Rapid and non-invasive prenatal diagnosis
Women are choosing to build their families at a later time in their lives. Older mothers have a higher chance of complications during pregnancy, and also have a higher risk of giving birth to babies with some form of fetal abnormality. Younger mothers are also at risk of delivering babies with fetal abnormalities, albeit at a lower risk. Newer tests are now available to screen these women for their individual risk of carrying an affected fetus.
Most parents who are at a generally higher risk of carrying an affected fetus tend to undergo fetal genetic testing (commonly, but less accurately known as prenatal diagnosis). The aim of fetal genetic testing is several fold: (1) to reassure most parents that their unborn child is healthy, (2) where there may be some abnormality to prepare the parents and family for the arrival of a child with special needs, (3) to plan for the appropriate care during the remaining pregnancy, and (4) where this is possible, to treat the fetus in utero.
Fetal abnormalities can be genetic, structural or chromosomal in nature. Genetic abnormalities include conditions such as cystic fibrosis, haemophilia, muscular dystrophy and thalassaemia. Spina bifida and congenital heart diseases are examples of structural malformations. In chromosomal abnormalities there may be some structural damage to the chromosome such as might occur in DiGeorge syndrome, or more often the number of chromosomes is incorrect as in Turner syndrome (too few) and Down syndrome (too many).
Structural abnormalities are usually diagnosed by ultrasound examination of the fetus in the second trimester. This test is non-invasive and immediate. This is the ideal model of care for the fetus, but is only available for structural malformations. Dr Choolani’s work focuses around creating the same model of care for genetic and chromosomal abnormalities.
Diagnosis of genetic and chromosomal abnormalities requires invasive testing by amniocentesis, chorionic villus sampling, and fetal blood sampling. These tests have two major limitations: (1) they are invasive and associated with a procedure-related risk of fetal miscarriage, and (2) that the results take a long time to be released.
The usual way that the fetal genetic studies are conducted involve growing the fetal cells and studying the chromosomes one by one (karyotyping). This can take anywhere from 8 – 21 days, depending on the laboratory that carries out the testing. Two new molecular tests, standard FISH (fluorescence in situ hybridization) and QFPCR (quantitative fluorescence polymerase chain reaction) allow key preliminary results to be released within 48 hours. These tests have become the standard of care in many countries. In Singapore, Dr Choolani and his team set up the QFPCR test for the National University Hospital.
But even a 48-hour wait can be agonizing for some parents, causing sleepless nights after the invasive procedure. Guided by requests from patients, Dr Choolani and his team developed a modified FISH procedure that can release amniocentesis results on the same day. This patented technology FlashFISH™ can be performed in just two hours. Singapore is the first centre in the world ever to offer Same Day Prenatal Diagnosis by using this technique.
Dr Choolani and his team have extended this concept of rapid diagnosis to other genetic conditions such as thalassaemia. A new way to diagnose thalassemia takes just one day compared to previously when it would take up to five days following an amniocentesis.
Giving mothers and couples the results of invasive testing faster has certainly benefited patients, but the ultimate aim is to make these tests non-invasive to eliminate the risk of procedure-related miscarriage altogether.
Two types of fetal genetic material are known to cross into the mother’s blood stream: (1) fetal cells and (2) fetal DNA.
The advancements in fetal DNA are far ahead of the fetal cell work, mainly because there is more fetal DNA circulating in the mother’s blood than fetal cells. Several Non Invasive Prenatal Tests for fetal chromosomal abnormalities such as Down syndrome, Edwards syndrome and Patau syndrome already available.
The advantage of fetal cells however is that if these could be recovered reliably from the mother’s blood, they would be a more versatile source of fetal genetic material as they carry the entire fetal genome intact.
Dr Choolani identified a new way to identify fetal cells that cross into the maternal blood and circulate there, and identified the problems of finding them routinely in maternal blood. His group also recently described a way to study new technologies that locate fetal cells in maternal blood.
Fetal Stem Cells and therapy
The natural progression from diagnosis of fetal genetic conditions is possible therapy. Dr Choolani is part of the team that is currently working actively to develop novel ways to treat affected fetuses in utero.
Rh disease in pregnancy (A haematological disorder)
Rh (sometime also known as Rhesus) disease is an unusual immune blood disorder where the fetus’ blood type is incompatible with the mother’s. This disease affects a small percentage of Caucasians and northern Indians. The combination of an Rh negative mother and an Rh positive father could lead to this condition due to maternal-fetal blood-type incompatibility. The antibodies in the mother’s blood destroy the baby’s red blood cells when they come into contact during pregnancy and after birth. Left untreated, this condition can cause serious complications, even resulting in the baby's death.