Q: How do you counsel patients after a failed IVF? What can you and patients learn from a failed cycle to help decide on next steps in fertility treatment?
Dr. Oskowitz: This is a very important visit- when a patient comes in and a pregnancy has not occurred yet after IVF. I certainly empathize with the patient and what the couple has been through. I go through a whole process of studying the details of their failed IVF cycle, along with a review of their reproductive history and medical findings.
I always make sure the couple is aware that in most cases, a failed IVF cycle is due to the fact that the embryos transferred were not genetically normal. That is the hidden part of the standard IVF process: We don’t know the genetics. We make a judgment call on which embryos are likely to be genetically normal based on their appearance under the microscope, and we transfer them to the womb.
Aneuploidy, or chromosomal abnormality, is a genetic condition -- usually random and infrequently heritable -- that is not easily recognizable. But it is very prevalent in the majority of infertility patients. The embryos we choose for transfer may be the wrong ones. If there is a sufficient number of good quality embryos, they would typically be cryopreserved [frozen], and I would counsel the patient to have those embryos thawed and transferred. That may just work. If that still doesn’t lead to a pregnancy or the patient does not have frozen embryos available, it may be a matter of simply repeating the cycle. We hope the next one or two embryos chosen will be normal and make all the difference for a successful cycle.
But if that isn’t the reason for the failed IVF cycle, there are two other big factors to explore. One is to look at how the patient responded to hormonal drugs stimulating the ovaries to provide the eggs. The other is to look at the receptivity of her uterine lining to enable a healthy embryo to implant.
Q: If the most common reason for a failed IVF is a genetic abnormality in the embryo, can pre-implantation genetic screening tests (PGS) help?
Dr. Oskowitz: We offer pre-implantation genetic screening tests, but only 1% to 2% of our patients choose to do this. It’s expensive. There is also some concern about the loss of the “power” of healthy embryos if you do a biopsy on them. Recent data came out showing a very nice success rate using PGS with the biopsy of embryos on Day 5. There is somewhat less of an impact on the embryo by Day 5, when the embryos are at the blastocyst stage.
Q: You also review other factors, including a past response to ovarian stimulation. What do you look for?
Dr. Oskowitz: We look at [the patient’s] response to ovarian stimulation to gauge factors that go into making a good egg and therefore a good embryo. We look at the follicle size, number of follicles, egg retrieval, the maturity and grading of the embryos, the number of embryos that were fertilized, and the growth pattern of the fertilized embryos. Clinically, one can get a fairly good idea of the prognosis, or what was expected from that response. A good response is anywhere from 10 to 15 eggs with 30% to 50% ultimately reaching the blastocyst stage. If the opposite was found, we can discuss improvements to be made on the next attempt.
Q: What specific changes could you make in the next cycle to improve chances of IVF success?
Dr. Oskowitz: For patients whose egg quality and embryo quality could be improved, we could adjust the ovarian stimulation, switch to alternative medication, lower or increase the dose. For instance, we can look to see if the patient’s estrogen rise was normal. If it was slow or excessive, we might make an adjustment in the starting dose. Most of the time, the medication is a pure FSH (follicle-stimulation hormone) product. Or, looking at multiple other factors, we may feel the patient’s LH (luteinizing hormone) is too suppressed, and we may add medications with some LH activity.
We may also want to lower the dose, so we don’t run into the problem of high estrogen. High estrogen can have negative effects on eggs and therefore, embryos. If the patient’s response to ovarian stimulation was too rapid, we may decide to switch to what’s called an antagonist hormone medication to “down-regulate” the cycle. That’s where you stimulate the patient to more of a resting phase before starting stimulation again. Occasionally, we will adjust the analog hormone medication used. GnRH analogs (gonadotropin-releasing hormone analogs) are used to control and prevent ovulation. If we feel a patient is over-suppressed, we can switch to an antagonist to have control over ovarian stimulation without too much suppression.
Q: What kinds of factors do you review to assess a patient’s uterine “receptivity”?
