From the Editor
The Middle Eastern Fertility Society is an international organization which has been working for over twenty-five years in the pursuit of the expansion of the art, science and practice of reproductive medicine in the Middle East. MEFS has been steadfast in its support of evidence-based practice in this field while fostering growth in Arab doctors’ knowledge about the field.
Our last meeting was held in Beirut, Lebanon, where over than 70 oral presentations were given by more than 50 region and world-leading researchers in the field in front of thousands of attendees. Our meetings have always been a platform for the presentation of the highest caliber of international research.
The Society has also been involved in the organizations of pre-congress courses and symposia in the annual meetings of ASRM and ESHRE, where our most recent contributions was in the meeting of ESHRE, Vienna on 23rd of June, 2019. Our international efforts also include joint meetings with national reproductive societies around the Middle East to yield a positive outcome in the endeavor towards the expansion of reproductive medicine research in the whole region.
In our pursuit to promote research in reproductive medicine in the region, we provide a 20,000 USD grant to aid in research aiming towards the improvement of successful pregnancy rates for infertile couples. In addition, the Dr. SAMIR ABBAS - MEFS Research Award is given to aid aspiring young researchers in the region pursuing research in the field of reproductive medicine.
MEFS is always looking for ways to expand and improve its contribution to research in the field, and we are thus looking forward to seeing you in our next meeting, which will be held in Cairo, Egypt, October 31 to November 2, 2019, where the latest advancements in regional research contributing towards the field will be presented.
Prof. Eman Elgindy, MD, PhD
Generation of Blastocyst-like Structures from Mouse Embryonic and Adult Cell Cultures
Author links open overlay panelRonghuiLi19CuiqingZhong19YangYu1239HaisongLiu1MasahiroSakurai145LeqianYu45ZheyingMin2LeiShi18YuleiWei456YutaTakahashi1Hsin-KaiLiao18JieQiao2HongkuiDeng7EstrellaNuñez-Delicado8ConcepcionRodriguez Esteban1JunWu45Juan CarlosIzpisua Belmonte110
A method that enables the generation of blastocyst-like structures from EPS cells
EPS-blastoids resemble blastocysts in morphology and cell-lineage allocation
EPS-blastoid formation recapitulates early developmental events in vitro
EPS-blastoids are able to implant in utero
A single mouse blastomere from an embryo until the 8-cell stage can generate an entire blastocyst. Whether laboratory-cultured cells retain a similar generative capacity remains unknown. Starting from a single stem cell type, extended pluripotent stem (EPS) cells, we established a 3D differentiation system that enabled the generation of blastocyst-like structures (EPS-blastoids) through lineage segregation and self-organization. EPS-blastoids resembled blastocysts in morphology and cell-lineage allocation and recapitulated key morphogenetic events during preimplantation and early postimplantation development in vitro. Upon transfer, some EPS-blastoids underwent implantation, induced decidualization, and generated live, albeit disorganized, tissues in utero. Single-cell and bulk RNA-sequencing analysis revealed that EPS-blastoids contained all three blastocyst cell lineages and shared transcriptional similarity with natural blastocysts. We also provide proof of concept that EPS-blastoids can be generated from adult cells via cellular reprogramming. EPS-blastoids provide a unique platform for studying early embryogenesis and pave the way to creating viable synthetic embryos by using cultured cells.
BEST OF ESHRE & ASRM 2019
Cutting Edge lectures:
(I) Stem Cells in Reproduction and Neurological Diseases
by KWANG YUL CHA, CHA Global Institute, Korea
In reproductive medicine: still experimental with only 2 valid registered studies in spermatogonial stem cells and one study for ovarian stem cells which is controversial.
The rising promising applications of stem cells are in
1) Parkinson’s application
- Human fetal mesencephalic dopamine neuronal precursor cells (FMD‐ NPCs can be generated in large quantities through a good manufacturing practice‐compliant and serum‐free cultivation system.
