Steve and I met and fell in love in our twenties. We both thought we would want children “some day.” Eleven years later we realized “some day” had finally arrived. I was thirty-six then, but I never thought we would have any problems conceiving. My mom had three children in her late thirties and into her forties.

After six months with no success, my doctor ran the usual tests and found nothing wrong, so my OB recommended going to PFC. We did one IUI, then decided to move on to IVF. My first IVF cycle failed. We were preparing for the second when we were delighted to findout I was pregnant naturally. I gave birth to a healthy baby boy.

We wanted more children, and as it had taken two and a half years to conceive Alan, we decided to start trying again straight away. We weren’t so lucky this time, so after 18 months we were back at PFC talking to Dr. Givens about doing IVF again. Then we discovered a new problem – my FSH was now elevated. So, now I also had decreased ovarian reserve in addition to unexplained infertility.

We tried four cycles of IVF with my own eggs. I did get pregnant on my third cycle, but sadly miscarried at eleven weeks. I was now forty-two and felt it was time to move on.

Now we faced decision time-do we give up, move on to donor egg, or move to adoption? We were both sure we wanted more children, and I felt that by carrying the child I would feel that it was truly mine, even if I didn’t have the biological connection. Oddly enough, it was harder for Steve to move on to an egg donor. But after lots of talking it through, he felt it was the best choice for our family too.

We met with Peggy the PFC counselor, who was very helpful. Dr. Givens thought an egg donor was a great option for us. She said that with a transfer of two blastocysts, our chances of conceiving were about 80%. We ended up with a short list of two potential donors. One was a perfect match on paper—my height, my hair color, my eye color, with the right ethnic background. The second wasn’t such a perfect match, but I just felt a really strong connection to her. I really felt that if we met in real life we would be friends. In my mind I kept going back to something Peggy had said “pick someone you really like”, it was great advice. We went with donor number two, and are very happy with our choice.

Initially everything went well, but then on day three we received a phone call asking us to come in. Our embryos were looking very stressed. Most were grade three with low cell count. We transferred the best three and prayed.

On the day of our beta pregnancy test, Ann (one of the nurses at PFC) called to give us the good news. I was pregnant! Once we saw the heartbeats, we told our son Alan, “Mommy has two babies growing in her tummy,” and he was thrilled. Feeling those babies kicking and squirming around inside, I had no doubt whose babies they were—I might not have provided the eggs, but my body turned those little seven or eight celled embryos into two beautiful children.

The first day Alan got to meet his new brother and sister the look on his face said it all. It was love at first sight. He has made a wonderful big brother, the twins adore him, and our family now feels complete. I feel truly lucky when I look at my three wonderful children. I am very grateful to Dr. Givens and all the wonderful staff at PFC, and especially to our donor.

Some people may wonder, if I love all of my children the same. They have three very different personalities, so I love them all differently; but I do love each one as much as the other. In the words of one of our favorite books, they are “all my favorites.”

—Submitted by Trisha (PFC patient)

It is always frustrating, both for patient and physician, when we perform a full fertility evaluation and conclude that that patient’s diagnosis is “unexplained infertility.” But unexplained infertility does not mean “no” infertility. It means that we recognize there is some abnormality or inefficiency in the process of getting pregnant, but that we do not have a good test to assess what is the actual problem.

There are many critical steps in the process of getting pregnant which we can not directly assess; such as how efficiently the eggs are captured by the fallopian tubes, how efficiently the tubes push the eggs along to the uterus, how well the sperm are fertilizing the eggs, how well the fertilized eggs are developing to embryos, and how efficiently the embryos find their way to the uterus. All these steps are critical—yet we have no direct test. If one were to proceed to an IVF cycle, we can then make some assessment of these steps, but not prior.

So, if the evaluation shows normal egg quality (FSH, Estradiol, ultrasound), dye study (HSG) shows open tubes, sperm test shows normal count and motility, and there is no evidence of endometriosis—this typically defines unexplained infertility.

