Dr. Ron Feinberg
The In Vitro Doc

In a poignant New York Times interview in 2010 with the highly revered Dr. Howard Jones, he asserted, “Fertility investigators today should figure out which one embryo is likely to make a baby rather than transfer several. That will reduce costs, the number of multiple births and significantly increase success rates of in vitro fertilization.”

Dr. Jones established the first U.S. IVF clinic over 30 years ago in Norfolk, VA with his wife, Dr. Georgeanna Jones, and their team achieved the first IVF pregnancy in the U.S. Since that time IVF treatments have become more complex, and thousands of women and men face a myriad of “alphabet soup” IVF jargon to learn. How intimidating does it sound when an IVF blogger writes, “I went to the XYZ Center for IVF, ICSI, TE biopsy, and PGS so I could have a euploid blastocyst SET with my FET”? Can some of this IVF “alphabet jargon" be more clearly explained?

IVF has actually become more efficient over recent years, with the development of newer and better lab culture conditions. Exciting research developments exploring genes and DNA have yielded a perfect collaboration between IVF centers and genetics experts. With these advances, Dr. Jones’ long-standing goal of “one embryo, one healthy baby” is now a reality. This advice can be embraced because we are able to learn more about the chromosome health of embryos through pre-implantation genetic screening, or PGS.

Approaches to PGS have become much more sophisticated and reliable over the past 10 years by utilizing streamlined DNA analysis, ensuring evaluation of all 46 chromosomes within a few cells carefully removed from each embryo. Some centers also refer to PGS as comprehensive chromosome screening, or CCS.

The key value of PGS and CCS is our ability to predict which embryo or embryos have a normal complement of 46 chromosomes prior to uterine transfer. When a normal mature egg containing 23 chromosomes is fertilized with a normal sperm (containing another set of 23 chromosomes), an embryo with 46 chromosomes can develop. However, many embryos start out with an incorrect number of chromosomes stemming from an abnormal egg, sperm, or improper chromosome movement within the fertilized egg.

As certain embryos develop in the lab to become blastocysts, usually four to five days after fertilization, it is not possible to accurately distinguish  normal (euploid) versus abnormal (aneuploid) embryos under the microscope, making accurate embryo selection a major challenge. This dilemma has led to several exciting discoveries demonstrating the importance of incorporating PGS into current IVF treatments:

• The chance of successful pregnancy after single embryo transfer (SET) and PGS is 55% to 65%.

When Dr. Jones and others performed IVF treatments in the 1980s, the success rates were only about 10% to 20%, even when multiple embryos were transferred. For many years, IVF doctors didn’t think success rates would ever surpass 20%, the average monthly chance of natural conception for a fertile couple in their 20s. Transferring multiple embryos at one time became the norm to enhance IVF success rates, but with that strategy came the unintended consequences of multiple gestation, profound prematurity, cost, and significant emotional turmoil.

• Age matters, but not as much with PGS.

If a 40-year-old woman has a euploid blastocyst transferred to her uterus, her chance of normal pregnancy is about the same as a 25-year-old IVF patient. While this is an astounding finding, it is very clear that older women are much less likely to create multiple embryos that are normal when compared to younger women. It is also more likely that older women might not produce any normal embryos in a given IVF cycle. A very high percentage of abnormal PGS results are caused by an abnormal number of chromosomes within the mature egg—a significant age-dependent event.

• A single normal embryo can be transferred in a fresh or frozen embryo transfer (FET) cycle following PGS, yielding similar success rates.

 This provides great flexibility in how and when treatments are carried out and empowers women and men to design their own specific family building pathways. Our colleagues in the maternal-fetal medicine and neonatal fields have published compelling data to suggest that FET actually yields fewer maternal and fetal pregnancy complications. They have also strongly urged that SETs be carried out to minimize risks. Most IVF clinics offering PGS utilize FET cycles.

• Miscarriage rates are much lower after PGS.

