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Birth Defects: Pre-implantation genetic testing to the rescue

By Chijioke Iremeka
25 March 2023   |   3:03 am
The use of pre-implantation genetic testing and screening techniques has increased dramatically in recent time. Since then, genetic testing strategies and diagnostic accuracy have continued to improve. With this latest technological breakthrough in the country’s reproductive medicine, the lifeblood of IVF has gone beyond being able to have babies, to being able to have healthy babies.

CONGENITAL disorders, including down syndrome, albinism, sickle-cell anemia, cystic fibrosis, Tay-Sachs disease, Duchenne muscular dystrophy and X-chromosome-linked disorders, that could be detected by Pre-implantation Genetic Testing (PGT) may soon be disappearing from the vocabulary of hereditary diseases in the country following the latest technological breakthrough in Nigeria’s reproductive medicine. CHIJIOKE IREMEKA writes that these genetic screening techniques – PGT, Pre-implantation Selection (PGS) and Pre-implantation Diagnosis (PGD) – are currently solving the problem of transferring unhealthy embryos into the woman’s womb in In-Vitro-Fertilisation (IVF) treatment.

The use of pre-implantation genetic testing and screening techniques has increased dramatically in recent time. Since then, genetic testing strategies and diagnostic accuracy have continued to improve. With this latest technological breakthrough in the country’s reproductive medicine, the lifeblood of IVF has gone beyond being able to have babies, to being able to have healthy babies.

These techniques have helped many individuals and couples and fertility experts to prevent delivery of children with severe genetic diseases and selective abortion associated with post-gravid antenatal screening techniques in IVF

According to the International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organisation (WHO) revised glossary of ART terminology, pre-implantation genetic diagnosis is the analysis of polar bodies, blastomeres, or trophectoderm from oocytes, zygotes, or embryos for the detection of specific genetic, structural, and/or chromosomal alterations.

Also, the application of pre-implantation genetic testing in IVF for improving success rates for fertility treatment or decreasing the chance of offspring with sporadic genetic disorders, is referred to as PGS, which is defined also in the ICMART/WHO glossary as the analysis of polar bodies, blastomeres, or trophectoderm from oocytes, zygotes, or embryos for the detection of aneuploidy, mutation, and/or DNA rearrangement.

More so, PGT is used for single gene disorders, chromosomal abnormalities, mitochondrial disorders, gender selection in non-Mendelian disorders with unequal gender distribution, aneuploidy screening, and other preconceptually identified genetic abnormalities in prospective parents, American College of Obstetricians and Gynecologists have said.

Clinically, applicable pre-implantation genetic testing was first brought to fruition in 1990 when it was announced that two women at risk of transmitting recessive X-linked diseases were pregnant with female fetuses as the result of IVF followed by embryo biopsy and sexing by Polymerase Chain Reaction (PCR) for the Y chromosome.

According to a laboratory technician, Dr. Odinaka Ndukwe, the PCR is a laboratory technique for rapidly producing or amplifying millions to billions of copies of a DNA sample, allowing scientists to take a very small sample of DNA and amplify it to a large enough amount to study in detail.

Since then, the use of pre-implantation genetic diagnosis has expanded to prevent the birth of children affected by a number of genetically lethal and other congenital diseases. Thus, there is no doubt that PGT has helped deliver remarkable gifts to many people.

Also, the PGT techniques are used clinically to prevent transmission of genes associated with late-onset diseases and increase, but not absolute, risk of disease. Additionally, pre-implantation genetic aneuploidy screening of embryos has been advocated as an adjunct to IVF for women of advanced reproductive age and women with recurrent pregnancy loss.

Ordinarily, there is no guarantee that an IVF cycle would be successful (result in a pregnancy or live birth), it is known that most IVF cycles fail as a result of random genetic abnormalities in the embryo (s). Of course, it is no secret that human reproduction is fairly inefficient and this inefficiency increases with age.

The Guardian learnt that there are different types of chromosomal variations in human body. In some cases, a child may be born with a chromosome missing from a pair (monosomy), or an additional chromosome (trisomy). In other cases, a portion of a chromosome may be missing, duplicated, or translocated. It was learnt that a human cell contains genetic materials arranged in chromosomes. It’s also said that a normal cell would contain 23 pairs of chromosomes.

Explaining how this works, a consultant gynecologist and obstetrician, Dr. Abayomi Ajayi, said fertilisation combines 22 chromosomes and an X chromosome from the mother’s egg with 22 chromosomes and either an X or Y chromosome from the father’s sperm.