One of the first studies addressing the efficacy of treatment for unexplained infertility was published in 1998 (1), and indicated that patients who underwent no treatment had a 1-4% pregnancy rate per month; insemination alone, 3.8% pregnancy rate/cycle; clomid alone, 5.6% pregnancy rate/cycle; Clomid plus insemination, 8.3% pregnancy rate/cycle; gonadotropins alone, 7.7% pregnancy rate/cycle; and gonadotropins plus insemination 17.1% pregnancy rate/cycle. This study was retrospective, and did include patients with mild endometriosis, so while providing good insight, more studies were needed to better define treatment efficiency for these patients. However, it was important to see that insemination alone did not provide an improvement, and best improvement was noted with combination therapy.

Next, Guzick and colleagues published a large randomized study addressing superovulation with gonadotropins and insemination, for patients with unexplained infertility (though again mild endometriosis was included) (2). The control group was patients who had intracervical inseminations (to assure sperm exposure). Pregnancy rates for this group were 10% per cycle. Those who underwent intrauterine insemination had an 18% pregnancy rate. Those who underwent gonadotropin stimulation plus intracervical insemination have a 19% pregnancy rate, verses 33% for those with gonadotropin plus intrauterine insemination. Therefore, couples who undergo superovulation and intrauterine insemination have a 3 times higher chance of achieving a pregnancy, than the control group.

The question of which type of ovulation induction agent to use, oral verses injectable, has been addressed in a meta-analysis published in 2002 (3). This review of 5 randomized controlled trials shows that pregnancy rates were higher in injectable cycles (gonadotropins), though live-birth rates were not different between oral and injectable cycles. Their conclusion was that oral agents may therefore be more suitable for ovulation induction, since the multiple rates were lower, and cost of the cycle less.

Last year, a prospective trial looking at using oral Clomid verses Letrozole with inseminations in patients with unexplained infertility was published (4). This study showed that the total number of follicles was greater for the Clomid users (3.1 vs 1.6), but the pregnancy rates were the same for each group (Letrozole 19%/cycle verses Clomid 18.3%/cycle). Therefore, both agents are equally effective, and the multiple rate may be less with Letrozole.

Last year, another randomized control trial evaluated expectant management (no treatment), verses Clomid alone or intrauterine insemination alone in patients with unexplained infertility ( though included mild endometriosis patients) (5). This study again confirmed that Clomid alone (14% live-birth rate) or insemination alone (23% live-birth rate) was not statistically different than expectant management (17% live-birth rate). They evaluated patient satisfaction with the treatment process, and patients who were randomized to the “expectant management” arm were much less satisfied than those who were doing Clomid or insemination therapy, despite no improvement for those patients’ live-birth rates.

So, some take home points are as follows:

• Unexplained infertility does not mean “no” infertility
• Empirical clomiphene and/or unstimulated intrauterine inseminations are unlikely to offer an improvement over expectant management (no treatment)
• Best options are to consider Clomid or gonadotropins with intrauterine inseminations (depending on patient age, etc..)
• If this fails, then IVF is best option
• Depending on age and other evaluation, IVF may be best first option

Footnotes:

1. Guzick DS, et al. Efficacy of treatment for unexplained infertility. Fert Ster 1998; 70:2, 207-213.
2. Guzick DS, et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. N Engl J Med 1999;340;177-83.
3. Athaullah N, et al. Oral vs injectable ovulation induction agents for unexplained subfertility. Cochrane Database Syst Rev 2002;3:CD00352
4. Badawy A, et al. Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial. Fert Ster Aug 2008
5. Bhattacharya S, et al. Clomiphene Citrate or unstimulated intrauterine insemination compared with expectant management fro unexplained infertility: pragmatic randomized controlled trial. BMJ 2008;337:a716

My husband and I have a long history together. We met in high school, and after 10 years of marriage, we were ready to have a family. My sister had experienced trouble getting pregnant, so as a result I worried that I might have the same problem.

