I was born in the Lower East side of New York City, my father’s hometown, to quite young parents. At six months of age, we moved to Paris, my mother’s hometown, and I played in the streets and parks of Paris until I was 9.  I spent every Wednesday with my maternal grandmother (schools were in session Saturday to Tuesday, and Thursday to Sat), often spending hours in the Bois de Boulogne (a park along the western edge of Paris).  We spent quite a few summers in the South of France where we would raise small chicks and rabbits, which became dinner at the end of our vacation.  I am the oldest of five children. 

My parents later divorced, and my father moved all 5 of us children to the States.  First, we lived in Washington DC, where I attended the French school for one year, and then soon enrolled in the local parochial school.  My childhood included ballet lessons, camping trips, art projects, and lots of neighborhood adventures with my best friend Lucia.

In high school, our family moved to Boston after my father changed jobs.  I spent 3 years at Brookline High School, where I was exposed to a broad palette of academic topics.  I knew that I loved science, so my father recommended I study Latin (the root of many scientific words).  However, I was also fascinated by Asian philosophy and art, so I started studying Mandarin.  I studied both for 3 years.

I applied to college knowing that I wanted not only a strong scientific program, but also the opportunity to continue my Mandarin studies.  Bridging both these diverse interests lead me to the University of Massachusetts at Amherst, where I majored in Microbiology.  My work-study job later evolved into a research opportunity that developed into my Honors thesis.  At the same time, I was also pursuing a minor in Asian Studies, and the opportunity came to be a member of the first group of ten American exchange students to attend Beijing Normal University (teaching university).  This was truly my dream come true, going to mainland China, as the country was slowly allowing westerners to visit.  I spent the summer in Taiwan to further improve my language skills, and then lived in Beijing at the University for one school year. I jumped on every travel opportunity that presented itself, and had some amazing experiences exploring parts of China where no foreigners had been to in many decades.  My language skills truly allowed me to have personal contact with the local Chinese which would otherwise not have been possible.  As the cliché goes, I learned more about myself in China than I did about the Chinese themselves, but this is the beauty of travel and stepping outside of one’s cultural comfort zone. I turned 21 years old in China.

Once I returned to the States, I matriculated and decided that I needed to spend some time with my French family.  I worked in Paris for a year, and traveled extensively throughout Europe.  I then returned to the States and lived in Palo Alto, doing research with a biotech startup company. During this time I was deciding what my next career steps would be.  Should I pursue medicine and apply for an MD, or should I pursue research and apply for a PhD?  Pursuing an MD was more in line with my overall goals, and two years later I was bound for medical school at UC Davis.

I knew that I wanted to pursue women’s health care.  I also was fascinated with the growing field of fertility treatment because it was a triumvirate of scientific, ethical and surgical frontiers, all of which resonated for me.  When I applied for residency, my mentor encouraged me to consider a new program at UCSF, which was a combination of residency and Reproductive Endocrinology (REI) fellowship. While this was a very big commitment to seven years of training, I knew after interviewing that this was a perfect combination for me.  Fortunately, I was accepted, and thus embarked on a long career at UCSF. 

I completed my residence, fellowship, and was on faculty at UCSF for a few years.  During this time, I was very active in basic science research investigating the role of endometriosis and fertility.  In 2000, I left UCSF and joined my 4 current partners at PFC.  We now have created a most unique fertility center, with a state of the art laboratory, dedicated and devoted staff, acupuncture center, research center, and a special combination of personal care with the benefit of input from the five MDs who are seasoned fertility providers. 

While I was a resident at UCSF I met my husband, who himself was an Internal Medicine resident.  After his Chief Residency year, he did a fellowship in Gastroenterology.  Fortunately we were both able to complete all of our training while staying in San Francisco, the city we call home.  We have three wonderful daughters who love adventure, travel, playing sports …… and while none of them will become doctors like their parents, all three have a giving heart and are involved in careers and activities of giving back to their communities.

When not at work, I enjoy time with my family, as well as good food and wine, foreign films, reading, photography, yoga, and just quiet times.

I am privileged to be in a profession where I touch so many people’s lives and dreams.  Every birth announcement is a reminder of this privilege, and every failed treatment cycle is a new commitment to do my best.

-Isabelle Ryan, M.D.

Engaging in well designed and executed research in the world of fertility treatment can be very difficult.  However, in order to advance in our field, and to counsel patients about expeditious and cost-effective plans for success, we need to conduct research.  When patients are diagnosed with Unexplained Infertility, it is both frustrating for the patient (why can’t my doctor figure out what’s wrong with me?), and for the treating physician (we like to be able to “show” where the problems are).  We have known for 10 years now, from a well designed study by Guzick and his team, that for patients with Unexplained Infertility the chances of success with “low tech” treatment options are still in a low range of 5-12% per cycle.  This range is dependent on the female’s age and use of Clomid or gonadotropins (1) (Ryan, I; A Most Frustrating Diagnosis (2)).  Now we have insight into comparing cost effectiveness of low-tech options (Clomid or gonadotropin therapy) versus IVF treatment (3).