Dr. Oskowitz: If we feel a patient’s embryo quality was good or in the high range, we focus more on receptivity. Receptivity is a term that’s fairly vague but describes the health aspects of a woman’s uterus, endometrium, general health, and emotional health. There are factors we can look at to see if they could explain why good embryos didn’t implant (see next question). We look also at background factors, including age, how long the patient has been trying, how many IVF cycles she has had, and ovarian reserve testing to factor into expectations and where we can look for improvements or alternative treatments.
Q: Can you give us some examples of uterine factors that you consider?
Dr. Oskowitz: We look at endometrial thickness. A well-developed, thick uterine lining is more likely to support implantation. We like seven millimeters or more. We also like the texture of the endometrium to be robust. We like a “trilaminar” appearance, or a triple-line pattern on ultrasound. That suggests development of a healthy uterine lining.
We also like to see if there is anything in the uterus itself that could negate implantation and lead to a failed IVF cycle. We may find multiple or large fibroids particularly if they abut or distort the endometrium. Or we may have known about fibroids but decided initially that they wouldn’t affect the IVF results. We may need to revisit the question and decide to remove fibroids surgically. Many other aspects of the uterus can also give us insights. Adenomyosis, where glands of the lining of the uterus are found deeper in the muscle of the uterus, may also lead to lower receptivity. Also, the cavity of the uterus can be revisited by a hysteroscopy, where scarring, septation, and other disorders may be corrected.
Q: What other factors might cause the embryo not to implant?
Dr. Oskowitz: We also look at the embryo transfer process itself. Was it easy and comfortable to place the catheter in uterus, or difficult? If it was difficult, it may be difficult for the embryo to implant in the uterus. If that’s the case, we can offer a mapping procedure. That would involve looking at the cervix with a hysteroscopy and looking into the cavity of the uterus to see if the opening to it (internal os) is deviated to one side or another, adding measurements, and even stretching the cervix to make an easier transfer in the future.
Q: What aspects of the patient’s general health do you assess to improve chances of IVF success the next time?
Dr. Oskowitz: The third component we look at to assess receptivity is the health of the mother. For example, we make sure her thyroid is functioning normally and that there are no other diseases that could cause IVF failure. So, if diabetes is poorly controlled, we insist that it be tightly controlled. If the patient is overweight, we place added emphasis on that, because an overweight patient might have lower receptivity. Other things such as Vitamin D levels can impact on receptivity, too.
Q:What steps can you take to improve receptivity for better chances of IVF success the next time?
Dr. Oskowitz: After making our assessment, we’ll have sense of direction where we feel improvements can be made, and I will discuss with the patient to see if she is comfortable with them. For instance, on the question of addressing fibroids, many patients may not want to address that, especially if it involves surgery. The data may not be that powerful in some areas of receptivity, such as the role of fibroids. The couple, with their physician, may make the decision to try another cycle without correcting the fibroid or adenomyosis where correction is difficult and unproven.
In the majority of cases, we may find nothing in this review of receptivity. We will simply repeat the cycle, or we will use some of the frozen embryos available from the prior cycle. Another technique gaining attention is the pre-cycle, so-called “scratch” endometrial biopsy. Even if this shows normal findings under the microscope, the tissue injury to the endometrium may create a more receptive immune response.
Q: Any concluding remarks?
Dr Oskowitz: As you can see most of our assessments on a failed IVF cycle may give only some insight into the expectations for another cycle. Also the corrections themselves are fraught with variability and some questionable effectiveness. For most patients who have reasonable probabilities for IVF to work, it may just be a matter of trying a few times.
“Fertility Chronicles” reposts an op-ed by Univfy Co-founder and CEO Mylene Yao, M.D., that first appeared on Wired.com on Sept. 26, 2013. In it, Dr. Yao responds to a Sept. 11 New York Times op-ed, raising concerns that fertility patients, encouraged by the medical community, continue to pursue treatments even if they are ineffective.
Dr. Yao explains that Univfy IVF Prediction Tests, which provide patients with highly accurate, personalized predictions of their chances of IVF success, offer an answer. When fertility patients know their probability of success, they can make more informed and effective choices regarding treatment and other family-building options.
From Wired.com, September 26, 2013:
Empower Fertility Patients to Understand Their Chances of IVF Success
Posted by Mylene Yao on September 26, 2013 at 9:30 a.m.
