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Usually when you hear “everything’s normal” from your doctor, it’s a good thing. But if you’ve been trying to get pregnant for a long time, it can be frustrating to find out there is no explanation for your infertility. Up to 30% of couples who experience infertility receive a diagnosis of “unexplained infertility.”
But that doesn’t mean there aren’t any treatment options available to you. So what does it mean? What can and can’t we explain in this diagnosis? Let’s break it all down.
What does unexplained infertility mean?
When a couple sees an infertility specialist, they typically undergo an initial battery of tests. This may include an assessment of whether the female partner’s menstrual cycles are ovulatory with ultrasound and blood work, as well as a hysterosalpingogram (HSG). The initial testing for the male partner includes a semen analysis to assess the amount of motile sperm. When a couple is experiencing continued infertility despite tests confirming ovulation, at least one open fallopian tube, and an adequate amount of motile sperm in the ejaculate, the diagnosis is called unexplained infertility.
There are many theories about possible underlying causes of unexplained infertility, but these largely cannot be tested for. Some theories suggest there may be issues with oocyte quality, making the eggs unable to develop into high-quality embryos. But unfortunately, we don’t have a blood test or ultrasound to diagnose poor egg quality. Similarly, the semen analysis assesses the amount of motile sperm and morphology, but it is not a test of sperm quality or the ability of the sperm to fertilize the egg. And while the HSG may show that the fallopian tubes are open, this still does not mean that they are functional in their role of allowing fertilization and then transporting the growing embryo back to the uterus for implantation.
How is unexplained infertility treated?
With all other infertility diagnoses, we can identify the cause and work to correct it. For example, if you don’t ovulate, we can give you oral medications to induce ovulation. Or if your fallopian tubes are blocked, we can bypass them with in vitro fertilization (IVF). Or if there aren’t enough motile sperm, we can assist fertilization during IVF. Other suspected causes of infertility, such as fibroids, can be fixed surgically. Making treatment choices for these types of infertility is relatively straightforward.
However, when there is no specific cause or source of infertility identified, it is challenging to determine which treatment approach (if any) is best. So many of the approaches for unexplained infertility are what we call empiric, meaning we have treatments that work but we aren’t sure exactly what we are “treating.”
There are several studies that show that up to 65% of couples diagnosed with unexplained infertility who continued trying without interventions eventually conceived without fertility treatments. We call this “expectant management.” After discussing your case with your doctor, as well as considering how long you have been trying and the age of the female partner, expectant management may be a reasonable first step. If it has not been successful, the approach to treatment is often stepwise, starting with the lowest-intervention treatments first and, if these fail, eventually moving on to IVF.
Intrauterine insemination (IUI)
Let’s start with undergoing an IUI in a natural, unstimulated menstrual cycle. This approach is often called natural cycle IUI, or NC-IUI, and typically involves some type of monitoring to assess for growth of an egg (on ultrasound we can’t actually see the egg, but we do see the fluid-filled follicle where the egg is housed), as well as how thick the endometrial lining is. We can then either use blood work to track for ovulation markers or induce ovulation with a trigger shot. Based on the estimated time of ovulation, an IUI is performed.
The goal of the IUI is to increase the amount of motile sperm in the uterus, making the trip out to the fallopian tubes a bit easier. Two studies comparing NC-IUI with expectant management in the treatment of unexplained infertility concluded that NC-IUI is not significantly more effective than expectant management. Furthermore, NC-IUI is cost-wise and logistically similar to medicated IUI treatment approaches but has a lower success rate. So you might end up spending just as much time and money doing NC-IUI as other forms of IUI, but with a lower success rate. Therefore, many physicians and patients choose to skip this option.
Hormone-stimulating medication
The next step in treatment often includes oral medications that stimulate your brain to produce more of the follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The FSH and LH then act on the ovaries to induce the development of more than one follicle. The goal here is to ovulate more than one egg, thereby increasing the number of chances for conception each month.
