Endometriosis was a puzzling disease when first described by pathologist Rokitansky in 1860. Though we now have a clearer understanding of some aspects of the biology of this disease, it still remains largely a mystery 150 years later.

Endometriosis affects about 5 million women in the U.S. Of women with infertility, approximately 25% are diagnosed with endometriosis. The symptoms fall into two categories: 1) pelvic pain, most significantly with menses, and 2) infertility. The definitive method to diagnose this disease is surgery. A laparoscopy is performed to obtain tissue biopsies of typical peritoneal lesions (peritoneum is the internal layer overlaying pelvic organs including the uterus, fallopian tubes and ovaries); and confirm the presence of endometrial glands in those biopsies. The American Fertility Society has created a classification scheme which grades the disease (Grade I-IV). It is important to understand that there is not necessarily a correlation between pelvic pain and the severity (or grade) of the disease. Another method for presumptively diagnosing endometriosis is with ultrasound, if the patient has endometriosis ovarian cysts (endometriomas), or with MRI if one there is endometriosis growth in the
uterine muscle layer (adenomyosis).

A diagnosis of even minimal to mild endometriosis (stage I and II) can have significant consequences on fertility success rates. A fertile 30 year old woman has about a 25% chance of pregnancy per month (fecundity rate). A patient diagnosed with minimal to mild endometriosis has about a 3% monthly fecundity rate (1, 2, 3). If surgery is performed to dissect and remove the visible endometriosis lesions, the fecundity rate improves to 6%; but this is still much lower than the 25% afforded a fertile 30 year old. If that same patient undergoes ovarian stimulation and insemination cycles, her monthly fecundity rate increases to 11% (4). If the combination of ovarian stimulation/IUI treatment is going to increase chances of pregnancy, results are usually seen within the first 3-4 treatment cycles. Undergoing additional IUI cycles is not typically beneficial, and proceeding to in-vitro fertilization (IVF) treatment would be the next step. For patients with severe endometriosis, gonadotropin/IUI therapy is of minimal assistance. Most patients with moderate to severe endometriosis (stage III and IV) will need to pursue IVF therapy (5).

IVF studies from the 80s and 90s indicate that patients with endometriosis have a slightly lower chance of achieving a pregnancy than patients with other infertility diagnoses (6). With current IVF laboratory techniques and current ovarian stimulation strategies, this difference will probably disappear—but up-to-date studies are needed as proof. When assessing if the lower pregnancy rate is because of a uterine or ovarian issue, it appears that the uterus of endometriosis patients is effective in providing a supportive environment for the embryo to attach (7). However, the oocytes (eggs) from endometriosis patients, particularly those with endometriomas, seem to have some compromised quality (8). This lower egg quality seems to lead to less healthy and effective embryos, and therefore overall lower pregnancy rates.

We clearly understand that strategies of suppressing endometriosis growth by using medications such as birth control pills, Danazol, Lupron or others, does not lead to improved pregnancy rates (9). The concept of a fertility “rebound” post-medical suppression has been proven false over-and-over again. These strategies only lose potentially precious time for the patient. Similar strategies of using medical suppression post surgical removal of endometriosis also fail to improve fecundity rates. The best approach is to move forward with an appropriate form of fertility treatment as soon as the patient desires fertility.

How to treat endometriomas has been debated, but we now have some studies to guide us. Collectively these studies indicate that patients who have undergone surgery for their endmetrioma(s) have the same IVF outcomes as those where the endometrioma(s) was left alone (10). We feel that the patient’s current clinical situation should be scrutinized carefully before recommending ovarian surgery for a patient who is seeking fertility. With surgical removal of an endometioma (ovarian cystectomy), we know that the ovary where surgery is performed will have fewer eggs and less normal ovarian tissue post surgery (11). This implies that we will have a lower chance of gathering eggs in an IVF cycle. Additionally, the patient will have a greater chance of having an elevated FSH after a cystectomy procedure, especially if she undergoes cystectomies of both ovaries (11). The risk of premature ovarian failure (POF or premature menopause) for a patient undergoing cystectomies of both ovaries for endometriomas is about 2% (12).

