IVF

A new, non-invasive test could help predict the quality of embryo used for IVF

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IVF Embryo
A human embryo is seen under a microscope.

Researchers from the University of California San Diego School of Medicine say a new method can better predict the quality of embryos used for in vitro fertilization, potentially raising the odds of a successful pregnancy for those relying on assisted reproductive technology.

For people struggling with infertility, IVF — which involves retrieving eggs and fertilizing them in the lab before implanting embryos in the uterus — often provides hope. But the process can be draining, at times requiring people to undergo multiple rounds of treatment.

“This is often a really trying experience, where we often say: ‘We don’t know why an embryo is good. We don’t know why an embryo doesn’t result in a baby.’ And we can’t know why until we better understand what’s happening in the embryo,” said H. Irene Su, one of the senior scientists involved in the study, who works as a professor at UC San Diego School of Medicine and as a reproductive endocrinologist and epidemiologist at UC San Diego Health.

A woman under age 35 has a 51% chance of having a live birth after one IVF cycle, with live birth rates dropping to 38% for women between ages 35-37 and 25% for women between 38-40, according to a 2019 report from the Society for Assisted Reproductive Technology. Clinicians wish success rates were higher, but one issue is that it’s difficult for doctors to know which lab-grown embryos will result in a successful pregnancy. That can mean multiple rounds of treatment, which get expensive at an average $12,400 per cycle.

The new method developed by Su and her colleagues seeks to assess embryo quality by looking at pieces of genetic material called extracellular RNA (exRNA) left behind in the liquid that embryos are grown in. Their findings were published last week in Cell Genomics. With this non-invasive approach, Su hopes that one day couples receiving assisted reproductive technology will have better outcomes.

Currently, embryo quality is assessed based on morphology (examining their physical characteristics) or by taking a biopsy of the cells. “Both morphology and chromosomal testing from a biopsy are limited in terms of predicting which embryos will become a healthy baby,” Su said.

The new technique could be meaningful for couples going through IVF in a number of ways, according to Victoria Jiang, a reproductive endocrinology and infertility fellow at Massachusetts General Hospital who was not involved with the study. 

Replacing biopsies with the exRNA technique “could be an incredible advancement as it is less invasive, less expensive, and less dependent on operator technical skill” compared to biopsies, Jiang said via email. That “can ultimately improve outcomes, both from a financial perspective and a pregnancy outcomes perspective,” Jiang said. Genetic testing for embryos can cost up to $5,000, according to Jiang.

The new method leaves the embryo completely undisturbed and looks at the culture medium left behind. When culturing a fertilized egg into an embryo, it is grown in a very small droplet of culture media, which helps the embryo develop before it is used for implantation. In this study, the scientists took the leftover liquid media, which was donated by 29 participants. Then, researchers isolated exRNA, converted it, and then mapped it to the human genome.

The researchers analyzed a total of 295 droplets, and created an atlas based on the type of exRNA they found. Su and her colleagues were able to characterize the RNA into five distinct genetic profiles or time periods of embryonic development: the oocyte or egg, zygote or fertilized egg, cleavage, morula and blastocyst stages. By identifying the different stages in each droplet, the researchers were able to track which embryos grew to the blastocyst stage, which is when they are ready for implantation, and which embryos were “arrested” or just stopped growing.

If this form of non-invasive testing “can lead to easier identification of those arrested embryos, then it will significantly help with selection, particularly when the morphology is the same,” said Jiang.

Su and her colleagues also identified certain genes in the embryos that stopped growing, but more research needs to be done to figure out those genes’ specific role in the process.

Putting these elements together, the researchers used the exRNA profiles to train a machine-learning model to identify higher-quality embryos. The researchers first graded 26 embryos and gave each a morphology-based score. Then they put them through the machine learning model and found that the predicted score correlated with the morphology-based score the embryologists came up with.

The researchers who spoke with STAT all agreed that this doesn’t mean that embryologists will be going away any time soon. But it could mean that one day, clinicians will be less reliant on biopsies.

“Most of these advances, even in the machine learning/AI realm, will be helpful adjunctive tools to streamline the work flow of embryologists, and help with the shortage of embryologists that our field is facing, but will not be replacing embryologists by any means in the near or distant future,” Jiang said.

