Introduction

Macrocytosis is described as abnormal cell size of red blood cells, its prevalence estimates ranging from 1.7% to 3.6%. Its significance tends to be underestimated by physicians, as about 60% of the affected patients do not present with associated anaemia unless other accompanying abnormalities are present. 

While macrocytosis can often be benign, it may also indicate underlying nutritional deficiencies, such as vitamin B12 or folate, or more serious haematological disorders. Addressing macrocytosis in pregnancy promptly and effectively is vital for ensuring both maternal and foetal health. This article aims to explore the causes, diagnosis, and management strategies for macrocytosis in pregnancy, highlighting the importance of timely intervention and comprehensive prenatal care.

Basics of macrocytosis

Macrocytosis refers to when the red blood cells(RBCs) end up being larger than normal. Macrocytosis can be detected if the MCV value on your blood test is higher than 100fl (femtolitres). This can be detected by completing a CBC test.¹

While macrocytosis itself does not cause complications, its identification can indicate an underlying disease. Therefore, in the appropriate clinical context, mean corpuscular volume (MCV) values above the normal range or significantly different from a patient’s baseline should prompt further clinical and laboratory evaluations to determine the cause of macrocytosis^.2

Macrocytosis can be divided into

Macrocytosis without anaemia

Normal variant

• Large red blood cells (RBCs) are not always due to disease.
• Newborns and infants typically have larger RBCs.
• Pregnancy can also cause larger RBCs without any obvious cause.

Genetic predisposition

• Macrocytosis without anaemia may run in families, suggesting a genetic factor.
• No treatment or further investigation is usually needed if no clinical problems are present.

Macrocytosis associated with anaemia

Macrocytic Anaemia

• Characterised by large RBCs in the blood
• Detected by automated blood cell counters and confirmed with a blood smear review.

Categories

1. Megaloblastic anaemia: Due to issues like vitamin B12 or folate deficiency.
2. Non Megaloblastic anaemia: Linked to other causes.

Macrocytosis in pregnancy

Macrocytosis impacts approximately 2% to 4% of individuals, with 60% of them developing anaemia. This type of anaemia is an important aspect of the overall spectrum of anaemia, although its prevalence and causative factors may vary among different populations. As macrocytosis becomes more prevalent in the general population, it is anticipated that the occurrence of macrocytic anaemia in pregnant patients will also increase.^{4 ,5}

​​During pregnancy, the size of red blood cells usually stays the same, but there's a small increase in a measurement called mean corpuscular volume (MCV), about 4 fl more in individuals assigned female at birth (ASFB) with enough iron. This increase is highest at around 30-35 weeks of pregnancy and doesn't mean there's a lack of vitamins B12 or folate. The body makes more red blood cells during pregnancy to meet the extra needs, and this can make the cells a bit bigger. However, MCV doesn't change a lot during pregnancy. If haemoglobin levels go below 9.5 g/dL and MCV is less than 84 fl, it might show there's not enough iron or something else going on.⁵

Causes of macrocytosis in pregnancy

 Megaloblastic anaemia: Due to issues like vitamin B12 or folate deficiency.

 Non Megaloblastic anaemia: Linked to other causes.

Causes

• Nutritional deficiencies: Deficiency of vitamin B12 and or folate.
• Drugs: Certain medications can cause macrocytosis, such as those used to treat cancer, seizures and autoimmune disorders, Common medications not already mentioned that may induce macrocytosis include the following: valproic acid, hydroxyurea, allopurinol, and reverse-transcriptase inhibitors such as zidovudine, stavudine, and lamivudine.³
• Bone marrow disorders: Conditions like myelodysplasia and leukaemia.
• Chronic illnesses: Various long-term diseases.
• Vitamin deficiencies:
  • Vitamin B12/folate deficiency:
    • Causes large, immature RBCs due to problems with DNA synthesis.
    • Leads to ineffective erythropoiesis (RBC production).
    • Marrow becomes hypercellular with increased myeloid cells and dominant erythroid elements.
    • Erythroblasts appear large, oval, with an immature, lacy nucleus.
  • Megaloblastic Anaemia: Indicates a deficiency or lack of vitamin B12 and or folate.
  • Other Hematologic Disorders: Similar marrow abnormalities can occur in diseases like myelodysplasia and leukaemia. Careful bone marrow examination is needed to differentiate between conditions.

Symptoms and diagnosis

• Macrocytosis is typically detected by a high mean corpuscular volume (MCV) value on a complete blood count (CBC), indicating larger red blood cells. Symptoms vary based on the underlying cause, such as weakness and pale skin in macrocytic anaemia or diarrhoea and cognitive issues in nutritional deficiencies. 
• The diagnostic process involves a methodical approach, including a thorough patient history, physical examination, and key lab tests like CBC, peripheral blood smear, and reticulocyte count. Sometimes, an examination of bone marrow may be required.
• Identifying the root cause of macrocytosis can be complicated, especially when conditions like thalassemia trait, iron deficiency, or other nutritional deficiencies coincide with vitamin B12 or folate deficiency. In these scenarios, the blood smear may reveal a mix of small and large red blood cells with an elevated distribution width.^1,2

Diagnostic tests and procedures

The diagnostic process involves a methodical approach, including a thorough patient history, physical examination, and key lab tests.