My worries were partially confirmed when my husband and I unsuccessfully tried to conceive. In our case, we discovered we had the unlucky combination of both male and female factor infertility. At that point we were under the care of our gynecologist. On our doctors’ recommendation, we went through IUI near the end of 2003. It was a nightmare for a lot of reasons. I reacted poorly to Clomid and did not conceive.

While I was still trying to conceive, my sister was happily on her way to having a family. She had gone to the next level of care: an expert reproductive endocrinologist at Pacific Fertility Center. We were of course delighted to hear the news of her pregnancy, but at the same time frustrated because we were still not pregnant. We had always thought that once we were ready to have a family, we would be able to get pregnant easily and naturally.

After our disastrous IUI cycle, we tried again naturally, but to no avail. Frustrated and tired, we took a break. After a while, I spoke with my sister Alison, who referred us to Dr. Herbert at Pacific Fertility Center. He was wonderful and had great bedside manner. He was positive and upbeat despite our combined infertility diagnosis. We went straight to IVF with Gonal F and Repronex. Unfortunately, my body didn’t respond well.

I really appreciated Dr. Herbert during this discouraging time. He was frank with us and indicated that my follicles were not looking good. Without good follicles, the ability to retrieve a reasonable number of quality eggs was in question, so we did not continue our IVF cycle. Dr. Herbert was very flexible; he listened, explained our options and didn’t dictate what we should do. He suggested IUI as a way to salvage the IVF cycle and much to our surprise, we became pregnant! When I got the good news that my husband and I were going to be parents for the first time, I was “over-the-top” happy calling everybody I knew. In addition, on our first ultrasound, we saw two beating hearts. We not only were pregnant, but also were pregnant with twins!

The irony is that after my sister Alison had twins, I too envisioned having twins. During our initial OB ultrasound, Dr. Herbert indicated that he saw two heartbeats. We had a scare at one point as we thought I had experienced a miscarriage. However, I had just had some bleeding and passed a blood clot. I appreciated Dr. Herbert during this time, as he remained calm at all times. Much to our delight, I gave birth to a healthy, beautiful set of twins (Justin and Eva) who are now over a year old.

I thoroughly enjoyed my experience at PFC. They were great from a logistical standpoint, and were great about getting all of the paperwork out of the way quickly. I appreciate the nurses—Anne was awesome and whenever we called she was very kind and understanding. I loved going to appointments as it was such as positive experience. Additionally, I appreciate PFC for their professionalism. Dr. Herbert was so experienced and knew what he was doing the whole time; I trusted him a lot. I truly love our children. It is wonderful for my sister and me to be able share experiences as we learn about the joys of parenthood firsthand. It is sweet irony indeed.

Leslie

Leslie’s journey to a successful pregnancy was a bit unconventional but contains several important messages for you, our patients. The stimulation of her ovaries during her first IVF attempt did not progress as we had hoped. There were fewer follicles and some were large and others small (follicle disparity). Had this been her final attempt on very high doses of medication, we might have proceeded on to egg retrieval. However, we felt the stimulation was suboptimal and we expected to improve this process in another cycle by changing the medication regimen. As Leslie and her husband were diagnosed with unexplained infertility, we also felt she might conceive by ovulating the few larger follicles which were present and using intrauterine insemination. Fortunately we were correct, and Leslie now has two wonderful children. These conversions from a planned IVF cycle to IUI cycle can produce pregnancies as often as 10% of the time as long as there are no other fertility factors like tubal damage or severe sperm problems and the age of the woman is not advanced (less than 38 years). Leslie’s story is a good example of persistence in spite of initial disappointment, of using all the options available in the most effective manner, and of “keeping the faith”. We hope Leslie’s story can be an inspiration to others who may face similar disappointments on their journey to parenthood.