The FASTT study started in September 2001 with 503 women between the ages of 21-39,   the average age was 33, and continued until April 2006.  A few months ago the final results were published, after a nine-year process.  The study took place at Boston IVF Center in Massachusetts, a state where fertility treatment is a covered health insurance benefit, including up to six IVF cycles.  After a full fertility evaluation confirmed that the couples had Unexplained Infertility, the patients were enrolled in the study.  Patients were randomly assigned to one of two treatment plans: 1) Three cycles of Clomid plus intra-uterine insemination (IUI), followed by 3 cycles of gonadotropin/IUI, then up to 6 IVF embryo transfer cycles (Conventional treatment), or 2) Three cycles of Clomid/IUI followed by up to 6 IVF embryo transfer cycles (Accelerated treatment).  All treatment protocols, medication dosing, and number of embryos transferred were practiced similarly among the patients.  In addition, the patients kept a diary of additional time and money spent in each treatment cycle.  This cost included time away from work, medication co-pays, and payment for additional care (e.g. emotional counseling). A financial analysis of the total charges incurred for each patient from the time of entry into the study until the patient had a delivery (including pregnancy and newborn care); the patient stopped treatment; or the study was closed.  The study’s two primary endpoints were comparing: 1) time to pregnancy, and 2) health care costs associated with that pregnancy/delivery.  Secondary endpoints were per-cycle pregnancy rates, per-couple pregnancy rates, and adverse outcomes.

Sixty-four percent of couples delivered at least one live-born baby by the close of the study in 2006 (150 conventional and 171 accelerated). The time-to-pregnancy was statistically shorter for the accelerated group compared to the conventional group.  The estimated time-to-pregnancy was 8 months in the accelerated arm and 11 months in the conventional arm.  This 3-month difference between the two groups would suggest that the additional 3 months doing gonadotropin/IUI cycles did not contribute to a shorter time-to-pregnancy than the 3 Clomid/IUI cycles alone.

Per-cycle pregnancy rates for Clomid/IUI, gonadotropin/IUI and IVF were 7.6%, 9.8% and 30% respectively.  The very slight increase seen in the gonadotropin/IUI rates did not have any impact on the “time-to-pregnancy rates” (as noted above), and yet are much more costly cycles than a Clomid/IUI cycle (average $500/cycle vs. $2500/cycle).

In the Guzick study, the greatest number of High Order Multiple (HOM) pregnancies (triplets or greater) was in the gonadotropin/IUI cycles.  This finding has been echoed by a number of other studies.  In the FASTT report, there were an equal number of HOM pregnancies in each group.  In the conventional group, there were two sets of triplets, both from gonadotropin cycles.  In the accelerated group, there were 3 sets of triplets, one from Clomid, and two from IVF.  The average number of embryos transferred in the IVF group was 2.3.  With the improvement in IVF laboratory techniques, many IVF centers currently advocate for transfers of only one embryo in women with an average age of 33.  This practice trend will likely decrease the number of HOM in IVF, and would most likely present further benefit (safety and financial) to the accelerated strategy.

A cost effective analysis shows the total charges per delivery to be $9,846 lower for the accelerated group ($61,553 per delivery) than the conventional group ($71,399 per delivery).  If the analysis is limited to charges of infertility treatment per delivery, the difference was $5,802 in favor of the accelerated arm.  The observed incremental difference in charges per couple was a savings of $2,624 for the accelerated treatment, and an increase in the proportion of couples with deliveries of 0.06.  In the parlance of cost-effectiveness analysis, accelerated treatment dominates conventional treatment.  This analysis holds true as long as the charges of an IVF cycle are <$17,749 (which, even in today’s dollar, is a realistic expectation for patients in their early 30s).

In summary, for patients with Unexplained Infertility, doing 3 cycles of gonadotropin/IUI after 3 cycles of Clomid/IUI was of no added benefit.  Accelerated treatment to IVF saves money and results in a greater proportion of couples with delivery of a live-born baby.  In terms of the financial benefit, the charges for treatment, pregnancy and delivery were less for couples in the accelerated arm compared to the conventional arm. 

Pacific Fertility Center strives to provide patients with treatment recommendations and protocols based on sound science.  We appreciate and are thankful to our IVF colleagues who have the tenacity and ability to proceed with studies such as this FASTT study.  We all benefit from their efforts!

