The causes of unexplained infertility are by their very nature unclear, and future research will probably reveal conditions we currently know little about. While it’s impossible to say exactly why couples are diagnosed with unexplained infertility, we’ve highlighted eleven factors that contribute to the diagnosis, and nine of them can be tested for.

Undetectable factors

(1) The function of the Cervix

The cervix has a complex role in pregnancies and is the “gateway” to the womb that opens and closes across the month and it has glands that release various types of mucus that support or prevent sperm entering the womb. Fertile cervical mucus is crucial as it activates a sperm’s “capacitation” ability to break down the shell around the egg, and the cervix also stores sperm and releases them over several days to enter the womb, but there’s no way to test this function. ⁱ While surgery to remove abnormal cervical cells changes the cervix structure, it doesn’t seem to alter fertility much unless surgery is repeated. ⁱⁱ

(2) The Fallopian tube environment

The environment in Fallopian tubes is quite complicated and involves different types of cells that move and nourish the sperm, eggs and embryos within them. It’s possible to check “tubal patency” with HyCoSy and other tests to see if the tubes can let an embryo reach the womb. However, it’s not possible to check tubes’ ability to nourish or transport a healthy embryo to the womb at the right time. ⁱⁱⁱ

Detectable factors

(1) Endometriosis

The early stages of endometriosis trigger a strong immune response in the pelvic cavity, and the body responds by increasing the white blood cell numbers and cytokine levels. The most common site for endometriosis is around the ovaries and the ends of the Fallopian tubes, which is precisely where sperm need to be to fertilise an egg. Sperm are tiny and easily destroyed by white blood cells or damaged by cytokines present to resolve the endometrial tissue. Many women with mild endometriosis are symptom-free, and without a laparoscopy, no one would suspect they were affected.

(2) Age

The diagnosis of unexplained infertility rises dramatically with the age of couples trying to conceive, which is a reflection of their eggs and sperm having less genetic integrity. The DNA in them becomes less robust and ordered, with higher fragmentation rates (as well as aneuploidy) which creates confusion in the cells and organs as a fetus grows. It’s possible to test the DNA Fragmentation levels of men’s sperm with additional semen tests, but “egg quality” tests don’t exist. The current best option is testing a woman’s ovarian reserve to assess likely DNA Fragmentation rates. ^iv

(3) Immune issues

Immune system imbalances are significant factors for unexplained infertility, and with a growing understanding of the immune system’s complex role in pregnancy, it’s getting clearer. However, few people have immune status tests as they’re relatively new and expensive, and the lack of testing prevents us from knowing how widespread immune dysfunction is for fertility. What is agreed is an unbalanced immune system makes it much harder to conceive and maintain a pregnancy.

(4) Hypothyroidism

It’s surprisingly common for the thyroid to reduce female fertility, even during IVF cycles, as thyroid function has a direct effect on fertility rates, and low thyroid hormone levels also contribute to endometriosis and other infertility conditions. What makes it worse is that the need for thyroid hormones rises significantly in pregnancy, which puts an additional strain on a system that’s already struggling. Many women are unknowingly trying to get pregnant with subclinical hypothyroidism that’s lowering their fertility, and the condition also affects male fertility, causing low libido, erectile dysfunction and low sperm counts.

(5) “Folate pathway replication of the DNA and RNA”

The folate pathway replication is about an embryo’s ability to develop and grow properly from a healthy start. The issue here is how accurately DNA and RNA (that code their genetic future) are copied in new cells because any imperfections can create abnormal cells in the embryo.^v When the immune system detects abnormal cells, it will work to remove them, which can cause abnormalities or miscarriages, which is why mums-to-be are advised to supplement with folic acid to reduce the chances of neural tube defects, premature birth or miscarriage for this reason. However, it’s also a good idea for fathers to have good folic acid levels, as it brings important health benefits to their children. We recommend “methylfolate” rather than folic acid (the most commonly sold form) as it’s natural and absorbed better.

(6) Uterine abnormalities

Re-examination of women who’ve had repeated implantation failure for physical structures that prevent implantation (polyps, fibroids, long septums or adhesions) finds these structures ¼ of the time. This is because the initial internal examination missed them, but thankfully, removing the structures improves the women’s chances of conceiving. ^vi This missed diagnosis could be equally valid for women in couples with unexplained infertility who’ve had internal investigations, and knowing this reinforces the importance of having an internal investigation in the first place!

(7) Thrombophilia

Thrombophilia is either an inherited condition or it can develop because of immune changes, and it alters the bonding properties of red blood cells. Blood needs to clot when blood vessels are damaged, which involves blood cells bonding to each other, but significant variations exist in how easily blood clots, with haemophiliacs having poor clotting ability. The risk of clotting increases in all pregnancies as blood gets thicker clotting in vessels near the womb dramatically increases the risk of unexplained infertility and implantation failure.

• A study of couples with unexplained infertility and repeated implantation failure (RIP) found that thrombophilia was an issue for 42.9% of women
• Thrombophilia is also present in 18.2% of women who had repeated implantation failure but without a diagnosis of unexplained infertility ^vii
• Whether a couple is diagnosed with RIP, unexplained infertility, or nothing at all; blood clotting is a major issue for women trying to conceive

(8) Unfertile Sperm

The standard semen analysis assesses whether enough sperm are likely to reach an egg, assuming they’ll fertilise it, but it can’t tell if the sperm can form healthy pregnancies. The additional sperm tests let us see if a man’s sperm can perform all the functions needed to make a healthy baby. Sometimes perfectly normal semen samples have sperm that can’t fertilise eggs, or they significantly increase the chances of miscarriage.

(9) Bacterial Vaginosis

Bacterial vaginosis (BV) often causes unwanted (sometimes unpleasant) vaginal discharges but can also be present without any apparent symptoms. But even if the BV is symptomless it can reduce a woman’s fertility by making the vagina a “hostile environment” for sperm. Lactobacillus species usually dominate the vagina microbiome, and they produce lots of hydrogen peroxide, which inhibits the growth of other bacteria and fungi that can cause Candida. Other bacteria and fungi can release toxins that harm sperm and make the vagina more acidic and difficult for sperm to survive, and unsurprisingly, BV is much more common in women who’re struggling to get pregnant: ^viii

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