Chlamydia Infection: Silent Cause of Female Infertility

The most common microorganisms that cause sexually transmitted infections (STIs) are Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium. Infection with any of the microorganisms can lead to pelvic inflammatory disease (PID) and, in turn, tubal factor infertility (TFI).¹ The most prevalent STI in Western countries remains C trachomatis, including serovars A-K and L1-L3.¹

In 2021, more than 1.6 million cases of C trachomatis were reported to the Centers for Disease Control and Prevention (CDC), with the highest incidence reported in women (Figure).² Almost two-thirds (58%) of cases were among persons aged 15 to 24 years. The decreased incidence of chlamydia cases reported from 2019 to 2020 likely reflect the lack of routine STI screening during the beginning of the COVID-19 pandemic as most infections are typically asymptomatic.  

Not all C trachomatis serovars are the same in terms of epidemiology and clinical presentation. C trachomatis types A-C commonly cause trachoma, or infection of the eye, while types L1-L3 cause lymphogranuloma venereum, or ulcerative disease of the genital area commonly misdiagnosed as inflammatory bowel disease (IBD).¹ In contrast, serotypes D-K may lead to urethritis and cystitis, and can potentially ascend to the upper reproductive tract to cause PID.¹

If symptomatic, common clinical manifestations of acute C trachomatis infection in females include mucopurulent discharge, dysuria, and pyuria. Symptoms associated with PID are usually nonspecific and include pelvic and/or lower abdominal pain, abdominal tenderness, as well as evidence of cervical motion tenderness, uterine and/or adnexal tenderness, and fever.^1,3 If a patient presents with suspected PID, a pregnancy test is vital to rule out an ectopic pregnancy. However, many patients with PID are asymptomatic making regular screening an essential component of care. The inflammatory response to the infection causes scarring, lacerations, and adhesions, and can ultimately prohibit fallopian tubes to capture ovulated ova and/or transport sperm and embryo.³

Patients with PID are typically only at risk for TFI if they have macroscopic fallopian tube inflammation or salpingitis.⁴ Studies show approximately 1 in 6 women with salpingitis develop PID and 15% of women with PID develop TFI.^1,3 Although 10% to 20% of women infected with N gonorrhoeae are likely to experience acute PID and possible tubal obstruction, C trachomatis remains the most common bacterial cause of tubal obstruction due to a higher prevalence of the disease. Each year C trachomatis is estimated to be acquired by 131 million people worldwide and N gonorrhoeae is estimated to be acquired by 78 million people worldwide.¹   

Chlamydia Screening

For females, the CDC recommends annual screening of all sexually active individuals younger than 25 years.⁵ Screening is also recommended for older females at increased risk for infection (eg, aged ≥25 years who have a new sex partner, more than 1 sex partner, a sex partner with concurrent partners, or a sex partner who has an STI).⁵

Pregnant patients younger than 25 years should be screened at the first prenatal visit as should older pregnant patients over 25 with risk factors for STIs.⁵ Regardless of age, all patients should be screened in the third trimester if risk factors are present. Screening at delivery is recommended for pregnant persons with risk factors who were not screened for chlamydia during pregnancy or with no prenatal care.⁵

Chlamydia Treatment

Uncomplicated C trachomatis infection should be treated with doxycycline 100 mg orally twice a day for 7 days, according to guidelines from the CDC.^3,5 Alternative regimens include azithromycin 1 g orally immediately or levofloxacin 500 mg orally once a day for 7 days. Pregnant patients should receive a single dose of azithromycin 1 g orally immediately. An alternative regimen is amoxicillin 500 mg orally 3 times per day for 7 days.⁵ Prophylaxis should also be given to identified sexual partners. Neonates should receive erythromycin base or ethylsuccinate 50 mg/kg/day orally, divided into 4 doses daily for 14 days.⁵

Tubal Factor Infertility Workup in Primary Care Settings

Although a nucleic acid amplification testing (NAAT) via endocervical or vaginal swab or first-void urine testing is sufficient to diagnose an active chlamydia infection (serovars D-K), the associated prognosis related to tubal infertility is not straightforward.⁵ No single diagnostic gold standard for assessing PID exists.

