Thalassemia is an inherited blood disorder primarily affecting haemoglobin production. This genetic illness is widespread around the world, specifically among those of medium and high risk residing around the Mediterranean, Southeast Asia, and the Middle East. There are several forms of the disease, the most common of which are beta-thalassemia and alpha-thalassemia. The treatment and safety measures required for the early detection of thalassemia during pregnancy must be enhanced to reduce the number of cases and enhance the quality of life of the people.¹

What is thalassemia?

Thalassemia is caused by a mutation in the genes that encode haemoglobin, the protein in red blood cells that carries oxygen.

• Alpha-thalassemia: This form of thalassemia is caused by mutations in the alpha-globin gene, and its severity depends on the number of affected alpha-globin genes (4 in total)
• Beta-thalassemia: Caused by mutations in the beta-globin gene. This variety is predominantly more severe, with symptoms ranging step by step from thalassemia minor (moderate) to thalassemia major (serious), the latter requiring regular blood transfusions to survive⁶

Both types of thalassemia can be avoided by prenatal diagnosis, genetic counselling, and reproductive technologies (e.g., preimplantation genetic diagnosis, PGD).²

Global overview of thalassemia

Thalassemia is a significant public health problem in many parts of the world. In fact, according to the World Health Organisation (WHO), more than 300,000 infants are born with severe thalassemia worldwide each year. In countries like India, Pakistan, and Bangladesh, where consanguinity is common, thalassemia has a significantly raised prevalence. Since the global prevalence of thalassemia requires efficient screening programs and management strategies to reduce the birth of affected babies, the story of early diagnosis and management becomes crucially important.

Prenatal diagnosis of thalassemia

Prenatal diagnosis refers to detecting thalassemia in the fetus before birth. Diagnosing at an early stage helps parents make informed reproductive decisions and allows for the early start of treatment if needed.³

For prenatal diagnosis of thalassemia

Carrier screening

Carrier screening is the first step in the prenatal diagnosis of thalassemia. A blood test identifies people with a gene mutation for thalassemia, but they do not have the disease. This is critical as carriers may pass the gene on to their offspring. Carrier screening for individuals with a family history of Thalassemia or belonging to high-risk ethnic group populations is recommended. Carrier screening assays screen the alpha- and beta-globin genes for mutations. If both parents are carriers of the gene responsible for thalassemia, prenatal diagnostic tests can be performed to determine if their fetus will develop thalassemia.⁴

Prenatal diagnosis 

Once carriers are identified, the fetus can be diagnosed with thalassemia using one of a few methods. The main technique used is:

Chorionic villus sampling (CVS)

It occurs between the 10th and 13th weeks of gestation. We take a small sample of the placenta for analysis. It is used for rapid diagnosis and applies to genetic diagnosis of Thalassaemia.

Amniocentesis

This procedure typically happens later, after the 15th week of pregnancy. We take a small amount of amniotic fluid and test for thalassemia mutations. 

Non-invasive prenatal testing (NIPT)

A novel technique for analysing the fetal genome in maternal blood. It can also detect some genetic diseases, such as thalassemia, without the risk of invasive tests such as amniocentesis or chorionic villus sampling. These prenatal diagnostic tests offer high specificity, permitting families to decide on reproductive choices when a fetus is diagnosed with thalassemia major.⁵

Non-invasive prenatal diagnosis (NIPD)

NIPD was recently established and is a useful alternative to invasive techniques such as chorionic villi sampling (CVS) and amniocentesis.

NIPT consists of the analysis of fetal DNA circulating in the maternal blood. This process is more common because it is not at risk of miscarriage, unlike intrusive tests. NIPT is typically used to screen for genetic issues associated with conditions such as Down syndrome. However, researchers can now detect genetic problems related to thalassemia - and they have found that diagnosis has become faster and more accurate with the use of a newer technique that detects both sickle-cell and thalassemia. 

Thalassemia prevention 

Thalassemia screening and selecting proper reproductive options can help decrease the incidence of the disease.⁵

Genetic counseling

It is one of the key preventive measures for thalassemia. For couples who are at risk of having a child with thalassemia, counselling helps to understand their chances of transmission, available screening tests, and options for prenatal diagnosis. Genetic counsellors consider options for starting a family, including in vitro fertilisation (IVF) with preimplantation genetic diagnosis (PGD). Both parents can learn whether they are carriers and learn about the hereditary risk involved by undergoing hereditary counselling, which helps parents make informed and confident family planning decisions.⁸ 

Preimplantation genetic diagnosis (PGD)

This, with in vitro fertilisation (IVF), enables the choice of embryos free from thalassemia. In IVF, eggs from a woman are fertilised outside the body, and a small number of cells from each embryo are analysed genetically. She inserts only embryos that lack thalassemia mutations into the mother's uterus, greatly lowering the risk that the couple's child will have the condition. PGD is particularly beneficial in cases where both partners are carriers of thalassemia and want to avoid passing the disease to their children. It offers a preventive approach with higher success rates than the alternative.

Sperm and ova donation

Couples who are both carriers for thalassemia and wish to prevent the risk of having an affected child may wish to use sperm or egg donors who are thalassemia non-carriers.
This method involves choosing donor gametes (egg or sperm) from genetically unrelated, Thalassemia non-carrier individuals. This prevents disease transmission, although it is impossible for all couples for ethical, financial, or cultural reasons. 

Neonatal screening

Newborn Screening for thalassemia plays an important role in the early diagnosis of affected infants. Early diagnosis facilitates treatment measures and interventions to reduce the risk of sequelae (anaemia, organ damage, or growth retardment). Today, many countries, including Italy and Cyprus, have widespread newborn screening programs for thalassemia and, consequently, early diagnosis and better long-term outcomes for affected children.⁷ 

Ethical and societal implications

Prenatal diagnosis and prevention of thalassemia pose some ethical dilemmas. The principal ethical issues surround the suitability of providing potential parents with options for genetic testing and preimplantation genetic diagnosis (PGD).⁹

Others say such technology enables parents to make an informed choice about severe genetic diseases, while some people argue it may spiral into the breeding of 'designer babies.' These discussions matter so that we can appreciate the ethical and societal implications of thalassemia prevention. In addition, sociocultural factors, including the extent to which genetic counselling and IVF are culturally sanctioned, may impact the uptake of these technologies. As a result, sperm or egg donation can seem controversial in many groups, so not all families can benefit from it.

Future strategies for thalassemia avoidance

The prevention of thalassemia lies in the continued development of genetic diagnostic tools. More accurate and less invasive prenatal screens, such as improved NIPT, could help find them early and facilitate gaining traction, too, as a potential thalassemia treatment. In this case, sick people can start making normal haemoglobin levels again with the help of genetically modified stem cells. Although experimental, gene therapy offers the possibility of a permanent cure for thalassemia.

Summary

Prenatal diagnosis and prevention are integral to managing the impact of thalassemia globally. Early carrier screening, prenatal diagnostic tests, and advanced reproductive technologies like PGD and IVF are essential for preventing the transmission of thalassemia to future generations. Genetic counselling plays a critical role in helping parents make informed decisions about family planning, while ongoing advancements in prenatal testing and gene therapy promise a brighter future for individuals at risk of thalassemia.