Isabelle Ryan, MD

(1)   Guzick et al.  Efficacy of superovulation and intrauterine insemination in the treatment of infertility, N Engl J Med 1999;340:177-83

(2)     Ryan, I; A Most Frustrating Diagnosis; June 2009, Fertility Flash Science Pulse, Vol 7, issue 4; http://www.pacificfertilitycenter.com/fertilityflash/vol7_issue4.htm#Article1

(3)   Reindollar et al.  A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial, Fert Ster 2010; 94:3,888-898

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

For patient(s) who need to use an egg donor to create or expand their family, medical scrutiny is performed on the chosen egg donor before she can proceed with the IVF cycle.

The medical screening of egg donors is an important process. Here at the PFC Egg Donor Agency, we proceed with an extensive screening process PRIOR to allowing the egg donor to become eligible for choosing by the intended parent(s). This extensive screening is performed to help determine and identify any medical factors which may disqualify the donor, or to identify information which may require additional testing prior to determining donor eligibility. At PFC, our philosophy is that we want to identify any issues prior to intended parents choosing the donor, so that the risk of identifying medical issues with the donor after the start of the IVF cycle is minimized, and the risk of canceling the cycle is much reduced.

Medical screening for the donor includes an extensive review of her personal and family medical history, physical exam and pelvic ultrasound, psychological evaluation (in-person visit with our MFT Peggy Orlin),

standardized personality assessment (PAI), and blood testing including ethnic appropriate genetic testing.

The PFC Egg Donor Agency complies with current recommendations by the American College of Obstetrics and Gynecology (ACOG), and the American College of Medical Genetics (ACMG). The donor identifies her ethnic background, and based on this information, appropriate testing is performed (see article by Lauri Black, Genetic Counselor, outlining current recommendations). This testing is done and results reviewed prior to approving the egg donor as eligible to be in the donor database. If the donor is a carrier for a genetic mutation, this may disqualify her from being an egg donor; some genetic mutations may not be disqualifying, but the sperm source may need to be screened for that mutation, prior to deciding to choose that egg donor. These tested mutations are for recessive disorders, so an embryo would only be at risk of having the disorder if BOTH the egg and sperm source were carriers for the identified mutation (see above noted article).

It is important to understand that new genetic mutations are identified almost every day; so recommendations for ethnic-based testing do potentially change year by year. While many genetic mutations have been identified on the human genome, many of these are very rare, and only mutations that are more frequently seen within one’s ethnic group are those that are recommended to be tested for. It is not appropriate, nor feasible, to check for all known possible mutations. The PFC Egg Donor Agency is kept apprised of current recommendation by our affiliated genetic counselors, so that our list of genetic screening tests may change over time. Rest assured that we keep informed of these changes, and comply with up-to-date recommendations.

While all this testing may seem cumbersome, it is to help assure that once you choose your egg donor, we can proceed with the IVF cycle with minimal risk of a cancellation, and start you on your way to achieve your dream of a healthy family.

In vitro fertilization (IVF) is perhaps one of the most effective options available for the treatment of infertility. This procedure has been available in the developed world for approximately 30 years, and has been responsible for 1-4% of all conceptions. While IVF was originally developed for the treatment of female tubal factor, it has evolved to include treatment of male factor infertility via intra-cytoplasmic sperm injection (ICSI), as well as oocyte quality factor (Decreased Ovarian Reserve, or DOR). With the development of embryo biopsy techniques, IVF has also grown to incorporate pre-implantation genetic screening of embryos (PGD) to avoid genetic diseases in embryos and to screen for normal chromosomes. In the history of mankind, IVF will undoubtedly remain the greatest development for the treatment of human infertility for the foreseeable future.

Since the introduction of IVF, there has been a directly proportional increase in multiple gestation births. Traditionally IVF centers have measured success as the number of live births, irrespective of outcomes. This increase in multiple births is driven by the clinical incentives for live births, but some may also be driven by patient request. Two studies have shown that 20% of European and US infertile couples wanted a multiple birth^{(1, 2)}. Even after counseling regarding the risks of a multiple gestation, many patients still wanted to transfer 2 embryos. As IVF success rates have increased, and as the embryo freezing technologies have improved, a shift in the philosophy of IVF providers is occurring. Success rates are more likely to be measured as “live birth of a singleton (single baby) pregnancy”—in other words, “one healthy baby at a time”.

As the number of babies born after IVF has grown, there has been increased interest in looking at the pregnancy and birth outcomes in the successful IVF population. While potential complications for mother and babies are increased with any multiple gestation, there may also be an increased risk for complications even with IVF singleton babies. However, it may not be the IVF treatment itself that results in this increased risk for complications. The questions that reproductive endocrinologists and high-risk pregnancy specialists are trying to answer are primarily: 1) Is there a higher risk for a baby of any adverse birth outcome if that baby is conceived in an IVF laboratory? and 2) Is there something inherent about a past diagnosis of infertility which places even a singleton gestation at greater risk of pregnancy and birth complications?

