Introduction

Pyruvate kinase deficiency (PKD) is the most commonly experienced enzyme-related glycolytic defect, leading to red blood cell hemolysis. Pyruvate kinase is an important enzyme in the metabolism of red blood cells and without it, cellular energy efficiency and longevity decrease. As there is a reduction in blood cells which carry oxygen throughout the body, PKD usually results in hemolytic anaemia, and presentations of symptoms can begin from the neonatal stage to adulthood. Other symptoms include jaundice, splenomegaly, gallstones and iron overload.^1,2

Pyruvate kinase deficiency (PKD) is a genetic disorder that mainly follows an autosomal recessive inheritance pattern, meaning that the affected individual (homozygous carriers) inherits two copies of the defective gene from each parent. Pyruvate kinase expression is regulated by the PK-LR gene, which is found on chromosome 1q21, and to date, around 300 PKD-causing mutations have been discovered.^1,3

PDK may also be inherited in an autosomal dominant manner, where only one copy of the mutated gene is required to showcase the condition and the individuals would be heterozygous carriers. Homozygous carriers can experience chronic hemolysis from an early age and require transfusions, while heterozygous carriers are typically unaffected clinically but under stressful conditions, hemolysis can happen.⁴

To date, there has been a small number of reported cases of pregnancy complicated by PKD so it is quite rare. From these cases, we understand that there are a few risks involved but many birth deliveries were successful.^5,6,7

Pathophysiology of pyruvate kinase deficiency in pregnancy

Role of pyruvate kinase in red blood cell metabolism

Red blood cell metabolism depends entirely on glycolysis to produce energy due to their lack of mitochondria. In the process of glycolysis, pyruvate kinase converts phosphoenolpyruvate to pyruvate, which is a step that yields 50% of the red blood cells' ATP. Notably, mostly young red blood cells are affected by PKD, but the result is a dramatic change in the function, metabolism and lifespan of red blood cells. PKD usually manifests with enzyme levels less than 25%.^1,8

Hemolytic anaemia and its impact on oxygen delivery

In hemolytic anaemia, red blood cells die at a faster rate than normal which is about 120 days. Because of this, the red blood cell count becomes distinctly low as the bone marrow is not able to compensate the replacement of red blood cells. Oxygen delivery throughout the body is therefore reduced which can cause numerous complications. In PKD, the clinical presentations vary depending on the levels of hemolysis and the resultant anaemia. In some cases, symptoms may be mild, leading to delayed diagnosis until adulthood and often requiring little or no treatment. Severe cases may require lifelong blood transfusions.²

Increased physiological demands of pregnancy on the maternal blood supply

During pregnancy, the pregnant parent’s body undergoes significant physiological changes to support the developing fetus and provide it with oxygen and nutrients. These changes include increased blood volume, elevated cardiac output, and higher oxygen demands. PKD can therefore aggravate any pre-existing anaemia, affecting both fetal health and development, maternal health, driving the need for careful medical management.⁹

Maternal and fetal risks associated with PKD

PKD impacts both the fetuses and pregnant parents due to pre-existing or resultant anaemia, pregnancy complications and possible issues from frequent blood transfusions.^1,2,4

Maternal risks

• Severe anaemia → weakness and fatigue, tachycardia, heart strain, shortness of breath, headaches, pale skin
• Increased risk of jaundice and gallstones
• Pre-eclampsia
• Need for more frequent transfusions
• Hemosiderosis
  

Fetal risks

• Intrauterine growth restriction (IUGR)
• Fetal anaemia → hydrops fetalis in severe cases
• Birth asphyxia
• Hyperbilirubinemia and jaundice
• Skin oedema
• Preterm birth or low birth weight
• Rapid shallow breathing (tachypnea)
• Pale skin (pallor)