Historically the strategy for treating endometriosis has been to surgically remove or hormonally suppress its growth with various medications. As we better understand the biology of this disease, we can use more targeted therapies which interrupt the biochemical pathways that promote the growth of endometriosis lesions: aromatase inhibitors, estrogen and progesterone receptor blockers, angiogenesis inhibitors, etc. All of these types of medications are being studied in endometriosis patients. The future may hold some promising new medical options.

In summary, endometriosis clearly affects fecundity rates, even with minimal and mild disease. Using hormonal medications to suppress endometriosis provides no improvement in pregnancy rates, and surgical intervention provides minimal improvement. Most patients will need to pursue fertility treatment. For patients with moderate to severe disease, they most often will need to pursue IVF. For patients with endometriomas, careful consideration has to be given to all factors (age, assessment of egg quality, prior fertility treatment, etc.). The patient needs to be fully counseled prior to surgery, including risk of diminished ovarian quality (DOR) and premature menopause (POF). Patients with adenomyosis seem to have impaired implantation rates, and those with severe adenomyosis may need to consider a gestational carrier. Having a clear understanding of endometriosis as it impacts fertility, and having realistic expectations with each treatment type is most important when choosing fertility treatment options.

– Isabelle Ryan, M.D.

References

1. Jansen RP, Fertil Steril 1986; 46:141-3
2. Marcoux et al, NEJM 1997; Jul 24; 337(4):269-70
3. Parazzini, Hum Reprod 1999; 14(5):1332-4
4. Tummon et al, Fertil Streil 1997; 68(1):8-12
5. Dmowsky et al, Fertil Steril 78:750 2002
6. Barnhart et al, Fertil Steril 2002; 77:1148-1155
7. Diaz et al, Fertil Steril 2000; 74:31-34
8. Simon et al, Hum Reprod 1994; 9, 725-9
9. Hughes et al, Cochrane Database Syst Rev 2007; 3:CD000155
10. Tsoumpou et al, Fertil Steril 2009; 92, 75-87
11. Li et al, Fertil Steril 2009; 92(4):1428-35
12. Busacca et al, Obstet Gynecol 2006; (195), 4

UPDATE: This study is currently on hold while we attend to some administrative details. Please check back to this blog often, as we will keep our readers updated.  You may also call the New Patient Coordinators at 415 834-3095 for more information.

PREVIOUSLY: Pacific Fertility Center is pleased to announce that as of October 1st we are enrolling patients into a groundbreaking research study to determine the value of combining acupuncture with IVF. Traditional

Chinese medicine has been practiced in throughout Asia for thousands of years:in the last decade, the west has been following suit.

There have been sufficient peer reviewed studies to warrant a clinical trial in which there are predictable parameters of patient involvement. One of the first studies involving acupuncture and IVF was published by Paulus et al in the journal Fertility Sterility in 2002. The Paulus study reported the influence of acupuncture on the pregnancy rate in patients who undergo assisted reproductive therapy. Clinical pregnancies were documented at 42.5% of patients in the acupuncture/IVF group, whereas pregnancy rates were 26.3% in the control group, using IVF alone. In this study, the acupuncture was performed before and after embryo transfer only.

How does acupuncture affect fertility? A review article in Alternative Therapies (Anderson 2007) suggested four possible mechanisms by which acupuncture could improve the outcome of IVF: modulatingneuroendocrine factors; increasing blood flow to the uterus and ovaries; modulating cytokines; and reducing stress, anxiety, and depression.

Stillbirth, loss of a baby at delivery, is a painful challenge.  The suffering associated with the loss of a child, even before birth, can be overwhelming.  Especially acute for women that have conceived utilizing assisted reproduction, the loss of a pregnancy fought through reproductive technology can overwhelm a couple.  Stillbirth is a rare risk of pregnancy; the challenge facing us as reproductive medicine experts and obstetricians is how to reduce that risk.

The technologies of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) have enabled pregnancy for thousands of families with sperm, egg, and uterine problems.  With IVF, egg quality can be optimized using fertility drugs to produce more eggs.  Blocked fallopian tubes can be bypassed.  Weak sperm can achieve pregnancy by ICSI, where, using a microscopic needle, the sperm cell can be introduced into the egg.