IVF Singletons:

A number of large studies have addressed the question of increased risk to IVF babies ^(3-7). They echo a similar theme concerning birth outcomes, most importantly preterm birth <37 weeks, and low birth weight. One study compares the differences in degree of risk of poor outcomes with IVF babies vs. naturally-conceived babies. There appears to be a 93% increased risk for IVF singletons as compared to naturally conceived singletons, and a 57% increased risk for IVF twins versus naturally conceived twins⁽⁶⁾. Certainly the overall chance of a preterm delivery is much smaller for singletons than twins, and a twin pregnancy carries much greater risks overall.

A review of the US birth registry indicates that the proportion of IVF singleton babies born at full term with low-birth-weight is decreasing, but the proportion of IVF singleton babies born prior to full term with low-birth-weight is stable. In either case, the incidence of low-birth-weight is higher in babies born after IVF when compared with the general population. While outcomes of low-birth-weight babies may be getting better, there are still elevated risks for singleton low-birth-weight babies conceived via IVF.

For most of these studies looking at risks for IVF babies, factors known to influence pregnancy and birth outcomes are taken into consideration in the analysis. These important factors include maternal age and prior birth history. However, other factors may also be important but are not as well accounted for: factors such as previous poor obstetrical outcome, smoking status, socio-economic status, performance of fetal reduction procedure (especially for the analysis of the singleton data), types of ovarian stimulation protocols, media used in the IVF laboratory, and/or use of laboratory techniques (ICSI, etc.).

Infertility per se may itself be a risk factor for poorer pregnancy and birth outcomes. In an attempt to answer this important question, IVF outcomes have been compared with either non-IVF fertility treatments such as ovulation induction (OI) or to spontaneous conception outcomes. Numerous studies ^(8-15) have evaluated this question, and shown a higher risk of preterm birth for both IVF and OI babies as compared to spontaneously conceived singleton pregnancies. When evaluating outcomes for sub-fertile women (infertility for greater than 1 year) who spontaneously conceive, again we see a greater risk of preterm deliveries, obstetrical complications and adverse birth outcomes ^(16-18). These studies strongly suggest that there is an inherent characteristic of infertile patients which place them at greater risk of poorer pregnancy and birth outcomes. Whether this is due to uterine or embryo issues is not yet known.

IVF Twins:

Many studies have compared the outcomes for twins conceived via IVF versus spontaneous conception. These outcomes were summarized and reviewed in a meta-analysis of birth outcomes of IVF twins in studies up to 2003 ⁽¹⁹⁾. The specific findings showed an increase in the chances of a preterm birth (57% increase), admission to the neo-natal intensive care unit (two-fold increase), and Cesarean section delivery (33% increase). No other parameters were significantly different from spontaneously-conceived twins.

These differences between twin gestations conceived via IVF versus spontaneously-conceived twins were similar for cycles of twin gestation conceived via ovulation induction (OI). The rate of prematurity seemed to be higher for the IVF than OI group ⁽²⁰⁾.

In conclusion, when comparing singleton or twin gestations conceived via IVF or spontaneously, the degree of difference in the overall risk is greater for the singleton-baby births than twins. This is especially true with regards to preterm delivery which is increased two-fold in IVF singletons and by 40% (adjusted for age) in twins. While most studies have made adjustment for factors which can affect birth outcomes, such as maternal age, some other potential factors are difficult to measure, such as history of infertility or direct effects of IVF technology itself. It appears as though infertility prior to conception may play a larger role in IVF outcomes, for both singleton and twin gestations.  