- Transplantations of human FMD-NPCs for the treatment of patients with PD showed favorable clinical outcomes
2) Cerebral Palsy Application
Treatment with allogeneic umbilical cord blood (UCB) alone improved motor outcomes in children with CP.
(II) Current Status of In Vitro Growth (IVG) of Human Primordial Follicles
Evelyn Telfer, The University of Edinburgh, United Kingdom
1- Multi step culture system supports human oocyte growth and development from Primordial stages
2- Optimization of each step is required
3- Further testing required (epigenetic status)
4- Physical Conditions are needed to improve polar body formation
5- There is a need to compare Culture systems (FastGrow) versus SlowGrow (Picton system
Next Steps Towards Clinical Application
1- Determining health and developmental competence of IVG oocytes (sequencing, epigenome, metabolome)
2- Fertilization of IVG human oocytes: HFEA approval
3- Embryo Testing
4- Parallel studies on a large animal model (sheep and cow) embryo testing and transfer
(III) The Feasibility and Associated Risks of Germline Editing Dr. Ben Davies University of Oxford
Revolution in genetic engineering.
● Changes to our DNA can now be made using molecular scissors (nucleases).
● Genes can be deleted and mutations can be corrected as will.
● The CRISPR/Cas family represent the most versatile site-specific nucleases.
● These nucleases can be designed against almost any target sequence.
The target site can be any 20 nt sequence followed by -NGG
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)
● Cas9 is the nuclease which cleaves its double stranded target site
● A guide-RNA (crRNA:tracrRNA) defines where the nuclease cleaves and repair template.
Problems – off-target mutation
1-The specificity of CRISPR is defined by only 20 nt and (near) identical sequences may be present elsewhere
2- Cas9 nuclease may tolerate certain mismatches
3- Mosaicism (Founder mice generated with CRIPSR are almost invariably mosaic)
4- Large deletions can occur following CRISPR/Cas9
5- Complex rearrangements can occur following CRISPR/Cas9
6- Biallelic modification, Insertion/deletion mutations are the most likely outcome. Knock-in mutation on one allele, Knock-out on the other!
Additionally, there was emphasize on the the reported human gene editing by Dr. He Jiankui from China, at the 2nd International Summit on Human Genome Editing
Dr. He Jiankui reported using CRISPR/Cas9 to introduce a “therapeutic” mutation into a gene in human embryos. The two embryos were implanted and twins were born – Lulu and Nana
Dangerous and nonsensical use of the technology on real embryos
● No clinical need for CCR5 gene editing
● Consent from the patients doesn’t appear to have been performed by qualified health-care professionals, but by the scientists involved in the study
● Institutional ethical approval uncertain
● The consequences of CCR5 knock-out throughout development and life in humans is unclear
● CCR5 loss in mouse leads to increased susceptibility to other viral infections and altered response to brain injury
● Embryos with a mosaic genotype knowingly implanted.
● Heterozygous embryo knowingly implanted – one normal copy of CCR5 remains.
● Biological activity of Nana’s de novo allele (15 bp deletion = 5 amino acids deletion) of CCR5 completely unclear.
● Future medical care plan for Nana and Lulu uncertain.
The final comment was that “What happened in China was a very premature use of the technology”
Great expectations, but evidence still lacking for recommending freeze-all for all
Dr Bruce Shapiro (Pro), Fertility Center of Las Vegas, United States tried to defend that freeze all could be applied for all cycles
However, Dr Abha Maheshwari, University of Aberdeen, United Kingdom, who is leading the nearly completed E-Freeze study in the UK, argues that the advantages of a freeze-all strategy in embryo transfer are still evident only in selected patients - those at risk of OHSS, hyper-responders, and those with a good prognosis.
Male infertility: Time for a rethink on semen analysis?
Semen Analysis - Is It Time for an Upgrade?
