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:
- Guzick DS, et al. Efficacy of treatment for unexplained infertility. Fert Ster 1998; 70:2, 207-213.
- Guzick DS, et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. N Engl J Med 1999;340;177-83.
- Athaullah N, et al. Oral vs injectable ovulation induction agents for unexplained subfertility. Cochrane Database Syst Rev 2002;3:CD00352
- 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
- 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
— Isabelle Ryan, M.D.
Isabelle Ryan, M.D. is recognized by prestigious medical associations for her pioneering research leading to new insight into the important clinical problem of endometriosis related infertility. Dr. Ryan is medical director of PFC’s Third Party Parenting Program and Egg Donor Agency.
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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.
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Being a single gay dad certainly suggests that I didn't get pregnant accidentally; my journey into parenting has been a long and deliberate one. Having my 6 month old son and daughter staring up at me all day reminds me that I really did want to do this 25 years ago, but being 50 still does not feel too late. They say it takes a village to raise a child. In my case it took a village to create a child. Thanks to a loving gestational surrogate, and longtime friends as both egg and sperm donors, my dream of parenting has come true.
A difficult pregnancy with many complications somehow made it to 36 weeks and 5 days with Ella weighing 5 lbs 12 ounces and Armstrong (Ari) weighing 5 lbs 11 ounces. Amazingly, at 6 months, they are 19 lbs each and have been sleeping 11 hours a night since week 13. For those of you who are soon to be parents, you will find that's pretty remarkable. Having hardy and healthy babies is such a blessing. I am forever indebted to Pacific Fertility Center, and Dr. Isabelle Ryan, for their essential roles in helping me achieve parenthood and having a healthy family.
Choosing PFC was not initially an easy decision. It took accessing the CDC nationwide fertility clinic website and comparing the data from clinic to clinic to make me feel confident about picking up the phone and scheduling a first meeting. I really analyzed the data from the clinics carefully, as I was interested in high success rates achieved with high total numbers of embryo transplants.
I had also heard about specific experiences that gay men had had with other local clinics that were less than heartwarming. As an HIV-positive individual, even though I was opting to not undergo sperm-washing to utilize my own genetic material, I did want a compassionate and professional environment in which to pursue my parenting dream.
To be perfectly honest, I had been told by other parents that PFC took a "conservative" approach to achieving pregnancy. Conservative is a term that can be interpreted in many ways. For leftist liberals, like myself, it can somehow seem like a dirty word. However, I have a newfound appreciation for the term. My first surrogate was a lovely married woman with 2 children. She had been a gestational surrogate for a San Francisco couple 2 years prior. They had worked with another local fertility clinic and she got pregnant, rather quickly, with twins. She carried to week 28 and the babies were each under 3 lbs and fortunately survived. I was excited to proceed with her, as we got along splendidly and my priority was finding someone who had her own family and had previous surrogacy experience. PFC screened her and immediately determined that she had an "incompetent cervix". I had no idea what that meant, though it seemed like the two most incongruous words to ever be placed back to back. Well, an incompetent cervix is a serious matter! I'm supposing that this was not previously diagnosed and was likely the cause of her prior preterm labor and delivery. PFC's screening saved me a lot of heartache, money and time. I should say that 3 times in a row, to really give it the weight it deserves. I don't think many people arrive at fertility clinics devoid of heartache, so having a clinician save you from avoidable disaster is an enormous gift.
Having now gone through a twin pregnancy, I more fully understand the roller-coaster process of which I was forewarned. Proceeding with a less than perfect surrogate would have been a tragedy. The second surrogate I found had actually conceived via PFC twice before and would have been a great surromom; but her insurance no longer covered surrogacy. I'm still in constant touch with her and she has nothing but great things to say about her experiences with PFC.
It would be easy for me to find the heart-space to simply rave about PFC. After all, I have the reward of two healthy babies to serve as living proof. For others considering parenting through assisted reproductive technology, there is so much more about my process that is crucial to know. I was insistent, from the get-go, about wanting twins. I had several discussions with Dr. Ryan about the risks that came with carrying multiples. Yes, I'd heard from many people that being a single dad with twins was going to be a "handful", but the potential clinical complications and risks were not something I'd widely considered. I was 48 years old and didn't want to go through the process over the course of several years and really wanted at least 2 kids.
Again, if a "conservative" approach is what I got from PFC, the counsel was so very right. My surrogate had previously carried twins and we were both confident that all would go well. We never imagined the complications that did arise during each trimester. It was a very difficult pregnancy. Even with a vaginal delivery, the recovery was tougher than I wish to describe herein. Everything I'd been told by PFC was absolutely accurate. Knowing what I know now, I would say that I, while not at all cavalier, was filled with excitement and anticipation that had me driving full speed through a string of yellow lights. Trust me; I drive now more carefully with twins on board.
Not a day goes by without my being awestruck by the wonder of my children. I have to say that, so far, this has not been a daunting experience. Maybe I have easy babies. Maybe being highly organized has provided them with the structure and consistency that I was told was essential to parental sanity. I'm not sure what it takes to be a great dad, but certainly the desire to parent was a good start towards just being a good dad. Certainly, being 50 has made me a bit more patient and knowledgeable than I might have been as a 20 or 25 year old dad. Being 50 also makes me appreciate having gotten pregnant on the first embryo transfer. At the time, every passing month was just another month of living without the children I knew I was going to have. It seemed like lost time. I heard the clock ticking; I felt the pangs of desire growing.
As crazy as it may sound, hardly a day goes by without my thinking about going back to PFC, thawing my remaining embryos and giving it another go. Through all the obstacles, PFC gave me a sense of direction, a grasp of the reality that I faced and clear information with which to proceed. Perhaps the confidence that I felt in PFC's expertise has given me a residual optimism that makes me feel willing to try again. For the moment, Armstrong and Ella find each other in sufficient and good company; but I'd be willing to consider a special unanimous request from the two of them for another sibling. But, maybe just an old-fashioned singleton next time!
—Submitted by Gedalia (G'dali) Braverman,
Dad to Armstrong and Ella who were born November 19, 2008
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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.
| Table 1 Patient Using Own Eggs |
| Patient Age |
<35 |
35-37 |
38-40 |
41-42 |
>42 |
| Cumulative Clinical Pregnancy Rate |
63% |
57% |
39% |
32% |
25% |
| Table 2 Patient Using Donor Eggs |
| Recipient Age |
<43 |
43-45 |
38-40 |
41-42 |
>42 |
| Cumulative Clinical Pregnancy Rate |
190 |
165 |
199 |
109 |
78 |
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.
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