1. Thurin A et al. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 2004; 351:2392-2402.
2. Ryan GL et al. The desire of infertile patients for multiple births. Fertil Steril 2004; 81; 500-504.
3. Jackson RA et al. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004; 103; 551-563.
4. Helmerhorst FM et al. Perinatal outcomes of singletons and twins after assisted conceptions; a systematic review of controlled studies. BMJ 2004; 328; 261.
5. McGovern PG et al. Increased risk of preterm birth in singleton pregnancies resulting from in vitro fertilization-embryo transfer or gamete intrafallopian transfer: a meta-analysis. Fertil Steril 2004; 82; 1514-1520.
6. McDonald SD et al. Perinatal outcomes of singleton pregnancies achieved by in vitro fertilization: a systematic review and meta-analysis. J Ostet Gynaecol Can 2005; 27; 449-459.
7. Bower C et al. Assisted reproductive technologies and birth outcomes: overview of recent systematic reviews. Reprod Fertil Dev 2005; 17; 329-333.
8. French National IVF Registry. Analysis of 1986 to 1990 data. Fertil Steril 1993; 59; 587-95.
9. Frydman R et al. An obstetric assessment of the first 100 births from the in vitro program of Clamart, France. Am J Obstet Gynecol 1986; 154; 550.
10. McFaul P et al. An audit of obstetric outcome of 148 consecutive pregnancies from assisted conception: implication for neonatal services. Br J Obstet Gynecol 1993; 100; 820-5.
11. Tan S et al. Obstetric outcome of In vitro fertilization pregnancies compared with normally conceived pregnancies. Am J Obstet Gynecol 1992; 167; 778-84.
12. Wang JX et al. The obstetric outcome of singleton pregnancies following IVF/GIFT. Hum Reprod 1994; 9; 141-6.
13. Tanbo T et al. Obstetric outcome in singleton pregnancies after assisted reproduction. Obstet Gyncol 1995; 86; 188-92.
14. Rufat P et al. Task force report on the outcome of pregnancies and children conceived by in vitro fertilization (France 1987-1989). Fertil Steril 1994; 154; 550-5.
15. Friedler S et al. Births in Israel resulting from in vitro fertilization/embryo transfer. 1982-1989: National registry of the Israeli association for fertility research. Hum Reprod 1992; 7; 1159-63.
16. Basso O et al. Subfecundity and neonatal mortality: longitudinal study within the Danish national birth cohort. BMJ 2005; 330; 393-394.
17. Basso O et al. Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort. Hum Reprod 2003; 18; 2478-2484.
18. Pandian Z et al. A review of unexplained infertility and obstetric outcome: a 10 year review. Hum Reprod 2001; 16; 2593-2597.
19. McDonald S et al. Perinatal outcomes of in vitro fertilization twins: a systematic review and meta-analysis. AM J Obstet Gynecol 2005; 193; 141-152.
20. Adler-Levy Y et al. Obstetric outcome of twin pregnancies conceived by in vitro fertilization and ovulation induction compared with those conceived spontaneously. Europ J Obstet Gynecol and Reprod Biol 2007; 133; 173-178.

Every year, several Pacific Fertility Center professionals participate in ASRM’s national meeting. They evaluate the research and share their findings with PFC and Fertility Flash.

Among those attending the conference from PFC were Dr. Philip Chenette and Dr. Isabelle Ryan and Peggy Orlin, MFT. Their reviews cover the following topics: Update #1: Ovarian Stimulation Techniques, Update #2: PGD and Aneuploidy Screening Techniques, Update #3: Egg Freezing, Update #4: Acupuncture, and Update #5: Men and ART.

Update #4: Acupuncture

The published study of German Paulus ⁽¹⁾ reported improved pregnancy rates with a one-time acupuncture treatment pre-and-post embryo transfer. This sparked great interest for providers of fertility treatment, in both the conventional and Chinese medicine (TMC) communities (see Fertility Flash March, 2004). A few years later, a study from Denmark ⁽²⁾ reported improved pregnancy rates in patients receiving pre-and-post transfer acupuncture, but no improvement if there were two post-transfer treatments. In both of these studies, there were no sham acupuncture (i.e. simulated but not real acupuncture) treatment controls.

Smith ⁽³⁾ and colleagues in Australia did compare acupuncture versus sham acupuncture (but did not include a no-treatment control group), using 3 treatment sessions: ovarian stimulation day 9, pre and post embryo transfer. There was no difference found in these different study groups. Interestingly, subjects in the sham control group were more likely to report relaxation as a side effect of acupuncture. Some studies indicate that sham acupuncture evokes acupressure, and in this way, may trigger physiological responses.

In all the above studies, the acupuncture treatments were performed within the IVF centers (patients did not have to travel off-site). In general, there were no more than 100 patients per treatment group.

At ASRM, Dr. Craig and colleagues reported an acupuncture study conducted in Seattle, using 3 IVF clinics. The acupuncture sessions were performed off-site by 2 acupuncturists. The patients were randomized to pre- and post-transfer acupuncture vs. no treatment. The physicians were not aware if the subjects were or were not receiving treatment. A total of 97 patients were studied (about 50 patients per treatment group). Clinical pregnancy and live birth rates were as follows: 54% and 39% for the acupuncture group, and 78% and 65% for the control group. These results were statistically significant. Of all the acupuncture studies thus far published, this is the first study to suggest a possible detriment to the use of acupuncture in IVF treatment.

