Recurrent miscarriages – how to succeed? (patients’ success stories)

In this webinar, Dr Laura García de Miguel, Medical Director at Clinica Tambre, Madrid, Spain, has discussed recurrent miscarriages and presented one of her past cases where a couple in their mid-30s struggled to have an ongoing pregnancy after conceiving naturally 3 times. Dr García started the presentation by covering the definition of recurrent miscarriages and took us step by step through all aspects of one of the clinical cases, starting with a general description and situation, diagnostics and procedures until the live birth. According to ESHRE, recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies, excluding ectopic pregnancy and molar pregnancy. It is considered when it happens before 20 weeks of gestation.

Recurrent miscarriages – real IVF patient case

• 34-year-old female, no previous IVF, 3 natural conceptions that ended in miscarriages

A couple in their mid-30s, the female was 34 years old, and the male was 37 years old. They had no previous unsuccessful IVF attempts, but after conceiving naturally 3 times, all ended in miscarriage. The couple had no family history, no diseases, no medications and normal BMI. We studied females’ ovarian reserve, karyotype testing, we also wanted to exclude uterine malformations, endometritis, coagulation disorders and immunological disorders. We also checked general spermiogram parameters and wanted to see if it’s necessary to do a FISH test, a genetic test, and DNA fragmentation to see if there are any fragmentation in the DNA and also karyotype. Partner’s results were normal with good volume, good concentration, good mobility and no problems with morphology. Karyotype was 46 XY. We started studying a female’s ovarian reserve, and it was pretty normal, she had 1.8 ng/ml of AMH, and she had 10 AFC. The karyotype revealed that she had a Robertsonian translocation (ROB) between chromosomes 13 and 15. In this particular couple, that was the issue. Nevertheless, we also did an ultrasound, and there were no uterine malformations or fibroids and no hydrosalpinx. We performed thorough coagulation testing, including thrombophilia, antiphospholipid syndrome, and everything was negative. We also excluded celiac disease, NK cells. She had a good vitamin D level, no problem with glucose-insulin metabolism or thyroid.

Robertsonian translocation (ROB)

It is extremely important to do a karyotype for both partners, even if there are no miscarriages, we always recommend doing a karyotype before going ahead with IVF. A karyotype is a blood test that confirms the number of chromosomes. All humans have 23 pairs of chromosomes, and we have structures that confirm if we are chromosomally normal or not. In that female patient, there was a structural problem, between chromosomes 13 and 15, instead of having 46 chromosomes, she only had 45 because an arm of chromosome 15 fused with chromosome 13. People who have Robertsonian translocation (ROB) have no phenotypical problems, so everything is healthy for them, however, they can have problems with reproduction. They can have more risk of miscarriage and less possibility of pregnancy. Translocations occur when the chromosome is joined with another chromosome. Robertsonian translocation (ROB) usually involves chromosomes 13, 14, 15, 21 and 22 and generally, the possibility to find euploid embryos in people who have this translocation is less likely. It’s a 33% probability of finding a euploid embryo, but when the translocation is in the female, the possibility is even less, it is 18%.

IVF-ICSI process

Therefore, we decided to do IVF with ICSI and PGT-SR to exclude problems in chromosomes in embryos having structural abnormalities. ICSI (Intracytoplasmic Sperm Injection) is a procedure where we inject sperm directly into each egg, we are always doing ICSI when we need to do genetic screening or genetic or PGT-SR, it is possible to do it with traditional IVF, but it is recommended to do it with ICSI procedure. We use a micropipette and a holding needle in our laboratory. We always use a microinjector, which is necessary for biologists. We always prepare eggs on the day of the egg retrieval, and we prepare sperm. When a woman has a period, we always confirm with our patient in the initial ultrasound if everything is okay to start with injections and do the ovarian stimulation. Five to six days later, we do ultrasound number 1, then every 48 hours, we do ultrasound 2 and ultrasound 3 to check the development of the follicles. Then we do the egg retrieval, this is called day 0, and it’s the same day when we ask the male for sperm. In a traditional IVF, we leave all these embryos from day 0 to day 5, and we do the embryo transfer, and 11 days later, we do the pregnancy test. However, when we need to do PGT, we don’t do the embryo transfer in this fresh cycle because we need to do the biopsy of the embryos, and embryos remain frozen. Once we have the results, we organize a call with the couple to explain the genetic results so that we can prepare endometrium before embryo transfer.

Double stimulation

That female patient had a low possibility to find at least 1 embryo within only 1 cycle, so we recommended doing the double stimulation. In the same month, we simulate twice. In the first round, we do the egg retrieval, and 4 or 5 days later, we start another stimulation. Then 2 weeks later, we start another stimulation and second egg retrieval. Why did we recommend that to this couple? That’s because she was only having an 18% possibility of normal embryos, so that was the reason we recommended doing the double stimulation and increasing the possibility of creating embryos.

PGT

We did an IVF cycle with ovarian stimulation, and we did a biopsy of the blastocyst. Every single embryo we study, and we are doing day-5 or day-6 biopsy before the transfer, increases the chances of having a healthy baby because it is offering the possibility to reduce the risk of miscarriage and increase the probability of pregnancy per transfer. It also reduces the duration of treatment and the number of cycles needed. PGT, in general, means Preimplantation Genetic Testing of embryos. PGT-A refers to Preimplantation Genetic Testing for aneuploidy, so it’s for people having problems in chromosomes such as maternal age or previous IVF failures. We also have PGT-SR, which stands for Preimplantation Genetic Testing for structural chromosomal rearrangements, and that was the test that was performed on the embryos of this couple. It detects alterations in the structures, not only the number of chromosomes. It also allows us to see if there are translocations. PGT-M (Preimplantation Genetic Testing for Monogenic Disorders) is for couples having risk to transmit any disease to their babies.

PGT – results

In their first round, the couple got 3 blastocysts, and in the second round, 5 blastocysts, they got 8 blastocysts in total. All the blastocysts were biopsied and sent to the genetics laboratory. PGT-SR revealed that only 1 embryo was euploid, so without translocation. A euploid embryo contains 23 pairs of chromosomes, whereas an aneuploid embryo has a gain or loss of genetic material, problems with chromosomes that could lead to miscarriage or babies born with chromosomes disorders such as Down syndrome. We did a natural cycle for endometrium preparation, we monitored ovulation and when the endometrium was more than 7 millimetres, and the follicle in the ovary was more than 16 millimetres, we triggered the ovulation and did the embryo transfer 7 days later to reproduce the window of implantation as she had in the natural cycle. Then we did support of the luteal phase with progesterone of 400 mg every 12 hours, and we did the embryo transfer with abdominal scan monitoring. Eleven days later, we did the pregnancy test, fortunately, we had an ongoing pregnancy with no complications.

Conclusions

It is very important to study all possible causes when we deal with repeated miscarriages, and we need to remember it could be more than one problem. Even if the karyotype is normal, PGS/PGT is recommended. When we deal with miscarriages, it is recommended to only focus on normal embryos. When we find translocations, it is necessary to talk with the couple and explain the possible percentage of normal embryos that we could find.