Getting Pregnant With Unexplained Infertility

What is the best way to get pregnant if you’re facing unexplained infertility? While there’s no straightforward answer, typically, when you can’t get pregnant, the first step is fertility testing. Then, once a cause (or causes) is found, an appropriate treatment is pursued.

If you’re not ovulating, Clomid may be tried. If sperm counts are low, IUI or IVF may be recommended. But what do you treat when your doctor doesn’t know what’s wrong?

Treatment Options

Unexplained infertility is treated empirically. This means a treatment plan is based on clinical experience and some guesswork.

The most common treatment map for unexplained infertility looks like this:

1. Lifestyle changes recommended (like weight loss, quitting smoking)
2. Continue to try on your own (if you’re young and willing) for six months to a year
3. Clomid or gonadotropins along with IUI for three to six cycles
4. IVF treatment for three to six cycles
5. Rarely, third-party IVF treatments (like using an egg donor or surrogate)

Sometimes, in cases of ongoing unexplained infertility beyond basic IVF, somewhat controversial treatments are considered.

Below is a closer look at each of these approaches and the odds of pregnancy success.

Lifestyle Changes

Especially when the cause of infertility is unknown, improving your overall health is important. The most commonly suggested lifestyle changes to improve your fertility naturally are to:

• Avoid excessive alcohol consumption.
• Cut back on caffeinated drinks.
• Lose weight (if overweight) and exercise.
• Reduce overall stress.
• Quit smoking.

With all that said, there’s no research showing that making these changes can actually help you conceive. However, these factors are associated with decreased fertility. That’s important to know.

Given the shot-in-the-dark approach to unexplained infertility treatment, whatever lifestyle changes you and your partner make to improve your overall health for the better can’t hurt and may help.

Trying to Conceive Naturally

You likely don’t want to hear from your doctor that the first step is to “keep trying on your own” for another six months. However, in some cases, it may be a good plan.

(But only after testing has confirmed your diagnosis as unexplained. It’s not a good idea to keep trying on your own before you’ve both been tested since some causes of infertility worsen with time.)

Expectant management is when your doctor doesn’t prescribe treatments right away, but does conduct basic fertility testing and may monitor the situation as you try on your own for a limited time.

A randomized clinical trial was conducted comparing expectant management (for couples with a good prognosis) with IUI plus fertility drugs. The study took place over a six-month period. For the women who received IUI plus fertility drugs:

• 33% of the women achieve pregnancy
• 23% of the pregnancies were on-going at study’s end

For the women who didn’t receive treatment and went the expectant management route instead:

• 32% got pregnant on their own
• 27% of the pregnancies were on-going at study’s end

So, IUI plus fertility drugs for those with good prognosis didn’t improve their odds of pregnancy success. The couples that kept trying on their own were just as likely to conceive as those who received treatment.

Building on this research, another study looked at what happens when couples are assigned a treatment plan based on prognosis. (Their prognosis was determined by looking at their age and how long they’ve been trying to conceive on their own.)

In this study, couples were assigned to one of three paths: start with expectant management, start with IUI with fertility drugs, or go straight to IVF treatment. A little over 90% of the couples were assigned to the expectant-management-first group.

By the study’s end, 81.5% of couples achieved pregnancy. Of those pregnancies, 73.9% were conceived without fertility treatment. Those are excellent odds, especially when you consider success rates for infertility in general. When looking at all infertility causes and cases, live birth rates after treatment are just under 50%.

Should You Keep Trying?

As always, discuss your options with your doctor. Both of the studies above only included couples with a good prognosis. They were on the younger side and had not been trying for years.

Generally speaking, expectant management for six months to a year is only a good approach if:

• A through fertility workup has been conducted, with both male and female fertility tested. (The diagnosis should truly be “unexplained.”)
• Ovarian reserve testing (FSH, AMH, and antral follicle counts) looks good.
• You have tried for less than one to two years on your own.
• You’re age 35 or younger.

Is Clomid a Good Choice?

Clomid is the most commonly prescribed fertility drug, and it can help women who are not ovulating. It can also boost sperm production for some causes of male infertility. The first doctor you will see when trying to treat your infertility is your gynecologist. They are most likely prescribe you Clomid, even if you have unexplained infertility, and send you on your way.

This may be a waste of time and expose you to risks and side effects for no benefit. A randomized control trial in Scotland included 580 women with unexplained infertility. The women were randomized to one of three groups for six months of treatment: 

• Clomid treatment
• Expectant management
• IUI alone (no fertility drugs)

The live birth rate for each group was:

• 13% percent for Clomid
• 17% for expectant management
• 22% for IUI treatment

It’s interesting to note that live birth rates using Clomid were slightly lower than expectant management, and this makes sense. Clomid side effects actually reduce some aspects of your fertility.