Dr Chris De Jonge (Pro), University of Minnesota, United States, presented the limited usefulness of conventional semen analysis. He tried to emphasize the importance of DNA fragmentation and the value of its introduction in practice in cases with recurrent failure and early pregnancy loss
However, Dr Allan Pacey (Con), University of Sheffield, United Kingdom, argued about the controversial available data of the usefulness of DNA fragmentation. Further, there is no available clear treatment for these cases. There is no approval for a certain protocol for treating these cases. Further, the suggested strategy of performing testicular aspiration for these cases is invasive and without reliable evidence.
ICSI: Fertilisation for all or only for male factor indications?
Behind a lively conference debate lay the unequivocal and ongoing trend that ICSI is generally favored over IVF as a method of fertilization, even in non-male factor cases.
ICSI in all indications?
Presenting the ICSI-for-all case, albeit reluctantly, was Gianpiero Palermo, whose inadvertent experiments with microinjection laid the foundations of the technique more in the very early 1990s with André Van Steirteghem and Paul Devroey at the Centre for Reproductive Medicine in Brussels.(1)
Palermo, now with Weill Cornell Medicine in New York, emphasized how ICSI, and not routine IVF, could explain a doubling in ART over the past 12 years in Europe. Indeed, at Cornell, the procedure is now used in around 80% of all ART treatments, compared with under a third in 1995.
This rise, said Palermo, has been driven by high rates of survival, fertilization and clinical pregnancy. Even with poor sperm motility, he added, ICSI achieves good fertilisation and pregnancy rates - 'as long as you find one sperm, no matter how long you search for it'. He argued that the technique was versatile (eg, ejaculated or dysfunctional sperm), and as safe as conventional IVF in terms of child development, based on Brussels follow-up data on motor skills and IQ at 10 years old. Risk of metabolic syndrome was the same for ICSI children as for IVF, although Palermo did note a recent study showing lower HDL cholesterol levels in ICSI boys (despite similar cardiometabolic risk).
Evidence also shows that birth weight outcomes are better for ICSI singletons than IVF. This is according to a Nordic study involving 92,137 ART singleton and twins born between 1988 and 2007, which also showed that women were generally healthier after ICSI-assisted conception, a finding attributed to their generally younger age and a male factor indication.(2)
The 'use and abuse' of ICSI
In a strong rebuttal against the idea of ICSI-for-all, Luca Gianaroli from the SISMeR clinic in Bologna and a former Chairman of ESHRE, said that ICSI 'works perfectly, but that's not the point.' The point is, he said, its 'use and abuse' in non-male factor indications, citing Palermo's own research that found pregnancy rates for ICSI to be no higher than for conventional IVF in such cases.(3) A body of evidence including a large-scale Australian study has shown that ICSI, when used in cases of female infertility, does not increase the cumulative live birth rate, and does not improve outcomes for advanced female age. Evidence suggests that, with low oocyte yield, fertility rate is higher with one oocyte for ICSI than for IVF, but this outcome goes into reverse with more eggs available - and thus warns against a policy of 'better to use ICSI because the quality of eggs is no good'.
Cost, said Gianaroli, is also a factor when clinics use ICSI in all indications. Global ICMART data from 2011, show that in 65 countries 741,656 ICSI and 373,616 IVF cycles were performed, with 262,450 births from ICSI and 132,212 from IVF. Countries including Egypt and Malta have increased ICSI as a policy to prevent fertilization failure in non-male factor cases. Similarly, according to ESHRE's data from European registries, the sue of conventional IVF fell from 60% to below 30% of ART cycles, while ICSI rose from to over 60% between 1994 and 2014. Gianaroli calculated that, assuming half of all ART patients need ICSI for male factor infertility, more than 100,000 additional ICSI cycles (excluding PGT) were carried out during that time in Europe without a male factor indication. In his estimate, this represented up to 45 million euros spent 'for nothing', given that ICSI does not improve pregnancy rates in such cases. This affects the national health systems in countries with reimbursement, said Gianaroli, and could prevent people seeking treatment in developing countries.
ASRM guidance is that ICSI 'could be' used for all kinds of fertilization failure but does not assist in all cases. What is needed therefore, said Gianaroli, is not new guidance but 'just common sense'.