Throughout this study, the researchers encountered some challenges that limited what data could be collected. They decided to use the leftover media from a group of embryos since embryos grow better when cultured together. As a result, it was also difficult to compare results from genetic testing of embryos, since embryos are usually individually tested and with the shared liquid researchers couldn’t tell from which embryo the exRNA was coming from.

“This model may help identify genes that are valuable in development, but I would want to see the model applied to individual embryos and it is far from being a tool for embryo specific selection,” Jiang said.

Su told STAT that it will take additional research to confirm whether the test can be used to successfully predict positive IVF outcomes. She said the reproductive field may be able to learn other valuable lessons from the technique as well.

“Mostly until now, how we understand parts of early human embryo development is actually looking at, you know, other mammals,” Su said. “But if you don’t have to perturb a normal human embryo, and be able to look at the spent media to understand its physiology, that’s really cool.”

Baby without sperm and egg? Scientists create ‘synthetic’ human embryos in major leap

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A ‘synthetic’ embryo could aid the understanding of human development during a ‘black box’ period |

STORY HIGHLIGHTS

The breakthrough is expected to further the scientific understanding of the development of human embryo and enhancement of the research into genetic disorders.

In a remarkable breakthrough that could revamp the existing understanding of In Vitro Fertilisation (IVF) in the area of human reproduction, scientists have created synthetic human embryos using stem cells. The development reportedly dodges the need for eggs and sperm for the creation of human embryos.

The work was reportedly described on Wednesday in a plenary address at the International Society for Stem Cell Research’s annual meeting in Boston. However, the full details of the latest work, from the Cambridge-Caltech lab, are yet to be published in a journal paper. 

“Our human model is the first three-lineage human embryo model that specifies amnion and germ cells, precursor cells of egg and sperm,” Professor Magdalena Żernicka-Goetz, of the University of Cambridge and the California Institute of Technology, was quoted as saying by The Guardian. 

“It’s beautiful and created entirely from embryonic stem cells.”

What is a ‘synthetic’ embryo like?

Created by stem cells, it does not have a beating heart or the beginning of a brain. However, they do have the cells which form the placenta, yolk sac and the embryo itself. 

Why is a ‘synthetic’ embryo needed?

A report in The Guardian cites scientists saying that these sythetically created embryos could provide crucial information on the biological causes of recurrent miscarriages. 

According to a paper published in The Lancet in April 2021, globally, an estimated 23 million miscarriages occur annually. 

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At the same time, the basic need for the work is for scientists to understand the “black box” period of human development, which is referred to the duration between the 16 or 17 days after fertilisation and more than a week after the free-floating embryo anchors itself to the lining of the womb.  

Scientists are currently allowed to cultivate embryos in the lab up to a legal duration of 14 days. Beyond that, they pick up on the course of the development by looking at pregnancy scans and embryos donated for research. 

“The idea is that if you really model normal human embryonic development using stem cells, you can gain an awful lot of information about how we begin development, what can go wrong, without having to use early embryos for research,” Robin Lovell-Badge, the head of stem cell biology and developmental genetics at the Francis Crick Institute in London, was quoted as saying by The Guardian. 

IVF treatment evolves to ‘open up doors’ for more diverse patient population

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Elizabeth Jordan Carr, the first infant born after in vitro fertilization in the United States, turned 40 on Dec. 28, 2021. During those 4 decades, the technology and the culture surrounding fertility have radically changed.

“She was really instrumental in putting the spotlight on fertility treatments for those who were unable to conceive and to have the media understand that there are couples who need assistance,” Jane L. Frederick, MD, FACOG, medical director at HRC Fertility in Laguna Hills and Newport Beach, California, told Healio.

“When Elizabeth Jordan Carr was born, we were only fertilizing an egg and a sperm in a test tube for 48 hours, and then that was it. We really didn’t have any technology about how to grow an embryo beyond that,” Frederick said.

The technology’s evolution

In the 1950s and 1960s, scientists began fertilizing mouse and rabbit embryos in the laboratory and transferring them into the womb. These animals then carried their offspring to term and experienced live births.

But there were challenges in achieving the same results in human beings. Instrumentation such as more powerful microscopes were necessary to analyze cell tissue. Also, researchers had to develop the media where the cells would grow and multiply.