Carl Herbert, MD

Our journey to parenthood is one we’ll never forget. Just a few years ago, we were both working professionals during the hey-day of the Silicon Valley. Fast-forward to today. Our work lives remain busy, albeit the settings have changed. We’ve said “so long” to the corporate life and “hello” to the entrepreneurial world and life as parents of four. We owe all the changes to parenthood, and frankly, we wouldn’t have it any other way.

We were married in 1992 and, at the time, were very much intensively focused on our dual career tracks so family building was simply not a big priority. Someday, if we were going to be parents, we wanted to have both adopted and biological children. We would have a nanny and a housekeeper to make sure things ran smoothly. However, we could see life without children very easily. However, in the late 1990s, we decided we wanted to be parents. We tried on and off for a couple of years, working around our work/travel schedules, but being fairly serious about the effort.

December of 2001 saw us going to India for a family wedding and as we were traveling a lot, we decided to look into adoption and visit several orphanages. At our first one, we had a very emotional time and left knowing that we wanted to be parents and that something would be missing for us if we did not follow that path. We came back and threw all the balls in the air, starting the adoption process and being “very serious” about trying to get pregnant.

The adoption route went much faster than we anticipated. Just two months after starting the process, we were able to get foster custody of Samir who was 10 weeks old at the time. Four months later, we adopted Samir (now 4.5) from Sisters of Charity, a Catholic orphanage near Bangalore, India. When we set out to be parents this time, we were not kidding around any more!

The biological route wasn’t as simple. We tried for several months but to no avail. Initially, we attributed this to stress. After all, with Samir we were embarking on parenthood for the first time. Sridhar started consulting. We also had to move out of our new home so the builder could address some major issues. We seriously tried to get pregnant for about 6 months and then decided to seek help.

We first learned about Pacific Fertility Center through a friend who referred us to Dr. Carl Herbert. We were impressed with his compassion and appreciated his candor. He didn’t pull any punches or provide false hope, which proved refreshing and uplifting. Dr. Herbert told us during our consultations that, regardless of the outcome of our infertility treatments, “we were going home to Samir” and that took a lot of the pressure off. Dr. Herbert was just one of many caring medical professionals that we dealt with along the way. We had glowing encounters with Dr. Chenette, also from the Pacific Fertility Center, as well as Dr. Laurie Green, Gina’s OBGYN at CPMC. They made us feel like individuals, not a number.

Our infertility treatment began with IUI cycles and Clomid which were unsuccessful. We did some basic testing but there were no explanations as to why we were not conceiving. Dr. Herbert suggested that we could try an IVF cycle, as it would address a number of factors, rather than do further testing. We decided to go for it and had success on the first try! Of the four embryos that were transferred, two implanted. Those two embryos resulted in our twins, Sanjeev and Serena, now 2.75 years old. One would think we were done, but we didn’t stop there. In Feb 2006 we adopted our fourth child, Sophia (1) from the same orphanage that we adopted Samir. We love them all equally and cherish every stage of their development.

It’s amazing how quickly things have changed for us. We went from two corporate professionals with our hands full with meetings, presentations, and reports to two parents with our hands full with diapers, toys, and baby clothes. Our vocabulary has changed as well. The corporate jargon now has to make room for occasional baby talk. (When speaking to our children, of course.)

The joys of having children cannot be understated. Whether it’s “soaping up” our kids in the bathtub or reading a bed time story, the little moments are precious. They seem to grow so fast, in every way that it is hard for us to keep up with the changes, so we try to enjoy the moments as they come.

This isn’t to suggest that life outside of parenthood is mundane. Work is as hectic as ever…but it is quite different. We no longer strive to climb the corporate ladder. I (Gina) stepped off it to stay at home and raise our children. I (Sridhar) did a complete 180 and am now the head of my own consulting practice. The beauty with this career move is the flexibility it affords in terms of raising the kids, which, as you can imagine, keeps us plenty busy.

