14.1 Iron Deficiency Anaemia

EXPLANATION OF CONDITION

Iron deficiency is the commonest cause of anaemia amongst women of child-bearing age and in particular pregnant women (51%) worldwide².

Symptoms vary from mild tiredness to potentially hazardous palpitations, breathlessness or symptoms of high output cardiac failure. In humans, mineral iron is present in all cells and carries oxygen to the tissues from the lungs in the form of haemoglobin (Hb), facilitates oxygen use in muscles as myoglobin, and also in cytochromes within cells for enzyme reactions in tissues.

Women have approximately 2.3 g total body iron of which most (80%) is found in the red blood cell mass as haemoglobin (Hb). Total body iron is determined by intake, loss and storage of this mineral. Any iron not in use is stored as the soluble protein complex ferritin, present primarily in the liver, bone marrow, spleen and skeletal muscle. Normal absorption mechanisms in the gastrointestinal system of the body are required to maintain the balance between functional iron (Hb) and stored iron levels. The body is able to absorb 1–2 mg iron daily from the diet, with the aid of absorption enhancers in the diet and a satisfactory rate of red blood cell production. The main factor controlling iron absorption is the amount of iron stored in the body and the type of iron in one’s diet³.

Anaemia results in a reduction in the oxygen-carrying capacity of the blood. Iron deficiency anaemia is defined by a low serum ferritin concentration of <30 micrograms/l and haemoglobin <11.0, 10.5 and 10.5 g/dl in the first, second and third trimesters respectively^2,4,5. Red blood cells are microcytic (small) and hypochromic (pale) on microscopic examination (see Figures 14.1.1 and 14.1.2). Iron deficiency anaemia arises from an increase in iron requirements or inadequate iron absorption.

Figure 14.1.1 The development of iron deficiency anaemia. Reticuloendothelial (macrophage) stores are lost completely before anaemia develops (Hoffbrand, 2011). MCH, mean corpuscular haemoglobin. MCV, mean corpuscular volume.

This figure is downloadable from the book companion website at www.wiley.com/go/robson

Figure 14.1.2 The peripheral blood film in severe iron deficiency anaemia. The cells are microlytic (small) and hypochromic (pale) with occasional target cells (Hoffbrand, 2011).

This figure is downloadable from the book companion website at www.wiley.com/go/robson

Iron requirements are increased to deal with:

• Growth
  
• Menstruation
  
• Blood loss/donation
  
• Pregnancy
  
• Haemolytic disorders
  
• Drugs that cause haemolysis (e.g. antiretrovirals)
  
• Genitourinary tract infections
  
• Hookworm infestation

Anaemia caused by inadequate iron absorption occurs from:

• Diet low in haem iron
  
• Malabsorption
  
• Gastric surgery
  
• Malaria infection resulting in poor use of dietary iron

The amount of functional iron in the body and the concentration of the iron-containing protein Hb in circulating red blood cells are measured by two simple blood tests, Hb and haematocrit and ferritin concentration.

Haemoglobin Concentration and Haematocrit

Haemoglobin and haematocrit (HCT) are both late indicators of anaemia. Haematocrit indicates the proportion of whole blood occupied by the red blood cells, and falls only after the Hb concentration has also fallen. Mean cell volume (MCV) is also important as it falls in iron deficiency, but needs further testing to distinguish it from other causes of microcytosis (see Section 14.6 Thalassaemia).

Serum Ferritin Concentration

Serum ferritin concentration is an early indicator of the status of iron stores and the most specific indicator of depleted iron stores routinely available. A serum ferritin concentration of ≤30 micrograms/l confirms iron deficiency among women who test positive for anaemia on the basis of Hb concentration or haematocrit⁶. Serum ferritin can be raised in infection and may need repeating for a definitive diagnosis of iron deficiency. Caution is advised in interpretation of normal levels in pregnancy since a low normal level (30–50 micrograms/l) may still indicate iron deficiency. Use of other tests should be confirmed with local laboratories.