No-one should expect these techniques to be foolproof.  While mechanical problems can be improved, other weaknesses in the reproductive system cannot.  Small deviations in the genetic code of the sperm or egg, missing chromosomes, aging, uterine defects, etc cannot be fixed by treating the sperm cell or embryo.

Thus the problem – these pregnancies established by high technology, are at higher risk.

A recent study from Denmark looked at stillbirth in children born after IVF/ICSI  and found that the risk was higher in children born after IVF/ICSI than natural pregnancy.  Out of 16,525 births to fertile women the chance of stillbirth was 0.37%, that is, 3.7 out of 1000 births.  Out of 742 babies born to women after IVF/ICSI there were 12 stillbirths, 1.62%, that is 16.2 out of 1000 births.

But more importantly to our patients, the liveborn baby rate after a successful IVF/ICSI treatment  and pregnancy is 98.4%.  The liveborn baby rate after a successful natural conception and pregnancy is 99.6%.  Almost all of the successful pregnancies after IVF/ICSI are liveborn.

Reproductive technologies, like IVF and ICSI, are enabling pregnancy and family building where it was not possible before.  All of our patients must be informed of and recognize the risks associated with fertility treatment.  These risks should not, however, dissuade anyone from considering these therapies.  On the contrary, the overwhelming likelihood is that, once a pregnancy is established, it will progress successfully to delivery and a healthy child.

We need to recognize these risks to provide help understand and take measures to reduce the risks to all children.  We will continue to watch these studies carefully in our ongoing effort to assure our patients of excellent pregnancy rates, at low risk.

Footnote:

1. K. Wisborg, H.J. Ingerslev, and T.B. Henriksen  IVF and stillbirth: a prospective follow-up study  Hum. Reprod. Advance Access published on February 23, 2010.

By the end of the year we will have started a new and very exciting research project in our lab. We have partnered with a company called Incept Biosystems (www.inceptbio.com) to do a clinical trial of a new embryo culture system called microfluidics.

The traditional culture dish with medium droplets under oil as described by Brinster, R.L., 1963, Exp. Cell Res., Vol. 32

This involves culturing embryos in very small volumes of culture media inside a chip specifically designed for this purpose. Tiny pumps regulate the flow of culture medium in and out of the chip without causing the embryos to move around.

The traditional vessel for embryo culture is the petri dish, where small droplets of culture medium are overlain with a highly purified mineral oil. The culture medium, regulated in much the same way as pharmaceuticals, is one of the most highly tested and expensive components of the IVF laboratory operation. We typically make droplets of medium that are in the 50-200µl size range, and the oocytes or embryos are placed in the droplets for 24-48 hours at a time. This is a static culture system where nutrients are depleted by the developing embryos and waste products (e.g. ammonia from amino acid breakdown) accumulate over time. The droplets are large enough to make sure that the supply of nutrients is more than adequate and that waste is diluted to the point of not harming the embryo in any way. The embryos are changed into fresh medium at least every 48 hours.

This system for embryo culture has been in use since human IVF began in the late 1970′s and early 1980′s. It was actually developed in the early 1960′s by a pioneer of mouse embryo culture, Dr Ralph Brinster, at the University of Pennsylvania. Some early human embryologists cultured embryos in small test tubes without the mineral oil, but nowadays, despite the age of this technique, it is very unusual to find a facility that does not use the droplets under oil method. After 45 years, perhaps it is time for a change?

A microfluidic system for embryo culture has been in development for over 5 years at the University of Michigan in Ann Arbor. Professor Gary Smith combined the talents of his graduate students in physiology with those of engineering students and came up with a device that has had outstanding results with growing mouse embryos. Professor Smith is no stranger to IVF, as he was the director of the University’s IVF Laboratory for many years and he was instrumental in designing and testing the vitrification system that we now use to preserve oocytes and embryos. He solicited venture capital to start Incept Biosystems with the intent to bring microfluidics into human IVF labs. Incept Biosystems were onsite at PFC during the last week of October to train our embryologists on the use of the system. We did several trials with mouse embryos to achieve proficiency with the system and then we will actively recruit patients to enroll in a clinical trial using the system.