 Since the majority of early miscarriages—including “chemical” pregnancies—are caused by chromosome errors in the embryo, it makes sense that many miscarriages can be prevented with PGS testing. Transfer of a single euploid (46 chromosome) embryo results in miscarriage in less than 10% of pregnancies. Miscarriage creates a significant emotional burden for our patients in addition to other costs and delays in care.

• PGS as performed in 2014 is just the beginning.

As DNA testing becomes more sophisticated and less costly, PGS will be fine-tuned to further enhance IVF success. IVF researchers are already discussing the use of DNA sequencing and other molecular modalities to better predict the health status of an embryo. The tiny trophectoderm  (TE) cells biopsied from the blastocyst for PGS contain a powerhouse of molecular information about the embryo, which can be analyzed for many different diagnostic markers.

In the future, it is possible that maternal age alone will not be the “done deal” many have come to accept. Univfy researchers and collaborators have clearly found that many factors other than age alone can greatly impact and predict IVF success. Individualized patient and clinic-customized prediction testing holds great promise when our patients seek guidance for their IVF decision-making.

One major goal of IVF physicians is to identify proven health interventions that will optimize the vitality of eggs, sperm, and embryos, leading to enhanced fertility and family building options for our patients. PGS has given us a significant glimpse into the mysteries and wonders of human reproduction. With PGS, the vision of Dr. Howard Jones and the future of IVF are looking much brighter.

In vitro fertilization (IVF) outcomes from over 1,000 treatment cycles spanning 2010 through 2012 demonstrate a significant improvement in successful pregnancies when pre-implantation genetic screening (PGS) of blastocyst embryos is utilized prior to uterine transfer, reports Reproductive Associates of Delaware (RAD). PGS utilizes molecular DNA tests for the presence of normal chromosomes within embryos.

Of 416 delivered and ongoing healthy pregnancies, 68 (16%) occurred when PGS was performed. In patients over 34, PGS led to 43% of RAD’s successful IVF pregnancies, and over 90% of these pregnancies occurred after single embryo transfer. When compared to IVF data published annually by the Centers for Disease Control, RAD had the highest total percentage of single embryo transfers and the lowest IVF multiple pregnancy rate in the U.S.

“Our results with IVF and PGS have clearly had an important impact on success rates, as well as increased utilization of single embryo transfer,” noted Dr. Ronald F. Feinberg, IVF Medical Director at RAD. “The higher implantation and ongoing pregnancy rates with PGS are both statistically and clinically significant for patients over age 34. Most IVF clinics utilize multiple embryo transfer to enhance pregnancy rates in these patients, whereas PGS allows us to select single embryos for uterine transfer yielding a safer and higher chance of pregnancy.” Embryos with abnormal chromosomes either fail to implant or commonly cause miscarriage, and are increasingly common in women over age 34.

When PGS is utilized, implantation and pregnancy rates for patients over age 34 at RAD are almost identical to the rates seen in younger women, and far surpass the rates seen in fresh non-PGS IVF transfer cycles. When PGS combined with frozen/thaw embryo transfer were carried out at RAD, the embryo implantation rates were over 60% across all ages, with a successful pregnancy rate of 56.2% and an average of 1.1 embryos transferred. The miscarriage rate was 10.5% in PGS cycles across all ages, whereas in non-PGS cycles the overall miscarriage rate was 18% in both fresh and frozen/thaw embryo transfers. Miscarriage prevention is a common indication for IVF and PGS.

“Our results suggest that PGS could prove to be highly cost-effective to help our patients maximize their singleton IVF pregnancy chances, along with much lower miscarriage risk, stated Linda Morrison, Director of Laboratory Services at RAD. "This should ultimately reduce the number of treatment cycles that many patients will need to achieve a safe and healthy pregnancy.”

IVF pregnancy outcome following embryo transfer is also enhanced when the uterine environment has been optimized. During a frozen/thaw treatment cycle, the uterus has not been subjected to very high hormone levels commonly created during fresh IVF cycles. And other risks of fresh IVF transfer, such as ovarian hyperstimulation syndrome, can be virtually eliminated when frozen/thaw transfers are employed. “Recently, a respected research group at New York University published their results with PGS and single embryo transfer during frozen/thaw cycles, and demonstrated a 58% implantation rate over a four-year period,” noted Dr. Feinberg. “This provides further evidence that single embryo transfer in conjunction with PGS is safe and effective.”

