It’s a bit of a Wild West out there when it comes to in vitro fertilization (IVF) tests and treatments. Many new tests and procedures have emerged that sound groundbreaking — and some might hold promise. Accurately predicting whether an IVF cycle will result in a baby still remains beyond our grasp.

“There have been studies in reproductive medicine looking at new things, but unfortunately, they’re not…randomized controlled trials with enough people to prove certain tests or treatments will help. Our field is riddled with these tiny studies that are largely observational,” said Clarisa R. Gracia, MD, MSCE, chief, Division of Reproductive Endocrinology and Infertility, University of Pennsylvania, and professor of obstetrics and gynecology, Penn Fertility Care, Philadelphia.

Unfortunately, once there is “a little bit of evidence,” companies market new tests and treatments such as endometrial receptivity arrays and immunotherapies directly to patients, added Gracia. “There is so much anxiety about wanting to have a baby — it leads people to chase down treatments that are unproven.” Patients may try new treatments or tests and only to later learn they’ve been proven ineffective.

Jacqueline N. Gutmann, MD, reproductive endocrinologist at Reproductive Medicine Associates and clinical associate professor of obstetrics and gynecology at Thomas Jefferson University, Philadelphia, agreed. “It’s not clear there is an ideal test,” she said. “We’re not there yet and data with respect to predicting outcomes is limited.”

Ovarian Reserve

“The most reliable predictor of IVF success is the age of the patient from whom the eggs will be retrieved,” said Jennifer Eaton, MD, MSCI, president of the Society for Assisted Reproductive Technology (SART) and director, Women and Infants Fertility Center. “Live birth rates from IVF are directly linked to the age of the egg source, with rates declining sharply in the late thirties and early forties.”

For patients planning to undergo IVF, SART typically recommends a blood test for anti-mullerian hormone and a vaginal ultrasound for antral follicle count, both of which help estimate ovarian reserve. These tests are quite good at predicting the approximate number of eggs that might be retrieved in an egg retrieval procedure, Eaton said. We may also measure other hormones, such as follicle-stimulating hormone and estradiol, as additional markers of ovarian reserve, she said.

Embryo Testing

The embryos created after retrieval of eggs and fertilization may be the next step in testing. “A lot of people who go through IVF don’t have usable embryos,” said Gutmann, who added that with tested embryos “the likelihood of success remains excellent over at least three cycles.” She cited a 2021 study in Fertility and Sterility, in which the cumulative live birth rate after up to three consecutive cycles (with tested embryos) was 92.6%. This suggests that true recurrent implantation failure with high-quality embryos is rare.

“The embryo is the major reason for failure of implantation, especially in older patients,” said Gracia. Unfortunately, there’s so much we don’t know about assessing embryo quality, she said.

It is possible to use preimplantation genetic testing (PGT) to check the number of chromosomes in an embryo (PGT-A), said Eaton. “This is helpful for embryo selection, but it is not perfect. For couples who carry one or more heritable genetic mutations, a different type of PGT (PGT-M) can be used to determine which embryos are at greatest risk for transmitting the condition.”

Current embryo tests involve making a hole in the shell of a blastocyte, which damages them. A very small subset of cells is assessed: five or six out of the 150-200 total cells per blastocyte and only from the placental layer. When the results indicate the presence of both chromosomally normal (euploid) and abnormal (aneuploid) cells, the embryo is deemed “mosaic.” Research suggests poorer clinical outcomes for mosaic embryos. Still, even if a blastocyte contains abnormal cells, that does not necessarily mean it will not develop into a healthy baby. In fact, low-level mosaicism is common in early embryos.

Yet over the years, blastocytes flagged for abnormalities have been discarded, many likely unnecessarily. Class action lawsuits have been filed against multiple US providers of PGT-A testing. “Patients were not informed these tests may not have been perfect,” said Gracia. Embryos were destroyed and some couples never had babies even though their embryos might not have been abnormal, she said.