The clinical trials are being run at 3 centers in the US. In addition to PFC, patients will participate at the Fertility Center of San Antonio and at Southeastern Fertility Center in Charleston, South Carolina.

A schematic of a microfluidic embryo culture device with fresh medium in blue and spent medium in red. The embryo is contained at the base of the chamber, where the blue medium ends.

Patients that are asked to participate will have to consent to the study, where their embryos will be divided into 2 groups for culture in the microfluidic device and in the traditional petri dish. The culture media will be the same for all the embryos, but half will be in a replenishing media current (microfluidics) and half will be in our traditional static culture.

Microfluidics has had impressive results with mouse embryos where it significantly increased rates of development and implantation over those for embryos grown in static culture. Cell numbers for the microfluidic embryos were almost twice as high as for traditional culture (110 vs. 65), and pregnancy rates from transferred embryos were increased by 22%. Incept Biosystems have tested the new technology extensively and have been able to obtain surplus IVF embryos donated for research for human trials. There are some nice videos on their website that showcase the equipment and procedure, and detail the mouse embryo results. Professor Smith presented the results and won the prize paper at the 2008 American Society for Reproductive Medicine (ASRM) meeting (Smith et al., 2008, Fertility and Sterility, Vol 90, pages S1-S2), and these results will soon be published in a peer reviewed journal.

We will be asking for participants to join the study, beginning in November and continuing for 2-3 months. This is a short study requiring enrollment of only 20 patients, but a larger study is planned for next year subject to favorable outcomes here. If you are interested in the study and would like more information, please ask your physician at your next visit.

Many populations of the world have specific genetic conditions that are prevalent within their ethnic group. Consequently, numerous medical organizations have recommended that genetic screening for these conditions should be offered when women are either planning for, or are currently pregnant. We are all carriers of genetic conditions: generally this is of little concern, as it is highly unlikely that we would have children with a partner who is a carrier for the same condition.

The genetic conditions listed in the table below are recessive. A recessive gene mutation is “carried” by someone who is unaffected by the disease, and thus unaware of their carrier status. Men and women have equal potential to be carriers for recessive conditions. Even if someone is a carrier, we would not expect to see a family history of the disease. If there is a family history, the likelihood of being a carrier of that condition is generally greater than in the general population. Being a carrier for a genetic condition typically has no impact on the carrier’s health and development. However, if a carrier has a child with another carrier of the same genetic disease, the chance that the child will be affected with the disease is 1 in 4 (25%).

If only one partner is a carrier, and the other tests negative, then the risk of an affected child is low, but not zero (a result of the limited ability to test for all defects that would make one a carrier; see table). These genetic screening tests are typically performed on a blood sample.

Below is a table listing the minimum number of tests for various ethnic groups recommended by the physicians at Pacific Fertility Center prior to starting assisted reproduction treatment. Additional genetic tests may be considered after a discussion with your physician.

If you know that both you and your partner are carriers of the same genetic defect, you may be able to have embryos created in an IVF cycle and tested for their status. Preimplantation genetic diagnosis (PGD) is a technology that allows embryos to be tested for specific disease causing mutations. PGD can identify unaffected embryos for transfer back to the uterus or freezing.

—Guest Contributor – Certified Genetic Counselor Lauri Black, M.S., C.G.C

*See lab specific accuracies on test result

Assisted reproductive technology (ART) has been a part of modern medicine now for over 30 years and in the US alone over 132,000 IVF cycles were performed in 2007. All birth outcomes are reported to the Centers for Diseases Control but there is no mechanism for long-term follow-up of IVF births.

Well over a million babies have been born world wide through IVF and new data are emerging about reproductive birth outcomes after conception. Some countries, particularly the Scandinavian countries, do an excellent job on gathering data for all births, including IVF-conceived births. One of the greatest risks of ART is prematurity from multiple gestation. From several of these databases, it has become apparent that even singleton IVF births are statistically associated with poorer birth outcomes. Lower birth weights, pre-term delivery and infants small for gestational age (i.e. lower weight than expected for number of weeks in utero) are some of the findings from follow up of IVF babies.