• Complete blood count (CBC)-A CBC (complete blood count): It is a typical blood test used to check your health by examining the full blood cells and their count. Of them, mean corpuscular volume (MCV), indicates the average size of the red blood cells. If the MCV is above 100 femtoliters (fL), it is indicated to have macrocytosis.¹
• Peripheral blood smear test: It is a method healthcare providers use to examine your blood cells. Unlike other blood tests analysed by a machine, providers look at your blood cells under a microscope.
• Serum vitamin B12 and folate levels: Vitamin B12 levels can appear normal or high in various conditions, including myeloproliferative disorders, liver disease, transcobalamin II deficiency, intestinal bacterial overgrowth, and recent administration. Factors like folate deficiency, pregnancy, oral contraceptive use, and multiple myeloma can also affect serum folate levels.
• Thyroid function tests: Anaemia linked to hypothyroidism is typically normocytic or macrocytic. Since thyroid hormone promotes erythropoietin production and influences blood cell formation, low thyroid hormone levels can cause anaemia. A thyroid function test can help diagnose this condition.⁶

Complications and risks

• Anaemia with large red blood cells (macrocytosis)
• Increased risk of recurrent pregnancy losses
• Higher likelihood of pre-eclampsia
• Greater risk of preterm delivery
• One study found higher neonatal deaths in babies born to mothers with macrocytosis (29.7%) than to those with microcytic anaemia (13.4%)
• Potential for neural tube defects.⁷

Management 

Treat macrocytic anaemia by treating the underlying causes and supplementing either with folate or vitamin B12.

• Take folic acid tablets (1 mg to 5 mg daily) and ensure a folate-rich diet (fortified cereals, leafy vegetables) in your food.
• Pregnant women and patients on folate supplements should have them on a daily basis to prevent deficiencies.
• Ensure vitamin B12 deficiency is treated, as resolving folate deficiency alone won’t address neurological symptoms.
• It is recommended to take 1 milligram of oral vitamin B12 daily for one month, followed by a reduced dose of 125 to 250 micrograms daily. Alternatively, administer 1000 micrograms of vitamin B12 intramuscularly weekly for four weeks, then switch to a monthly schedule. Intramuscular administration is preferred for pernicious anaemia altered digestion or gut biology.
• Consider folate supplementation (400 micrograms to 1 g/day) alongside vitamin B12 treatment.
• Expect reticulocyte improvement in 1 to 2 weeks and anaemia resolution in 4 to 8 weeks.
• Regular monitoring of RBC indices or rechecking folate/vitamin B12 levels during active treatment is unnecessary, though annual complete blood counts may be checked for long-term vitamin B12 therapy.
• Neurological symptoms from vitamin B12 deficiency may take longer to subside.
• Macrocytosis related to alcohol use improves with abstinence.
• Treating the underlying conditions will improve other non-megaloblastic anaemias.⁴

Prevention

Regular prenatal check-ups are essential to ensure the health of both the mother and the developing foetus. These appointments enable early detection and management of abnormalities, including macrocytosis, promoting a healthier pregnancy outcome.

Identifying and addressing nutritional deficiencies early can prevent macrocytosis. Pregnant women should be screened for folate, vitamin B12, and iron deficiencies, and provided with appropriate supplements.

Educating pregnant women on the importance of a balanced diet rich in essential nutrients, such as folate and vitamin B12, can help prevent macrocytosis. Highlighting the risks associated with nutritional deficiencies and the benefits of proper supplementation can encourage adherence to dietary recommendations and supplement regimens.

Summary

Macrocytosis in pregnancy is a condition where RBCs are larger than normal, often due to nutritional deficiencies or underlying health issues. While it can be benign, it requires attention to prevent complications. Early diagnosis and treatment are crucial for maternal and foetal health. Healthcare providers should emphasise the importance of understanding macrocytosis, recognizing symptoms, and seeking timely medical advice. Besides diagnosis, treatment and management of macrocytosis during pregnancy, prevention also plays an important role as it promotes healthier pregnancy outcomes.

FAQs

1. Can pregnancy cause macrocytosis?

During pregnancy, in newborns and infants, and in some families, macrocytosis can be a normal variation without anaemia, possibly due to genetics. However, certain factors like cold agglutinins, high blood sugar, increased white blood cells, elevated reticulocytes, and delayed sample handling can falsely increase the MCV value.⁸

2. Is MCV high during pregnancy?

During pregnancy, the mean corpuscular volume (MCV) increases slightly by about 4 femtoliters (fl) in women with enough iron. This increase is highest around 30 to 35 weeks of pregnancy.⁵

3. Can folic acid cause macrocytosis?

Yes, folic acid can lead to macrocytosis as it is a vitamin B that aids in the production of red blood cells.