References

1.\ Busso CE, Reis Soares S, Pellicer A. In: Martin KA, editor. Management of ovarian hyperstimulation syndrome. Waltham, MA: UpToDate; 2021a. Accessed 1 May 2022.

2.\ Busso CE, Reis Soares S, Pellicer A. In: Martin KA, editor. Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome. Waltham, MA: UpToDate; 2021b. Accessed 1 May 2022.

3.\ Chen D, Burmeister L, Goldschlag D, Rosenwaks Z. Ovarian hyperstimulation syndrome: strategies for prevention. Reprod Biomed Online. 2003;7(1):43–9.

4.\ Kashyap S, Parker K, Cedars MI, Rosenwaks Z. Ovarian hyperstimulation syndrome prevention strategies: reducing the human chorionic gonadotropin trigger dose. Semin Reprod Med. 2010;28(6):475–85.

5.\ Navot D, Bergh P, Laufer N. The ovarian hyperstimulation syndrome. In: Adashi EY, Rock JA, Rosenwaks Z, editors. Reproductive endocrinology, surgery and technology. Philadelphia, PA: Lippincott-Raven; 1996. p. 2215–32.

6.\ Practice committee of the American Society for Reproductive Medicine. Ovarian hyperstimulation syndrome. Fertil Steril. 2008;9(5 Suppl):S188–93.

7.\ Practice committee of the American Society for Reproductive Medicine. Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril. 2016;106(7):1634–47.

(IUI) for 3 months. She had a good response to the clomiphene citrate with 2 or 3 follicles developing each time but unfortunately, no pregnancy resulted. Options were reviewed with the couple including continuing clomiphene citrate with IUI for up to 2–3 more cycles or proceeding with in vitro fertilization (IVF). During the consultation, the couple raised the question about genetically testing their embryos for aneuploidy. They mentioned that they have many friends who underwent IVF and were told to proceed with genetic testing of their embryos as it would increase the probability of pregnancy while reducing the chance of miscarriage.

Discussion

Is IVF the next appropriate step for this couple? The simple answer to that question would be “yes.” This couple is experiencing secondary infertility and the most likely cause of the pregnancy loss of the rst pregnancy statistically would be embryo aneuploidy. Since the workup has been unrevealing, and medicated IUI has not worked, IVF is an appropriate next step. As the majority of pregnancies with controlled ovarian stimulation and IUI occur within the rst three attempts, continuing with IUI treatment is less likely to be successful.

IVF involves stimulation with gonadotropins to induce multi-follicular development with the retrieval of mature metaphase II (MII) oocytes. The number of oocytes that can be retrieved is directly correlated to the individual’s ovarian reserve. In this patient with an AMH of 1.4 ng/mL and an AFC of 14, one would anticipate that the average number of oocytes available each month would be ~14 ± 2. Assuming that the majority of oocytes (80%) will be mature and that 70% fertilize, this will result in approximately eight fertilized (2PN) zygotes each cycle. Now, assuming that between 25 and 50% of 2PN zygotes survive extended in vitro culture to blastocyst stage, there would be between 2 and 4 blastocysts from which to select for transfer on day 5. In fact, in one study [1], the mean # of blastocysts available in a 35-year-­ old woman was 4. The mean # blastocysts was in younger patients was 6, decreasing to a mean of 2 at age 40.

Generally, there is agreement that IVF is the most ef cient step forward for this couple in order to achieve a successful pregnancy. We should also agree that the reason why older women have a lower probability of implantation/pregnancy along with a higher miscarriage rate is because each egg they ovulate and embryos they create has an increased probability of being chromosomally abnormal. Why should we then not recommend to genetically test every embryo for aneuploidy before transfer when performing IVF?

Taking a closer look at pre-implantation genetic testing (PGT) of embryos, there are many reasons to genetically test an embryo, PGT-M, PGT-A, and PGT-SR. PGT-M is the acronym used for “M”onogenic diseases which can be autosomal recessive, dominant or sex linked. For recessive disorders like cystic brosis, the risk of each embryo being affected is roughly 25% (50% will be unaffected carriers) and for dominant disorders each embryo has a 50% of being affected (consider BRCA or

rate (>20 weeks gestation) was 41.5% in the PGT-A group and 45.6% in the control group. Since the patient population covered a wide range of ages, a careful analysis comparing younger patients (aged <35) and older patients (aged 35–40) is warranted. Younger patients were potentially negatively impacted by testing their embryos. Implantation rate (+BHCG/embryo transferred) of highly selected embryos was not different between the two groups either (49.3% and 53% for PGT-A and control, respectively). The ongoing pregnancy rate was lower in the PGT-A group (42.5%) compared to the control group (50.3%).

In the older group (aged 35–40), where aneuploidy rates are higher, the implantation rate was noted to be higher for PGT-A tested embryos (50.8%) than in the control group (37.2%). But when evaluated by intention to treat (ITT) including the patients who did not have an embryo suitable for transfer, ongoing pregnancy rates were not statistically different between the two groups, 41.1% and 35.7% for the PGT-A and control groups, respectively. Additionally, miscarriage rates were also not different between the two groups, even in the older population with 8.2% miscarriage rate for tested embryos and 11% for untested embryos. Interestingly, as discussed previously, random biopsies reveal mitotic errors with the sample of cells being “mosaic” mixes of normal and abnormal cells. This mosaic nding was present in about 16.5% of all embryos regardless of patient age. When we take into account the number of mosaic but potentially viable embryos discarded with PGT-­ A, the cumulative pregnancy rate per stimulated cycle may be even lower in the PGT-A group.

In a recently published trial in the NEJM [3], cumulative live birth rates per stimulation cycle were evaluated using PGT-A compared to controls. Patients ages 20–37 were randomized when they had at least three blastocysts. There were 606 patients randomized to the PGT-A group and 606 randomized to the control group for 1212 patients in total. Cumulative live birth rates within the rst year were analyzed until no embryos remained within the rst year. In the PGT-A group, the total number of live births was 468 (77.2%) per started cycles. In the control group, this rate was actually higher at 81.8% (496 live births)! In fact, even the miscarriage rate was not signi cantly different (12.6% for untested embryos vs. 8.7% in the tested embryos).

In conclusion, PGT is the process of removing one or more cells from a developing embryo for genetic testing. PGT can be performed for patients at risk of having children with a serious monogenic condition, recurrent pregnancy loss due to one of the parents carrying a balanced translocation or a de-novo aneuploidy. Disease avoidance and reducing the probability of miscarriage can be done with the primary outcome being the birth of a healthy child without disease. PGT-A on the other hand has been promoted as a means to improve live birth rates, decrease the time to pregnancy and reduce miscarriage rates. As can be seen from the data presented herein, PGT-A does not deliver on any of these indications. While implantation rates per embryo transferred were higher in women >35, this improvement comes at the expense of a lower take home baby rate, especially if you consider that the patient most likely to have only 1 or 2 embryos available per stimulation cycle is the patient over 35.