To study how the attributes of mosaicism identified during preimplantation genetic testing for aneuploidy relate to clinical outcomes, in order to formulate a ranking system of mosaic embryos for intrauterine transfer.
Design
Compiled analysis.
Setting
Multi-center. PATIENT(S): A total of 5,561 euploid blastocysts and 1,000 mosaic blastocysts used in clinical transfers in patients undergoing fertility treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation (gestational sac), ongoing pregnancy, birth, and spontaneous abortion (miscarriage before 20 weeks of gestation). RESULT(S): The euploid group had significantly more favorable rates of implantation and ongoing pregnancy/birth (OP/B) compared with the combined mosaic group or the mosaic group affecting only whole chromosomes (implantation: 57.2% vs. 46.5% vs. 41.8%; OP/B: 52.3% vs. 37.0% vs. 31.3%), as well as lower likelihood of spontaneous abortion (8.6% vs. 20.4% vs. 25%). Whole-chromosome mosaic embryos with level (percent aneuploid cells) <50% had significantly more favorable outcomes than the ≥50% group (implantation: 44.5% vs. 30.4%; OP/B: 36.1% vs. 19.3%). Mosaic type (nature of the aneuploidy implicated in mosaicism) affected outcomes, with a significant correlation between number of affected chromosomes and unfavorable outcomes. This ranged from mosaicism involving segmental abnormalities to complex aneuploidies affecting three or more chromosomes (implantation: 51.6% vs. 30.4%; OP/B: 43.1% vs. 20.8%). Combining mosaic level, type, and embryo morphology revealed the order of subcategories regarding likelihood of positive outcome. CONCLUSION(S): This compiled analysis revealed traits of mosaicism identified with preimplantation genetic testing for aneuploidy that affected outcomes in a statistically significant manner, enabling the formulation of an evidence-based prioritization scheme for mosaic embryos in the clinic.
Chromosome imbalance (aneuploidy) is the major cause of pregnancy loss and congenital disorders in humans. Analyses of small biopsies from human embryos suggest that aneuploidy commonly originates during early divisions, resulting in mosaicism. However, the developmental potential of mosaic embryos remains unclear. We followed the distribution of aneuploid chromosomes across 73 unselected preimplantation embryos and 365 biopsies, sampled from four multifocal trophectoderm (TE) samples and the inner cell mass (ICM). When mosaicism impacted fewer than 50% of cells in one TE biopsy (low-medium mosaicism), only 1% of aneuploidies affected other portions of the embryo. A double-blinded prospective non-selection trial (NCT03673592) showed equivalent live-birth rates and miscarriage rates across 484 euploid, 282 low-grade mosaic, and 131 medium-grade mosaic embryos. No instances of mosaicism or uniparental disomy were detected in the ensuing pregnancies or newborns, and obstetrical and neonatal outcomes were similar between the study groups. Thus, low-medium mosaicism in the trophectoderm mostly arises after TE and ICM differentiation, and such embryos have equivalent developmental potential as fully euploid ones.
To evaluate the benefit of next-generation sequencing (NGS)-based preimplantation genetic testing for aneuploidy (PGT-A) for embryo selection in frozen-thawed embryo transfer. Randomized controlled trial. Not applicable. PATIENT(S): Women aged 25-40 years undergoing IVF with at least two blastocysts that could be biopsied. INTERVENTION(S): Randomization for single frozen-thawed embryo transfer with embryo selection based on PGT-A euploid status versus morphology. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate (OPR) at 20 weeks' gestation per embryo transfer. RESULT(S): A total of 661 women (average age 33.7 ± 3.6 years) were randomized to PGT-A (n = 330) or morphology alone (n = 331). The OPR was equivalent between the two arms, with no significant difference per embryo transfer (50% [137/274] vs. 46% [143/313]) or per intention to treat (ITT) at randomization (41.8% [138/330] vs. 43.5% [144/331]). Post hoc analysis of women aged 35-40 years showed a significant increase in OPR per embryo transfer (51% [62/122] vs. 37% [54/145]) but not per ITT. CONCLUSION(S): PGT-A did not improve overall pregnancy outcomes in all women, as analyzed per embryo transfer or per ITT. There was a significant increase in OPR per embryo transfer with the use of PGT-A in the subgroup of women aged 35-40 years who had two or more embryos that could be biopsied, but this was not significant when analyzed by ITT. CLINICAL NCT02268786.
restorative-reproductive-medicine/restorative-care-and-assisted-reproduction/outcome-comparisonsinfertility/evaluation/diagnostic-workupassisted-reproduction/outcomes/live-birth-rates
Open Access
Recently, editorials have been published in reproductive medical journals that have misunderstood and misrepresented the origin and meaning of “restorative reproductive medicine” (RRM).1,2 This term was first used in 2000 when a group of physicians established the International Institute for Restorative Reproductive Medicine (IIRRM, iirrm.org ). I am a founding member and am currently president of the IIRRM.
The IIRRM was founded as a secular, not a faith-based organization. We adhere to time-honoured medical principles to understand and treat underlying factors responsible for infertility. We are always seeking to improve our diagnosis and treatment of those factors, the training of clinicians who offer RRM, and the quality of clinical practice of RRM. We believe that in the clinical realm, in vitro fertilization (IVF) is often offered quickly without sufficient efforts first made to help couples conceive naturally.
