Haematology and pregnancy

Published on 09/03/2015 by admin

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Chapter 50 Haematology and pregnancy

Amy Mellor

Haematologic changes in pregnancy

Plasma volume increases during pregnancy by up to 50%, and is maximal at around 34 weeks gestation. Red blood cell mass increases by only 17%, resulting in a relative haemodilution. This leads to a reduction in haemaglobin, haematocrit and red blood cell count, without changing the mean corpuscular volume or mean corpuscular haemaglobin concentration.

Iron requirements increase throughout pregnancy, with 60 mg/day of elemental iron needed during the second and third trimesters. Folate requirements increase from 50μg/day in the non-pregnant woman to around 400 μg/day. Pregnancy has minimal impact on vitamin B12 levels, as most adults have a 2–3-year store available.

Platelet count remains in the normal range for most pregnant women, though the average is slightly lower than in the non-pregnant population. The lower limit of normal is between 106 and 120 x109/L. Pregnancy is associated with a leucocytosis due to an increase in circulating neutrophils. The average white blood cell count in the second and third trimesters is between 9 and 15 x109/L.

Anaemia in pregnancy

Anaemia is a reduction in red cell mass relative to plasma volume, measured as the amount of haemaglobin (Hb) per litre of blood volume. Anaemia in pregnancy is defined as an Hb <110 g/L in the first and third trimesters, and <105 g/L in the second trimester. Around 20% of women are anaemic in the third trimester of pregnancy. Anaemia should be investigated and treated, as severe anaemia has been associated with miscarriage, preterm birth, intrauterine growth restriction (IUGR) and fetal death.

Causes of anaemia

• microcytic: iron deficiency, haemoglobinopathies, chronic disease
• normocytic: haemolysis, haemorrhage
• macrocytic: vitamin B12 or folate deficiency

Iron deficiency

• Iron requirements average around 1000 mg over the course of a normal pregnancy; 300 mg is required for the fetus and placenta, 500 mg for the expansion of maternal Hb, and 200 mg is lost through the gut, urine and skin.
• Iron deficiency is responsible for 75% of cases of anaemia in pregnancy.
• Prevalence may approach 50% of pregnancies.
• It results in a microcytic, hypochromic anaemia with low plasma iron, high iron-binding capacity and low serum ferritin.
• Treatment is with oral iron (e.g. 325 mg of ferrous sulfate) once to three times daily.
• Absorption is enhanced by administration of 500 mg of vitamin C.
• Side effects of iron include nausea, vomiting, abdominal pain, constipation and diarrhoea.
• Parenteral administration via intravenous or intramuscular routes is rarely required (malabsorption syndromes, severe anaemia with intolerance to oral preparations). Anaphylaxis occurs in 1%.

Folic acid deficiency

• This is much more common than vitamin B12 deficiency as a cause of megaloblastic anaemia. It occurs due to poor nutrition or decreased absorption.
• Findings include macrocytic (or normocytic), normochromic anaemia with hypersegmentation of leucocytes. Reticulocyte count is normal or low. White blood cell and platelet counts are often reduced.
• It is defined as red blood cell folate level <165 ng/mL or serum folate <2 μg/L. Vitamin B12 is within the normal range.
• Treatment is with oral folic acid, 1–5 mg/day.

Vitamin B12 deficiency

• Deficiency is rare except in strict vegans and women with intrinsic factor deficiency.
• It may manifest as neurological defects. It is critical that women with vitamin B12 deficiency not be treated with folic acid alone, as neuropathy may worsen.
• Treatment is with 1 mg of intramuscular vitamin B12 daily for 1 week, then weekly for 4 weeks.

Thalassaemia

Thalassaemia is an inherited defect in Hb, resulting from decreased globin chain production. Both alpha-thalassaemias and beta-thalassaemias result in defective synthesis of HbA. Alpha-chain synthesis is controlled by two pairs of genes on chromosome 16, and alpha-thalassaemia results from one or more gene deletions. Beta-chain synthesis is controlled by one pair of genes on chromosome 11, and beta-thalassaemia results mostly commonly from a point mutation.

Alpha-thalassaemia

• Alpha-thalassaemia is most common in South-East Asian populations.
• A single gene deletion is known as the ‘silent carrier’ state and is clinically undetectable.
• Two genes are deleted in alpha-thalassaemia minor, resulting in a mild hypochromic, microcytic anaemia.
• A deletion of three alpha genes results in HbH disease, the most severe form compatible with life. Abnormally high levels of HbH (β4) and Hb Barts (γ4) accumulate, resulting in severe haemolytic anaemia.
• In the homozygous state, all four genes are deleted. The fetus is unable to synthesize HbF or any adult Hb, resulting in high output cardiac failure, hydrops and fetal death. This is associated with significant maternal morbidity and mortality if pregnancy continues.

Beta-thalassaemia

• Beta-thalassaemia is autosomal-recessive and occurs most commonly in Mediterranean populations.
• Beta-thalassaemia minor or trait results in a variable clinical picture, depending on beta-chain production. If both parents are carriers, there is a 25% chance of a child affected with beta-thalassaemia major.
• In homozygous beta-thalassaemia or beta-thalassaemia major, unimpeded beta-chain production results in severe haemolytic anaemia. The fetus is protected by the production of HbF. This protection disappears after birth, with the infant becoming anaemic by 3–6 months of age.