These findings beg the question: is it something about IVF, namely the culture of the early embryo in a lab for the first three to five days of life, that results in these poorer outcomes, or is it something about the couples that need IVF to conceive that is associated with them? This can be a difficult issue to sort out because relatively few people undergo IVF who are not infertile.

A recent study from Norway was published in the British medical journal Lancet that tried to address this question by comparing IVF babies with their spontaneously-conceived siblings. The study compared 1,200,922 spontaneously-conceived live births and compared them with 8,229 live births after ART between January 1984 and June 2006. Of those women who had given birth to a singleton infant after ART, 2,456 also delivered a singleton infant after spontaneous conception. In 56% of the cases, the ART baby was born first and in 44% the ART baby was conceived after the birth of the spontaneously-conceived infant. The researchers looked at birth weight, gestational age as well as a number of other factors.

Compared with women in the general population that delivered a spontaneously-conceived birth, the women that delivered after IVF were older, less likely to smoke and had fewer previous births. Induced labor and cesarean section were more common in the IVF moms. The difference in birth weight between ART and non-ART babies was 131 grams (4.6 ounces). That is, the ART babies weighed, on average, 4.6 ounces, or about 3/4 pound less than the spontaneously-conceived babies. After statistical adjustment for gestational age, maternal age, prior births, year of birth, the difference in birth weight between ART and non-ART babies was 25 grams (0.88 ounces). The ART babies were born, on average, 3.7 days earlier than the controls. After statistical adjustment, the number of days of total gestation was 2 fewer days. Because of the large sample size, these were statistically significant differences but realistically, they were probably not clinically significant.

In comparing the sibling relationship ART vs. non-ART births, the differences were even smaller. The difference in birth weight was only 87 grams (about 3 ounces) for the ART babies as compared to their spontaneously-conceived siblings. The gestational age differences at birth were 1.3 days less for ART. After adjustment, these differences were only 9 grams and 0.6 days. These differences were not even statistically significant.

From these data, we can see that ART births do show statistical differences in some birth outcomes as compared to spontaneously conceived births. However, none of the differences seem are to an extent that would have any real clinical meaning. These differences tend to disappear to a large extent when comparing siblings from both spontaneous and IVF conception, suggesting that it is something about the families that utilize ART, rather than the technique itself that may be associated with the outcome differences.

In the press today we see that the “world’s oldest new mom dies” at age 69 (see our earlier blog post clarifying that PFC did not treat this patient), three years after giving birth to twins conceived through IVF. Maria del Carmen Bousada apparently lied about her age to the Los Angeles Physician who helped her become pregnant, creating a firestorm of criticism in the press.

The case demonstrates one of the most basic dilemmas that we face in helping women become pregnant: at what age is a woman too old to become a mother?

Most of us might agree that a 25 year old woman is young enough to receive help, but that a 70 year old is too old. However, drawing the cut-off line at some point between these extremes is not easy. With the help of in vitro fertilization and donated oocytes, women like Maria can become pregnant at an age where nature would naturally prevent the possibility of conceiving. Typically, women run out of oocytes in their early 50’s and without oocytes and the granulosa cells that surround them, they lose their ability to make estrogen. This natural process, called menopause, can happen earlier or later for a given individual, but the ability to get pregnant and deliver a healthy baby declines rapidly for women in their late 30’s and on into their 40’s. The age of the woman is a determining factor of her since a 40 year old woman is trying to get pregnant with a 40 year old oocyte, and these older oocytes don’t perform well. For example, the older oocyte is not good at keeping track of its own DNA, as evidenced by the increasing incidence of genetic defects such as Down syndrome in older mothers. And as if this wasn’t bad enough, the rate at which oocytes are lost from the ovaries (also know as a woman’s biological clock) doubles at about age 38. If this doubling didn’t happen, we think that women wouldn’t reach menopause until their early 70’s. It is thought that the speeding up of the biological clock in the late 30’s is nature’s way of clearing out the remaining oocytes, so that women lose their ability to become pregnant but are then around to raise the children that they already have.

