10 Years of Fertility Advances

How a decade of major discoveries has dramatically changed how we think about conception.

By Julia Calderone

  • April 19, 2020
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This article was originally published on December 11, 2019 in NYT Parenting.

On July 24, 2003, Robert G. Edwards, a physiologist who pioneered the in vitro fertilization technique, made the following remark: “I wanted to find out exactly who was in charge, whether it was God himself or whether it was scientists in the laboratory,” adding, “It was us.”

Since the first I.V.F. baby was born in 1978 — 25 years before Dr. Edwards made that statement and 32 years before he would win the Nobel Prize in Medicine for developing the technique — the seemingly supernatural ability to unite sperm and eggs outside the body and implant them directly into the womb has been heralded as the most remarkable achievement in fertility to date. “It’s allowed millions of babies to be born that otherwise would not have been born; I think it’s been revolutionary,” said Dr. Mindy Christianson, M.D., medical director of the Johns Hopkins Fertility Center.

Now, as this decade comes to a close, what kinds of major advancements in fertility science have we seen since 2010? While we’re still a far cry from a future in which a woman can analyze her egg reserve with the tap of a smartphone, or in which a man can get a running tally of his sperm count with the flick of a smartwatch, the past 10 years have been no less remarkable than decades past. Here are some of the biggest breakthroughs in fertility since 2010.

1. Egg freezing is no longer considered experimental

Scientists have been able to easily freeze embryos and sperm for decades, but it wasn’t until 2012 that egg freezing went from an experimental procedure to a promising insurance policy for thousands of women in the United States, including cancer patients, single women and those who want or need to delay having children. “The ability to successfully freeze eggs over the last 10 years has been one of the bigger, if not the biggest, achievement,” Dr. Christianson said.

This is largely because of the development of a flash-freezing technique called vitrification. Previously, human eggs — which are the largest cells in the human body and hold a lot of water — were challenging to freeze because ice crystals would develop and damage the cell. But with vitrification, experts can freeze the cells so quickly that ice crystals don’t have a chance to form.

2. We can more reliably select the best embryos for I.V.F.

I.V.F. is expensive, not to mention emotionally and physically taxing. It’s important, then, that providers select the best and most competent embryos from the petri dish in the lab to implant into the womb. While experts have for more than 10 years been able to scan the genetic material of these rudimentary cells for signs that they might fail to implant or result in miscarriage or birth defects, genetic testing of embryos has become more mainstream, affordable and reliable in the past decade.

 “When I was still in training seven or eight years ago,” Dr. Christianson said, “it was cost-prohibitive for most patients to do genetic testing of their embryos.” Today, she said, companies charge per embryo, making it much more affordable.

Another advancement that has allowed providers to select the most robust embryos to implant: the ability to grow them in the lab until they reach what is called the blastocyst stage (which occurs five or six days after fertilization). If an embryo is healthy enough to survive until this stage outside the body, the thinking goes, it has a higher chance of sticking around after implantation. Such advances in selecting the best embryos have also allowed providers to transfer just one, rather than multiple, embryos into the womb at a time, reducing the risk of twins or more — and thereby reducing risk in the pregnancy.

“With the right embryo, most women will have a very high chance of live birth, and we’re able to decrease that risk of multiples,” Dr. Christianson said. “So I think that’s one of the revolutionary breakthroughs.”

3. Uterus transplants have become less like science fiction

Before the 2010s, the only parenting options for women who didn’t have a uterus or who couldn’t carry a pregnancy were adoption or surrogacy. But in 2013, doctors in Sweden made history after a 35-year-old patient, who had had a uterus from a 61-year-old woman transplanted, gave birth to a healthy boy. In 2016, doctors in Brazil advanced the technique even further, announcing that a 32-year-old woman had given birth with a uterus that had been transplanted from a deceased donor.

While these breakthroughs are huge for reproductive science, Dr. Christianson said, uterine transplants are also expensive. “It’s the only transplant we know of that is for a one-time use to make a baby and then you don’t need the transplant anymore,” she said. So while this procedure is revolutionary for the right type of patient, it most likely won’t become mainstream.

