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