Jane L. Frederick

“There was a lot of trial and error during that time in trying to figure out what the cells really needed,” said Frederick. “Glucose, carbon dioxide, oxygen — everything has to be equilibrated to simulate what would occur in the human body.”

Cultures now can sustain embryos for up to 5 days, allowing them to grow to a hundred cells. Doctors can then biopsy one cell out of that hundred for a clear idea of each embryo’s chances for success.

“We can genetically test for all 24 chromosomes, which helps me figure out which embryo is healthy enough for transfer and which one is not,” Frederick said. “I can better select the right embryo for implantation instead of randomly selecting one and hoping for the best.”

When patients have family histories or previous births with genetic disorders such as cystic fibrosis, Tay-Sachs disease or hemophilia, doctors can select embryos unaffected by those genes.

“If the disease has a gene related to it, we build a probe for that specific gene, and I can give them a healthy child on their next pregnancy,” Frederick said. “This has greatly helped a lot of couples who suffer from genetic disorders.”

This preimplantation genetic testing also eliminates the need for multiple implantations and resulting twin, triplet and quadruplet births, which are more prone to preterm births and related risks for developmental disorders.

“The uterus doesn’t handle multiple births very well,” Frederick said. “We really try to limit the number of multiple births that we are producing through IVF, and the way we do that now is to transfer a single healthy embryo.”

While this is going on in the lab, the uterus needs to be prepared to receive the embryo as well. In the 1950s, studies described how the uterus responds to different levels of estrogen and progesterone during the menstrual cycle.

“That follows through to what I do today, which is sequentially preparing the uterus with estrogen of different levels and then adding progesterone to help implantation,” said Frederick. “That technology was very critical. There’s a lot of synchronization between the embryo and the uterus. It has to be right, or it doesn’t work.”

There have been developments with low sperm counts, too. Previously, clinicians would place the sperm next to the egg in the test tube and hope it would fertilize. Intracytoplasmic sperm injection, however, takes a single sperm and injects it directly into the egg.

“It’s not 100%. We need to understand the genetics of the sperm and why it doesn’t always produce a fertilized egg. We don’t have a lot of information about male infertility,” Frederick said.

“We have limited ability to study the DNA in the sperm head. There’s still some selection there. Our technology is getting closer to that, but it’s not there yet,” she added.

Evolving motivations for treatment

The demographics of the patients seeking treatment have changed over the decades as well.

“I used to just treat heterosexual couples who were infertile back in 1990 when I started,” said Frederick, noting that one in eight couples have fertility problems and that there are many reasons why women seek fertility treatment now.

“We noticed that women are waiting until their late 30s to try to have their first baby, and many of them are waiting until their 40s,” she said. “A lot has gone into how we can help preserve the fertility of the younger patient.”

Many women choose to freeze their eggs — a technology that has only been around for about 15 years, Frederick said. Some of these women do so because they do not have a partner for a family yet and hope to in the future. Also, women who are cancer patients may freeze their eggs before chemotherapy and radiation therapy may cause sterility.

“We are much better able today to screen for cancer. We have a lot more cancer survivors than we did 30 years ago, and because of that I’m seeing more referrals for patients who want to freeze their eggs. And then they’ll come back when they’re survivors,” Frederick said.

Frederick also sees many same-sex couples.

“I’ll see two men using a donor and a surrogate to have a family. I see reciprocal IVF patients, with two women, where one has an egg harvested and the other carries the embryo so they both can participate in pregnancy,” she continued. “The LGBTQ community is aware that they do have options to build a family.”

Economic and social barriers

Technology has enabled Frederick and her colleagues to treat a broader range of parents than was possible when treatment began 4 decades ago. Yet hurdles remain.

“Hopefully, the cost of procedures will go down so everybody can have access to the treatment,” said Frederick. “That’s really the issue I see right now. It’s cost-prohibitive for a lot of patients.”

Insurance companies have increased coverage for this treatment since it first began, and Frederick said that approximately 30% of her patients have coverage for infertility.

“It was 0% when I first started,” she said. “However, the definition of what they cover varies.”

Some coverage may stop with the initial consultation, while other coverage will fund the full treatment cycle. Frederick said that she and her colleagues have lobbied state legislatures to make infertility treatment a fully covered benefit.