One of the important differences for this study versus other randomized controlled trials is that all the patients had to go to an off-site acupuncture center for their treatment. This may be an important factor when a patient has to travel to the acupuncture clinic immediately before and immediately after an embryo transfer. Perhaps this factor would increase stress levels. Another important difference for these Seattle IVF centers was that baseline pregnancy rates are much higher than the previously-studied non-US centers. The higher the baseline pregnancy rate, the more difficult it is to show a difference in treatment results— so a statistically significant result would be more credible.

Ideally, a multi-center randomized-controlled-trial should be performed where the following comparisons can be evaluated: acupuncture pre-and-post transfer, no-acupuncture control group, sham-acupuncture control group, and these 3 groups can be compared at both on-site and off-site acupuncture centers. Each study group would require at least 100 patients, so this would require about 1000 patients total.

As we have a chance to collaborate with TCM providers, and as patients are willing to participate in these large multi-center randomized clinical trials, we will gain a better understanding about whether a mix of allopathic and TCM medicine improves overall care, and which combination of treatments may be the most beneficial for our mutual patients.

Isabelle Ryan, MD

References:

(1) Influence of acupuncture on the pregnancy rate in patients who undergo assisted reproduction therapy. Fertil Steril. 2002, Apr; 77(4):721-4.

(2) Acupuncture on the day of embryo transfer significantly improves the reproductive outcome in infertile women: a prospective, randomized trial. Fertil Steril. 2006 May; 85(5):1341-6.

(3) Influence of acupuncture stimulation on pregnancy rates for women undergoing embryo transfer. Fertil Steril. 2006 May; 85(5):1352-8.

Question: How do I decide which one of your “Shared Risk” plans is best for me?

Answer: It is estimated that there are approximately 2 million infertile patients in the US. Approximately 1.5 million will seek treatment. Of these, about 750 K conceive with standard treatment and 750 K remain infertile. Of the 750 K who remain infertile, 50 K adopt, 50 K undergo IVF, and 650 K drop out of treatment. Only about ¼ to ¹/3 of infertile patients see a Reproductive Endocrinologist; most patients are only treated by gynecologists. The remaining ¹/3 don’t seek treatment because they believe that they can’t afford it, and ¹/3 don’t proceed to adequate treatment secondarily to financial barriers.

Given these daunting statistics, we understand that it is important for IVF clinics to help maximize access to all levels of fertility care, by sharing the financial burden and the risk of an IVF cycle. With these goals in mind, PFC offers two “shared risk” financial plans to our patients. We call our two plans: the Refund Plan and the Option 2 Plan.

When engaged with you in a shared risk plan, we are indicating that if you meet the appropriate medical criteria, we feel confident that we have a reasonable chance to help you achieve your goal of parenthood, and we are therefore willing to share in the financial risk associated with IVF. Sharing in the financial risk of treatment is a statement of confidence in our ability to help you overcome infertility.

As physicians, we are often asked by our patients to recommend a financial plan. Each patient’s case is different, and choosing the best plan for you has to do with your own comfort level in taking financial risk, dovetailed with your emotional comfort and commitment to treatment. These levels of comfort can only be addressed on a personal and individual level.

Some general questions to consider in analyzing the plans are the following:

• • What are your estimated chances of success with your fresh embryo transfer?
• • What are the chances of having any frozen embryos?
• • What are your estimated chances of success with your frozen embryos?
• • If you are not pregnant with this IVF cycle, would you want to proceed to another IVF cycle?
• • If you do not become pregnant after a treatment cycle, would you rather receive a refund and then decide on the next steps for treatment?

Depending on the answers to these questions, you can begin to define which financial plan may make the most sense. For patients who want some financial buffer if their cycle is not successful, the Refund Plan may be the best choice. It allows you to receive a refund and then decide if the next steps will be to do nothing more, to continue treatment, or to use the refund for other options such as adoption. For those who are ready to commit to a second IVF cycle attempt if the first cycle is not successful, the Option 2 Plan may be the preferred choice. This plan provides the option of 2 cycles for only a little more cost than a single cycle. In general, the Option 2 Plan is for those whose chances of having frozen embryos is less—making the probability of needing a second fresh IVF cycle greater. At PFC, we have two financial coordinators dedicated to providing all the information about costs which can then help you to make these important decisions.

As in any financial decision, there is no right or wrong answer, but only an answer which best fits your particular situation. This decision is then matched with your personal comfort level in sharing risk. For some patients, neither of these plans may seem appealing, and the Single Cycle Plan (pay for services as provided) will be most appropriate. For patients with insurance coverage for IVF, the Single Cycle plan is the only option.

While Pacific Fertility Center can not choose a financial plan for you, if you need more information about your specific fertility situation before deciding on a “shared risk” plan, please do not hesitate to discuss this with your physician or your financial coordinator.

