We are pleased to introduce the collection Frontiers in Reproductive Health – Highlights in Assisted Reproduction 2021/22. This collection will welcome and showcase a selection of high impact articles authored by leaders in the field. The work presented here highlights the broad diversity of research performed across the Assisted Reproduction section, and aims to put a spotlight on the main areas of interest. This collection aims to further support Frontiers’ strong community by shining a spotlight on our authors' highly impactful research.

Barzilai Medical Center

Al-Azhar University

University of California, San Francisco

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Frontiers in Reproductive Health

Assisted Reproduction

Highlights in Assisted Reproduction 2021/22

IntroductionUniform chromosome abnormalities are commonly seen in early pregnancy loss, with analyses of the product of conception suggesting the presence of mosaic autosomal trisomy in ∼10% of cases. Although chromosomal mosaicism occurs in a minority of embryos, their relative commonality and uncertainty regarding associated transfer outcomes have created discussion at both the clinical and research levels, highlighting the need to understand the clinical conditions associated with the incidence of embryo mosaicism.</sec>MethodsWe took advantage of a preimplantation genetic testing for aneuploidy (PGT-A) database created from 2019 to 2022 in more than 160 in vitro fertilization (IVF) clinics in Brazil, the second-largest world market for IVF. We carried out descriptive statistical and associative analyses to assess the proportions of mosaicism associated with clinical conditions and reported incidence by chromosome, clinic origin, and biopsy operator.</sec>ResultsChromosomal analysis revealed that most mosaic aneuploidies occurred in the last three chromosomes, with 78.06% of cases having only one chromosome affected. Low mosaicism in trisomy represented the most ordinary form, followed by low mosaicism in monosomy. We identified associations between low (negatively-associated) and high mosaicism (positively-associated) and maternal age, indication (male factor and uterus/ovarian factor negatively associated with low and high mosaic, respectively), day of blastocyst development (day five has an overall better outcome), morphology grade (lower quality increased the chances of low and high mosaicism), origin (vitrified oocyte and embryo increased the rates of low and high mosaicism, respectively), and embryo sex (male embryos negatively associated with low mosaic).</sec>DiscussionWith these results, we hope to foster an improved understanding of the chromosomal mosaicism linked with distinct clinical conditions and their associations in Brazil.</sec>

Introduction: Uniform chromosome abnormalities are commonly seen in early pregnancy loss, with analyses of the product of conception suggesting the presence of mosaic autosomal trisomy in ∼10% of cases. Although chromosomal mosaicism occurs in a minority of embryos, their relative commonality and uncertainty regarding associated transfer outcomes have created discussion at both the clinical and research levels, highlighting the need to understand the clinical conditions associated with the incidence of embryo mosaicism.Methods: We took advantage of a preimplantation genetic testing for aneuploidy (PGT-A) database created from 2019 to 2022 in more than 160 in vitro fertilization (IVF) clinics in Brazil, the second-largest world market for IVF. We carried out descriptive statistical and associative analyses to assess the proportions of mosaicism associated with clinical conditions and reported incidence by chromosome, clinic origin, and biopsy operator.Results: Chromosomal analysis revealed that most mosaic aneuploidies occurred in the last three chromosomes, with 78.06% of cases having only one chromosome affected. Low mosaicism in trisomy represented the most ordinary form, followed by low mosaicism in monosomy. We identified associations between low (negatively-associated) and high mosaicism (positively-associated) and maternal age, indication (male factor and uterus/ovarian factor negatively associated with low and high mosaic, respectively), day of blastocyst development (day five has an overall better outcome), morphology grade (lower quality increased the chances of low and high mosaicism), origin (vitrified oocyte and embryo increased the rates of low and high mosaicism, respectively), and embryo sex (male embryos negatively associated with low mosaic).Discussion: With these results, we hope to foster an improved understanding of the chromosomal mosaicism linked with distinct clinical conditions and their associations in Brazil.