RAD has previously presented its IVF and PGS results at the American Society for Reproductive Medicine annual meetings. To view details of RAD’s comprehensive PGS and non-PGS results for the three-year period visit http://ivf-de.org/pgs-pgd/ and http://ivf-de.org/success-rates/.

RAD’s IVF Center, established in 1995, is part of a full service subspecialty fertility practice with locations in Newark, Wilmington, and Dover, Delaware. RAD’s Board certified physicians are Drs. Barbara McGuirk, Ronald Feinberg, George Kovalevsky, Adrienne Neithardt, and Lenore Tietjens-Grillo. RAD’s IVF, Fertility Care, and Fertility Wellness Centers are located on the main campus of the Christiana Care Health System in Newark. For more information about Reproductive Associates of Delaware visit http://www.ivf-de.org.

With apologies to The Bangles, the implications of AMH testing is causing some real mania and concern throughout infertility clinics worldwide.

What exactly is AMH, and what information does it provide?  What impact does AMH have on IVF success?  Should women interested in future fertility have their AMH level checked now?

AMH stands for Anti-Mullerian Hormone.  This is a rather paradoxical name for this hormone, particularly in women, where the embryologic female organs known as the Mullerian system develop into the uterus, cervix, and fallopian tubes.  (In male fetuses, it has been known for decades that the developing testes produce AMH to prevent development of a Mullerian system).

In women, AMH has not been assigned a biological function.  However, it is produced by a very specialized group of ovarian cells called granulosa cells.  Granulosa cells directly surround eggs within follicles, and are the key cells that divide and grow throughout each menstrual cycle, producing cyclical levels of estrogen and progesterone.  So it might be presumed that AMH serves some functions associated with follicle and egg development, and possibly menstrual cycle regulation.

Many fertility centers, including ours, measure AMH levels for patients as part of the diagnostic evaluation.  Based on available literature it appears that AMH levels correlate with the number of active and viable follicles present within our patients’ ovaries.  AMH levels appear to correlate with how the ovaries respond to fertility medications, particularly during IVF.  So women with high AMH levels tend to be “super-responders” to ovarian stimulation, whereas women with low AMH levels are often “low responders” during IVF stimulation.

The general assumption about low AMH (typically less than 1.0 to 1.5), particularly in women who are suffering with infertility, is that a low AMH could be a marker for diminishing ovarian reserve.  Diminishing ovarian reserve is a “gentle” description of having reduced numbers and quality of eggs.  The implication of a low AMH is that perhaps fertility treatments should be more timely and aggressive, including IVF sooner than later.  AMH levels may correlate with the normal genetic and chromosomal makeup of the eggs.

A low AMH level has also been correlated with endometriosis, and we are caring for many younger women (under age 30) who present with both endometriosis and very low AMH.  We have wondered if AMH somehow regulates endometriosis, and if a low AMH allows “permission” for endometriosis cells to grow and flourish.  There is some scientific evidence that endometrial cells are regulated by AMH, which may give some insight into the actual function of AMH.

On the opposite end of the spectrum, women with a high AMH (greater than 2.5 to 3) tend to be “high responders” to fertility medications, produce many follicles during IVF stimulation, and often fall into the polycystic ovary group.  Many women with polycystic ovary syndrome (PCOS) have ultra-high AMH levels; we’ve seen levels of AMH as high as 30 to 40 in some PCOS patients, suggesting extremely high numbers of follicles within these women’s ovaries.

So AMH results can cause tears or cheers, depending on the results obtained.  More information is desperately needed to determine what AMH actually does, whether it is a hormone closely related to future fertility potential, and how it might impact a disease like endometriosis and/or the metabolic hormone disorder known as PCOS.

In a somewhat sexist and backhanded taunt it has been said: “if men suffered with endometriosis, we’d have a cure by now.”