4. Men who were previously considered ‘infertile’ have more options

One of the biggest achievements for male infertility, said Dr. Peter Schlegel, M.D., urologist in chief at New York-Presbyterian Hospital/Weill Cornell Medical Center and president of the American Society for Reproductive Medicine, has been in the treatment of those with severe infertility. Particularly in men who produce little to no sperm, he said, or who had previously been rendered “sterile” because of treatments like chemotherapy.

A technique called micro-TESE — which was developed in the late 1990s, improved in the 2000s and more popularized in the past decade, Dr. Schlegel said — involves identifying areas of the testicle that have the best sperm production and microsurgically removing those sperm for use with assisted reproductive technologies like I.V.F.

“A lot of those men are now considered treatable,” Dr. Schlegel said, “whereas before, our understanding of how and whether you could treat them was pretty limited.”

[What to know about male infertility.]

5. We have more IUD options

Intrauterine devices have had a decidedly rocky past. The first known IUD-like device for humans, developed in 1909, reportedly involved inserting a “ring made of silkworm gut” — seriously — into the uterus. Since then, IUDs have advanced from silkworm rings wrapped entirely in silver (which, surprise, turned women’s gums blackish-blue) to countless variations of loops, coils and plastic Ts. In the 1970s, the Dalkon Shield IUD was infamously pulled from the market after its poor design increased women’s risk of infection and infertility. But in the late 1980s and early 2000s, the IUD regained popularity with the Food and Drug Administration’s approval of the copper ParaGard and levonorgestrel-releasing Mirena.

It wasn’t until 12 years later, in 2013, that the F.D.A. approved the next IUD, the Skyla, which is a low-dose hormonal option. In 2015 and 2016, the agency approved even lower-dose options — the Liletta and the Kyleena. “These IUDS have really revolutionized contraception because they’re highly effective and they are very well tolerated,” Dr. Christianson said.

They are also valuable therapies for women with certain conditions, like heavy uterine bleeding, which in the past was mainly treated by performing a hysterectomy. “Less women are undergoing hysterectomies because their symptoms can be treated with an IUD,” Dr. Christianson said.

6. We’re better at freezing ovarian tissue for later use

For women who can’t freeze their eggs, like prepubescent girls or women who suddenly need cancer treatment, ovarian tissue freezing has offered a chance for them to preserve their ovaries for later reimplantation and use. The procedure has been available for about 20 years, Dr. Christianson said, but within the past 10 years, there have been several advances in the technique and more live births as a result.

Because most people who have frozen ovarian tissue haven’t needed to use it yet, the procedure is still considered experimental. “Hopefully at some point the experimental label will be lifted,” Dr. Christianson said.

7. We’re getting a better understanding of how lifestyle affects fertility

It’s perhaps not surprising that diet, sleep and exercise play a role in fertility. And while scientists are still in the early stages of sussing out how the food we eat and the sleep and exercise we get translate to prolificacy, recent — albeit limited — evidence is offering more clues.

2018 review from scientists from Harvard University, for instance, found that folic acid, vitamin B-12, omega-3 fatty acids and a Mediterranean diet were linked with better fertility in women, while “unhealthy” diets, like those high in trans fats, red and processed meats, added sugars and sugar-sweetened beverages, were associated with worse fertility. In men, similarly, researchers have found that those who follow healthy diets tend to have better fertility, while those with diets high in saturated and trans fats are worse off.

There is also budding evidence about how exercise and sleep affect virility in men, Dr. Schlegel said — and some of the results seem counterintuitive. Moderate exercise, for instance, seems to be beneficial, but when those men exercise more vigorously — such as by cycling for more than five hours per week, he said — their sperm counts can be reduced by nearly half. Men who get six to eight hours of sleep per night tend to have better sperm production and fertility than those who get more or less, Dr. Schlegel said.

While many of these studies are promising, most are based on observational data, Dr. Schlegel said, so it’s not yet clear why researchers are seeing such associations, or whether changes to diet, sleep and exercise can really alter your fertility in the first place.