– Gina and Sridhar

I have pondered at length what my wildest dream would be if Oprah, or some other fairy godmother, were to grant it. Which famous person would I love to meet? What exotic location would I love to visit? Try as I might I cannot see past the sixth-month-old bundle in my arms. My baby girl and her three-year-old sister are my wildest dreams. Climbing Mt. Everest, running a marathon or meeting a superstar might be some people’s wildest dream, but for me conquering infertility and raising my daughters is my wildest dream.

At age 30 I started trying to get pregnant. I had endometriosis, I hadn’t used birth control for almost ten years and I had never been pregnant. I had also never imagined I would have difficulty conceiving. There was a great deal of irony in the amount of energy I put into trying not to get pregnant before my husband Red and I mutually agreed we were “ready”. After trying for more than a year, we went to see Dr. Carl Herbert and I was diagnosed with unexplained infertility. Thankfully, Dr. Herbert took excellent care of us and at age 34 I conceived my first daughter with the help of Clomiphene and IUI.

Conceiving my second daughter, however, proved more challenging, but was accomplished through IVF three years later. Even though I had tried IUI again and had produced many follicles, my IVF cycle revealed that the quality of my eggs was inferior. Dr. Herbert had the unhappy task of relating this distressing news to us during my embryo transfer, but he did so with tremendous grace and kindness. I have the utmost trust and confidence in Dr. Herbert and I feel blessed that he gave us the opportunity to conceive. Despite the quality of my embryos, we beat the odds and I conceived anyway. Yahoo!

Ultimately my goals were met, but it was the journey through infertility that has brought light and clarity into my life. With the help of my amazing doctor and with nurses like Ann McGovern (to whom I cried countless times), the laborious process of conceiving against the odds was made easier by their warmth and encouragement. I don’t know if it ever got “easier” being met with my period after each month’s unsuccessful attempt, however. By far the most searing memory, beyond all the shots and ultrasounds, was news, from what seemed like every woman on the planet, of other people’s pregnancies. And not only were they pregnant, but, their pregnancies were achieved unaided and on their first try. Of course!

What saved me and my marriage both times was a combination of therapy, friends and family. My husband was amazing through it all and our marriage is stronger and brighter as a result. When all is said and done and both my girls are strapped in their car seats or cuddling with me on the couch, all of the infertility effort seems like a distant memory. I feel so blessed to have conquered my infertility. My wildest two dreams have been realized.

– Jennifer

You may have heard about Preimplantation Genetic Screening as a technique provided in the IVF laboratory, and may have wondered if this technology is one you should consider incorporating in your IVF cycle. When considering various technologies in your IVF cycle, it is always important to clearly define what information you wish to gather with this technology, and also understand the pitfalls of the technology.

We have two methods of screening embryos. The first is called Preimplantation Genetic Diagnosis, for couples that have a known and defined genetic disease (e.g. Cystic fibrosis, Huntington’s disease, thalassemia), or are carriers of a single chromosome abnormality (chromosomal translocation). In this case we screen the embryo(s) for that particular genetic disorder, and transfer appropriate embryos. For this type of genetic screening, the aim is to conceive a healthy, unaffected child.

The other type of genetic screening is called Preimplantation Genetic Screening, where we screen the embryos for abnormalities in chromosome number. We all have 23 pairs of chromosomes. Embryos that have extra or missing chromosome(s) (aneuploid embryos) are much more likely to not implant, or to produce a miscarriage. The incidence of implantation failure, or of miscarriage, depends on which chromosome(s) are missing or duplicated. We therefore can screen an embryo with a “five or nine chromosome panel.” At PFC we utilize the nine chromosome panel. We look at the nine chromosomes that have been identified as most commonly being associated with implantation failures or miscarriages to see if that particular embryo has the correct number of those nine chromosomes. If so, this embryo is deemed “normal”, and can be transferred back to the uterus.