Uterus and Endometrium

Even with healthy embryos, “sometimes there is recurrent implantation failure,” said Gracia. Structural abnormalities (like cysts, polyps, fibroids, scar tissue, adenomyosis, or a dilated fallopian tube) might be the cause. “To evaluate the uterine cavity, we typically obtain a saline infusion sonogram or visually inspect the cavity with a camera (hysteroscope),” said Eaton.

Otherwise, “predicting implantation remains an unsolved problem,” said Alan B. Copperman, MD, director, Division of Reproductive Endocrinology and Infertility, Icahn School of Medicine at Mount Sinai, and CEO, Reproductive Medicine Associates of New York.

“Endometrial diagnostics haven’t kept pace. There’s still no reliable, validated test that tells us whether the uterus is ready to support a pregnancy.” Tests for inflammation, microbiome balance, or hormone timing provide interesting data but haven’t consistently improved outcomes, Copperman said.

Take tests for chronic endometritis. “We know endometritis in general reduces the rate of implantation and that the more severe the endometritis is, the worse it is,” Gracia said. But “there’s a whole controversy around what endometritis is and how to diagnose it. If you talk to pathologists, they say there is no gold standard way of diagnosing endometritis.”

Despite the lack of evidence, some practices biopsy and culture endometrial cells and, if they find inflammation, prescribe antibiotics or probiotics, Gracia said.

Endometrial receptivity arrays, genetic tests to identify ideal windows of “receptivity” to help time implantation, are another type of testing not backed by sufficient data. “Testing for altered hormonal timing has not proven to be beneficial in recent studies,” said Eaton. “There was huge hype around this five or 10 years ago” — the idea being to change the receptivity window so you could increase the odds of implantation, Gracia said. “Everyone started doing it. But then a trial showed it didn’t work, and now it’s fallen out of favor.”

Immunotherapy is another area where providers are “doing crazy stuff with limited data.” The concept is that natural killer immune cells in the endometrium might help with implantation. Despite no positive trials, people are taking filgrastim to increase their inflammatory cells, Gracia said. “They’re getting IVIG infusions, which can cost thousands.”

In some cases, companies bundle together multiple tests, Gracia added. “If you look at the success rates published by SART, some programs with the worst success rates conduct the most tests,” she said.

On the Horizon

Platelet-rich plasma might offer some promise for improving the endometrial lining or immunologic factors, said Gracia. A new test from Simbryo Technologies is intriguing conceptually, said Copperman. The company recently released a personalized functional assay of endometrial fertility to help IVF patients avoid repeated failed transfers. The assay, whose goal is to predict the likelihood of implantation before transfers, uses a patient’s cells to model implantation in a lab.

Still, “these are the early days,” Copperman said. “This is a research platform, not a proven clinical tool. It is certainly innovative but requires independent validation and reproducibility…If this test can truly pinpoint correctable uterine issues, it could be valuable.”

In a few months, the American Society for Reproductive Medicine is releasing new practice guidelines for recurrent implantation failure, said Gracia. Along with adhering to these guidelines, Gracia advised setting realistic expectations for patients. Let them know IVF can be a long road, she advised. “One failure is not unexpected. The odds of success are 50/50 for the youngest patients. It’s a little bit of a numbers game and expected to have repeat cycles.” 

Gracia also suggested giving patients a heads-up that they might hear about enticing-sounding treatments, which are not backed by quality research. “It’s a leap of faith to have a healthy baby, to some extent,” she said.

Gracia said she has no relevant financial disclosures; she is the chair of Reproductive Endocrinology and Infertility, Division of the American Board of Obstetrics and Gynecology and chair of the practice committee for the American Society for Reproductive Medicine. Her statements are her own and not on behalf of the American Board of Obstetrics and Gynecology or the American Society for Reproductive Medicine. Gutmann had no conflicts of interest. Copperman had no conflicts of interest. Eaton reported serving on the Scientific Advisory Board for CooperSurgical, she has received compensation from Elsevier and the American Society for Reproductive Medicine for her editorial roles with American Journal of Obstetrics and Gynecology and Fertility & Sterility, respectively.