“Many insurance companies don’t consider it a disease. It’s just a condition that you have. But we really want insurance companies to acknowledge that everybody should have access to treatment,” she said.

Employers such as Facebook, Apple and Disney offer infertility coverage, with Facebook, Apple and Google offering egg freezing for new hires, Frederick said.

“They see that as an opportunity to hire more women in their 30s. I think that’s incredible. We need to get more employers to understand that it really isn’t a choice and that our biological clock is real,” she said.

While insurance and companies have been more receptive to providing fertility treatment, society has become more accepting as well.

“It used to be very hush hush. You didn’t tell your neighbors or family how the baby was born or how you went to infertility treatment,” Frederick said. “Nowadays, children are aware that they were born through IVF. Mom and dad are okay with discussing it.”

Research has shown that when parents are honest with their children about how they were conceived, those children and families have a more positive outlook on infertility treatment, Frederick said.

“When we have our big baby reunion every year, these couples come back to visit us, and it’s so great to see them. And the first thing they say to me is, ‘Wow, all these people went through infertility like I did,’” she said.

“It’s very common, and people definitely feel more comfortable,” she continued. “I hope that brings hope for couples to say, ‘Well, so and so had treatment. Let’s go talk to the doctor and see what’s available.’ That will open up doors for patients who really need to understand why they’re not getting pregnant and how we can help them.”

‘Reassuring’: Researchers find no link between COVID-19 vaccination and IVF outcomes

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Researchers found no associations between the Pfizer-BioNTech and Moderna mRNA vaccines and adverse effects on stimulation or early pregnancy outcomes with IVF, according to a study published in Obstetrics & Gynecology.

“This is one of the largest studies to review fertility and IVF cycle outcomes in patients who received COVID-19 vaccinations,” author Devora A. Aharon, MD, a fellow in reproductive endocrinology and infertility at Icahn Mount Sinai and Reproductive Medicine Associates of New York, said in a press release.

Devora A. Aharon

Researchers conducted a retrospective cohort study that included patients at RMA of New York who received controlled ovarian hyperstimulation or single euploid frozen-thawed embryo transfer between February and September 2021.

The new study builds on findings reported in October 2021 at the ASRM Scientific Congress & Expo, which involved a smaller number of patients who were examined between February and July 2021.

Vaccinated patients had received two doses of the Pfizer-BioNTech or Moderna vaccines 14 days or more before the start of their fertility treatments.

In an adjusted analysis, Aharon and colleagues found no association between COVID-19 vaccination and fertilization rate (B = 0.02 ± 0.02) among the 222 vaccinated and 983 unvaccinated patients who had controlled ovarian hyperstimulation cycles.  

The researchers also found no association between COVID-19 vaccination and eggs retrieved (B = 0.01 ± 0.57), mature oocytes retrieved (B = 0.26 ± 0.47), mature oocytes ratio (B = 0.02 ±  0.01), blastulation rate (B = 0.02 ± 0.02) or euploid rate (B = 0.05 ± 0.03).

Further, the researchers examined associations between vaccination and pregnancy, defined as a positive pregnancy test on blood work; clinical pregnancy, defined as a pregnancy seen on ultrasound; and ongoing pregnancy, meaning a healthy pregnancy that continued with discharge to the obstetrician at approximately 8 to 9 weeks gestation.

The researchers found no association between COVID-19 vaccination and clinical pregnancy (adjusted OR = 0.79; 95% CI, 0.54-1.15) among the 214 vaccinated and 733 unvaccinated patients who had single euploid frozen-thawed embryo transfer, with no statistically significant differences between the groups. Chances did not change because of vaccination.

Additionally, there was no significant association between COVID-19 vaccination and pregnancy (aOR = 0.88; 95% CI, 0.58-1.33), ongoing pregnancy (aOR = 0.9; 95% CI, 0.61-1.31), biochemical pregnancy loss (aOR = 1.21; 95% CI, 0.69-2.14) or clinical pregnancy loss (aOR = 1.02; 95% CI, 0.51-2.06).

“This study found no significant differences in response to ovarian stimulation, egg quality, embryo development or pregnancy outcomes between the vaccinated compared to unvaccinated patients,” said Aharon. “Our findings that vaccination had no impact on these outcomes should be reassuring to those who are trying to conceive or are in early pregnancy.”