According to him, an embryo has 46 chromosomes and if it’s a female, with two X chromosomes and if it’s a male, with an X and a Y chromosome. He noted that a gene is a sequence of DNA (genetic material) on a chromosome with a particular function.

“One way of overcoming this inherent inefficiency of human reproduction is through PGT. When you want to screen embryos for random genetic events that could make IVF to fail, PGT is quite useful. These genetic problems with the embryo that has nothing to do with the parents’ age, contribute significantly to the reasons an IVF cycle could fail.

“If you could determine which embryos are genetically normal (euploid), you could increase the odds of success, minimise the chances of miscarriage and increase the general pregnancy rates, though success rates vary from patient to patient and clinic to clinic,” the expert said.

Ajayi, who is also the Managing Director, Nordica Fertility Centre, further said: “With the standard IVF cycles where eggs are retrieved and sperm is obtained, embryos are created and then cultured to the blastocyst stage. That process takes five to six days. On the 5th or 6th day, an embryo biopsy is performed.

“A few cells are removed from the portion of the embryo destined to become the placenta. The cells are sent for genetic testing and the embryos are frozen, awaiting the genetic report and then a frozen embryo is transferred.

“Normally, PGT identifies abnormalities that could affect the success of your pregnancy or the development of your baby, but after the testing, healthy embryos without identified chromosomal defects are transferred. PGT can only be done in conjunction with an IVF cycle.”

On who needs these services, Ajayi said: “If you and your partner have an inherited genetic disease or you are concerned about chromosomal abnormalities, you are at risk of having a child with a genetic disease. So, you would need PGT. But the bottom line is, if you would like to consider PGT, contact your doctor who would refer you to a suitable specialist.
“Thanks to PGT, tests can be done for over 600 specific genetic disorders to eliminate the risk of transferring a specific genetic disease to the unborn baby. You may consider PGT if you or your partner has a family history of chromosome rearrangement, repeated unsuccessful embryo transfers, or terminating a pregnancy affected by chromosomal variation.

“The test can lower your risk of miscarriage and increase your chances of having a successful IVF cycle at first embryo transfer. It can also reduce your risk of having a baby with chromosomal abnormalities.”

On how the latest techniques would help the reproductive medicine to screen embryos with a view to detecting congenital disorders and implant healthy ones, and how it has helped the reproductive medicine in the country, Ajayi said reproductive medicine is constantly moving as what was available earlier is now being refined.

“There has been some refinement. Now, we know better. Purpose of IVF is no longer being able to have babies but being able to have healthy babies. Now, we know that we carry some gene mutation and it’s now possible for us not to transfer it to our offspring by choosing embryos intact. That is what PGD and PGS can do for us. Now, people with haemoglobin AS are marrying those with haemoglobin AS without having sickly children. We can now pick albinism and Down syndrome from the embryos. Very soon, things like these would disappear from our vocabulary,” he revealed.

The Guardian learnt that it’s easier to defect a baby with any congenital disorder since the mother’s blood could be taken to check whether a child is Down syndrome or not within a few weeks of pregnancy. Then the mother has a choice to make.

“There are so many things happening now that make the world a very interesting place to live in. There have been cases of male gender selection for medical and nonmedical purposes in IVF clinics in Nigeria and many people are apt to believe that it’s illegal.”

Amber Cooper and Emily Jumgheim, who authored “Pre-implantation Genetic Testing: Indications and Controversies” published in the National Library of Medicine, National Centre for Biotechnology Information, said perhaps more contentious is the use of PGT to sex embryos for family balancing and to select for specific genetic traits.

“With our ever-increasing knowledge of the human genome and stem cell biology, the full potential of pre-implantation genetic testing has yet to be realised. In 1986, a group of experts met to discuss the feasibility of prenatal testing in the human pre-implantation period to avoid the need for selective abortion associated with other antenatal screening techniques like chorionic villus sampling and amniocentesis.

“These experts determined that two groups of people would be candidates: those with low risk of having a child affected by sporadic genetic disorders like aneuploidy among older mothers, and those at persistent high risk of having a child with a genetic disease.

“The experts concluded that this second group of patients was most likely to benefit from PGD, and they predicted that PGS would not be widely applied to all IVF patients, but only in order to detect the specific disease or diseases for which a particular couple is at high risk,” the authors said.

It was learnt that shortly after this meeting, in 1988, it was reported that expression of the human genome occurs between the fourth and eighth cell stage of pre-implantation development, and in 1990, a group of researchers and clinicians in London announced the pregnancies of two women who conceived female twins after transfer of IVF-created embryos that were biopsied and sexed by PCR for the Y chromosome.