The embryo mosaicism profile of next-generation sequencing PGT-A in different clinical conditions and their associations

Objective: Small non-coding RNAs, known as microRNAs (miRNAs), have emerging regulatory functions within the ovary that have been related to fertility. This study was undertaken to determine if circulating miRNAs reflect the changes associated with the parameters of embryo development and fertilization.Methods: In this cross-sectional pilot study. Plasma miRNAs were collected from 48 sequentially presenting women in the follicular phase prior to commencing in vitro fertilization (IVF). Circulating miRNAs were measured using locked nucleic acid (LNA)-based quantitative PCR (qPCR), while an updated miRNA data set was used to determine their level of expression.Results: Body mass index and weight were associated with the miRNAs let7b-3p and miR-375, respectively (p < 0.05), with the same relationship being found between endometrium thickness at oocyte retrieval and miR-885-5p and miR-34a-5p (p < 0.05). In contrast, miR-1260a was found to be inversely associated with anti-Mullerian hormone (AMH; p = 0.007), while miR-365a-3p, miR122-5p, and miR-34a-5p correlated with embryo fertilization rates (p < 0.05). However, when omitting cases of male infertility (n = 15), miR122-5p remained significant (p < 0.05), while miR-365a-3p and miR-34a-5p no longer differed; interestingly, however, miR1260a and mir93.3p became significant (p = 0.0087/0.02, respectively). Furthermore, age was negatively associated with miR-335-3p, miR-28-5p, miR-155-5p, miR-501-3p, and miR-497-5p (p < 0.05). Live birth rate was negatively associated with miR-335-3p, miR-100-5p, miR-497-5p, let-7d, and miR-574-3p (p < 0.05), but these were not significant when age was accounted for.However, with the exclusion of male factor infertility, all those miRNAs were no longer significant, though miR.150.5p emerged as significant (p = 0.042). A beta-regression model identified miR-1260a, miR-486-5p, and miR-132-3p (p < 0.03, p = 0.0003, p < 0.00001, respectively) as the most predictive for fertilization rate. Notably, changes in detectable miRNAs were not linked to cleavage rate, top quality embryos (G3D3), and blastocyst or antral follicle count. An ingenuity pathway analysis showed that miRNAs associated with age were also associated with the variables found in reproductive system diseases.Conclusion: Plasma miRNAs prior to the IVF cycle were associated with differing demographic and IVF parameters, including age, and may be predictive biomarkers of fertilization rate.

Objective: Small non-coding RNAs, known as microRNAs (miRNAs), have emerging regulatory functions within the ovary that have been related to fertility. This study was undertaken to determine if circulating miRNAs reflect the changes associated with the parameters of embryo development and fertilization.Methods: In this cross-sectional pilot study. Plasma miRNAs were collected from 48 sequentially presenting women in the follicular phase prior to commencing in vitro fertilization (IVF). Circulating miRNAs were measured using locked nucleic acid (LNA)-based quantitative PCR (qPCR), while an updated miRNA data set was used to determine their level of expression.Results: Body mass index and weight were associated with the miRNAs let7b-3p and miR-375, respectively (p &lt; 0.05), with the same relationship being found between endometrium thickness at oocyte retrieval and miR-885-5p and miR-34a-5p (p &lt; 0.05). In contrast, miR-1260a was found to be inversely associated with anti-Mullerian hormone (AMH; p = 0.007), while miR-365a-3p, miR122-5p, and miR-34a-5p correlated with embryo fertilization rates (p &lt; 0.05). However, when omitting cases of male infertility (n = 15), miR122-5p remained significant (p &lt; 0.05), while miR-365a-3p and miR-34a-5p no longer differed; interestingly, however, miR1260a and mir93.3p became significant (p = 0.0087/0.02, respectively). Furthermore, age was negatively associated with miR-335-3p, miR-28-5p, miR-155-5p, miR-501-3p, and miR-497-5p (p &lt; 0.05). Live birth rate was negatively associated with miR-335-3p, miR-100-5p, miR-497-5p, let-7d, and miR-574-3p (p &lt; 0.05), but these were not significant when age was accounted for.However, with the exclusion of male factor infertility, all those miRNAs were no longer significant, though miR.150.5p emerged as significant (p = 0.042). A beta-regression model identified miR-1260a, miR-486-5p, and miR-132-3p (p &lt; 0.03, p = 0.0003, p &lt; 0.00001, respectively) as the most predictive for fertilization rate. Notably, changes in detectable miRNAs were not linked to cleavage rate, top quality embryos (G3D3), and blastocyst or antral follicle count. An ingenuity pathway analysis showed that miRNAs associated with age were also associated with the variables found in reproductive system diseases.Conclusion: Plasma miRNAs prior to the IVF cycle were associated with differing demographic and IVF parameters, including age, and may be predictive biomarkers of fertilization rate.

