Scientific details of CAPA-IVM

CAPA-IVM – The Technology

The CAPA-IVM technology uses five proprietary components in combination with four media for the pick-up of cumulus-oocyte-complexes (COCs) from 2-8 mm follicles (Collection step), for the search of COCs (Search step), for the capacitation of the oocytes (CAPA Step) and for the in-vitro maturation of the oocytes (IVM step).

The CAPA-IVM procedure includes an extra CAPA culture step of 24 hours followed by the IVM step of 30 hours. In the CAPA step the spontaneous maturation of the COCs is prevented in-vitro through an effective arrest of the meiosis. In addition, cumulus-oocyte gap junctional communication is maintained.

During the procedure, high intrafollicular cAMP levels in the COCs will be retained after oocyte collection during the early phase of the oocyte capacitation.

What is the difference between IVF and CAPA-IVM?

A) Principle of In-vitro Fertilization (IVF) – Treating the patient

In classical IVF, the patient will receive 8–10 days of hormone stimulation with gonadotropins in order to induce the growth of follicles to a size of 12–20 mm. After a hCH trigger, the COCs are then picked up by the gynecologist from the ovaries (oocyte pick-up) and then processed in the embryology lab. After ICSI, embryos are cultured 3 or 5 days at 37 degrees and then on Day 3 or Day 5, one or two embryos  will be transferred into the uterus. In the last years more and more labs prefer to culture embryos to Day 5 and vitrify all  blastocyst (freeze-all). A single blastocyst is then transferred at a later time point when the endometrium has been synchronized.

B) Principle of CAPA-IVM – Treating the oocyte

In CAPA-IVM, the patient will not receive any hormone stimulation with gonadotropins.

It is also critically important that no hCG trigger will be applied. Immature COCs from unstimulated follicles of 2–8 mm in size are then picked up by the gynecologist from the ovaries. The pick-up procedure is  similar to the pick up in IVF. After the oocyte pick up (“Collection Step”), the immature oocytes (COCs) need to be identified and washed. This second step is called “Search Step”. Both the “Collection” and “Search Steps” will be done in the presence of nanomolar concentrations of C-Naturetic Peptide 22 (CNP-22) and Estradiol. The COCs will then undergo a 24 hour culture step, named “CAPA Step” using a special basal media in the presence of CNP-22, and also supplemented with Estradiol FSH and Insulin. In all 3 steps (Collection, Search, CAPA) the spontaneous meiosis of the immature oocytes is prevented and inhibited by CNP. In the 24 hour CAPA Step the cytoplasm is allowed to mature for around 24 hours. The prevention of the spontaneous meiosis and the capacitation of the oocyte for at least 24 hours in the presence of CNP and other important growth factors are critical for the oocyte to acquire the necessary capacity and quality to support the embryo growth after fertilization.

After the CAPA Step, the COCs are washed and placed in a new basal medium, this time supplemented with Amphiregulin, FSH, Insulin and Estradiol. In this IVM step of 30 hours, the meiosis is initiated and fully resumed with the aim of maturing the nucleus, meaning that oocytes will reach the MII stage. The matured oocytes (COCs) are then further processed in the embryology lab. ICSI, embryo culture to Day 5, embryo vitrification and  blastocyst transfer to the uterus are done in the same way as in classical IVF.

The main difference between the two approaches is that in CAPA-IVM NO systemic ovarian stimulation is applied and no hCG trigger is needed, while in classical IVF patients undergo up to 10 days of hormone treatment and a hCG trigger is needed. Thus, In CAPA-IVM the oocyte is treated and matured outside the woman’s body, while in classical IVF the patient itself is treated. As a consequence, patients undergoing CAPA-IVM are not confronted with the typical risks and burden of systemic ovarian stimulation.

The CAPA-IVM technology based on C-Natriuretic Peptide has undergone pre-clinical human safety and a number of efficacy trials and its adoption into clinical practice resulted in healthy live birth rates not different from conventional IVF.

WIDER IMPLICATIONS: Over many decades, improvements in clinical IVM have been gradual and incremental. However, in the past few years, landmark discoveries have been made in animal oocyte biology finally making their way into clinical practice leading to improved outcomes for patients. Demonstration of favorable clinical results with CAPA-IVM, as the first clinically tested biphasic IVM system, has led to renewed interest in IVM as an alternative, low-intervention, low-cost, safe, patient-friendly ART approach, especially for patients with PCOS. The same new approach is being used as part of fertility preservation in patients with cancer and holds promise for egg freezing applications for young women wishing to preserve their fertility.

Key Publications in CAPA-IVM

Basic Research

  • Romero S, et al.: Immature oocytes from unprimed juvenile mice become a valuable source for embryo production when using c-type natriuretic peptide as essential component of culture medium.
    Biol Reprod. 2016;95:64.
  • Sanchez F, et al.: An improved IVM method for cumulus-oocyte complexes from small follicles in polycystic ovary syndrome patients enhances  oocyte competence and embryo yield.
    Hum Reprod. 2017;32:2056-68.

Safety Data

  • Saenz De Juano MD, et al.: DNA methylation and mRNA expression of imprinted genes in blastocysts derived from an improved IVM method for  oocytes from small follicles in PCOS patients.
    Hum Reprod. 2019: Aug 9. pii: dez121.

Clinical Trials

Proof-of-concept: standard IVM versus CAPA-IVF (n= 40)

  • Sanchez F,  et al.: Biphasic in vitro maturation (CAPA-IVM) specifically improves the developmental capacity of oocytes from small antral follicles.
    Journal of Assist Reprod Genet. 2019 Aug 9. doi: 10.1007/s10815-019-01551-5.

Randomized clinical trial: standard IVM versus CAPA-IVF (n = 80)

  • Vuong L. , et al.: Live Births after oocyte in vitro maturation with prematuration step in women with polycystic ovary syndrome.
    Journal of Assist Reprod  Genet. 2020, 37(2):347-357.

Randomized clinical trial: standard IVF versus CAPA-IVF in ICSI (n = 546)

  • Vuong L, et al.: In-vitro maturation of oocytes versus conventional IVF in women with infertility and a high antral follicle count: a randomized non-inferiority controlled trial.
    Hum Reprod.  2020 Nov 1;35(11):2537-2547.

Follow up data on babies born using CAPA-IVM

  • Nguyen et al.: Development of children born after in vitro maturation with a prematuration step versus natural conception: a prospective cohort study.
    J Assist Reprod Genet. 2022, 39 (8): 1959-1965
  • Vuong et al.. Development of children born from IVM versus IVF: 2-year follow-up of a randomized controlled trial.
    Human Reprod. 2022, 37 (8), 1871-1879