So who might consider PGS? Patients who have had a number of failed IVF cycles (documented failed implantations), those with a poor response to ovarian stimulation or those with poor embryo development (poor responders), those with recurrent miscarriages (>2 first-trimester miscarriages), those with a prior aneuploid pregnancy, those who are at least 35 years old are all candidates for PGS. The chances of improved pregnancy rates with PGS are dependent on the indication for PGS.

When we started doing PGS for various indications, we expected a dramatic improvement in implantation rates, and therefore pregnancy rates, as we were transferring pre-selected embryos. As it turns out, we have not necessarily seen those expected improvements in all patient groups. Patients who are younger than 35 yeas of age have a better chance at improved implantation and pregnancy rates using PGS. Improvements can still be obtained for older patients, if the 9 chromosome probe set is used (some centers use a 5 chromosome panel). Studies now indicate that patients who have at least 6 fertilized eggs to screen will also have a better prognosis than those with 5 or fewer. For those patients who have five or fewer fertilized eggs in their IVF cycle, we may actually recommend not proceeding with the PGS. In this case less manipulation of embryos may provide the patient with the best overall chance at pregnancy. Patients who have had less than 3 failed IVF cycles may have greater benefit from PGS than those with > 3 failed cycles. Patients with a prior aneuploid pregnancy or with recurrent pregnancy losses can also expect an improvement.

For patients who have had repetitive IVF cycle failures, or repetitive pregnancy losses, a PGS cycle may be diagnostic (explain if those failures/losses are from a high number of abnormal embryos), and in that sense may provide important information that explains those fertility failures. With those answers, the patient can then decide about pursuing similar treatment cycles, or choosing other options (using a donor egg, pursuing adoption, or choosing to live child-free). Studies indicate that results from one PGS cycle are indeed predictive of probable results in subsequent PGS cycles. In other words, if we have a cycle with a higher than expected percentage of abnormal embryos, we have to anticipate that we will probably have a similar result in subsequent PGS cycles.

There are many proposed reasons to explain why we are not achieving a higher implantation/ pregnancy rate in PGS cycles. There clearly is added stress placed on the embryo(s) when one cell is biopsied out, and when the embryo is kept in culture for an extra day or two while waiting for the results of the genetic testing. We currently can only test for 9 chromosomes, and it is possible that there may be undiagnosed abnormalities on one of the untested chromosome pairs. There is also a small possibility that an embryo we deem “normal” may actually not be normal (false negative result). It also may be that simply looking at chromosomes is not the final answer. Most likely the integrity and health of the cytoplasmic structures, and other important structures of the egg are also critical in the ability of the embryo to develop into a viable and healthy pregnancy.

Who Benefits Most?

• Patients with < 3 failed cycles, and > 5 fertilized eggs
• Patients 35 year and older (if using a 9 chromosome panel)
• Patients with a history of recurrent pregnancy losses
• Patients with a previous aneuploid pregnancy
• Patients using PGS as a Diagnostic Tool for:
  - Repeated IVF failure
  - Non-obstructive Azospermia

So, while PGS is a wonderful tool that can be incorporated into the various techniques of your IVF cycle, you need to be aware of the strengths and limitations of PGS testing. Your physician can help guide you in terms of the appropriate use of PGS and whether you may benefit from incorporating PGS in your IVF cycle.

Our 7 year old daughter sneers when we joke about why she is a fanatic about ice cream: “Because you were a frozen embryo for 9 months.” To our 4 year old twin boys, also conceived by ICSI/IVF, we sometimes say, “double trouble – we wanted one more boy, and we got two!” They, along with our adopted Korean son, don’t realize that they are true miracles, particularly since the most recent IVF attempt was given a 2-5% chance of success by Dr. Schriock, because “age was an issue,” and to our dismay Emily’s FSH level had tripled since our prior successful IVF cycle.

