The 3 most frequently missed diagnoses in infertility work-ups

When couples fail to conceive within an expected time frame (which, of course, changes with advancing age), we assign them the diagnosis of infertility. Conception is, however, enormously complex, and potential causes for a couple’s infertility, therefore, are almost unlimited. Many are, likely, still unknown.

Fortunately, however, most causes of infertility are relatively easy to diagnose, which makes it so surprising that, even some quite common diagnoses are so frequently missed. A major reason why even simple diagnoses are often overlooked is the (false) assumption that, one diagnosis is made, this diagnosis alone explains the couple’s infertility. Approximately 25% of all couples, however, demonstrate infertility-causing problems in both partners, and women can have more than one cause of infertility.

Multifactorial infertility, of course, has to be tackled all at once. Often, once one partner is diagnosed, the erroneous assumption is made that the sole cause of the couple’s infertility has been established. That is, of course, not the case and should never be assumed. An initial diagnostic infertility work-up always has to involve both partners and consider the possibility of multiple possible causes. Only once all likely causes of infertility have been identified and treatment addresses all of them at the same time, will treatments be successful because, whenever multifactorial infertility is diagnosed in a couple, it is always almost impossible to accurately assign relative responsibilities for the infertility from the various causes.

In CHR’s experience, aside from these very general rules to avoid missed diagnoses, three specific diagnoses are disproportionately frequently missed in diagnostic work-ups. They are:

1: Premature ovarian aging (POA)/occult primary ovarian insufficiency (oPOI)

Regular readers of the VOICE are, of course, eminently familiar with this diagnosis; yet, quite surprisingly, the most frequently overlooked diagnosis we see in patients who come to CHR after prior consultations/treatments at other fertility centers, is POA/oPOI. The reason is simple: While most colleagues correctly assess the ovarian reserve (OR) of patients as part of an initial work-up, surprisingly, they often don’t use age-specific assessments of follicle stimulating hormone (FSH) and anti-Müllerian hormone (AMH) or of antral follicle counts (AFCs). Without looking at OR in an age-specific way, it, however, becomes impossible to assess whether a woman’s OR is appropriate for her age or not.

2: Tubal disease

The second most frequent diagnostic miss we see at CHR is tubal disease, especially distal tubal disease, involving the fimbriae of fallopian tubes. Those are the very delicate mucosal folds at the end of tubes that have the function of “catching” the egg when it is released from the ovary at time of conception. If those fimbriae stick together, as is frequently the case especially in association with mild endometriosis (the medical term for this is “clubbing” of fimbriae), the egg cannot enter the tube, where it is supposed to meet sperm and be fertilized. The consequence is infertility.

This diagnosis is frequently overlooked by radiologists because, when they during hysterosalpingography (HSG) see contrast die spilling into the peritoneal cavity, they, often incorrectly, assume that the fallopian tubes are patent. What they do not recognize is that the pressure of the fluid column of contrast die on an only very temporary basis during the procedure opened the “clubbed” fimbrial end of the fallopian tube, and that, literally within days, “clubbing” will reoccur, again functionally re-occluding the tube.

CHR’s physicians, therefore, never rely on written HSG reports, and always insists on reviewing the HSG films, which nowadays usually are easily available for such reviews on discs. As a CHR study a number of years ago demonstrated, CHR’s physicians significantly disagree with written radiology reports in over 50% of cases. Accurate diagnoses of tubal status are, of course, essential for reaching appropriate treatment recommendations.

3: Immunological abnormalities

We elsewhere in this issue of the VOICE announce CHR’s new Reproductive Immunology Initiative. For decades CHR, however, has in its diagnostics and treatment protocols always paid careful attention to the female immune system. By doing so, we are convinced to have facilitated pregnancies and deliveries that, otherwise, might not have occurred. In addition, we with great likelihood have avoided large numbers of miscarriages.

Yet, most fertility centers do not even investigate a patient’s immune status as part of the basic infertility work-up. Because the implanting embryo is a so-called semi-allograft (i.e., it is in its paternal half “foreign” to the mother’s immune system), it, theoretically, should be rejected by the mother’s immune system. That, however, in normal pregnancies, fortunately, does not happen. Some pregnancy abnormalities, we here at CHR, however, believe are caused by inadequate immunological tolerance of the pregnancy by the maternal immune system.

In early gestation, this includes implantation failure and pregnancy loss (i.e., spontaneous miscarriages), and in later pregnancy conditions like premature labor, pre-eclampsia and so-called gestoses (rashes) of pregnancy.

Especially in women who have a medical history compatible with autoimmunity and/or inflammation or a close family history for immunological problems, CHR, therefore, strongly recommends that appropriate immunological testing become part of any infertility work-up.

This is a part of the October 2017 VOICE.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned reproductive endocrinologist, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.