Medications commonly used to induce growth of more than one follicle include clomiphene citrate (brand name Clomid) and letrozole (Femara). The clinical logistics of monitoring a patient on Clomid or letrozole are similar to those described above. The medication starts on the second to fourth day of the menstrual cycle and is taken for five days. Two to three days after the last pill, the patient generally has monitoring with ultrasound and/or blood work until a natural surge is detected, or until a trigger shot is administered. The patient may then be instructed to have appropriately timed intercourse or undergo an IUI. A large randomized controlled trial as well as a systematic review have shown that Clomid paired with intercourse is no more effective than expectant management. Similarly, a large RCT revealed that letrozole paired with intercourse is no better than expectant management. The studies do, however, show that pairing Clomid or letrozole with an IUI increases the likelihood of live birth. Clomid paired with IUI (Clomid-IUI) was shown in an RCT to have a significantly higher birth rate compared with expectant management and is estimated to be 23% to 25%. Many studies show that letrozole paired with IUI (letrozole-IUI) achieves similar live birth rates compared with Clomid-IUI.
The drawback to using an oral medication to induce more than one egg to ovulate is twins. The risk of twins varies in different studies but probably ranges from 5% to 13%. This sounds low, but is much higher than for those who conceive without any medical intervention. It is worth taking time to consider this risk, as we know that twin pregnancies are associated with an increased rate of issues for both the mother and babies later in the pregnancy, during delivery, and postpartum.
Injectable gonadotropins
Approaching treatment in a graduated stepwise fashion brings us to the use of injectable gonadotropins. These medications are recombinant forms of FSH and LH, and they act directly on the ovary to increase the number of follicles that are recruited to grow. Gonadotropins can be paired with intercourse or IUI, or used for IVF. While gonadotropins paired with timed intercourse or IUI have a similar pregnancy rate to oral medication with intercourse or oral medication with IUI, using gonadotropins (especially at higher doses) is associated with a much higher twin pregnancy rate. For example, some studies have demonstrated that with high-dose gonadotropins paired with IUI, the pregnancy rate does increase, but the twin risk skyrockets to 32% to 33%. Given that there is minimal increase in pregnancies and a higher twin risk, combined with the fact that gonadotropins are more expensive and complex to administer and monitor, this is another step that many couples choose to skip.
In vitro fertilization (IVF)
The most common usage of injectable gonadotropins is with IVF. The goal of IVF is to collect oocytes, fertilize them in the lab, assess embryo development, and then select the best-quality embryo and replace this embryo in the uterine cavity. Here we are overcoming possible barriers due to egg quality, fertilization, and embryo development in the IVF laboratory, as well as bypassing the fallopian tubes. Because IVF selects for the best embryo and bypasses the fallopian tubes, it can be a very useful modality for many patients with unexplained infertility. For those with unexplained infertility who are under 38 years old, the studies show that a stepwise approach starting with three to four rounds of Clomid-IUI followed by IVF has the highest pregnancy rates and is a cost-effective strategy. However, for those with unexplained infertility who are older than 38, going right to IVF likely leads to a higher pregnancy rate and a shorter overall treatment course until pregnancy is achieved.
When considering IVF as a possible treatment option for unexplained infertility, it is worth exploring the role of intracytoplasmic sperm injection (ICSI). During the IVF process, the oocyte can either be incubated with a small droplet of semen — often called conventional fertilization — or a single sperm can be injected into the egg during ICSI. Most studies show that there is no difference in the pregnancy or live birth rates when comparing ICSI versus conventional fertilization among patients undergoing IVF for unexplained infertility.
However, ICSI use in this subset of patients has been shown to lead to a higher fertilization rate and lower risk of fertilization failure, which means there are potentially more fertilized oocytes, leading to a possibility of more embryos available to choose from. Because we replace only one embryo at a time, the use of gonadotropins with IVF does not increase the risk of twins. Instead, the main drawbacks to gonadotropin use in IVF are the risks associated with the IVF process, such as the surgical risks of the oocyte retrieval, ovarian torsion, and the possibility of ovarian hyperstimulation.
The bottom line
- Unexplained infertility occurs when a couple has normal test results for ovulation, fallopian tube function, and sperm count but no clear cause for their infertility can be identified. There are many theories about possible underlying causes of unexplained infertility, but these largely cannot be tested for.
- With unexplained infertility, because there is no specific cause or source of infertility identified, it is challenging to determine which treatment approach (if any) is best.
- After discussing your case with your doctor, as well as considering how long you have been trying and the age of the female partner, the approach to treatment is often stepwise, starting with the lowest-intervention treatments (IUI, hormone-stimulating medication, injectable gonadotropins) and, if these fail, eventually moving on to IVF.
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