For what it’s worth, the world’s biomedical literature is not ignoring endometriosis, with PubMed (the online repository of the U.S. National Library of Medicine) containing 19,232 journal articles with the search term “endometriosis” as of this morning.  About 10% of these articles were published just in 2012.  By contrast, the male-only disease “prostate cancer” yields 106,342 entries, and a less deadly (but highly Pharma-profitable) condition “impotence” yielded 19,861 entries.  So do endometriosis and impotence get about the same attention in the world’s biomedical literature?

To be fair, we have learned a great deal about endometriosis since Dr. Sampson first proposed the somewhat simplistic theory of retrograde menstruation almost 100 years ago.  Back then it seemed “obvious” that some menstrual tissue could, every month, flow backwards through the fallopian tubes and land in the pelvis, where some viable cells implanted and continued to growth.  In fact these commonly-seen implants of endometriosis, whether found in the ovaries or on the surfaces of peritoneum, do resemble the glands and connective tissue of the uterine lining, known as the endometrium.

At one extreme, women who have an anatomic blockage or abnormality within their uterus or cervix appear to be at very high risk of developing endometriosis.  And at the other extreme, women who lack a uterus or never menstruate rarely have endometriosis.  So a dose effect of “seeding” the pelvic cavity with endometrial tissue, whether with a lot of menstrual tissue or virtually none, does seem to directly impact risk of the disease.  And as stated, it’s a rare male that has endometriosis (I did find one case report in PubMed published in 1985; this male had a embryologic remnant of the uterus embedded in his prostate).

In Dr. Sampson’s day we didn’t know much about genetic predisposition, how the immune system reacts to or promotes growth of endometriosis cells, or how stem cells can magically form new cells in our bodies.  We also weren’t exposed to reproductive toxins and food additives that act like estrogen.  Or plastics that leach out hydrocarbons and disrupt our endocrine systems.  The average age of puberty was older in Dr. Sampson’s era, and the average number of menstrual cycles women experienced were many fewer.  Birth control pills didn’t exist, and fertility and pregnancy rates were higher.

So our best bet on this disease of theories is that there are many interlocking modern factors that contribute, and there is not likely just one theory that will adequately explain the origins of endometriosis.

And to all biomedical researchers, both male and female, if you unlock the many mysteries of endometriosis you might find new cures for other major diseases with similarly curious abnormal cells, such as cancer.

“My embryos were normal but I didn’t get pregnant” is one of the most common statements we hear from many of our patients coming to us for second or third opinions.

So how do we know that embryos created by IVF are normal before we transfer them to the uterus?

Simple answer: We really don’t.

Keep reading

Endometriosis hurts.  There’s no question about it.  Millions of women suffer in the U.S., and around the world.  The clinical terms that doctors use to define the pain and suffering are well-known to many women, particularly as they try to seek some answers.  These pain words all start with “dys”: painful menstruation (dysmenorrhea); painful intercourse (dyspareunia); painful bowel movements (dyschezia); and painful urination (dysuria).  And all of these “dys” problems are strongly associated with chronic and unpredictable bouts of pelvic pain, spastic bladder, irritable bowel, abnormal bleeding, back pain, and infertility.

Keep reading

“My husband and I heard all of these and worse. I think it is so difficult for people struggling with infertility to be advocates because it is a such a painful situation, people don’t understand it (especially if it was easy for them to conceive) and it feels embarrassing and awkward to speak about. My husband and I actually deeply explored adoption before looking to addressing our medical issues and it was nearly impossible, mostly because we had been married for less than 5 years, so it really infuriates me when people suggest that adoption is such an easy alternative.”

1)  Advocate for better insurance for people needing infertility & IVF care

2)  Improve recognition and treatments for endometriosis

3)  Educate our patients and community about preconception genetics, very real age challenges, and fertility wellness

4)  Enhance acceptance of preimplantation genetic screening (PGS) for comprehensive chromosome assessment of blastocyst embryos

5)  Extoll the virtues of single embryo transfer with IVF to yield the healthiest babies possible