Genetics & IVF case studies – patients stories

In this session, Dr Laura García de Miguel, Medical Director at Clinica Tambre, Madrid, Spain, has discussed genetic issues, available treatment options and provided some real-life cases with detailed examination and performed treatment.

Genetics – real IVF patient case

• a 33-year-old female with normal BMI, no previous IVF cycles, 2 pregnancies, 2 natural pregnancies were terminated

Dr Garcia started with the presentation of the couple with no personal history, no toxic habits, no known allergies, and no previous IVF cycles. As a couple, they had 2 natural pregnancies, one with intrauterine fetal death due to multiple bone malformations, it was induced natural childbirth without complications. The second was also a natural pregnancy that ended in a fatal death at 22 weeks of pregnancy because of multiple bone malformations as well. Then come to the clinic (Clinica Tambre) because they were afraid of a new natural pregnancy, and they have not undergone genetic testing because they have been told that it might be just bad luck with these 2 pregnancies in their home country. They were afraid to go ahead with another pregnancy and risk this happening again. We recommended doing the Genetic Carrier Status Test (HERES) and also the PGT-A to study their embryos. The couple had never done any genetic testing before, they had no genetic counselling.

HERES – The HERES carrier screening offers sequencing of deletion/ duplication analysis for a number of genes (over 300 mutations). We perform this on the female and the male to see if they are carriers of any recessive mutations.

PGT-A – is performed with Next Generation Sequencing (NGS) to read the DNA code of 1 or several genes to determine the genomic sequence of an individual. For each embryo, we are going to test the karyotype with NGS to be sure if they have any chromosomes disorders.

First results

As a result, it was found that both partners are carriers of an autosomal dominant mutation which is glycine substitution in the COL1A1 or COL1A2 gene, which results in a significant defect in the production of type 1 collagen.

Collagen type 1 is a structural component of the extracellular matrix of connective tissue, whose function is to provide support of tensile strength to tissues. This protein is most abundant in bone and skin. This mutation leads to Osteogenesis Imperfecta Syndrome, and that was the cause of the fatal death of both children.

The Osteogenesis Imperfecta Syndrome – The Osteogenesis Imperfecta Syndrome is colloquially known as brittle bone disease, and it is a rare disease due to its low incidence. It is 1 every 15000 babies born or even 1 every 20000 newborns that can be affected. It impacts both sexes, races and ethnic groups equally. It comprises a group of diseases caused by a heterogeneous disorder of the connective tissue. It can cause hearing impairment and dental and pulmonary abnormalities.

After learning of this genetic alteration, the couple was advised to proceed with IVF to obtain embryos in the blastocyst stage to carry out the PGT-A. After examing the couple, it was discovered that the female had a low ovarian reserve, and the male partner had asthenozoospermia, as well as a DNA fragmentation of 20%, making it suitable for ICSI (The Intracystoplasmatic Sperm Injection), which is an IVF procedure where a single sperm cell is injected into the cytoplasm of an egg.

Therefore, in this case, because of asthenozoospermia, which means the mobility of the sperm is not in the normal range, it should be at least 32% of mobile sperm, but this man had only 20%. Also, when PGT-A diagnosis is performed, it’s best to do ICSI because we want to exclude other sperm in the external of the embryo, which means that we are more specific in the results of the embryo and do not obtain genetic results of the sperm.

The treatment

As the female had a low ovarian reserve, 2 rounds of IVF/ICSI cycles were done. In the first cycle, 10 stimulation with dual trigger was performed, we got 6 eggs, and 5 were mature and fertilized correctly. We obtained 2 blastocysts, one AB and one BA. PGT-A and PGT-M exams were performed to check for chromosomes problems. PGT-M was performed to exclude babies that were affected with The Osteogenesis Imperfecta Syndrome.

After a month’s break with Yasminelle, other cycles started. We did a dual trigger again, where we use 2 medications to retrieve more mature eggs. We obtained 7 eggs, 6 were mature, 3 were fertilized after ICSI, and again we obtained 2 blastocysts of good morphology, AB and BB. PGT-A and PGT-M have been performed again.

Outcomes

In the first cycle, 1 aneuploid blastocyst was found, which means there was 1 extra chromosome (23), and there was also 1 less chromosome (11), a Monosomy of 11 and a Trisomy of 23. We also obtained 1 euploid blastocyst, it was a healthy embryo. In the second cycle, the result was 2 blastocysts, 1 euploid blastocyst, and the second was aneuploid with a Trisomy 14 and carrier of the mutation.

The first endometrial preparation with Estrogen (Pogenova 6 mg/d) and Progesterone (400 milligrams Utrogestan, every 12 hours, 5 days prior to transfer). The embryo transfer with abdominal scan monitoring was performed, and 11 days later, the pregnancy test was negative.

The couple was very disappointed since they were able to conceive naturally, and now, with IVF/ICSI, it did not work. Therefore, before going ahead with the second embryo transfer, we decided to do EndomeTRIO testing, which is a test that analyses endometrium. As the patient had 2 previous natural pregnancies, we decided to do the endometrial testing in a natural cycle, which means monitoring the ovulation, the follicular development. Once the endometrium was ready, in terms of thickness, and ready to ovulate, we did the trigger for the ovulation with Ovitrel, we added progesterone and did the biopsy.

EndomeTRIO test consists of 3 tests, including the ERA test, to check the window of implantation and be sure what is the ideal moment for the embryo transfer. In this case, it was revealed that it was receptive to LH+7, which means a normal window of implantation. The second test is ALICE to check for infections which were not found. The third test was EMMA revealed dysbiosis, so there was a recommendation to take probiotics.

Before going ahead for the second transfer, we recommended doing treatment of 15 days of vaginal probiotics, for the endometrial preparation, we did a natural cycle using Ovitrel and progesterone 400 milligrams every 12 hours 5 days before transfer. The embryo transfer was done with abdominal scanning, and this time, we had a positive result and ongoing pregnancy that ended in delivery at 40 weeks.

Conclusions

It’s extremely important to talk with patients about Genetic Testing and The Carrier Status test. Plus, a natural cycle for embryo transfer is recommended if previous natural pregnancies have been achieved.

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Genetics And Embryo Biopsy – Success Stories
Preimplantation Genetic Testing (PGT) – For Whom, and How Does It Help?