PGT-A for all
Carmen Rubio (Pro), Igenomix, Spain presented the value of PGT-A and its possible value in improving ART outcome
However, Rick Paulson (Con), University of Southern California, United States argued about the little available evidence and cost-effectiveness of this procedure
Endometrial Receptivity, is it an actionable function to improve the reproductive process?
Carlos Simon (Pro), University of Valencia; Igenomix, Spain tried to advocate for the value of testing receptivity using ERA test
However, Christos Coutifaris (Con), University of Pennsylvania, United States has highlighted the major limitations of this test and a number of rising studies about its noneffectiveness
Plenary lecture: The health hazards of multiple pregnancy
Registry studies provide unequivocal evidence of both short- and long-term health risks in ART offspring born from multiple pregnancies. SET and vitrification now provide the means to reduce the risks.
Dr Anja Pinborg from the University of Copenhagen, has outlined both the short and long-term consequences of multiple births, attributed the turnaround to new Danish guidelines on single embryo transfer (SET) and co-operation among public and private clinics. Multiple delivery rates in ART have now declined to 5% in Denmark, but elsewhere in Europe huge variations still exist - and the rate in African countries and even the USA is above 20%. Pinborg, who is a member of ESHRE's Executive Committee, is a veteran of important registry studies, which show beyond doubt that multiple pregnancies represent the 'most serious health factor' that ART patients face.
In her opinion, freezing surplus embryos after SET may now offer a realistic way forward for reducing the incidence of multiples, given vitrification's high survival rates. Frozen embryo transfer, emphasized Pinborg, gives 'almost the same pregnancy rate as fresh' especially in women with a regular cycle.
Short-term health risks
Using data largely from Danish registries such as the Danish National Birth Cohort, Pinborg reported that impaired brain development and growth is arguably the severest health consequence faced by babies born following double and multiple embryo transfer. Outcomes in IVF twin pregnancies are worse than for two consecutive singletons, she added, and worse in general even in normal birthweight multiples, especially those born very preterm.
Research on children aged 15-16 years shows that a lower proportion of twins pass 9th grade exams, with disabilities the 'most likely' reason for poor performance. A 2010 study concluded that cerebral palsy risk increases after both IVF and ovulation induction, and is strongly associated with multiplicity and preterm delivery .(1) The prevalence of the lifelong condition is nearly three times higher in ART babies than those naturally conceived, as indicated by a Western Australian cohort study published last year.
Survivors of vanishing twins also face challenges. One in ten ART singletons from a double embryo transfer shared a uterus with a sibling who was spontaneously lost. Findings from a study by Pinborg herself showed that these babies who survive have higher perinatal risks which increase according to the gestational age at which their 'sibling' is miscarried.
A 2010 study investigated all IVF deaths in the Netherlands over a period of more than 20 years. Of 17 deaths during pregnancy, nearly half related to a twin pregnancy and included factors such as pulmonary embolism. Several other studies have reported up to a 10-fold risk of very severe outcomes in multiple pregnancies, and an analysis of WHO multi-country survey data concluded that twin pregnancy was significantly associated with severe maternal morbidity and with worse perinatal outcomes, especially for the second twin.
As for long-term consequences, Pinborg presented evidence of a link between multiple-birth babies who are small for gestational age with metabolic syndrome, which is associated with type 2 diabetes and cardiovascular disease. But despite these serious implications, she said, some would-be parents still persist with a mindset of 'more is better' and that two makes up for lost time. However, she noted that around 90% would choose SET in return for a healthy baby - once the risks of a multiple pregnancy are explained.
A woman delivered the first baby in the US born from the transplanted uterus of a dead donor
Date: July 9, 2019
Source: CNN - https://edition.cnn.com/2019/07/09/us/first-us-baby-transplanted-uterus-of-dead-donor-trnd/index.html
In a first for the United States, a clinic has delivered a healthy baby from the transplanted uterus of a deceased donor.
It's a promising development in reproductive options for women who are infertile due to uterine problems, according to the research team behind the delivery.
