequent urinary tract infections are common and require prompt treatment.
• Pregnancy-associated hypertension is also more common and may affect almost 1/3 of pregnancies.

Folate supplements of 1 mg per day minimum should be given from confirmation of pregnancy, although iron supplements are not needed unless serum iron and ferritin levels are reduced.

If given routinely, iron supplementation causes iron overload leading to haemochromatosis.

Women with anaemia have a mortality rate 3-5 times higher than normal and a stillbirth rate 6 times higher than normal.

1. Blackwell S; Merck Manual 2008.
2. Antenatal care: routine care for the healthy pregnant woman, NICE Clinical Guideline (March 2008)
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4. Pena-Rosas JP, Viteri FE; Effects of routine oral iron supplementation with or without folic acid for women during pregnancy. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004736. [abstract]
5. Pena-Rosas JP, Viteri FE; Effects and safety of preventive oral iron or iron+folic acid supplementation for Cochrane Database Syst Rev. 2009 Oct 7;(4):CD004736. [abstract]
6. Mishra V, Thapa S, Retherford RD, et al; Effect of iron supplementation during pregnancy on birthweight: evidence from Zimbabwe.; Food Nutr Bull. 2005 Dec;26(4):338-47. [abstract]
7. Siega-Riz AM, Hartzema AG, Turnbull C, et al; The effects of prophylactic iron given in prenatal supplements on iron status and birth outcomes: a randomized controlled trial.; Am J Obstet Gynecol. 2006 Feb;194(2):512-9. [abstract]
8. Reveiz L, Gyte GM, Cuervo LG; Treatments for iron-deficiency anaemia in pregnancy. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD003094. [abstract]
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11. Weinberg ED; Are iron supplements appropriate for iron replete pregnant women? Med Hypotheses. 2009 Nov;73(5):714-5. Epub 2009 May 31. [abstract]
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13. Mahomed K; Prophylactic versus selective blood transfusion for sickle cell anaemia during pregnancy; (Cochrane Review). In: The Cochrane Library. Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. [abstract]
14. Sun Y, Bauer MD, Lu W; Identification of the active site serine of penicillin-binding protein 2a from J Mass Spectrom. 1998 Oct;33(10):1009-16. [abstract]
15. Proudfit CL, Atta E, Doyle NM; Hemolytic transfusion reaction after preoperative prophylactic blood transfusion Obstet Gynecol. 2007 Aug;110(2 Pt 2):471-4. [abstract]
16. Marti-Carvajal AJ, Pena-Marti GE, Comunian-Carrasco G, et al; Interventions for treating painful sickle cell crisis during pregnancy. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD006786. [abstract]