Infertility, Pregnancy Loss, and Infection: New Insights

Many of us are familiar with a typical investigation for the causes of infertility and miscarriage: hormones, polycystic ovarian syndrome, endometriosis, poor cervical mucus, autoimmune issues, and male factor. Typical tests for a woman will include cycle charting and blood specimens for hormones, blood sugar and insulin resistance, immune antibodies and nutritional markers. In addition, assessing anatomy with ultrasound, imaging studies of the fallopian tubes and sometimes diagnostic hysteroscopy and laparoscopy are performed. We find that in women 25-40% have ovulatory problems, the most common being PCOS. Endometriosis is present in 35-40%. Blocked tubes, poor mucus, uterine factors such as fibroids and polyps can also be present. Autoimmune conditions are often an issue. And “unexplained” infertility can occur 15-40% of the time.

However, infection is often an afterthought. It may not even be mentioned in some summaries of infertility testing. Typically testing for sexually transmitted disease (gonorrhea and chlamydia) is performed in a fertility workup. Results of old infection (scarred fallopian tubes) are not uncommon and occasionally an active infection will be found. Awareness and more thorough testing of another condition, chronic endometritis, is often not done or not done thoroughly. EndomeTRITIS, infection of the endometrium (uterine lining), is a different condition from endomeTRIOSIS (in which endometrial tissue is found in abnormal locations such as the ovary or behind the uterus). Usually, chronic endometritis has NO SYMPTOMS. We are fortunate with insights from NFP charting, and suspect endometritis when tail end brown bleeding is seen at the end of a menstrual period. Low progesterone levels in the previous cycle can cause this also.

How often does chronic endometritis occur? Older literature cites about 15% with infertility and 30% with recurrent pregnancy loss (RPL). But when more thorough studies are done, substantially higher percentages are seen— 37.6% of women with infertility and 46.7% of women with recurrent pregnancy loss have endometritis. Studies reporting “unexplained infertility” have found an especially high incidence of 56.8%. Some studies have found this condition in as many as 66.7% of women with recurrent pregnancy loss.

How do we diagnose endometritis? There are pitfalls! The best way is with an endometrial biopsy or with curettage with a D&C. Pathologists analyze the specimens microscopically looking for plasma cells infiltrating the tissue. Plasma cells are a type of lymphocyte (white blood cell) that produces antibodies to fight bacteria. However, plasma cells are not well seen with usual methods used in biopsies. Pathologists must use a special stain for CD-138, a protein on the surface of plasma cells. And the biopsy must be done in the early part of the cycle, so that the plasma cells are not suppressed by the anti-inflammatory action of progesterone. Plasma cells are then counted, although there is not a consensus as to how many plasma cells are significant.

Endometritis can also be detected on hysteroscopy. The uterine lining is red, or with patches of red. Micro polyps and polyps are other indicators. One problem is that the surgeon may quickly do the hysteroscopy, only looking for big lesions like fibroids, and not note these other signs.

Identifying the bacteria involved in infection is important. There has been a revolution in diagnosis with molecular methods using PCR or probes identifying bacterial DNA or RNA. These methods can much more accurately identify and quantify bacteria, compared to the old methods of culture swabs, transporting them rapidly to the lab (so they don’t die), and plating them on petri dishes. We used to think the uterine lining was sterile, but now we know it should contain numerous “good” bacteria in the lactobacillus category. Both older and newer types of testing can be performed to test for antibiotic resistance to select the best antibiotics for cure. Endometrial biopsy or menstrual blood can be used for microbial testing. Sometimes cervical-vaginal swabs can be used as a proxy for endometrial testing that is related, but not identical.

Clearly there are difficulties and expense in doing good testing and treatment of endometritis. Clinicians need better education. Sometimes “empirical” treatment is given based on tail end brown bleeding, or plasma cells on biopsy. Sometimes doxycycline, alone or with other antibiotics, is used, calculating that this will treat the some of the most common microbes, mycoplasma and Ureaplasma. When this is done after hysteroscopy and biopsy, a success rate of 50-80% for RPL can sometimes be achieved. More through testing can then be done for women with failed treatment. In Europe antibiotic washes, instilling the medications directly into the uterus, are used for resistant cases, requiring multiple doses.

Another important aspect of treatment, in addition to eradicating bad bacteria, is replenishing good bacteria. Some newer molecular methods used by NXGEN, Evvy, Fertilysis and other labs, quantitate the normal lactobacillus bacteria. In women with reproductive problems, lactobacilli can be scanty or even absent. But they can be replenished with oral and vaginal probiotics. There is now evidence that a healthy microbiome—the community of microorganisms, and especially lactobacilli—is crucial to cellular communication, implantation and early embryonic survival and growth.

What about the man? There is not as much known, but a healthy semen microbiome with lactobacillus is related to better fertility and healthy partner pregnancies. Infection can affect sperm fragmentation and is related to pregnancy loss. Sometimes (but not always) white blood cells are seen on semen analysis. Unfortunately, many labs do not test for these, and additionally chronic infection can be asymptomatic and not generate white blood cells. Molecular testing and antibiotic resistance can be performed on semen. Currently the male partner of a woman with infection is not routinely tested or treated (except with sexually transmitted infections or mycoplasma/Ureaplasma). But especially when testing the semen microbiome shows abnormal bacteria matching the woman’s, definitely both partners should be treated.

A healthy reproductive microbiome is essential for preventing preterm labor and ensuring a full-term pregnancy, beyond its role in infertility and pregnancy loss. Healthy bacteria are always in balance with abnormal ones. There also is evidence that the use of progesterone, especially generous doses, is very helpful in suppressing inflammation when bacterial colonization or mild infection may be present. This reinforces the experience of many of us who have used progesterone for decades. The more we learn, we find more and better testing and specific treatment for infection of women and their male partners. These newer technologies can significantly help many couples who are challenged by infertility and reproductive loss.

Dr. Davenport will present New Insights on Recurrent Pregnancy Loss (RPL) at CANFP Tune Up Tuesday June 23, at 7p. This June session, which will focus on Chromosomal Loss and Infection, is open to ALL CANFP Members. This is important information for all women, especially those who have suffered pregnancy loss, in addition to the NFP professionals who serve them. These monthly Tune Up Tuesdays are a benefit of CANFP Membership. Interested? You can Become a Member at CANFP.org where you will find convenient monthly subscriptions, as well as our most popular best buy annual plans. Join us!