The girl was born in June via cesarean section to a patient in her mid-30s, said the Cleveland Clinic, which performed the transplantation and birth.
The patient was born without a uterus and entered the clinic's trial for women with uterine factor infertility, said Dr. Tommaso Falcone, a member of the transplant team. Women with this condition either are born without an intact uterus or have had uterine damage through an infection, procedure or hysterectomy.
The unnamed patient elected to remove the transplanted uterus after the birth, he said.
"This was always a question mark that required research," he said. "But this goes to the idea that a deceased donor can give her uterus, and it will function amazingly well."
The process took 15 months
It's the second time that physicians have delivered a baby from a woman with a transplanted uterus from a deceased donor. The first occurred in 2017 in a Brazilian trial involving a 32-year-old woman born without a womb who received a uterine transplant from a 45-year-old woman who'd died of a stroke.
The Cleveland Clinic trial accepts donor uteruses only from premenopausal women, ages 18 to 40, though Falcone noted that the uteruses of living postmenopausal women have been successfully transplanted in separate trials.
The process for this patient took about 15 months from transplantation to birth, he said. Her pregnancy was "not excessively complicated," and she was able to leave the hospital within three days of her C-section.
The trial involves seven phases
The Cleveland Clinic trial team delivers the healthy baby after a uterine transplant from a dead donor.
The process for trial candidates can be lengthy, spanning seven phases: Women are screened twice for their medical history. Then, they must obtain medical clearance. If they're viable candidates, they can begin the in vitro fertilization process, removing eggs from the candidates' ovaries and mixing them with the fathers' sperm to provide sufficient embryos for implantation.
Next comes womb transplantation. In this patient's case, a team retrieved the uterus from the deceased donor and took it back to the hospital, where it was transplanted.
Patients are given immunosuppressive drugs in post-op to prevent their body from rejecting the foreign uterus. The team studied pregnant women who underwent kidney and liver transplants and the way their bodies reacted to those anti-rejection drugs to ensure the safety of the patient, he said.
If all goes well, as it did in this instance, the patient completes the trial with the birth of a healthy infant.
It's a delicate balancing act
A deceased donor presents a unique set of challenges. In a living donor transplant, Falcone explained, surgeons are able to immediately to transfer a uterus to the recipient, usually in an operating room only steps away.
Physicians remove the lifesaving organs, like the heart, liver and kidney, from a deceased donor before they can remove "life-enhancing" organs such as the uterus, he said, so they maintain a balancing act to ensure that neither set is compromised during removal.
It was a gamble, he said, because the team wasn't sure whether the uterus would remain viable after its extraction.
There's a risk of rejection
With both living and nonliving donors, there's a persistent risk that the patient's body will reject the transplanted uterus. The leading cause of previous failed uterus transplants is thrombosis, or blood clotting in the transplanted womb, followed by infection, Falcone said.
Less than a month after the Cleveland Clinic performed the first uterus transplant in the nation in 2016, physicians removed the organ from the 26-year-old patient due to a sudden complication, the clinic said.
Falcone said researchers study such factors as the position of the uterus upon implantation and when infection was spotted to prevent future mistakes. But because the procedure is still experimental, teams studying uterus transplants lean on each other to solve problems.
Prenatal testosterone linked to long-term effects in females who share womb with male twin
Date: march 18, 2019
Summary: women who shared their mother's womb with a male twin are less likely to graduate from high school or college, have earned less by their early 30s, and have lower fertility and marriage rates when compared with twins who are both female, according to new Northwestern University research.
The researchers used data on 13,800 twin births between 1967 and 1978 to show that females exposed in utero to a male twin are less likely to graduate from high school (-15.2 percent), to complete college (-3.9 percent) or to get married (-11.7 percent). They also have lower fertility rates (-5.8 percent) and life-cycle earnings (-8.6 percent).
The study supports the (twin testosterone-transfer hypothesis) which posits that females in male-female twin pairs are exposed to more testosterone in utero via the amniotic fluid or through mother's bloodstream.