– Dr. Isabelle Ryan

Many of our patients are undergoing fertility treatment for male factor indications, and undergo insemination therapy. This may be patients who are using donor sperm from a sperm bank, or patients who are using their partner’s sperm, but the sperm has been frozen (partner out of town, or other indications). We are often asked if the success rates will be affected by the use of frozen versus fresh sperm. As well, we are asked if the number of inseminations performed per cycle will affect the success rates. There is a body of studies that have been done to address these specific questions, and our clinic’s interpretation of the literature is the following.

The first consideration addresses which type of insemination provides the best outcome when using frozen sperm. A number of studies have looked at this question, and when all the data from those studies are compiled and analyzed, results indicate that if an intrauterine insemination (IUI) is performed (sperm placed directly in the uterus), the odds are 2.5 times greater that a pregnancy will occur, than if an intracervical insemination (ICI) is performed (sperm placed at the entrance of the cervix) (5% vs. 14% monthly chance of pregnancy) (1, 2). When sperm are placed at the cervix, many of them are “lost” as they travel through the cervix and into the uterus, to then find their way to the fallopian tubes. This dilutes the actual numbers that make it to the egg in the fallopian tube, and therefore decreases chances of success. Performing 2 intracervical inseminations in one cycle (9% chance of pregnancy) did not bring success rates close to what one intrauterine insemination achieved (15% monthly chance of pregnancy) (2).

Next consideration addresses if fresh sperm is better than frozen sperm. Two studies have addressed this best, and indicate that the critical components that will provide comparable pregnancy rates are the performance of an intrauterine insemination (IUI), accurate timing of the insemination (relative to the ovulation event), and adequate concentration of sperm inseminated (called total motile count=TMC) (3, 4). The most accurate way to time the insemination is by using ovulation predictor kits (OPK), or by administration of an HCG injection to trigger the ovulation event. Ovulation predictor kits have been evaluated and the kit we recommend is the Clear Blue Easy ovulation kit. First detection of an LH surge is most likely to occur in the morning, and our recommendation is to do one test/day, in the morning (5). The best timing for an intrauterine insemination using frozen sperm is within 24-48 hours after a positive LH surge as detected by an Ovulation Predictor kit. In a well-designed study, using first positive OPK results to time insemination, 5% of total pregnancies resulted in cycles where the IUI was done within 24 hours of the positive OPK result, 90% of total pregnancies if within 24-48 hours, and 5% of total pregnancies if past 48 hours (5). Quite a few studies have evaluated the minimum number of inseminated sperm required to achieve an adequate pregnancy rate. Most indicate a total motile count between 6-15 million. This means that after thawing the frozen sperm specimen, the lab must recover between 6-10 million moving sperm. Most sperm banks provide a post thaw guarantee of 10-15 million/vial if prepped for an IUI (sperm already washed), or 15-20 million/vial if prepped for an ICI (unwashed sperm).

Next consideration addresses sperm washing techniques. There are a number of different laboratory techniques for washing and preparing sperm for insemination. As it turns out, there is no difference in pregnancy rates based on the sperm preparation technique. This holds for both the freezing technique and the post thaw washing technique (if ICI prepped) (6). This also applies if the sperm is pre-washed by the laboratory prior to freezing (if IUI prepped) (7). As long as an adequate TMC is reached post freeze-thaw, pregnancy rates hold steady.

The last consideration is: would one IUI per cycle reach adequate pregnancy rates, or would 2 IUI’s be better? Many studies have been done evaluating this question, and while individual studies may show different results, the majority of studies indicate that one IUI/cycle is adequate, and 2 IUI’s does not improve pregnancy rates, as long as the IUI is well timed, and the TMC inseminated is adequate (2, 8, 9, 10, 11).

In conclusion: We take guidance from the best published literature, and use the following guidelines for managing frozen sperm intrauterine insemination cycles at Pacific Fertility Center:

• Determine best timing of intrauterine insemination or IUI:
  First positive ovulation predictor kit (OPK) if OPKs are reliable, or HCG injection as administered according to our instructions.
• Do one IUI 24-48 hours after first positive OPK, or 24-48 hours after administration of HCG
• Do intrauterine insemination (not intracervical insemination or ICI)
• Assure insemination with adequate total motile count or TMC
  We will thaw sperm until we have a TMC of 10 million

If attention is paid to these management points during your treatment cycle, you should feel reassured that your chances of achieving a pregnancy is comparable to those if you were using fresh sperm.

– Isabelle Ryan, M.D.

