An embryologist looks through a microscope as he performs an ICSI – intracytoplasmic sperm injection.
CLEARWATER – Local women who have had a hard time getting pregnant may now have another option available to them.
Normally, if a woman fails to get pregnant after several cycles of in vitro fertilization, doctors do not have any techniques left to offer them other than using donor eggs, donor sperm or both. For many families, they have their hearts set on using their own sperm and eggs. The new, free THRIVE-IFV study could make that happen.
Doctor Edward Zbella, medical director for The Florida Fertility Institute in Clearwater, is administering one of the 20 study sites at his office. He said the study is for women who have had three unsuccessful attempts at in vitro fertilization, at least two of those being “fresh cycles” and, at most, one of those three being a frozen cycle, yet they’ve had good eggs and embryos.
“This study is looking at an immunogenetic agent to give to those women, in hopes that it would improve their chances of getting pregnant,” Zbella said. “And the thought is that these women, they have something going on within their uterus that basically is attacking the embryos. So macrophages. And by taking this research agent – or medication – it changes that and hopefully increases their chance of conception.”
Other inclusion criteria are that the women must be younger than 38, produced good quality eggs and at least two good quality embryos that are classified as “grade A.” They must have gone through three transfers of embryos with good quality embryos, with none of those resulting in a live born baby, Zbella said.
“The advantage of qualifying (to participate in the study) is that, one, we have something different to offer them for IVF,” Zbella said. “And two, the cost of the program – the entire IVF cycle, is going to be covered by the participating pharmaceutical company.”
The facts about infertility
There are many reasons someone may struggle with infertility, Zbella said. But in general, half of the fertility issues are on the male side, so some kind of trouble with the sperm. Most likely in this case, it is a low sperm count. The other half of the cases involves an issue on the female side.
“The most common reason a woman is not conceiving is that she’s not ovulating,” Zbella said. “So she has very irregular cycles. And usually that’s the easiest to solve and the easiest to evaluate. So those women have some hormonal tests done, and depending on those results, they typically go on fertility pills or fertility injections. If they have regular cycles, then the basic workup includes hormone testing, semen analysis, and then an X-ray called a hysterosalpingogram. And that X-ray determines whether their uterus is normal and whether their fallopian tubes are open.”
The results of those tests help determine the treatment of the patient. However, by the time Zbella sees them, usually they have already had all of those tests, and they come in with more advanced issues. Perhaps they have had a history of severe endometriosis, which may have caused scarring on the fallopian tubes. Perhaps the man has had a vasectomy reversal but his sperm count is still low.
Other more serious problems on the female side include blocked tubes due to infection, damage from prior surgeries or a previous tubal ligation, Zbella said.
“And then another large group is unexplained infertility,” Zbella said. “Meaning, they’ve been tested for all types of fertility factors, and nothing has come up. So there’s no apparent reason why they’re not getting pregnant. And a lot of times, those are the ones we do in vitro on. And a lot of times they may be unsuccessful because they may have some underlying immune issue that we can’t identify. And that’s why this study may be important to them.”
The first successful IVF pregnancy was in 1978 in England, and the first successful one in the United States was in 1981, Zbella said. The procedure stimulates the ovaries using fertility injections so they produce several eggs, he said. Doctors monitor the development of the eggs using ultrasounds and a blood test called estradiol. When the eggs appear mature, the patient is brought into the office to extract the eggs.
“They’re sedated, an ultrasound is then used to place a needle through the back of the vagina into the ovaries,” Zbella said. “The eggs are aspirated out. The procedure typically takes 10 minutes. The eggs are then fertilized in a Petri dish with the partner’s sperm. We would expect 70 percent of those matured eggs to fertilize. And then, in our program, three days after we retrieve the eggs, we would place the embryo or embryos back inside the uterus. And that’s dependent on the age of the patient and the quality of the embryos, which determines the number of embryos that we put back.”