COMPLICATIONS

Iron deficiency can interfere with vital body functions leading to morbidity and mortality including:

• Palpitations
  
• Tiredness
  
• Irritability
  
• Depression
  
• Breathlessness
  
• Poor memory
  
• Muscle aches
  
• Poor appetite
  
• Cardiac failure
  
• Increased vulnerability if small amounts of blood are lost

NON-PREGNANCY TREATMENT AND CARE

Encourage iron-rich foods in the diet and treat with iron supplementation 60–120 mg/day for 4 weeks⁷. If no response to treatment, investigate using other tests: reticulocyte count and serum ferritin concentration. Conditions such as sickle cell trait or thalassaemia minor in women of African, Mediterranean or Southeast Asian ancestry cause mild anaemia unresponsive to iron therapy. The normal Hb level for this group can be as low as 10 g/dl. However, the lowest normal Hb in healthy non-pregnant women is defined as 12.0 g/dl². Iron absorption can be increased in a vegetarian diet by careful planning of meals to include other sources of iron and enhancers of iron absorption⁸.

PRE-CONCEPTION ISSUES AND CARE

A non-pregnant woman of reproductive age has an average iron requirement of 1.3 mg/day. This increases when pregnant by an extra requirement of 3.0 mg/day mainly for increases in maternal red cell mass, placental and fetal growth, blood loss at delivery, physiological intestinal blood loss and menstruating loss over the child-bearing years. A further iron requirement of 6–8  mg/day occurs after 32 weeks’ gestation.

Provide culture-specific dietary advice with information on iron body stores and avoidance of absorption inhibitors, e.g. tea, bread and chapatti. A reliable system for investigation of anaemia and monitoring of response to treatment is paramount².

Pregnancy Issues

• Prevention of anaemia by early recognition of iron deficiency in those at risk is paramount
  
• Anaemia in the third trimester increases the risk of poor recovery from blood loss at birth, as well as tachycardia, shortness of breath and maternal exhaustion
  
• Parenteral iron, intravenous or intramuscular using the z-track technique (Figure 14.1.3), is used in cases of non-compliance or malabsorption, but contraindicated in cases of allergy
  
• Be aware of potential skin staining when administering iron, if the z-track technique is not used (see Figure 14.1.4)
  
• A rise in reticulocyte counts and Hb of 0.8 g/dl/week occurs 5–10 days after starting oral iron treatment⁹; the increase in Hb is similar for parenteral iron¹⁰
  
• Randomised controlled trials have been inconclusive on the effect of universal iron supplementation in pregnancy versus adverse maternal and fetal outcomes¹¹
  
• Ensuring normal Hb and adequate iron stores is part of promoting higher likelihood of normality

Figure 14.1.3 Z-track technique for administration of iron to prevent iron staining, as in Figure 14.1.4.

This figure is downloadable from the book companion website at www.wiley.com/go/robson

Figure 14.1.4 Iron-stained skin of a pregnant woman (© C. Oppenheimer).

This figure is downloadable from the book companion website at www.wiley.com/go/robson

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Medical Management and Care

• Assess cause of anaemia by adequate dietary and medical history and appropriate testing. See algorithm for management (Figure 14.1.5)
  
• Prescribe ferrous sulfate 200 mg 2–3 times daily, or a proprietary combined iron and folate tablet with a higher elemental iron content until Hb normalises and thereafter to replenish stores. Advise to take iron preparations on ‘an empty stomach’ with orange or apple juice
  
• If required, im or iv dose is calculated according to iron deficit and body weight
  
• Administer iron dextran or sucrose iv in 0.9% sodium chloride infusion as total or divided doses
  
• Consider blood transfusion only if severe anaemia in a situation with a high risk of blood loss (blood products and transfusion are outlined in Appendix 14.1.1)

Figure 14.1.5 Protocol* for community management of anaemia in pregnancy.

* Clinical protocol used for University Hospitals of Leicester, adapted and used with permission. This figure is downloadable from the book companion website at www.wiley.com/go/robson

Midwifery Management and Care

• Severe/chronically anaemic women to be booked at consultant unit
  
• Encourage consumption of iron-rich foods with orange juice to enhance iron absorption, and provide information on nutrition in pregnancy¹²
  
• Be aware that inhibitors of iron absorption include polyphenols (in certain vegetables), tannins (in tea), phytates (in bran) and calcium (in dairy products)
  
• Screen all women at booking visit and at 28 weeks’ gestation¹³ and ensure the result is acted upon
  
• Women with known anaemia need testing at each antenatal visit
  
• Ensure anaphylactic emergency treatment is available during parenteral iron administration
  