Reference:

  • Aharon D, et al. Obstet Gynecol. 2022;doi:10.1097/AOG.0000000000004713.

New sperm-sorting device to improve IVF success

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https://speciality.medicaldialogues.in/new-sperm-sorting-device-to-improve-ivf-success/

Men Experience Their Own Biological Clock, IVF Study Shows

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Male fertility doesn’t last forever.

 

While it’s well known that women start to experience a decline in fertility in their thirties, scientists have found new evidence suggesting men also have a ‘biological clock‘ that limits their ability to reproduce as they get older.

A new study shows that in vitro fertilisation (IVF) delivery rates are affected by the age of the male partner, with successful IVF procedures becoming less likely as would-be fathers get older.

 The research, led by reproductive biologist Laura Dodge from Harvard University, shows that when it comes to producing babies through IVF, it’s not just the age of the woman that matters, even though that may be the dominating factor affecting successful outcomes.

Dodge’s team analysed 15 years’ worth of IVF treatments conducted in Boston between 2000 and 2014, encompassing some 19,000 IVF cycles performed for almost 8,000 couples.

What they found is that as the males in the couples got older, the chances of live birth were reduced – but the effect was only apparent in couples where the woman wasn’t older than 40.

From the data set, the researchers divided the IVF participants (both male and female) into four age bands: under 30, 30–35 years old, 35–40, and 40–42.

The cumulative live birth rate – measured from up to six cycles of IVF treatment – was lowest in couples where the female partner was aged 40–42, which wasn’t a surprise, given what we know about decreasing female fertility as women age.

In this band, where females were aged 40–42, the age of the male partner had no impact on birth rate, but in the younger female bands, cumulative live birth rates were found to decline as male partners grew older.

 “Generally, we saw no significant decline in cumulative live birth when women had a male partner the same age or younger,” says Dodge.

“However, women aged 35–40 did significantly benefit from having a male partner who is under age 30, in that they see a nearly 30 percent relative improvement in cumulative incidence of live birth when compared to women whose partner is 30–35 – from 54 percent to 70 percent.”

And just as birth outcomes were more successful when older females paired with younger males, they stood a greater chances of failure when younger females attempted IVF with older males.

In the study, couples where the female partner was under 30 and the male was aged 40–42 had a cumulative birth rate of 46 percent, but if the male partner’s age was 30–35, this improved significantly to 73 percent.

“Where we see significant decreases in the cumulative incidence of live birth is among women with male partners in the older age bands,” says Dodge.

“For women age 30–35, having a partner who is older than they are is associated with approximately 11 percent relative decreases in cumulative incidence of live birth – from 70 percent to 64 percent – when compared to having a male partner within their same age band.”

As for why older males enjoy less success with IVF, the researchers aren’t entirely sure and intend to pursue the question further, but suggest it could be related to damaged sperm that affect fertility prospects as men get older.

While the effects reported here are significant, it’s worth pointing out that the study – which is being presented this week at the annual meeting of the European Society of Reproduction and Embryology in Switzerland – hasn’t yet been peer-reviewed by other scientists, so we should bear that in mind when considering the findings.

But in the meantime, researchers say these preliminary results could help would-be parents to consider the broader range of factors that may affect their family prospects – and which aren’t simply limited to how old the female partner is.

“The value of this is not only in counselling couples,” obstetrician Nick Macklon from the University of Southampton in the UK, who was not involved in the study, told Ian Sample at The Guardian.

“It may help women to encourage their male partners to get a move on. We know from a number of studies that one of the reasons why women are having babies later is because men are sometimes slow to support the idea. This reminds us that it takes two to tango and it’s not just down to the age of the woman.”

Older mothers have healthier babies if they conceive using IVF

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Babies born to older mothers are more likely to be healthy if they have been conceived through IVF rather than naturally, a major new study has found.

A survey of more than 300,000 live births revealed that women aged 40 or over were more than twice as likely to have a child with birth defects than those of the same age who had undergone a widely used method of assisted reproduction.

Scientists behind the study say the “remarkable” findings may be explained by a hormonal stimulation provided by IVF that helps reverse the decline in ovulation control experienced as women get older.