8. More women are included in clinical trials

For the bulk of the past century, fertile and pregnant women have been excluded from most clinical trials over fears of potential harms to future or current pregnancies. But as a result, there is a huge gap in knowledge about how safe and effective certain drugs are for women in general (case in point, the thalidomide debacle of the 1950s and 1960s).

More recently, there has been a major push for better representation of women in medical research.

“For women’s health in general, I think that this is a breakthrough,” Dr. Christianson said. “When we look at cardiology studies and other types of studies, a lot of times there’s been more men than women. So I think focusing studies on women has been revolutionary for women’s health.”

9. We’re getting a better grasp on pre-eclampsia

While the textbook signs and symptoms of pre-eclampsia have been well understood — high blood pressure, protein in the urine, swelling, headache, trouble breathing and more — scientists still don’t understand what causes the condition, and diagnosing it and predicting those who will develop it are challenging. Similarly, the most effective treatment for pre-eclampsia is also the least satisfying one — delivery.

But research in recent years has helped improve our understanding of how the condition progresses in the body, said Dr. Ananth Karumanchi, M.D., a professor of medicine at Cedars-Sinai Medical Center in Los Angeles. And that research has led to development of the first blood test — which has been widely used abroad — that can accurately diagnose the condition in women who have pre-eclampsia. While the test has not yet been approved in the United States, Dr. Karumanchi said that its development was a big deal because it might lead to new therapies for pre-eclampsia within the next decade.

The definition of pre-eclampsia was revised in 2014, based on new evidence, to capture women who have the condition but who don’t have only the classic signs, like high blood pressure and protein in their urine. Now, for instance, it is well understood that some women may have only organ problems, such as with their liver or kidneys, before high blood pressure and protein in the urine set in.

New research has also offered clues on how women who are high risk might thwart the condition completely. A double-blind, placebo-controlled trial published in 2017, for example, found that taking 150 milligrams of aspirin daily from 11 to 14 weeks of pregnancy through the 36th week could reduce the chances of developing pre-eclampsia. Though because high doses of aspirin can also be associated with certain risks to a pregnancy, like pregnancy loss or certain birth defects, you should never start taking it without consulting your doctor.

10. We have better fertility-preserving surgeries for cancer patients

In the past, a cervical cancer diagnosis might have meant the end of your ability to conceive, because standard treatment was to remove all or part of the uterus. But recent advances in fertility-conserving surgeries have given cancer patients more options. A procedure called a trachelectomy, for instance, which has been around for decades but has become more commonly used in recent years, allows doctors to remove only the cervix in patients who have cervical cancer. “And as a result, she’s able to preserve her uterus for future pregnancy,” Dr. Christianson said.

Similarly, there has been a push in recent years to treat endometrial cancer more conservatively, Dr. Christianson said, by trying hormonal therapies before removing the uterus.


Julia Calderone is a senior staff editor for NYT Parenting. Follow her @juliacalderone.

(Source: The New York Times)

Improving IVF success rates

Faster, cheaper and less damaging to DNA, a microchip device that pits sperm racing against one another is being developed by Afrouz Ataei from Florida Atlantic University and may help to improve IVF success rates in the future.

Ataei is presenting the fitness stats on the sperm sorted by her device this week at the American Physical Society March Meeting in Boston, and she will also participate in a press conference describing the work. Information for logging on to watch and ask questions remotely is included at the end of this news release.

“An integral part of in vitro clinical procedures is the isolation of motile and morphologically normal viable sperm from the semen,” said Ataei, who explained that this step increases the chances of successful egg fertilization in plastic dishes outside the body (in vitro).

However, the conventional method used to sort the speediest sperm involves centrifugation and several high-speed, G-force inducing spinning steps, which can damage the delicate DNA encased within a sperm’s head. And an egg fertilized with sperm damaged in this manner is unlikely to progress to a viable embryo for implantation into the womb.