IVF was originally developed to treat patients with bilateral tubal occlusion who could not conceive through sexual intercourse. Most patients who undergo IVF today do not have blocked fallopian tubes. Intracytoplasmic Sperm Injection (ICSI) was developed for patients with severe male factor infertility. Most patients who undergo ICSI today do not have severe male factor infertility. Remarkably, the most recent Cochrane review of IVF indicates ongoing uncertainty about whether IVF improves the live birth rate compared to expectant management for previously untreated couples with “unexplained” subfertility.3
I am an active RRM clinician since 1998 and I have treated thousands of couples. When patients present for fertility treatment, I do not ask them what religion, political view, or philosophy they support, because that is irrelevant to people who want a solution for their infertility. If they have a condition that is better treated by IVF, I tell them that at the first appointment. If natural conception is possible with RRM, I explain what is involved and outline the treatment process which can take up to 12 cycles (most often less) to reach a healthy ongoing pregnancy, or a full course of treatment.
RRM honours patient autonomy. We do not seek to prohibit patient access to IVF. Patients seek us out. RRM expands their choices and options. Many of my patients were previously seen in fertility clinics that offer IVF. Patients repeatedly tell me they did not receive the same depth of investigation or non-IVF treatment in the IVF clinics. I recently received these comments from patients, “RRM empowered us in our fertility journey. It provided a personalised approach. We are so grateful.” And “even if we didn’t conceive, we’d never regret trying RRM as my health improved immeasurably…”
The World Health Organization states that “Infertility is a disease of the male or female reproductive system defined by the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse”.4 As RRM physicians, we respectfully suggest a slight but essential alteration: “Infertility is a medical condition defined by failure to achieve a pregnancy after 12 months or more of regular sexual intercourse without contraception, which is caused by one or more underlying diseases and conditions involving the male or female reproductive system.” This definition indicates that infertility is not a singular condition to be treated solely by treatments to generate a pregnancy and birth. Rather, it is “a canary in the coal mine” for human health, indicating the need to identify and address underlying health concerns. 5,6
As RRM physicians and clinicians we have training and backgrounds that allow us to treat infertility patients with a focus on treatments and approaches that restore and optimize natural function. The specialty of reproductive endocrinology and infertility has extensive training with a particular focus on IVF and treatments to improve the success of IVF. But we can and should be in agreement to offer patients evidence-based information and treatments that meet the needs and preferences of patients.
Further research is needed and is currently ongoing on patient-relevant questions, such as: How does an RRM evaluation differ in process and results from a fertility evaluation before initiating IVF? How do the outcomes of RRM and IVF compare on multiple levels including live birth rates, premature delivery, patient satisfaction, health improvement, and repeat successful births?7
For the sake of our patients with infertility, let us strive to be objective about the scientific facts, and meet all patients with respect. Surely as we challenge and learn from one another and strive for excellence, the patients will be the ultimate beneficiaries.
restorative-reproductive-medicine/restorative-care-and-assisted-reproduction/outcome-comparisonsinfertility/evaluation/epidemiology-and-risk-factorsassisted-reproduction/outcomes/live-birth-rates
Open Access
Restorative reproductive medicine (RRM) is an emerging approach that can be used to treat infertility. Our goal was to compare RRM to IVF outcomes in 2019.
We conducted a retrospective clinic-based analysis and referenced it against publicly available data from IVF registries, as published by the Centers for Disease Control and Prevention (CDC) or the Society for Assisted Reproductive Technology (SART) in the USA, and the Human Fertilization and Embryology Authority (HFEA), in the UK. Data from 2019 was collected from routine medical records following treatment at one clinic in Dublin, Ireland during 2019. We defined the demographics, diagnoses, and treatments and then calculated the crude percentages of conception, live birth, multiple pregnancy, prematurity, and low birth weight. These results were benchmarked against data reported in IVF databases. 249 couples had at least one RRM consultation, 187 committed to the RRM treatment program and met the inclusion criteria. The average female age for all included patients was 36.4 years and couples were trying to conceive for a mean of 32.2 months. Of the 187 patients/couples who underwent treatment, 28% had a previous live birth, 30% had a previous miscarriage, and 42% had never conceived;19% (35/187) had previously had IVF, 2.3 + 1.6 IVF cycles per couple. Of the 187 couples, 52% (98/187) conceived, 41% (77/187) had a documented live birth. There were 75 singletons and 2 sets of twins, producing 79 babies. Time to conception for live birth patients averaged 12 + 8 months. The average birth weight was 3422g (7lb 9oz) and average weeks’ gestation at delivery was 39 + 1.5 weeks. 4.0% (3/75) of singleton babies were premature (33-37 weeks) and none were very premature (< 32 weeks). 5.3% (4/75) of singleton babies had low birth weight (< 2,500g). When we compared births across age groups, the RRM percentages with live birth were comparable to those in a single cycle of IVF with multiple subsequent embryo transfers, and greater than a single cycle of IVF with a single embryo transfer. Furthermore, RRM babies had fewer multiple pregnancies, and singleton RRM pregnancies had less than half as many premature deliveries compared to IVF, (6.5% RRM all pregnancies or 4.0% RRM, singleton pregnancies vs 14.4% SART, all pregnancies or 11.8% CDC, singleton pregnancies). 74% (26/35) of couples who remained in contact with us and tried for another pregnancy had a repeat successful live birth. In our clinic, a comprehensive RRM assessment and treatment followed by up to 12 optimal cycles of timed intercourse resulted in a 41% live birth rate (crude rate). We propose that using RRM may improve a couple’s chance of having a healthy pregnancy and reduce the demand for IVF. Furthermore, RRM reduces the risk of multiple pregnancy, low birth weight and premature delivery compared to IVF. The majority of couples who sought a second live birth were successful.
Limitations and Future directions: This is a retrospective analysis with a small number of RRM patients, compared to large IVF databases of patients using one cycle of IVF, including all transfers made from the IVF retrieval. While useful for benchmarking, conclusions are limited by sample size, and the lack of relevant prognostic data (other than female age) for the IVF patients. Larger prospective studies with full prognostic data are needed to make a proper comparison of RRM and IVF outcomes.