Screening and treatment

• All pregnant women should have a full blood count with red cell indices as screening for thalassaemia. A mean corpuscular volume (MCV) <80 fL in the absence of iron deficiency necessitates further testing, as does a significant family history or high-risk ethnicity.
• Hb electrophoreisis identifies the presence of excessive or deficient amounts of globin chains. More than 3.5% of HbA2 (α2δ2) suggests beta-thalassaemia, while a normal amount of HbA2 with an MCV <80 fL suggests alpha-thalassaemia.
• The definitive diagnosis of alpha-thalassaemia requires DNA analysis.
• When an abnormality is identified, the father should be tested to determine the risk of disease to the fetus. Diagnosis can be made by analysis of fetal DNA obtained through chorionic villus sampling, amniocentesis or fetal blood sampling. Genetic counselling to discuss treatment options should follow. Preimplantation genetic diagnosis can also be used by at-risk couples.
• Pregnant women with thalassaemia require adequate iron and folate intake. Severe disease may necessitate regular blood transfusion.

Thrombocytopenia in pregnancy

Gestational thrombocytopenia

• Gestational thrombocytopenia occurs in 5% of women and accounts for more than 70% of cases of maternal thrombocytopenia.
• The platelet count rarely falls below 80 x109/L, and lies between 130 and 150 x109/L in the majority of cases.
• It is defined by the following criteria:

• mild, asymptomatic thrombocytopenia
• no history of thrombocytopenia outside of pregnancy
• occurs in the latter stages of pregnancy
• no association with fetal thrombocytopenia
• spontaneous resolution after delivery

• It may be a mild and transient manifestation of idiopathic thrombocytopenic purpura (ITP) (see below).
• There is no associated increased risk to the mother or fetus/neonate, so routine obstetric management should be employed.
• The maternal platelet count should be checked postnatally to ensure resolution.

Idiopathic thrombocytopenic purpura (ITP)

ITP is a syndrome in which antibody-bound platelets are destroyed by the reticuloendothelial system, predominantly in the spleen. The rate of destruction exceeds that of production in the bone marrow, resulting in thrombocytopenia. The diagnosis is one of exclusion, being no definitive clinical or laboratory parameters. The condition may be difficult to distinguish from gestational thrombocytopenia when first encountered in pregnancy.

ITP and pregnancy

• Prevalence of ITP is 1–5 per 10,000 pregnancies.
• The platelet count nadir occurs most commonly in the third trimester.
• The course of ITP is not changed by pregnancy. ITP impacts upon pregnancy by increasing the risk of maternal haemorrhage. Immunoglobulin G (IgG) antibodies can cross the placenta and cause thrombocytopenia in the fetus/neonate.

Treatment

• Treatment of the mother does not affect the fetal platelet count, so should be based on maternal need only.
• Asymptomatic women with platelets >30 x109/L do not require treatment until delivery is imminent.
• First-line treatment is with corticosteroids (prednisone 1 mg/kg/day). Once platelets are normal, the dose can be tapered until the lowest possible dose to maintain platelets >50 x109/L is reached.
• Intravenous immunoglobulin (IVIg) can be used in cases refractory to steroids, or in emergency situations.
• Splenectomy is the most effective treatment for severe symptomatic ITP, but should be avoided in pregnancy if possible. Indications may include ongoing bleeding or a platelet count <10 x109/L despite treatment with steroids or IVIg. When necessary, splenectomy is ideally performed in the second trimester.

Delivery

• Platelet counts of >50 and >80 x109/L are considered safe for vaginal delivery and caesarean section respectively.
• Local protocols vary, but a platelet count >80 x109/L is generally considered safe for regional anaesthesia.
• Labour and delivery is managed normally, with caesarean section reserved for routine obstetric indications. Fetal scalp electrodes, fetal blood sampling and vacuum extraction should be avoided in case of fetal thrombocytopenia.

Neonatal issues

• Around 10% of neonates born to mothers with ITP are thrombocytopenic at birth. The risk of neonatal intracranial haemorrhage during delivery is <1%.
• Cord blood should be tested for platelet count at delivery. If <20 x109/L or abnormal bleeding occurs, treatment is with IVIg.
• Neonatal platelet count reaches a nadir 2–5 days after delivery due to an increase in splenic activity. Levels should be rechecked at this time if abnormal at delivery or if clinical signs of thrombocytopenia are present.

Thrombotic thrombocytopenic purpura

• characterised by thrombocytopenia, microangiopathic haemolytic anaemia, fever and neurological and renal dysfunction
• caused by profound intravascular platelet aggregation, resulting in multiorgan ischaemia
• associated with absence of plasma enzyme ADAMTS13
• incidence in pregnancy of 1 in 25,000
• can be difficult to distinguish from severe pre-eclampsia/HELLP syndrome (i.e. H—haemolysis, EL—elevated liver enzymes and LP—low platelets); diagnosis is clinical
• can present any time in pregnancy or postpartum
• 33% chance of perinatal mortality
• unlike pre-eclampsia, delivery does not result in resolution of disease
• treatment is with plasmapheresis, which has increased the maternal survival rate to around 80%

Further reading

Bowden D.K. Screening for thalassaemia. Australian Prescriber. 2001;24:120-123.

British Committee for Standards in Haematology, General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. British Journal of Haematology. 2003;120:574-596.

George J.N., Knudtson E.J. Thrombocytopenia in pregnancy. Up To Date, January. 2009.

Kilpatrick S.J. Anemia and pregnancy. In: Creasy R., Resnik R., editors. Maternal–fetal medicine: principles and practice. 6th edn. Philadelphia: Saunders Elsevier; 2009:869-884.

Lockwood C.J., Silver R.M. Coagulation disorders in pregnancy. In: Creasy R., Resnik R., editors. Maternal–fetal medicine: principles and practice. 6th edn. Philadelphia: Saunders Elsevier; 2009:825-854.

Mueller B.U. Prenatal testing for the hemoglobinopathies and thalassemias. Up To Date, January. 2007.

Paidas M.J. Hematologic changes in pregnancy. Up To Date, January. 2009.

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