There is something quite remarkable occurring with women over the age of 40 who use assisted reproductionProf Michael Davies
 IVF in action

The team from the University of Adelaide collated data from every live birth in South Australia between 1986 and 2002, which revealed that the overall proportion of birth defects among naturally conceived babies across all age groups was 5.7 per cent, compared to 9.9 per cent for traditional IVF births.

For babies conceived using Intracytoplasmic sperm injection (ICSI), a variety of IVF used in about 70 per cent of cases worldwide, just under 10 per cent had birth defects.

For women aged 40 or over, however, the relative likelihood of having a healthy baby reversed, with an 8.2 per cent chance of birth defects for those conceived naturally against just a 3.6 per cent chance for those conceived using ICSI.

Professor Michael Davies, who led the research, said: “There is something quite remarkable occurring with women over the age of 40 who use assisted reproduction.

“There is some aspect of IVF treatment in particular that could be helping older women to redress the maternal age issues we see among natural conception, where we observe a transition at around the age of 35 towards a steadily increasing risk of birth defects.

“We don’t know what that is quite yet – it could be an aspect of hormonal stimulation that helps reverse the age-related decline in control of ovulation.”

The study also revealed that the age at which women who are treated with both IVF and ICSI combined are most at risk of giving birth to an unhealthy child is 29, with a 9.4 per cent chance.

Professor Davies said his findings could have significant implications for infertility treatment if researchers can understand why older women do better on assisted reproduction.

However, Yacoub Khalaf, a consultant gynaecologist at Guys and St Thomas’s hospitals in London, pointed out that, despite the size of the overall study, the number of births in the over 40 group were “relatively small”, and said Professor Davies’ inferences could be the result of a statistical anomaly.

Frozen embryos are now as successful as fresh embryos in IVF treatments.

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Success rates in IVF cycles using frozen and thawed embryos are now equal to those using fresh embryos, a new report on reproductive technology (ART) treatments in Australia and New Zealand has found.

In the five years leading up to 2013, the birth rate for frozen embryo transfers grew by a quarter to 23 percent, whereas the rate of fresh embryo IVF cycles that led to a baby remained steady, also at 23 percent. Effectively, both methods now offer equal chances of a successful birth for parents looking into IVF.

 

In addition to success rates for frozen embryos rising, Australian and New Zealand parents are also turning to the technique in greater numbers, with IVF treatments using frozen embryos increasing from 39 percent of IVF cycles in 2009 to 45 percent in 2013.

The figures are contained in the Assisted Reproductive Technology in Australia and New Zealand 2013 report, authored by researchers at the University of New South Wales (UNSW) in Australia.

“Rapid freezing techniques, known as vitrification, and optimisation of the timing of embryo transfer have made a real difference to the success of frozen embryo birth rates,” said Michael Chapman, a professor of obstetrics and gynaecology at UNSW and vice-president of the Fertility Society of Australia (FSA), in a press release.

“Other techniques, such as culturing embryos for five to six days to a blastocyst, before transfer to a woman, and the use of pre-implantation genetic screening have also increased over the last five years of reporting,” said Chapman.

Another significant trend observed in the figures is a marked reduction in multiple births in IVF treatments, which have decreased by a third in the past five years to 5.6 percent in 2013.

Multiple births result in the delivery of twins, triplets, or higher-order multiples. As women age, they are more likely to experience multiple births, as their bodies may release more than one egg in order to fall pregnant – and the likelihood of multiple births is also significantly increased by the use of IVF and fertility treatments. However, delivering multiple babies can be dangerous to both a mother and her infants.

“Multiple births are by far the greatest health risk to mothers and babies from IVF, and multiple embryo transfer clearly increases this risk,” said Chapman. “This is one of the lowest rates of multiple deliveries from IVF treatment in the world.”

By comparison, the multiple birth rate is 16 percent in the UK and 26 percent in the US.

According to Chapman, the new figures suggest that Australia and New Zealand are the safest regions in the world for women to undergo IVF treatments. “Australia and New Zealand have the lowest IVF multiple birth rates of any region in the world,“ he said, ”and yet also maintain consistently high success rates.”

Test-tube baby pioneer Sir Robert Edwards dies.

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http://m.bbc.co.uk/news/uk-england-cambridgeshire-22091873