Baby girl becomes first born after womb transplant from deceased donor
Date: December 5, 2018
Summary: A32-year old Brazilian woman born without a uterus has become the first person to give birth to alive baby born at 35 weeks and three days by caesarean section , thanks to a womb transplanted from a deceased donor. While there have been 11 births using a live uterus donor, with the first in 2013, this has usually only been an option where the recipient has a close family member who is willing to donate. The numbers of people willing and committed to donate organs upon their own deaths are far larger than those of live donors, offering a much wider potential donor population.
Marijuana smoking linked with higher sperm concentrations
Date: February 5, 2019
Summary: men who have smoked marijuana at some point in their life had significantly higher concentrations of sperm when compared with men who have never smoked marijuana, according to new research led by Harvard T.H. Chan School of Public Health. The study, conducted in the fertility clinic at Massachusetts General Hospital, also found that there were no significant difference in sperm concentration between current and former marijuana smokers.
Artificial womb for premature babies successful in animal trials
Date: April 25, 2017
Source: The Guardian
Summary: in a study published in Nature Communications, six premature lambs were placed in artificial wombs immediately after caesarean deliveries at the equivalent of 23 weeks human gestation. Within minutes of birth, the lamb was sealed in the biobag, linked to a gas exchanger by their umbilical cord, allowing their blood oxygen to be replenished and nutrients to be infused.
In the biobag, the lambs were immersed in a substitute amniotic fluid containing nutrients and chemicals designed to stimulate growth. While floating inside the transparent plastic vessel –in some cases for four weeks- the lambs appeared to develop normally. This may transform outlook for very premature babies.
Healthy mice with the same sex parents born for first time
Date: October 11, 2018
Source: The Guardian
Summary: healthy mice with two mothers have been born for the first time in a study that pushes the boundaries of reproductive science. Mice with two fathers were also born, but only survived a couple of days, the Chinese team behind the work reported that there is imminent prospect of the techniques being used clinically in people, but the findings demonstrate that the biological barriers to same-sex reproduction can, technically, be overcome.
A major barrier in mammals is a phenomenon known as imprinting. Without the right pattern of male and female imprinting, a viable embryo cannot be produced. The apparent barrier could be overcome using the gene-editing tool (Crispr-Cas9).
World's first gene-edited babies created in China, claims scientist
Date: November 26, 2018
Source: The Guardian
Summary: the researcher He Jiankui of Southern University of Science and Technology in Shenzhen, claims to have created the world s first genetically edited babies, in a potentially ground-breaking and controversial medical first. Many scientists think that it is too unsafe to try, and some denounced the Chinese report as human experimentation.
Using gene editing tool called (Crisper Cas9), embryos for seven couples during fertility treatment were altered, with one pregnancy resulting. He said his goal was not to cure or prevent an inherited disease, but to try to bestow a trait that few people naturally have: an ability to resist possible future infection with HIV.
Gene editing itself is experimental and is still associated with off-target mutations, capable of causing genetic problems early and later in life including the development of cancer.
Bangladesh woman with two wombs has twins one month after first birth
Date: 28th march,2019
Source: BBC NEWS
Summary: a Bangladeshi woman has given birth to twins 26 days after delivering a premature baby boy . Arifa Sultana, 20 years old, gave birth to a baby in late february , but 26 days later was rushed again to another hospital after feeling pain . Doctors found she was still pregnant with twins in a second uterus, and performed an emergency caesarean. She delivered a male and a female baby with good health. The patient was diagnosed to have uterus didelphys.
Frozen semen retains its viability in outer space conditions
Date: june 24th , 2019
Source: European Society of Human Reproduction and Embryology
Summary: in a study reported at the 35th Annual Meeting of ESHRE, investigators said that the lack of difference in a range of sperm characteristics observed in frozen sperm samples exposed to microgravity and those maintained in ground conditions, open the possibility of safely transporting male gametes to space and considering the possibility of creating a human sperm bank outside Earth