Anaemia management strategies

Monitoring

Regular fetal and maternal surveillance must be conducted to detect any signs of maternal cardiovascular dysfunction and fetal growth retardation. Routine blood tests can be done on the pregnant parent to check the levels of haemoglobin (Hb), hematocrit (Hct), haptoglobin, reticulocytes and bilirubin. Checking the levels of serum ferritin and transferrin saturation can differentiate between iron deficiency and iron overload following usual transfusions.^1,2,5

Ultrasounds are used to monitor the growth and development of the fetus, blood flow and the structure of the placenta.^2,4,5 

Nutritional support and supplementation

PKD increases the demand for key nutrients that are critical for red blood cell (RBC) production. Folic acid is a common recommendation for infants, children, and adults with PKD as it helps the body make red blood cells and even prevents fetal malformations.^1,3 

Medication 

Mitapivat is suggested for pyruvate kinase deficiency and hemolytic anaemia. However, its use during pregnancy has not been specified.³

Transfusions 

Transfusion helps to improve anaemia but its use must be warranted based on each patient’s case and is normally reserved for symptomatic anaemia. A haemoglobin level of less than 8 g/dL is an indicator of a transfusion. Iron overload and alloimmunisation can occur because of repeated transfusions but monitoring, increasing intervals and blood type match can reduce the likelihood of each respectively. Other than severe cases where lifelong transfusions are needed, anaemia in children can ameliorate so transfusions are not needed as adults.^1,3,4 

For a foetus with a low red blood cell count, an intrauterine fetal transfusion may be required before birth. An exchange transfusion can be done in neonates with jaundice, where their blood gets replaced with a donor’s blood.³

Phototherapy

This is used for newborns with jaundice to help break down the excess bilirubin in their blood.³

Iron chelation

There may be too much iron in the body because of PKD or frequent blood transfusions and, hemosiderosis is strongly possible. Iron chelation uses drugs like desferrioxamine that bind to iron and help to remove the excess amount. This treatment is normally stopped before pregnancy due to potential teratogenic effects.^1,3,4

Surgery 

A splenectomy (spleen removal) and a cholecystectomy (gallbladder removal) are the surgical options that may be necessary based on complications of PKD.^1,3,4

Multidisciplinary care approach

The care and management of pyruvate kinase deficiency (PKD) require close collaboration between a haematologist and an obstetrician.¹ 

Summary 

Pyruvate kinase deficiency (PKD) is a rare genetic disorder affecting red blood cell metabolism, leading to hemolytic anaemia and associated complications such as jaundice, splenomegaly, gallstones, and iron overload. Inheritance involveseither an autosomal recessive or, less commonly, an autosomal dominant pattern. While cases of pregnancy complicated by PKD are rare, successful deliveries have been reported. The disease’s impact on red blood cells results in reduced oxygen transport, which can be further exacerbated by the increased physiological demands of pregnancy, potentially leading to maternal and fetal complications.

Maternal risks include severe anaemia, fatigue, tachycardia, increased transfusion needs, jaundice, gallstones, and a heightened risk of preeclampsia. Fetal risks include intrauterine growth restriction (IUGR), fetal anaemia, hydrops fetalis, preterm birth, low birth weight, and neonatal jaundice. Managing anaemia during pregnancy requires routine monitoring of haemoglobin levels, fetal growth assessments via ultrasound, and differentiation between iron deficiency and iron overload. Nutritional support, particularly folic acid supplementation, is crucial for red blood cell production, while iron supplementation must be carefully managed to avoid overload.

Blood transfusions are used when haemoglobin levels drop below 8 g/dL, though they carry risks such as iron overload and alloimmunization. In severe fetal anaemia, intrauterine transfusion may be necessary. Neonatal jaundice is often treated with phototherapy or exchange transfusion if severe. Iron chelation therapy, typically used to manage excess iron from frequent transfusions, is usually avoided during pregnancy due to teratogenic risks. Surgical interventions like splenectomy or cholecystectomy may be needed in some cases. Given the complexity of PKD in pregnancy, a multidisciplinary approach involving haematologists, obstetricians, and maternal-fetal medicine specialists is essential to optimise outcomes for both mother and baby.