Footnotes

1. Goldberg et al, Fertil Steril. 1999 Nov; 72(5):792-5

2. Carroll et al, Fertil Steril. 2001 Apr:75(4):656-60

3. Subak et al, Am J Obstet Gynecol. 1992 Jun; 166:1597-604

4. Bordson et al, Fertil Steril. 1986 Sept;46(3):466-9

5. Khattab et al, Hum Reprod. 2005 Sep;20(9):2542-5

6. Byrd et al, Fertil Steril. 1994 Oct;62(4):850-6

7. Wolf et al, Fertil Steril. 2001 July;76(1):181-5

8. Centola et al, Fertil Steril. 1990 Dec;54(6):1089-92

9. Lincoln et al, J Assist Reprod Genet. 1995 Feb;12(2):67-9

10. Khalifa et al, Hum Reprod. 1995 Jan;10(1):153-4

11. Matilsky et al, J Androl. 1998 Sept-Oct;19(5):603-7

Question: My wife and I have been trying to have a child for a while now. I have been told that she is “allergic” to my sperm. What are our best treatment options at his time?

Answer: Many people say that they are allergic to their partner’s sperm, and that can mean different things, depending on the testing done. True incompatibility with sperm is very uncommon. Some female patients may have had a blood test to see if they have “anti-sperm antibodies” circulating in their blood stream. A positive test result actually does not correlate well to a true problem of incompatibility and infertility, and therefore this blood test is no longer recommended as part of infertility testing. An uncommon, but more relevant problem would be if the MALE partner were making sperm antibodies against his OWN sperm. Men who are at risk of this are those who have had testicular injury (scrotal trauma) or testicular surgery (torsion, tumors, or other indications). Antibodies are also commonly found in men who have undergone vasectomy reversal, especially if the interval between vasectomy and vasectomy reversal is a long one.

The sperm has 3 parts: the head, midpiece and tail. If the male patient makes sperm antibodies against the sperm midpiece or tail, this is probably of no consequence. If he makes antibodies against the sperm head, then this can prevent the sperm head from fusing with the egg membrane, and progressing with the important steps of fertilization. The remedy for this condition is to proceed to IVF, and have the embryologist inject the sperm directly into the egg membrane and cytoplasm. This injection process is called ICSI (intracytoplasmic sperm injection), and will restore normal fertilization rates for that couple.

It therefore is important to be clear about the appropriate testing to be done, if one suspects a sperm incompatibility. The anti-sperm antibody test is done directly on the SPERM, and done in a laboratory which has the ability to do this specialized testing (usually an IVF or an Andrology laboratory). If you have a history that might place you at risk of making antibodies against your own sperm, please discuss this with your fertility physician.

– Isabelle Ryan, MD

Question:
What is my fertility physician looking for in conducting an antral follicle count?

Answer:
Women are born with all of the eggs (oocytes) that they will ever have. This is a set number, which is determined before birth. This pool of eggs is never replenished. A female fetus will have the greatest number of eggs around 16-20 weeks of pregnancy (6-7 million); at birth this number decreases to about 2 million; and by puberty to about 300,000. This constant and dynamic process of decline continues until menopause and is not interrupted by birth control pills, pregnancy, or ovulation. From this reservoir of eggs, fewer than 500 eggs will ovulate during a woman’s reproductive life.

There is a continuous process occurring in the ovaries, where eggs are constantly being prepared for the maturation process. It takes 3-6 months for eggs to develop and mature. As the eggs are developing, they transition from a primordial, to preantral, to then antral follicle. Antral follicles are visible by vaginal ultrasound. Antral follicles therefore represent the reserve of eggs in our ovaries and those that are candidates for selection and growth by fertility stimulation medications (gonadotropins).

When assessing one’s ovarian reserve (potential for a successful pregnancy), a number of parameters are evaluated. One of these is called the “antral follicle count” (AFC). An antral follicle count is typically done during the 2nd-4th days of menstrual flow, though it can probably be as accurately done during other times of the menstrual cycle. Studies show that the AFC is predictive of the expected ovarian response to gonadotropins. An AFC less than 6 total (between both ovaries), predicts a poor stimulation response. For those undergoing IVF, a similarly low AFC will be associated with a higher cancellation rate. As women approach their 40s, and as day-3 FSH results rise above 10 mIU/ml, this typically correlates with fewer eggs overall in our ovaries, and therefore a low AFC. Indirectly, a low AFC can correlate with diminished ovarian reserve.

In the same way that there can be monthly variability in day-3 FSH test results, there can be monthly variability in the AFC. More variability is observed in the AFC of young infertile women than in older women. However, overall a single AFC is still quite predictive of ovarian response under gonadotropin stimulation, and there is fairly good agreement between repeated AFC over consecutive cycles. In conclusion, doing an AFC is an adjunct to the day 3-FSH test to predict ovarian reserve and ovarian response to fertility medications.

– Isabelle Ryan, MD