Association of microRNAs With Embryo Development and Fertilization in Women Undergoing Subfertility Treatments: A Pilot Study

Objective: The aim of the present study was to analyze the IVF success rates and the economic cost per delivery in all the public funded IVF Units in Lombardy in the 2017–2018 period and to assess any significant difference in ART outcomes among the enrolled centers.Methods: Analysis of costs for the 2017 and 2018 fresh transfer delivery rate (DR) and Cumulative delivery rate (CDR) considering both fresh and frozen cycles were extracted from the ART Italian Registry on oocytes retrievals, fresh and frozen embryos and oocytes embryo transfer performed in 22 Lombardy IVF Units.Results: In 2017, 29,718 procedures were performed, resulting in 4,543 pregnancies and 3,253 deliveries. In 2018, there were 29,708 procedures, 4,665 pregnancies and 3,348 deliveries. Pregnancies lost to follow up were 5.0% with a (range of 0–67.68%) in 2017 and 3.4% (range of 0–45.1%) in 2018. The cost reimbursement for the cycles were €2,232 ($2,611) for oocyte retrieval and €2,194 ($2,567) for embryo transfer, excluding ovarian stimulation therapy and luteal phase support. 19.33 (5.80). The DR was 13.23 ± 5.69% (range 2.86–29.11%) in 2017 and 19.33 ± 5.80% in 2018 (range 11.82–34.98 %) and the CDR was 19.86 ± 9.38% (range 4.43–37.88%) in 2017 and 21.32 ± 8.84% (range 4.24–37.11%). The mean multiple pregnancy delivery rate (MDR) was 11.08 ± 5.55% (range 0.00–22.73%) in 2017 and 10.41 ± 4.99% (range 1.33–22.22%) in 2018. The mean CDR cost in euros was 26,227 ± 14,737 in 2017 and 25,018 ± 16,039 in 2018. The mean CDR cost among centers was 12,480 to 76,725 in 2017 and 12,973 to 86,203 in 2018.Conclusions: Our findings show impressive differences in the DR and CDR among centers and the importance of cryopreservation in patients' safety and economic cost reduction suggesting the formulation of specific KPI's (Key performance indexes) and minimal performance indexes (PI) as a basis for the allocation of public or insurance resources. In particular, the reduction of multiple pregnancy rates costs, may lead to a more widespread use of ART even in lower resources countries.

Objective: The aim of the present study was to analyze the IVF success rates and the economic cost per delivery in all the public funded IVF Units in Lombardy in the 2017–2018 period and to assess any significant difference in ART outcomes among the enrolled centers.Methods: Analysis of costs for the 2017 and 2018 fresh transfer delivery rate (DR) and Cumulative delivery rate (CDR) considering both fresh and frozen cycles were extracted from the ART Italian Registry on oocytes retrievals, fresh and frozen embryos and oocytes embryo transfer performed in 22 Lombardy IVF Units.Results: In 2017, 29,718 procedures were performed, resulting in 4,543 pregnancies and 3,253 deliveries. In 2018, there were 29,708 procedures, 4,665 pregnancies and 3,348 deliveries. Pregnancies lost to follow up were 5.0% with a (range of 0–67.68%) in 2017 and 3.4% (range of 0–45.1%) in 2018. The cost reimbursement for the cycles were €2,232 ($2,611) for oocyte retrieval and €2,194 ($2,567) for embryo transfer, excluding ovarian stimulation therapy and luteal phase support. 19.33 (5.80). The DR was 13.23 ± 5.69% (range 2.86–29.11%) in 2017 and 19.33 ± 5.80% in 2018 (range 11.82–34.98 %) and the CDR was 19.86 ± 9.38% (range 4.43–37.88%) in 2017 and 21.32 ± 8.84% (range 4.24–37.11%). The mean multiple pregnancy delivery rate (MDR) was 11.08 ± 5.55% (range 0.00–22.73%) in 2017 and 10.41 ± 4.99% (range 1.33–22.22%) in 2018. The mean CDR cost in euros was 26,227 ± 14,737 in 2017 and 25,018 ± 16,039 in 2018. The mean CDR cost among centers was 12,480 to 76,725 in 2017 and 12,973 to 86,203 in 2018.Conclusions: Our findings show impressive differences in the DR and CDR among centers and the importance of cryopreservation in patients' safety and economic cost reduction suggesting the formulation of specific KPI's (Key performance indexes) and minimal performance indexes (PI) as a basis for the allocation of public or insurance resources. In particular, the reduction of multiple pregnancy rates costs, may lead to a more widespread use of ART even in lower resources countries.