In women under 35 there is only a 21.5 percent chance of a single round of in vitro fertilization, or IVF, resulting in a full-term live birth. And with each round of IVF in the U.S. costing an average of $10,000-$15,000, this makes improving the odds of IVF success key for the financial and emotional well-being of many of the couples who experience fertility problems.

Ataei’s device manages to select the faster swimmers without any damaging centrifugation steps. Instead, her device exploits the observation that sperm swim against an opposing flow of liquid at certain flow rates. The microchip is designed to induce hydrostatic pressure, which generates liquid flow without the use of other equipment.

“No other devices generate the flow in this way, and our device is much easier to use,” said Ataei.

An unprocessed semen sample is injected into the chip’s inlet until it fills the lower microchamber, and the sperm gradually swim upstream against the flow. If fit and fast enough, the sperm make it past the ultrathin membrane filter, which acts as the finish line, and into the top chamber. Ataei has analyzed the winner’s fitness stats.

“After 45 minutes we collect the sample from the top retrieval chamber and start observing and analysing the sperm’s velocity, whether they have DNA fragmentation, and what’s the percentage of this compared with current methods like centrifugation,” said Ataei. “We found that at a specific flow rate, we get the most motile sperm with highest motility.”

“I think this device has potential for clinical use,” Ataei added.

The team at Florida Atlantic University is continuing to optimize the microfluidic device, hoping to increase the concentration of sperm collected in the top chamber before they file a patent on their design.

Date: March 4, 2019

Source: American Physical Society Source: https://www.sciencedaily.com/releases/2019/03/190304095727.htm

New mathematical model can help explain why so many pregnancies and IVF attempts fail

Reviewed by James Ives, M.Psych. (Editor)Apr 13 2020

Scientists have created a mathematical model that can help explain why so many pregnancies and in vitro fertilization attempts fail.

The Rutgers-led study, which may help to improve fertility, is published in the journal Proceedings of the National Academy of Sciences.

Mistakes in female meiosis, the cell division process that creates egg cells, result in eggs with an abnormal number of chromosomes (too many or too few). This phenomenon is strongly associated with the repeated loss of pregnancies and the failure of in vitro fertilization (IVF) procedures, as well as developmental disorders such as Down syndrome.

Our study demonstrates that in the future, mathematical models can be powerful tools for predicting the outcomes of in vitro fertilization for infertility patients and/or provide the basis for considering alternative family planning options, such as adoption.”

Jinchuan Xing, senior author, associate professor in the Department of Genetics in the School of Arts and Sciences and at the Human Genetics Institute of New Jersey at Rutgers University–New Brunswick

“Modeling efforts such as ours can provide guidelines on, for instance, how many eggs must be collected during a single IVF cycle to ensure there will be at least one chromosomally normal conception,” said co-author Karen Schindler, an associate professor in the Department of Genetics and at the Human Genetics Institute of New Jersey.

Pregnancy loss is extremely common, with nearly 20 percent of clinically recognized pregnancies resulting in miscarriage, and many more unrecognized pregnancies end earlier, the study notes.

A leading cause of early miscarriage is called aneuploidy, when eggs have the wrong number of chromosomes, and it’s also the main cause of IVF failure. The vast majority of eggs with chromosome problems are linked to errors in female cell division that increase as women age. Understanding how that happens is crucial because the average age at conception is rising in developed countries.

“Such basic knowledge is required to pave the way for future diagnostic and therapeutic innovations to improve human fertility,” the study says.

The scientists developed a mathematical model describing all possible abnormal chromosome count issues in eggs due to cell division errors. Using data on 11,157 early stage human embryos (blastocysts), the model revealed previously unknown patterns of errors.

The model can be used to identify IVF patients who produce an extreme number of abnormal embryos. It’s also a powerful tool for understanding why abnormal numbers of chromosomes arise when cells divide and for predicting the outcomes of IVF reproduction. The model potentially could provide guidance for clinicians on the expected number of IVF cycles needed to get a normal conception for each patient. The modeling framework can also be expanded and adapted to address other processes, such as predicting errors in sperm.