A meta-analysis of several randomized control trials of Clomid for unexplained infertility considered the results of seven different studies. A total of 1,159 couples were included in this study. This study also found that there is no evidence that Clomid alone is an effective treatment for unexplained infertility.

Clomid treatment is not harmless. Treatment is also only recommended for up to six cycles, due to the possible increased risk of cancer. If your doctor suggests Clomid alone, discuss whether it would be better to continue trying on your own for awhile longer, or discuss whether they would consider moving straight to IUI with Clomid.

This may require moving onto a fertility clinic and reproductive endocrinologist. Few gynecologists are comfortable or experienced at administering IUI treatment.

IUI and Fertility Drugs

For those with unexplained infertility, IUI alone or with fertility drugs has been shown to slightly increase your odds of pregnancy. The evidence isn’t very strong. However, due to the very high cost and invasiveness of IVF, IUI with fertility drugs is worth trying.

For unexplained infertility, Clomid with IUI seems to be the preferred choice over IUI with gonadotropins. In a randomized control study, couples were randomized to three cycles of IUI and Clomid, or IUI with gonadotropins, or IVF.

The pregnancy rates were:

• 7.6% per cycle for Clomid with IUI
• 9.8% per cycle for gonadotropins with IUI
• 30.7% per cycle for IVF

Gonadotropins are more expensive and are more likely to lead to ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy. But they may not improve pregnancy rates enough to justify those risks.

How many cycles of IUI should you try? This depends on your age and your interest in pursuing IVF treatment if IUI should fail. For those that are open to IVF, three cycles of IUI with Clomid is likely a good enough trial before moving onto IVF.

According to the same study mentioned above, couples who tried IUI with gonadotropins before moving onto IVF took longer to get pregnant and spent more money on treatment overall. For those that are not willing or able to pursue IVF treatment, research shows IUI with fertility drugs are worth trying for up to nine cycles.

When to Use IVF

When it comes to treating unexplained infertility, IVF has the best odds for pregnancy success. The pregnancy rates for IVF treatment are three times what they are for IUI with Clomid. This will vary with age, however. As mentioned above, the pregnancy rate for Clomid with IUI is 7.6%. The pregnancy rate per cycle for IVF is 30.7%.

Only during IVF can egg quality, the fertilization process, and embryo development be observed closely. All that said, IVF is invasive and expensive.

You might think going straight to IVF is the best choice (given it’s superior success rates). It is actually better for the vast majority of couples to give IUI with Clomid a try first. Most insurance companies (that offer any sort of IVF coverage) require less expensive treatments to be attempted first. However, proceeding straight to IVF and skipping IUI may be the best choice if you’re age 38 or older. This is something to discuss with your doctor.

Beyond IVF

What if IVF alone isn’t enough? Or what if traditional IVF fails? There may be other options.

Reproductive Immunological Treatments

There is a theory that natural killer cells may play a role in unexplained infertility, repeated IVF failure, or recurrent miscarriage. Despite their name, “natural killer cells” aren’t bad. You want them. You just don’t want them to be overly reactive or have too many of them.

Intravenous infusion with a substance known as intralipids during IVF treatment may reduce the impact of excessive natural killer cells. However, there’s currently no strong evidence this treatment can improve IVF live birth rates.

Removal of Endometrial Deposits

Some believe that unexplained infertility may be caused by mild endometriosis. In this case, the endometrial deposits may not be causing pain or directly interfering with ovulation or the fallopian tubes, but their presence may increase “irritation” of the reproductive system.

This may be the cause for repeated IVF failure, according to this theory. Some doctors will suggest laparoscopic surgery to diagnosis and remove mild endometriosis before IVF is attempted. Others only suggest it after repeated IVF failure. Whether this treatment can improve live birth rates isn’t clear.

Gamete Donation

If egg, sperm, or embryo quality problems are discovered during IVF, your doctor may recommend using a gamete or embryo donor for your next IVF cycle. Egg donation is the most expensive option, followed by embryo donation, and then sperm donation. Success rates for egg donors are generally high, which is good news.

Embryo donation rates will vary depending on the source of the embryo. For example, many embryo donations come from extra embryos created for another infertile couple’s IVF treatment.

Surrogacy

If IVF treatment repeatedly fails after embryo transfer, surrogacy may be the next step. Surrogacy is extremely expensive and not (easily) legally available in all areas. For those that can afford and access surrogacy services, it can be their path the parenthood.