• Treat selectively with iron^1,7 and folate preparations¹⁴ and if needed reduce gastrointestinal complaints¹⁵

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14.2 Megaloblastic Anaemia

EXPLANATION OF CONDITION

Megaloblastic anaemia is an acquired condition characterised by macrocytosis – the MCV of the red blood cells (erythrocytes) is above the normal range of 80–95 femtolitres (fl). It is called megaloblastic because the developing red blood cells in the bone marrow are larger than normal and have immature nuclei. A full blood count may reveal an increased number of immature red blood cells (megaloblasts) in the blood, reduced platelets and haemoglobin levels unresponsive to treatment with iron supplements, as well as the raised MCV.

Megaloblastic anaemia is usually caused by deficiency of folic acid or vitamin B₁₂ (cyanocobalamin), but more rarely may be drug-induced or associated with myelodysplastic syndrome. It is also possible to see a non-megaloblastic macrocytic picture in liver disease, hypothyroidism and alcoholism.

In pregnancy a relative macrocytosis is common and normal.

Folate deficiency is associated with nutritional and socio-economic status² and may cause complications in pregnancy. Megaloblastic anaemia develops insidiously following:

• Poor dietary folate intake
  
• Excessive alcohol consumption^3,4
  
• Increased cell turnover due to:
  
  
  
  • pregnancy (demands of mother and fetus)
    
  • chronic haemolytic anaemia (e.g. sickle cell anaemia, hereditary spherocytosis)
    
  • chronic inflammatory conditions
  
  
• Renal loss
  
  
  
  • chronic renal failure
    
  • dialysis
  
  
• Malabsorption disorders, e.g. gluten-induced enteropathy (coeliac disease)
  
• Drug-induced
  
  
  
  • some anticonvulsants
    
  • sulfasalazine
    
  • methotrexate

Mainly stored in the liver, cellular folates help to build DNA and protein in all tissues. This includes those required for growth of the fetus, placenta, maternal red cell mass and uterine development in pregnancy. Folate is found in beans, rice and green vegetables and some food stuffs have folic acid supplemented.

Vitamin B₁₂ deficiency is caused by veganism or poor quality diet, pernicious anaemia, gastrectomy or ileal resection (as occurs with Crohn’s disease).

COMPLICATIONS

The consequences of true megaloblastic anaemia include:

• Pallor and jaundice
  
• Increasingly severe anaemia
  
• Heart failure
  
• Pancytopenia (low white cell and platelet counts)

Other complications of vitamin B₁₂ deficiency include:

• Neuropathy involving peripheral nerves and spinal cord
  
• Psychiatric disturbances
  
• Visual disturbance
  
• Fetal neural tube defects

Both deficiencies can cause epithelial disturbance, e.g. the smooth painful tongue (glossitis), and, if low serum homocysteine levels are present (part of this metabolic pathway), arterial obstruction and venous thrombosis.

NON-PREGNANCY TREATMENT AND CARE

Advise a diet rich in vitamin B₁₂ and folate, such as cheese, cereals, leafy green vegetables, fortified cereals, fruit and egg yolks. The recommended daily intake of folate is 3 micrograms/kg of body weight for non-pregnant and non-lactating women.

A daily intake of 5 mg folic acid is recommended for women with hereditary haemolytic disorders, epileptics on anticonvulsants and women of reproductive age with a family history of neural tube defects who are planning a pregnancy^4–6.

PRE-CONCEPTION ISSUES AND CARE

Estimated dietary requirements of folates in pregnancy are 100–600 micrograms/day with an average daily intake of 237 micrograms/day^7,8.

An association exists between periconceptual folic acid deficiency and neural tube defect, cleft lip and cleft palate in the fetus⁵, hence the recommended folic acid supplementation of 400 micrograms/day for the first 3 months pre-conceptually and throughout the first trimester^4,9.

A daily oral supplementation of 5 mg folic acid is recommended for those with a previously affected fetus and family history of neural tube defects and to epileptics^4,10.

Other factors such as genetic factors, pre-conceptual diabetes and first trimester hyperglycaemia and drugs such as sodium valproate used for epilepsy also contribute to the development of megaloblastic anaemia. Also relevant are the increased demands of pregnancy, multiple pregnancy, grand multiparity or frequent pregnancies³ which may exacerbate other factors or in extreme cases precipitate megaloblastic anaemia.