Based on nature’s model, we might consider limiting IVF treatment to women that are in their early forties or younger. But with donated oocytes, this limit can be pushed and there are no legal age limits for pregnancy. So, who gets to decide when it’s too late to become pregnant? As far as following “nature’s model”, is age different than other factors that lead to infertility? Do we make rules? And do the rules apply to men too, where nature doesn’t have limits?

Note: Pacific Fertility Center does have both lower and upper age limits in place.

News broke earlier today about the death of a 69 year old mother who had undergone fertility treatment at age 66. She gave birth to twins in December 2006.

This is a very unfortunate incident and we express condolences to the loved ones, especially the children who are left behind. However, it is necessary to clarify that Pacific Fertility Center was not involved in the treatment of this patient. The AP article printed the name of the clinic as “Pacific Fertility Center”, which is an error of ambiguity since there are two fertility clinics with similar names. The fertility clinic where this woman received services was Pacific Fertility Center-Los Angeles. Our center, which is located in San Francisco, has no affiliation with the clinic in Los Angeles. While our names are similar, our standards of practicing medicine are much different. To begin, here at Pacific Fertility Center in San Francisco, it is standard procedure to verify the identity and age of the persons being treated at every visit.  Our physicians would not have treated a woman at the age of 66, since we believe this to be unethical. At Pacific Fertility Center in San Francisco, we believe it is our foremost and ethical responsibility to assure the children that are a result of our services are provided loving and caring families.

At Pacific Fertility Center, we consider very carefully the number of embryos we transfer to each patient. Our goal is to create a healthy singleton pregnancy. We do our best to avoid multiple gestations. Consequently, in many cycles where we think that the chance of pregnancy is extremely high, we transfer only a single embryo. Our outstanding and robust embryo cryopreservation program preserves all embryos that were not transferred in the fresh cycle. Patients who transfer only a single embryo can feel secure in knowing that there are frozen embryo(s) available should they be needed.

Recently, we completed our analysis of the cumulative pregnancy rates per cycle for 2007. This type of report represents the overall pregnancy chance from a single IVF treatment cycle. This data was not available previously as many patients delay their use of frozen embryos. This cumulative analysis looks at the chance of pregnancy from a single IVF cycle when using both fresh embryos and subsequent frozen embryos, if needed.

Table 1 shows the rates for patients that used their own eggs (oocytes).
Table 2 shows pregnancy rates for patients that were the recipients of donor oocytes.

Please note that these are not delivered pregnancy rates. Many of these pregnancies are ongoing. There are also some patients that have not yet achieved pregnancy, but have frozen embryos remaining.

Question: I’m 38 years old and have been trying to get pregnant for about a year. All of my lab tests and my husband’s semen analysis have been normal. What do you think is the problem?

Answer: For women in their late 30s, it is naturally going to take longer to get pregnant. They are experiencing what I like to call “age-related sub-fertility.” Some may be lucky and become pregnant right away. However, for the majority of women, as we age fewer of the eggs we ovulate are chromosomally normal; and therefore fewer ovulations result in the release of a normal egg. It just may take more ovulations before that normal egg is released, fertilized, implants, and succeeds in becoming a baby. It is estimated that about 1 in 5 eggs are normal at age 35, about 1 in 10 at age 40, and only 1 in 25 at age 45. So, at age 38, if about 1 in 8 eggs are normal, you may have only 1 or 2 chances a year for successful conception. If your intercourse was not well-timed that cycle or there was some other subtle inefficiency, the chance for conception may be lost. The catch-22 with age-related sub-fertility is that it takes longer to get pregnant and meanwhile, you are getting older and your egg quality is also declining. For this reason, many women seek treatment with fertility medications or IVF as they get older. These treatments can increase the number of eggs produced and exposed to sperm in a single month, thus improving the odds that normal eggs will be found. The good news is that for most women still in their 30s, fertility treatments for age-related sub-fertility are often successful.

– Carolyn Givens, M.D.