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  • Nathan Riley, MD

Obgyno Wino Podcast Episode 56 - Hemoglobinopathies in Pregnancy

Updated: Jan 19

“The meanings of life aren’t inherited. What is inherited is the mandate to make meanings of life by how we live. The endings of life give life’s meanings a chance to show. The beginning of the end of our order, our way, is now in view. This isn’t punishment, any more than dying is a punishment for being born.” - Stephen Jenkinson



2018 Sainte Marie Corbieres from Domaine Faillenc


PB#78 - Published January 2007 (Reaffirmed in 2018)


Five Pearls

1. Sickle cell trait (heterozygous for the mutation) is generally asymptomatic; sickle cell disease can have severe consequence

2. Sickle cell disorders are more common among individuals of African descent, whereas the thalassemias are more common among individuals of Southeast Asian and Mediterranean descent.

3. Alpha thalassemia results from deletion of any number of the four genes that code for the alpha chain. The more deletions, the worse the presentation.

4. Beta thalassemia results from mutation of one or both of the genes that code for the beta chain. Severity of disease is determined by presence and degree of functionality within intact genes.

5. Sickle cell disease is a risk factor for preterm delivery, IUFD, IUGR, etc., therefore, antepartum fetal surveillance is recommended


Structure of hemoglobin

- four polypeptide chains + heme

- the six chain types: alpha (α), beta (β), gamma (γ), delta (δ), epsilon (ε), and zeta (ζ)

- adult hemoglobin consists of two alpha chains + either two β-chains (hemoglobin A), two γ-drains (hemoglobin F), or two δ-chains (hemoglobin A₂)

- hemoglobin F predominates in the developing fetus from 12 -24 wga, after which hemoglobin A begins to increase

- the genes that code for α-chains are on the short arm of chromosome 16

- the genes that code for β-chains are on the short arm of chromosome 11


Sickle cell disease - genetics

- hemoglobin A (HbA) forms abnormally, resulting in "hemoglobin S"

- this is due to a single nucleotide substitution in a gene that codes for the β-chain

- if this mutation occurs on just one copy of the gene (heterozygous), the patient is said to have "sickle cell trait"(generally still large amounts of happy, healthy HbA) --> generally asymptomatic

- the severe form of the disease, "sickle cell anemia" is seen in individuals homozygous for hemoglobin S (HbS/HbS); there may also be trace amounts of HbF and HbA₂

- sickle cell disorders can also be seen in individuals who have one HbS allele with an otherwise non-sickle β-chain allele, like HbS/β-thalassemia

- HbC results from a different mutation in the same gene that is mutated in HbS

- all of these conditions can result in varying expressions of sickle cell phenomena

- most common in people of African origin (1-in-12)

- 1-in-300 African American newborns have some form of sickle cell disorder; 1-in-600 have sickle cell disease

- HgS is also found in high frequency among Greeks, Italians, Turks, Arabs, and Southern Iranians, and Asian Indians


Sickle cell disease - clinical presentation

- low oxygen tension in the environment causing a sickling of the red blood cells

- this distortion makes it hard for RBCs to pass through the tiny capillaries

- this can cause ischemic pain (acute chest syndrome) in the chest and lead to organ damage and "death by a thousand vaso-occlusions"

- adults with SS disease are functionally asplenic

- acute chest syndrome can occur during sickling episodes is often associated with fever and the appearance of infiltrate on chest x-ray; can lead to hypoxemia and acidosis

- pain crises can be precipitated by extreme heat/cold, heavy physical exertion, dehydration, and stress

- hydroxyurea can help reduce the frequency of painful crises in non-pregnant women (not recommended in pregnant women)


Alpha thalassemia

- there are four copies of the α-chain gene, two on each short arm of chromosome 16

- deletion of only one gene (α-/αα) is clinically unrecognizable

- deletion of two or more of these genes results in alpha thalassemia

Two copies missing

- alpha-thalassemia trait, a mild microcytic anemia

- two options: cis or trans deletions

- cis (--/αα) = two genes on the same allele deleted; offspring are at risk for Hb Bart's (--/α-) or Hb H disease (--/--); more common in Southeast Asians

- trans (α-/α-) = one gene on each allele deleted; more common in Africans


Three copies missing

- Hb H disease (--/α-)

- mild to moderate hemolytic anemia


Four copies missing

- Hb Bart's disease (--/--)

- hydrops fetalis, intrauterine death, and preeclampsia


- alpha thalassemia can be inherited along with sickle cell trait/disease because the latter only involves β-chains

- symptoms are generally less severe in sickle cell trait or sickle cell disease when alpha thalassemia is present concurrently

- mutations in the α-chain genes can also occur, rendering the genes dysfunctional even though there are present