It was gathered also that in the first reported case of PGT, five women at risk of transmitting recessive X-linked diseases underwent ovarian stimulation with exogenous gonadotropins, oocyte retrieval was performed, and the oocytes were fertilised in vitro.

“On day three of embryo culture, one to two cells were aspirated from the embryos after zonapellucida thinning, and Y-chromosome specific DNA from the biopsied cells was amplified by PCR. Day-3 embryos identified as female were transferred back, and two of the women became pregnant with twins. Female sex of these fetuses was confirmed at 10 weeks by chorionic villus sampling,” Amber and Jumgheim added.

Speaking on the positive sides of the PGS, a consultant surgeon and gynecologist/Obstetrics with Epe General Hospital, Epe, Lagos, Dr. Cynthia Obiora, said: “Only embryos presenting no abnormalities in terms of the number of chromosomes would lead to the birth of a healthy child.

Therefore, when working with good embryos, when PGS techniques are applied, we are able to select chromosomally normal embryos and rule out those which would never be capable of leading to the birth of a healthy child even when their appearance would suggest that they are good quality embryos.”

Obiora advised her colleagues in reproductive medicine: “Avoid the transfer of embryos that would not implant. Certain chromosomal abnormalities are incompatible with life and prevent the embryo from developing during its early stages and even from implanting in the mother’s uterus. PGS means that embryos of this kind can be ruled out, thus optimising the number of transfers.

“We should also avoid the transfer of embryos that would lead to pregnancy loss or the birth of children with a variety of syndromes. Within the range of possible chromosomal abnormalities, some are less harmful to the embryo and allow it to implant.

“However, they do stop the pregnancy from developing correctly and can lead to pregnancy loss or the birth of a child with a number of possible syndromes such as Down syndrome, Patau’s syndrome or Edwards’ syndrome. PGS means that embryos that will be the cause of situations of these kinds can be ruled out.

“This screening technique reduces the time required to get pregnant. By using PGS, we are able to avoid transferring embryos that will not lead to the birth of a healthy child since they would have been ruled out using the technique.”

According to Obiora, in-depth knowledge of the characteristics of each embryo means that those that would appear to be healthy but, in fact, are not healthy from a genetics point of view are not frozen and stored. “The cost of transferring embryos that will not lead to a pregnancy is avoided,” she added.

Asked whether she would like to go for these screenings if she had a history of Down syndrome (DS) in her family, Blessing Ogui, said: “If I have the money, I will not hesitate to do it. Seeing these DS children shatters my heart. I can imagine what a mother would be going through, seeing her child behave in such manner. The pain, the agony of it would push me to do it. In any case, I could borrow to do this. It will secure my future happiness.”

An AS genotype single lady who lost three suitors at the point of proposing to her, Uche Okala said if she was aware of the techniques when she was going through the traumatic times, she would have convinced one of the suitors who were also AS, to sponsor her.

“I didn’t know, I hope this would be made known to other women, in fact, both male and females so that these separations occasioned by having a partner with the same AS genotype should end.” Uche said she eventually married another man with AA genotype.

According to the American College of Obstetricians and Gynecologists, further work is needed to determine if pre-implantation genetic screening for aneuploidy is an effective way to improve the chances of having a child and healthy children after IVF.

“Also, increased knowledge of the human embryo and the genetic basis of human disease coupled with the development of new genetic tests would likely lead to increased application and use of pre-implantation genetic testing.

“As predicted, pre-implantation genetic testing has helped many individuals to prevent the birth of children with severe genetic diseases. Collaborative efforts amongst clinicians of different disciplines, scientists, and policy makers would be necessary to ensure that this increased application and use of testing is done responsibly,” the college advised.

“Unfortunately, there is no law in Nigeria that prohibits PGD and PGS, or simply put, gender selection for medical and nonmedical purpose. In some countries, there are laws but none in Nigeria. Nigeria doesn’t have such law. In fact, there is no regulation concerning (IVF) practice in Nigeria. However, we are working to evolve. It will evolve on its own,” Ajayi said.

Sequel to this, the Principal Partner, Lawrence Ndukwe and Co., Barr Emeka Ndukwe, said: “Because there is no law in the country to govern the practice of PGD, PGT, PGS and IVF, it’s easier for some quacks to gain entry into the profession and defraud unsuspected patients. This is the reason many of these professionals are working on legislation to enable them to secure this practice in the country.

“It’s also important to inform those who need these services to conduct their research to know the clinics with success story and integrity to register with. So, we can’t really prosecute defaulters successfully except it falls within certain kinds of misdemeanor.”