2017–2018 Assisted Reproduction Cost Analysis Performance Indexes: Lombardy County Case Study

We report a rare case of ovarian hyperstimulation syndrome (OHSS) in a 28-year-old woman with breast cancer and with a history of polycystic ovary syndrome (PCOS) despite treatment with letrozole and gonadotropin-releasing hormone agonist (GnRH-a) triggering in a GnRH antagonist (GnRH-ant) protocol without the administration of any human chorionic gonadotropin (hCG) for luteal-phase support. The patient, who underwent controlled ovarian syndrome (COS)-oocyte cryopreservation before chemotherapy, required hospitalization. Complete recovery was achieved after treatment with volume expanders, human albumin, and cabergoline. Based on our case and literature review, it is possible to establish that estradiol (E2) modulation with letrozole and GnRH-a triggering does not eliminate the risk of OHSS. Furthermore, it is advisable to postpone GnRH-a depot to minimize the risk of OHSS after the suspension of letrozole, following menstruation or at least 7–8 days after triggering. It would be desirable to identify high-risk patients, also on a genetic basis, in order to avoid delays in oncologic treatments that could strongly impact life expectancy.

We report a rare case of ovarian hyperstimulation syndrome (OHSS) in a 28-year-old woman with breast cancer and with a history of polycystic ovary syndrome (PCOS) despite treatment with letrozole and gonadotropin-releasing hormone agonist (GnRH-a) triggering in a GnRH antagonist (GnRH-ant) protocol without the administration of any human chorionic gonadotropin (hCG) for luteal-phase support. The patient, who underwent controlled ovarian syndrome (COS)-oocyte cryopreservation before chemotherapy, required hospitalization. Complete recovery was achieved after treatment with volume expanders, human albumin, and cabergoline. Based on our case and literature review, it is possible to establish that estradiol (E2) modulation with letrozole and GnRH-a triggering does not eliminate the risk of OHSS. Furthermore, it is advisable to postpone GnRH-a depot to minimize the risk of OHSS after the suspension of letrozole, following menstruation or at least 7–8 days after triggering. It would be desirable to identify high-risk patients, also on a genetic basis, in order to avoid delays in oncologic treatments that could strongly impact life expectancy.

Severe Ovarian Hyperstimulation Syndrome in a Woman With Breast Cancer Under Letrozole Triggered With GnRH Agonist: A Case Report and Review of the Literature

The implementation of oncofertility services is of great importance among cancer survivors of reproductive age to ensure a good quality of life. However, the uptake of this service among Muslim patients is very challenging because of inconclusive laws or evidence based on the Islamic perspective. Hence, we summarized the limited evidence available to consolidate current recommendations for oncofertility practices in the Muslim population in Malaysia. The available “fatwa” and “muzakarah” regarding reproductive procedures and gamete cryopreservation in Islam was searched from the recommendations of local and international bodies, including published and unpublished sources. The relevant information was then extracted according to the current understanding of dilemmas in oncofertility practices in Malaysia, tabulated, and consolidated. Most of the available “fatwa” has been revised by recent “muzakarah” to suit current oncofertility practices. Most Islamic organizations support the practice of oncofertility in Muslim hence indicates that oncofertility services are permissible. Therefore, proper recommendations and counseling are paramount to ensure understanding among Muslim patients.

The implementation of oncofertility services is of great importance among cancer survivors of reproductive age to ensure a good quality of life. However, the uptake of this service among Muslim patients is very challenging because of inconclusive laws or evidence based on the Islamic perspective. Hence, we summarized the limited evidence available to consolidate current recommendations for oncofertility practices in the Muslim population in Malaysia. The available &#x201c;fatwa&#x201d; and &#x201c;muzakarah&#x201d; regarding reproductive procedures and gamete cryopreservation in Islam was searched from the recommendations of local and international bodies, including published and unpublished sources. The relevant information was then extracted according to the current understanding of dilemmas in oncofertility practices in Malaysia, tabulated, and consolidated. Most of the available &#x201c;fatwa&#x201d; has been revised by recent &#x201c;muzakarah&#x201d; to suit current oncofertility practices. Most Islamic organizations support the practice of oncofertility in Muslim hence indicates that oncofertility services are permissible. Therefore, proper recommendations and counseling are paramount to ensure understanding among Muslim patients.