For younger women under age 35, doctors would place one or two embryos back so they would not need to worry about having three or more babies at once. For older women, they may replace an additional embryo. Any extra embryos after the transfer can be frozen. That way, if the patient does not get pregnant in that round, they can thaw the embryos to use instead of having the patient go through all of the injections and the whole cycle again. Or, if the couple does get pregnant and want an additional child a few years later, they could use the frozen embryos at that time, Zbella said.
Many times it is unknown why someone suffers from infertility, but there are risk factors that can contribute to its likelihood. For instance, being overweight or obese could cause someone to have irregular periods, because as women gain weight, it affects their hypothalamus, which affects their pituitary gland, Zbella said. This affects their ovulation cycle, resulting in difficulties in getting pregnant. Tubal problems sometimes can be attributed to having a history of gonorrhea, chlamydia or prior abdominal surgeries, he added.
The ticking clock
There are many misconceptions about how long a woman is able to get pregnant, Zbella said. He said that women often feel they can get pregnant until they’re 50 or for as long as they are still having their period regularly.
“That’s a misconception,” Zbella said. “Because it’s extremely rare for a woman in their mid- to late-40s to conceive. Even though they’re typically ovulating on a regular basis. And the reason for that is their A-quality (eggs) have diminished so that those eggs don’t fertilize. Or if they do fertilize, they don’t result in a pregnancy because those embryos are typically genetically abnormal.”
It doesn’t help that many celebrities are seen having babies in their 40s and 50s, and many of Zbella’s patients point to them as proof that they, too, can get pregnant at an older age.
“What I say to them is look at what they had,” Zbella said. “Many have twins, and the reason they have twins is that they used donor eggs. Eggs from a younger woman that they fertilize and that the movie star carried. But that’s not mentioned in the stories on the birth of these children. So a lot of laypeople feel that they can conceive just like the movie stars. But we have an inside connection with a friend of ours in Hollywood, and most of these women have used donor eggs.”
When a girl is born, she already has all the eggs she will ever have. By the time she reaches puberty, it is estimated that she has about 300,000 eggs, Zbella said. Each month, about 1,000 eggs start to process toward maturation. However, at the end of that month, only one egg matures and ovulates, and that is the egg that could result in conception. The other 999 eggs die.
“So basically, women use up their best quality eggs when they’re young, and when they get older, that A-quality diminishes. And as that A-quality diminishes, that results in lower fertilization rates, therefore lower chances of conception and decreased fertility,” Zbella said. “It results in a higher rate of chromosomal abnormalities like Downs syndrome. And because it has a higher risk of chromosomal abnormalities, miscarriages also increase with age.”
Therefore, Zbella said that most reproductive endocrinologists say that up until age 35, the average woman has a good chance of conception. But after that, the ovarian reserve starts to diminish. Typically, age 43 is the last year Zbella said his office can usually get someone pregnant using their own eggs.
The success of a normal IVF process – without being a part of this study – depends on each woman’s situation, Zbella said. If the initial issue was lack of ovulation, for the women who are put on fertility pills, about 70 percent of those women will be able to ovulate, he said. Of those who are then able to ovulate, another 70 percent of those women will conceive within six months, he added. For those patients placed on fertility injections, Zbella said 99 percent of them will be able to ovulate, and a majority of those women will conceive within three months.
If the problem is with the sperm, it depends on the sperm count and the quality of the sperm motility, he said. One solution could be insemination, which could get the couple up to the normal pregnancy rate, which is typically about 20 percent a month. If the sperm count is very poor, the chance of them getting pregnant is about 5 percent, and those are the cases Zbella says his office pushes toward IVF. At that point, success largely depends on the age of the woman. For a 21-year-old woman, she has a 75 percent chance of pregnancy per cycle with IVF, Zbella said. With a 30-year-old woman, the likelihood decreases to 50 percent. A 40-year-old woman would have just a 10 percent chance for pregnancy per cycle.
What is this study all about?
Infertility treatment can be relatively inexpensive if all one needs is fertility pills – the initial tests are either covered by insurance or else cost maybe $100, Zbella said. If fertility pills are needed, those cost maybe about $25 a month, he said. However, then things start to get more expensive. If the woman had previously had her tubes tied, a tubal reversal costs around $5,000, he said. But by far, IVF is the most expensive procedure, which is about $12,000 each time. Therefore, an additional – and big – benefit for participating in the study is getting the IVF for free.