Most men and women are hard-wired to give birth, nurture and raise families. That biological drive, as important as survival instinct, has kept our species alive. For over 7 million American couples 1 who suffer from infertility, this drive is just as alive and present, and it has become a source of great controversy.
When over 5 million babies around the world have been born thanks to IVF, we know the science can work. We also have an opportunity -- and a responsibility -- to mitigate the risks and sorrows of ART with rigorous knowledge and data, rather than rejection. 14 million Americans, more than the number living with treated and active cancer, are depending on that.
Never mind what is generally believed to be the IVF success rate. The most important questions are: What are your chances of having a baby with your first IVF? What are your chances without IVF? If you’ve had IVF before, what are your chances of having a baby if you do IVF again? What is the success rate that you will tolerate, and at what emotional and financial costs?
I have devoted the last fifteen years to researching reproductive medicine with the support of the National Institute of Health (NIH), Stanford University and other academic centers and institutions. Over the past few years, I have had the privilege of learning about patients’ concerns directly, and through surveys and social media. I have also discussed with many IVF doctors how they counsel their patients about IVF success rates.
Doctors whom I’ve met have diligently compiled ART statistics and have provided the rates of treatment success and failure to patients with sincerity and honesty. However, most national online reporting of IVF success rates across clinics are designed for safety monitoring and quality assurance, and do not provide the level of personalization and accuracy necessary to support an individual’s decision-making.
My research team, originally from Stanford University, has conducted studies with leading IVF clinics and has repeatedly demonstrated that analyses of a patient’s comprehensive health data can provide more accurate than conventional age-based estimates and can better distinguish patients with truly different probabilities of success. With prediction technology, we found that up to 60-80 percent of patients have different success rates than those estimated by age, and more than half of patients have a higher predicted probability of success than what is estimated by age. 2,3,4,5
We found that by the time a woman has experienced one failed IVF, her age contributes to only 40 percent of the IVF success prediction, while her health data, including data learned from her failed IVF (e.g. blood and ultrasound test results during IVF stimulation and embryo quality), contributes to 60 percent of the prediction. That means age-based estimates are no longer useful after a patient has had one IVF. Therefore, the key to saving women from a missed opportunity—or a slippery slope—is to illuminate the meaningful use of comprehensive health data and its predictive value when counseling patients faced with these tough decisions. 3,4
Make no mistake about it: patients will continue to face tough decisions. But with dedication, scientific rigor and collaboration, we can help to empower patients to make better decisions with confidence.
1. U.S. Department of Health and Human Services, CDC, NCHS. Fertility, family planning, and reproductive health of U.S. Women: Data from the 2002 National Survey of Family Growth. Vital and Health Statistics. 2005. 23(25).
2. Banerjee P, Choi B, Shahine LK, et al. Deep phenotyping to predict live birth outcomes in in vitro fertilization. PNAS 2010;107(31):13559-60.
3. Choi B, Bosch E, Benjamin ML et al. Personalized prediction of first-cycle in vitro fertilization success. Fertil Steril. 2013. doi: 10.1016/j.fertnstert.
4. Choi B, Santo-Domingo K, Penzias A.S. et al. Turning past IVF data into personalized prognostics through a validated, multi-center IVF prediction model. Abstract. Presented at the Society for Gynecologic Investigations, Orlando, FL. 2013.
5. Although knowing an accurate and personalized prediction of IVF success (in terms of having a baby) is important, patients need to learn the information that is conveyed in a probability. For example, if a patient has 50% chance of having a baby with her first IVF treatment, that puts her within the top 40% of all women taking their first IVF treatment.1 While 50% chance is considered very high, there is still a 50% chance of not having a baby from her first IVF. When the patient is deciding whether to go for her first IVF, she does not yet have IVF data that can inform her of her chances of success in the second or third IVF cycles, if needed. Therefore, it’s fair to assume that her chance of success in each of the first 3 cycles will be 50%, such that her chance of having a baby within the first 3 cycles will be 88%. However, after her first IVF – even if it has failed – she will be able to use her IVF data to best inform her of her chances of IVF success in subsequent cycles, rather than continue to rely on an assumption that was made before her IVF data became available.
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