Beta-thalassemia

- one gene on each allele that codes for the β-chains (instead of four as we saw with the α-chains)

- one or both genes mutated

- heterozygous individuals have beta-thalassemia minor (mild anemia)

- homozygous individuals have beta-thalassemia major (Cooley's anemia) or a milder form called thalassemia intermedia

- Cooley's: severe anemia resulting in extramedullary erythropoiesis (spleen takes over); also associated with delayed sexual development and poor growth

- high levels of HbF compensate partially for the absence of HbA, but death usually occurs if periodic blood transfusions are not initiated at an early age

- thalassemia intermedia presents as varying amounts of HbA due to varying amounts of β-chain production

- if no β-chains are produced (both genes are problematic and absent), no HbA produced (bad news)




Who should be screened for hemoglobinopathies?

- individuals of African, Southeast Asian, and Mediterranean ancestry

- if both parents are carriers, genetic counseling should be offered





- solubility tests like Sickledex are not great as primary screening because they can miss many hemoglobin gene abnormalities that could affect the fetus (e.g. A patient with β-thalassemia minor trait has a baby with another patient who has β-thalassemia minor trait. While they may both be asymptomatic, they may produce offspring who has β-thalassemia major.)

- thalassemias result in microcytic anemia (low MCV) on RBC indices

- if patient is anemia but MCV is normal, iron deficiency anemia has been excluded, and the hemoglobin electrophoresis is not consistent with β-thalassemia trait (ie, there is no elevation of Hb A2 or Hb F), then DNA-based testing should be used to detect α-globin gene deletions characteristic of α-thalassemia



credit: www.learnhaem.com

MCV --> macrocytic versus microcytic

Ferritin --> protein that stores iron in tissues

Transferrin --> protein that carries iron

TIBC --> reflects the available binding sites on transferrin


What to do if a couple is at high risk of having a fetus with a hemoglobinopathy?

- prenatal diagnostic testing for sickle cell disease is widely available

- prenatal testing for α- and β-thalassemias is also available if the specific mutations are known in both parents

- genetic material is collected by CVS (10-12 wga) or amniocentesis (>15 wga)

- pre-implantation genetic testing is also an option for patients pursuing IVF


How should pregnancy be managed in patients with sickle cell disease?

- pregnancy is a risk for patients with sickle cell disease, the magnitude depends on genotype and severity of anemia

- homozygous patients (HbS/HbS) have increased risk for preterm labor, SAB, IUFD, PROM, antepartum hospitalization, IUGR, and postpartum maternal infection

- increase daily folic acid from 400 mg to 4mg given continual overturning of RBCs

- routine c-section is not recommended

- epidural anesthesia is fine as long as you pay close attention to avoid hypotension and hypoxemia

- hydroxyurea is not recommended in pregnancy


Management of pain crisis in pregnancy

- opioids

- O2 if necessary based on pulse oximetry (<95%)

- don't become myopic: if your patient has chest pain and hypoxemia, consider any other etiologies or precipitating factors! (pulmonary embolism, dehydration, severe anemia, infection, etc.)


Transfusions

- may be beneficial to some but not all patients

- risks include viral infection, iron overload, and alloimmunization

- the idea is that as a sickle cell patient loses blood, they are losing both HgA and HgS in equal parts, so their oxygen carrying capacity will be even worse than a woman without sickle cell, as the remaining blood won't be all HgA; transfusing will increase the proportion of HgA

- indications include hemorrhage, concealed abruption, sepsis, worsening anemia or acute chest syndrome (anything that could compromise their oxygen carrying capacity either from sickling or loss of whole blood)

- prophylactic transfusion before delivery is not recommended


Is fetal antepartum surveillance recommended?

- Yes. Generally start at 32 wga

- why? remember that sickle cell disease is a risk factor for preterm delivery, IUFD, IUGR, etc.


How should pregnancy be managed in patients with thalassemia?

α-thalassemia

- no major difference in patients with α-thalassemias, even in the rare event of pregnancy in a patient with HbH disease (apart from mild to moderate anemia)


β-thalassemia

- β-thalassemia minor is no big deal, but is associated with higher risk for IUGR and oligohydramnios

- pregnancy used to be rare in β-thalassemia major due to delayed sexual development, and then it became challenged by fertility caused by hypothalamic dysfunction resulting from hemosiderin deposition by macrophages in the hypothalamus; but then! iron chelation was developed, and now results are promising for pregnancy (only recommended if patient has been receiving ongoing transfusions for many years and in patients with normal cardiac function)

- in β-thal major pregnancy, keep Hgb >10 g/dL through transfusions, but don't do iron chelation therapy

- monitor fetal growth; if growth is compromised, fetal surveillance is recommended

- c-section is indicated only for normal obstetric indications

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