When you go to the doctor with a problem like infertility, you generally expect two things to happen.
First, you expect the doctor to figure out what is wrong with you, and second, you expect he or she to treat it. This is called diagnosis and therapy.
In the field of infertility, advancements in therapy have progressed more rapidly than the advancements in diagnosis. As a result, many patients end up with a diagnosis of unexplained infertility.
A simple way of looking at the basic infertility evaluation is summed by trying to answer four questions:
- Are there sperm?
- Are there eggs?
- Can they find each other?
- Is the uterus a good place for a baby to be?
This seems pretty straightforward. So why is it so difficult to find the cause of infertility?
An Underlying Problem
Some mammals get pregnant every cycle with litters. In contrast, humans don’t seem to get pregnant every cycle even at the peak of our fertility. In reality, at the peak of our fertility, humans get pregnant a lot more often than they recognize but they have repetitive unrecognized miscarriages, i.e. before they miss their period.
This is a problem that gets worse as we get older, which is what we call age-related decline in fertility.
The problems that most couples are worried about the first time they come to the infertility doctor are problems that we can diagnose, which are superimposed on this inefficient reproductive system. So in a way making the diagnosis of infertility is a lot like trying to hear someone talk in a noisy room.
Repetitive Pregnancy Losses
You may wonder how we know that humans naturally experience repetitive pregnancy losses. There are basically two ways that we can observe early human pregnancies before a woman misses her menstrual period.
The first way is in the in vitro fertilization (IVF) laboratory after eggs are fertilized and before embryos are returned to a woman’s uterus. In the lab, we have the ability to watch embryos develop for the first six days of life. Embryologists know that it is quite common to see embryos stop dividing before they reach the blastocyst stage of development, which occurs around day five of life. 1
Most likely, embryos stop dividing because they are not normal. Abnormal embryos could result from an abnormal sperm, an abnormal egg, or a normal embryo that makes a mistake during cell division.
Interestingly, at about the 16- to 32-cell stage human embryos go through an stage of development called “gene activation.” This is when we believe that the embryo takes the DNA that it receives from its parents and for the first time it begins to use it to direct its own future. Prior to that, it appears that a fertilized egg blindly copies the DNA that it receives from its parents.
The second time that we can observe early human pregnancies is after a blood or urine pregnancy test turns positive. Pregnancy test today are so sensitive that a woman can detect a pregnancy with a urine pregnancy test several days before she misses her menstrual period.
Alan Wilcox and his colleagues at NIEHS demonstrated that it is quite common for a urine pregnancy test to turn positive and then negative before a woman has her menstrual period. 2 If she wasn’t looking for the positive test, she would never know that she had been pregnant. Furthermore, it is very likely that there are additional pregnancy losses that we can’t detect between these two times.
Another way to think about the frequency of unrecognized pregnancy loss is to examine the fertility of young couples with no known fertility problem. These couples average “getting pregnant” about every four months. It is possible that this reflects a miscarriage rate as high as 75 percent at the peak of our fertility.
When we think about human fertility this way, the difference between infertility and miscarriages is not as clear as we think. The primary difference is whether we were aware of the pregnancy or not.
1 Blake et al, Cleavage stage versus blastocyst stage embryo transfer in assisted conception. [update of Cochrane Database Syst Rev. 2005;(4):CD002118; PMID: 16235296].
2 Wilcox AJ. Weinberg CR. O’Connor JF., Baird DD. Schlatterer JP. Canfield RE. Armstrong EG. Nisula BC. Incidence of early loss of pregnancy. New England Journal of Medicine. 319(4):189-94, 1988 Jul 28.