Never as a couple did we predict that we would be challenged with unexplained infertility. Emily took for granted that she would some day have children, having put career and studying as a top priority throughout her second decade. But as a pediatrician and geneticist, we too became part of the Bay Area epidemic of infertility as we struggled to start a family. Each day at work Emily became ever-so-more aware of the challenge as she counseled pregnant women about genetic testing. I myself, a psychiatrist, became concerned about the emotional roller coaster, because Emily seemed obsessed with the goal of having a child.

Despite the lack of control we felt, now that we have completed our quest to be parents, we are truly appreciative of the expertise, wisdom, and compassion of PFC doctors and staff.

We feel blessed by what we have learned:

1. We never take our children for granted;
2. Each child, no matter how he/she came into the family, is loved equally for the joy each one brings – adoption is just as much of a gift as a pregnancy;
3. There are some advantages to raising twins;
4. Our lives are enriched from the relationships we formed with health care providers and friends;
5. Life is precious – we more deeply cherish our own lives and value friendships, hobbies, nature, family time;
6. We have more sensitivity towards others who have similar struggles.

We are also compelled to share what we learned:

1. Don’t hesitate to ask questions or seek multiple consultations;
2. It is useful to record all notes in a journal to help think of questions, and to feel more knowledgeable and in control;
3. Take advantage of scientific journals on infertility, RESOLVE and their resources;
4. Start therapy and counseling if needed;
5. Use the internet to research and read the many available books, but also keep in mind that some information is not substantiated by good, sound data;
6. The field of infertility advances quickly, and given new choices – there is always hope;
7. Look into other options, even though at times it may seem there is no light at the end of the tunnel. Adoption does not have to be a last resort;

Don’t forget, after the challenge of infertility, there is perhaps an even greater challenge – parenting!!!!

– John and Emily, San Francisco

Q:
I am 40 years old and have been experiencing unexplained infertility for about 2 years. I have been reading that PGD may help to improve my chances of success with IVF. Is this true?

A:
PGD, or Pre-implantation Genetic Diagnosis is a technique, when used in combination with IVF, that can help to determine if the embryos have what it takes to successfully establish a pregnancy. As women get older, there are more errors in the chromosomal make-up of eggs. The most well-known of these defects is Down Syndrome or Trisomy 21, a condition in which the fetus or baby has an extra chromosome number 21. Having a missing or an extra chromosome may make the embryo unable to develop much past a few days of life or may result in a first trimester miscarriage. PGD uses a DNA-binding technique to determine if there are a correct number of chromosomes in the embryo. To do this, embryos on Day 3 of culture (5-10 cells) undergo a biopsy to remove a single cell. The rest of the embryo remains in culture in the IVF laboratory. The biopsy cell is analyzed for the correct number of chromosomes. Currently, PFC with its cytogenetic partner, St. Barnabas Medical Center, tests for 9 chromosome pairs which represent the most common abnormalities seen and some of the most serious in terms of a potential birth defect. As this technology continues to evolve, we expect to be able to assess all 23 pairs. IVF with PGD cannot correct defects in chromosomes. It can only diagnose whether an embryo is abnormal for these 9 chromosomes. The embryo could still be abnormal for one of the other 14 pairs. PGD may decrease the possibility of a miscarriage due to abnormal chromosomes. It may allow for the selection of the embryos most likely to implant and cause a normal pregnancy. If a woman has a good number of fertilized eggs to work with, it may eliminate having an excess number of embryos returned to the uterus at any one time and may eliminate having frozen embryos that really are not genetically normal. Because the embryos will have been screened for some of the major chromosomal abnormalities, theoretically, the remaining embryos should provide a patient who is older a better chance at a viable pregnancy. Some studies have shown that the implantation rates (chance that any one embryo will successfully implant) can be doubled with IVF/PGD. Also, miscarriage rates have been reduced by one-half and the delivered pregnancy rate is increased. Women or couples interested in this procedure should discuss it with their Reproductive Endocrinologist. At PFC, we also refer our PGD patients for a special genetic counseling session in preparation for this process.