Source: https://www.news-medical.net/news/20200413/New-mathematical-model-can-help-explain-why-so-many-pregnancies-and-IVF-attempts-fail.aspx

Researchers develop safe, accurate 3D imaging method to improve IVF treatments

Tel Aviv University (TAU) researchers have developed a safe and accurate 3D imaging method to identify sperm cells moving at a high speed.

The research, a study of which was published in Science Advances on April 10, was led by Prof. Natan Shaked of the Department of Biomedical Engineering at TAU’s Faculty of Engineering together with TAU doctoral student Gili Dardikman-Yoffe.

The new technology could provide doctors with the ability to select the highest-quality sperm for injection into an egg during IVF treatment, potentially increasing a woman’s chance of becoming pregnant and giving birth to a healthy baby.

The IVF procedure was invented to help fertility problems. The most common type of IVF today is intra-cytoplasmic sperm injection (ICSI), which involves sperm selection by a clinical embryologist and injection into the woman’s egg. To that end, an effort is made to select the sperm cell that is most likely to create a healthy embryo.”

Natan Shaked, Professor, Department of Biomedical Engineering, Faculty of Engineering, TAU

Under natural fertilization in the woman’s body, the fastest sperm to reach an egg is supposed to bear high-quality genetic material. Progressive movement allows this “best” sperm to overcome the veritable obstacle course of a woman’s reproductive system.

“But this ‘natural selection’ is not available to the embryologist, who selects a sperm and injects it into the egg,” Prof. Shaked says. “Sperm cells not only move fast, they are also mostly transparent under regular light microscopy, and cell staining is not allowed in human IVF.

“Existing imaging technology that can examine the quality of the sperm’s genetic material may cause embryonic damage, so that too is prohibited. In the absence of more precise criteria, sperm cells are selected primarily according to external characteristics and their motility while swimming in water in a dish, which is very different from the natural environment of a woman’s body.

“In our study, we sought to develop an entirely new type of imaging technology that would provide as much information as possible about individual sperm cells, does not require cell staining to enhance contrast, and has the potential for enabling the selection of optimal sperm in fertilization treatments.”

The researchers chose light computed tomography (CT) technology for the unique task of sperm cell imaging.

“In a standard medical CT scan, the device rotates around the subject and sends out X-rays that produce multiple projections, ultimately creating a 3D image of the body,” says Prof. Shaked. “In the case of the sperm, instead of rotating the device around this tiny subject, we relied on a natural feature of the sperm itself: Its head is constantly rotating during the forward movement.

“We used weak light (and not X-rays), which does not damage the cell. We recorded a hologram of the sperm cell during ultrafast movement and identified various internal components according to their refractive index. This creates an accurate, highly dynamic 3D map of its contents without using cell staining.”

Using this technique, the researchers obtained a clear and accurate CT image of the sperm at very high resolution in four dimensions: three dimensions in the space at resolution of less than half a micron (one micron equals one millionth of a meter) and the exact time (motion) dimension of the second sub-millisecond.

“Our new development provides a comprehensive solution to many known problems of sperm imaging,” Prof. Shaked says. “We were able to create high-resolution imaging of the sperm head while it was moving fast, without the need for stains that could harm the embryo. The new technology can greatly improve the selection of sperm cells in vitro, potentially increasing the chance of pregnancy and the birth of a healthy baby.

“To help diagnose male fertility problems, we intend to use our new technique to shed light on the relationship between the 3D movement, structure and contents of sperm and its ability to fertilize an egg and produce a viable pregnancy,” Prof. Shaked concludes. “We believe that such imaging capabilities will contribute to other medical applications, such as developing efficient biomimetic micro-robots to carry drugs within the body.”

Source:

American Friends of Tel Aviv University

Journal reference:

Dardikman-Yoffe, G. et al. (2020) High-resolution 4-D acquisition of freely swimming human sperm cells without staining Science Advancesdoi.org/10.1126/sciadv.aay7619.

(Source: https://www.news-medical.net/news/20200508/Researchers-develop-safe-accurate-3D-imaging-method-to-improve-IVF-treatments.aspx)