“And keep in mind, if you’ve done this three times and have not been successful, no matter what someone offers you (otherwise,) it’s really a roll of the dice,” Zbella said. “So the problem is, up until this study, there was not anything else to offer these women. And on top of it, for those women, there’s no cost to participate in the study.”
The women in the study will be given a medication by injection – they will be trained how to give these to themselves, similar to an insulin shot. This agent – medication – has never been used for IVF, Zbella said, which is why this offers an advantage and uniqueness.
“So in theory, what it’s doing is having an affect on the immune system within the uterus itself,” Zbella said. “Basically it’s saying to the uterus that we’re going to decrease the rejection of the foreign tissues, i.e. the embryo. And it does that by increasing neutrofils and increases stem cells and it probably has some unknown effects.”
This drug may increase pregnancy rates for all women, Zbella said. But they are taking the most difficult group of women – those who have already failed to have a baby through three or more IVF cycles with good quality embryos – and seeing if this helps increase pregnancy rates.
This will be a double-blinded study, meaning the patient will not know if they are getting the actual drug or a placebo. Likewise, the doctors, like Zbella, will not know which the patient is getting, either, until the study is complete. At the end, professionals will look at the two groups out of the 120 total participants, and see if one group had more pregnancies than the other.
A Phase I safety study has already been conducted, and now the study is in Phase II. Observations have shown that this drug increases one’s white blood cell count, Zbella said. The patients are monitored to make sure that this level starts to decrease after the initial spike.
“In this case, it’s thought that the nutrofils will have a positive affect on any of the immunosuppressant problems (that may be preventing a pregnancy,)” Zbella said. “It will override that and may help with the implantation of the embryos and may stimulate stem cells, which may have the same type of benefit.”
A crude example to help explain this, he said, is to imagine taking a kidney and placing it in one’s spouse. In all likelihood, the partner would reject the kidney because the tissue types are different.
“We give patients immunosuppressant agents when we do kidney transplants, even when the tissue type is very, very similar, because the chance of rejection is so high,” Zbella said. “When a woman becomes pregnant, the resulting embryo is a combination of her tissue type and her partner’s tissue type. And so when that embryo enters the uterus, whether it’s naturally or through in vitro fertilization, in theory, it should not implant. The uterus should reject that embryo because it has different tissue types than the woman. But that obviously doesn’t happen. In most women, it implants and it grows. And the reason for that is there are blocking antibodies that prevent the immune system from recognizing that tissue and allowing it to not be attacked by the immune system.”
The uterus has its own immunosuppressant factors and its own macrophages, Zbella said. While in normal circumstances, an embryo is not rejected, obviously there are some women that even with good quality embryos, they cannot get pregnant. The doctors involved in the study wonder if this is because of factors in the immune system. If so, they hope that this new drug can help override the system and allow embryo implantation to occur.
The Florida Fertility Institute is one of a number of clinics in the nation to participate in this study. So far, Zbella has several women in the study, including one from Melbourne, one from Orlando, and a few from his practice. So far, one of those patients is pregnant with twins. He does not know if she was one of those given the actual drug, but he is hopeful, because if this works, it could make a huge difference for so many women.
Gradually, women across the country will be added to this study, and any resulting pregnancies will be monitored. It will probably take about a year to fully recruit patients, then another year to await the outcome of the pregnancies and analyze the data, Zbella said. If it seems the drug was successful, then it will be presented to the FDA. At that point, the FDA may want another study, or it could say this study was enough, he said. Then, the sponsoring pharmaceutical company – NORA Therapeutics – will apply for a new drug application, get screened, and all the studies that have been done will get analyzed by a committee with the FDA, Zbella said. If all goes well, it would get approved. Though even if everything goes perfectly, it probably is at least three years before this drug would make it to the market.
If women think they may qualify and are interested in participating in the study, they can call the Women’s Medical Research Group at 724-9730 or the Florida Fertility Institute at 796-7705. For more information about the clinical trial, visit www.thriveivf.com