Despite the overwhelming success of In Vitro Fertilization (IVF) in helping couples to conceive in the past 25 years, there remains a group of women for whom there is no obvious explanation for repeated IVF failures. This has led to hundreds of theories, most debated and subsequently discarded, to explain these inexplicable, yet relatively uncommon embryo implantation failures.

One popular theory that lingers is that the implantation process is facilitated in part by the maternal immune system, acting at the contact point of the uterine lining and the normal embryo. While there is little doubt that many biological processes are likely at work here, the exact mechanisms of embryo implantation remain poorly understood. More basic research is underway to further understanding of this complex process.

Taking off on this theory that some abnormality in the immune system is responsible for implantation failures, some IVF practitioners will run a battery of tests for antibodies to phospholipid molecules on their IVF patients. These phospholipids are everywhere on cell surfaces. At high levels, such as with some auto-immune diseases, the presence of antibodies to phospholipids can lead to clotting disorders and sometimes repeated, mostly second trimester pregnancy losses. Much more controversial is the question of whether or not anti-phospholipid antibodies play any direct role in inhibiting embryo implantation. Approximately 9% of normal fertile women can be found to have anti-phospholipid antibodies in their blood.

A well designed study from 1997 by Denis and colleagues found that in a large number of patients undergoing IVF, the presence or absence of these anti-phospholipid antibodies prior to treatment had no effect on IVF outcome. This is why the majority of reproductive endocrinology and infertility specialists, including Pacific Fertility Center, do not run anti-phospholipid antibody tests on their infertility patients. But some IVF practitioners routinely run these tests and, based on the presence of any positive titers of antibodies, will prescribe a regimen of twice daily injections of heparin and a tablet of children’s aspirin daily. Heparin is a blood thinner and is known to inhibit the binding of anti-phospholipid antibodies to phospholipids on cell membranes.

Prior studies examining heparin use have resulted in conflicting findings, some studies showing amazing benefits and others finding none at all. Most of the prior studies had design limitations that made it difficult to form firm conclusions. This conflict, coupled with the inherent potential risks of heparin use, have limited the use of this controversial therapy to a very small number of centers.

A new study, recently published in the August issue of Fertility and Sterility (an official professional journal) may finally put the debate to rest. The study was designed as a randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with prior in vitro fertilization failure, and with positive signs of anti-phospholipid antibodies or anti-nuclear antibodies. This study protocol is considered the “gold standard” design for a clinical trial and when performed as designed, the results are very hard to dispute.

Basically, some of the women, all of whom had had at least 10 embryos transferred over several prior IVF cycles and who had no known explanation for the implantation failure, were randomly assigned to receive either heparin and aspirin or a placebo (blank) during their IVF or frozen embryo transfer cycle. Neither the researchers nor the patients were aware whether or not the patient was receiving the active drug until the study was completed, to eliminate any potential study biases.

For the women receiving heparin and aspirin, a total of 296 embryos were transferred. This resulted in 20 cases with positive fetal heartbeats on early ultrasound (7%). For the placebo group, 259 total embryos were transferred and there were 22 positive fetal heartbeats (8%). Keep in mind that these patients had been through several prior IVF attempts so their overall chances for success would be low to start with. The live birth rate for the heparin and aspirin group was 6% and was 7% for the placebo group. There was no statistical difference in these numbers.

The bottom line on this study is that even with positive anti-phospholipid antibody tests, women with repeated IVF failures were no more likely to conceive if they received a treatment regimen with heparin and aspirin or with nothing at all. This study provides Class A medical evidence that recommendations to use heparin for infertility must be viewed very cautiously, as heparin’s effect on certain patients can be even detrimental to their overall health. For more information regarding the use of low-dose aspirin while attempting conception, please see our Sept. ’03 issue of Fertility Flash.