14.3 Disseminated Intravascular Coagulation

EXPLANATION OF CONDITION

Disseminated intravascular coagulation (DIC), also known as consumptive coagulopathy, is an acquired disorder of haemostasis, which often heralds the onset of multi-organ failure².

Underlying causes³:

• Infection – especially Escherichia coli, Neisseria meningitidis, Streptococcus pneumoniae and malaria
  
• Cancer – especially lungs, pancreas³, gynaecological⁴
  
• Trauma, burns, surgery and snake bite⁵
  
• Pregnancy – especially:
  
  
  
  • placental abruption
    
  • major haemorrhage
    
  • pre-eclampsia
    
  • retained dead fetus or placenta
    
  • amniotic fluid embolism³

Endothelial damage arising from one of the above results in thromboplastins being released from the damaged cells⁶, triggering the extrinsic pathway to initiate a coagulation cascade³. With DIC, the tissue damage is so severe that blood clotting occurs at the original site and throughout the vascular tree, hence the term disseminated intravascular coagulation. This process consumes large quantities of fibrinogen, thrombocytes (platelets) and clotting factors V and VIII³. The micro-thrombi produced occlude some small blood vessels, resulting in ischaemic damage (dead tissue) to body organs⁶. The damaged tissue releases more thromboplastins and a vicious cycle develops⁶.

Eventually all the clotting factors and platelets are consumed and bleeding results⁵. The patient is in the ironic situation of having both widespread blood clotting and a clotting deficiency. Bleeding occurs, petechiae develop in the skin and, if untreated, major haemorrhage can result^7,8.

DIC can be subclinical, only detected on laboratory investigations, or may present with massive haemorrhage^7,9 Bleeding is observed at vascular access points, GI tract, nose, genitourinary tract, intravenous cannulation sites and wounds⁸. Investigations² reveal:

• Increase in prothrombin time
  
• Increase in partial thromboplastin time
  
• Increase in fibrin degradation products
  
• Decrease in platelets
  
• Decrease in fibrinogen

COMPLICATIONS

• Damaged kidneys – renal failure and anuria⁶
  
• Damaged liver – liver failure and jaundice⁶
  
• Damaged lungs – dyspnoea and cyanosis⁶
  
• Brain damage – convulsions or coma⁶
  
• Retinal damage – damaged sight or blindness⁶
  
• Pituitary damage – Sheehan’s syndrome⁶
  
• Major haemorrhage – hypovolaemia then death

NON-PREGNANCY TREATMENT AND CARE

• DIC is essentially a clinical diagnosis; laboratory tests confirm the diagnosis and guide replacement of blood component⁷
  
• Coagulation screen comprising:
  
  
  
  • whole blood film
    
  • FBC, especially platelet count⁸
    
  • fibrinogen degradation products/D-dimers^5,8,9
    
  • prothrombin time (normal 10–14 seconds)⁸
    
  • thrombin time (normal 1–15 seconds)⁸
    
  • partial thromboplastin time (normal 35–45 seconds)
    
  • fibrinogen levels (normal 2.5–4 g/l)⁸
  
  
• Insert indwelling urinary catheter, ideally with a measuring chamber, and monitor urinary output
  
• Strict monitoring and recording of fluid balance
  
• Repeat the coagulation screen as clinically indicated
  
• Central venous pressure (CVP) monitoring¹⁰
  
• IVI fresh frozen plasma², which contains all the clotting factors¹¹
  
• IVI platelets⁶
  
• IVI packed cells (blood)^6,11
  
• Identify and treat the underlying cause if possible²
  
• Institute high dependency care, transfer if necessary
  
• Respiratory support if indicated¹²
  
• Intravenous antibiotics for suspected septicaemia²
  
• Correct exacerbating factors, especially:
  
  
  
  • dehydration
    
  • acidosis
    
  • renal failure
    
  • hypoxia²
  
  
• Analgesia¹²
  
• Anticoagulation with heparin rarely used and requires supervision by a haematologist^5,9
  
• Concentrates of blood factors (antithrombins and/or protein C) are effective in the non-pregnant state
  
• Recombinant activated protein C is used for sepsis in non-pregnant patients⁹
  
• Steroids may be used for precipitating factors

PRE-CONCEPTION ISSUES AND CARE

If a woman had DIC in a previous pregnancy, the recurrence risk will be that of the precipitating cause. Follow-up and de-briefing of any woman who had acute DIC is essential.

Women with chronic DIC may be at high risk of pregnancy complications and need to be assessed and advised by a haematologist before cessation of contraception.

14.4 Von Willebrand’s Disease and Other Bleeding Disorders

EXPLANATION OF CONDITION

A familial haematological disorder, characterised by bleeding, was described in 1926 by von Willebrand in Finland³, hence the term von Willebrand’s disease (VWD). This is a condition in which there is either a defect, or deficiency, of the von Willebrand factor (VWF), a carrier protein for clotting factor VIII⁴. There are three⁵ basic types:

VWD is the most common inherited bleeding disorder in pregnancy⁶, and is inherited as an autosomal dominant condition. Hence, children of either gender may inherit the clotting deficiency⁷. However, women are more likely to present with symptomatic VWD due to menstruation and childbearing⁴. There are no ethnic differences⁸.

Non-pregnant patients usually present as young adults with excess bleeding, in the form of:

• Epistaxis (nosebleeds)^1,5
  
• Menorrhagia (heavy and prolonged periods)^1,2,5,9
  
• Bleeding after dental extraction or surgery^1,5
  
• Bruising^1,5

Screening tests⁸ entail:

• FBC – usually normal but a mild thrombocytopenia may occur in Type 2 patients⁸
  
• Serum ferritin
  
• Clotting screen – prothrombin time is normal, but the activated partial thromboplastin time may be prolonged
  
• Bleeding time – usually prolonged, but may be normal in mild forms of VWD⁸
  
• Platelet aggregation test – measures platelet efficiency⁸
  
• Von Willebrand factor antigen, factor VIII, Ristocetin cofactor (RiCof)

Other Bleeding Disorders

• Factor XI deficiency – similar problems to VWD Type 3
  
• Haemophilia A and B – female carriers can have low levels, and an associated bleeding risk
  
  
  
  • Bleeding history and non-pregnant levels of factor VIII or IX should be identified

COMPLICATIONS

• Haemorrhage (severity varies from VWD Type 1 to 3)
  
• Joint bleeding and pain (in VWD Type 3)
  
• Anaemia and fatigue
  
• Pregnancy problems

NON-PREGNANCY TREATMENT AND CARE

Common Treatments

• Combined oral contraceptive pill (COCP) – to increase levels of factor VIII and von Willebrand factor, reduce menstrual blood volume, and prevent pregnancy⁸
  
• Iron supplementation – if clinical condition necessitates
  
• Vaccination against hepatitis A and B⁵
  
• Tranexamic acid (to inhibit bleeding) – slows the breakdown of blood clots; tablet form, or syrup for children¹
  
• Desmopressin – a synthetic hormone (not a blood product) that enables VWF to be released into the blood circulation
  
  
  
  • given iv at specialist centres¹
    
  • nasal spray is available
  
  
• Clotting factor concentrate – derived from human plasma, and used to treat severe cases of VWD¹

Advice¹

• Avoid aspirin
  
• Carry ‘green card’ from haemophilia centre at all times in case of accident or emergency
  
• For children, parents should inform the school
  
• Caution with certain holiday destinations, and a ‘travel pack’ of drugs may have to be issued
  
• Encourage exercise, but discourage contact sports
  
• Maintain a healthy lifestyle with an iron-rich diet

PRE-CONCEPTION ISSUES AND CARE

Women with a history of heavy menstrual bleeding since menarche, and a family history suggestive of a coagulation disorder, should be screened for coagulation disorders¹⁰.

Von Willebrand’s Disease

• There is no evidence that fertility is impaired⁴
  
• Pre-conception care aims to optimise maternal health
  
• The risk of a mother with Type 1 transmitting the condition to her child is 50% but only 33% of these will be clinically affected⁷
  
• Opportunity for pre-natal diagnosis for women with Type 3, whose genetic mutation is identifiable⁷
  
• If parents already have a child with Type 3, the chance of each subsequent child being affected is 25%⁷

Haemophilia

• Women with relevant family histories are assessed for carrier status and counselled over reproductive options⁷

Factor XI Deficiency

• Pre-natal diagnosis should be discussed if the woman’s condition is severe⁷

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