Clinicians often use a chlamydial antibody titer (CAT) as a surrogate marker for TFI because of the strong association between C trachomatis immunoglobulin G (IgG) antibodies in serum and tubal pathology.¹ However, a simple blood test does not provide details on the anatomy of the fallopian tubes. Studies conducted in the last 12 years show that C trachomatis seropositivity is insufficient to diagnose upper vs lower genital tract infections and cannot assess CT outcomes. C trachomatis antibody assays may also be confounded by several factors including other infections that may cause TFI.⁴ Therefore, serology should only be used as an initial screening test in assessing TFI until a more accurate C trachomatis IgG antibody test becomes available.⁴

For decades, hysterosalpingography (HSG) has been considered the most robust imaging test after laparoscopy in assessing pelvic anatomy. Fallopian tube patency is assessed via HSG by instilling a contrast medium into the uterine cavity and fallopian tubes while radiography is performed.^6,7 Hysterosalpingography may be performed in the outpatient setting without the need for general anesthesia or laparoscopy but is associated with risks and patient discomfort.⁷

Clinicians began using a less invasive diagnostic test in 1986 called hysterosalpingo-contrast sonography (HyCoSy), which has since been replaced with hysterosalpingo-foam sonography (HyFoSy) because of limited availability of the echogenic median required for HyCoSy. HyFoSy involves instilling 10 mL of foam via a small cervical balloon-less catheter and assessing patency with a transvaginal ultrasound. When spilling is seen on both sides, the fallopian tubes are considered to be patent. HyFoSy is especially useful for patients allergic to contrast or who have an active pelvic infection. Other advantages to HyFoSy such as accessibility without radiation exposure, lower cost, and less time-consuming, have recently led clinicians to consider replacing HSG with HyFoSy as the initial diagnostic test of choice.

Hysterosalpingo-foam sonography may be used in an outpatient setting and allows observation of pelvic organs in real time. A drawback to HyFoSy is operator dependency and potential subsequent misdiagnosis.⁸ Also, if spilling into both fallopian tubes is not seen, the test may be considered inconclusive as the spasm of the uterus can temporarily occlude the opening of the fallopian tubes and further workup may be indicated.⁷ Clinicians should discuss each of these factors with their patients before proceeding with diagnostic workup. A potential benefit of HyFoSy on fertility is an increased proportion of patients obtaining spontaneous pregnancy after the procedure. One study found that the pregnancy rate after HyFoSy was 31% within 6 months of the procedure and 36% within 12 months. The tubal flushing aspect of the procedure may improve the probability that an embryo will implant.⁹

Patient Education on Chlamydia and Infertility

In a primary care setting, the risk of reproductive complications including infertility after chlamydia infection is a relevant point for adolescents and adults counseled on safe sex practices, particularly those younger than 25 years of age.^2,5 Patients should also be educated that 70% to 95% of infected women are asymptomatic and the first symptoms occur 3 to 7 weeks after intercourse.¹ The incubation period of symptomatic disease ranges from 5 to 14 days and the disease duration in asymptomatic individuals is unclear. Therefore, routine screenings and early treatment are vital to decreasing transmission and reproductive complications.

Clara Easterlin, PA-S, is a student in the Physician Assistant Program at Augusta University in Augusta, Georgia; Kelly S. Reed, PharmD, MPA, PA-C, is an assistant professor in the Physician Assistant Program at Augusta University.

References

1. Smolarczyk K, Mlynarczyk-Bonikowska B, Rudnicka E, et al. The impact of selected bacterial sexually transmitted diseases on pregnancy and female fertility. Int J Mol Sci. 2021;22(4):2170. doi:10.3390/ijms22042170.

2. National overview of STDs, 2021. Centers for Disease Control and Prevention. Updated April 11, 2023. Accessed May 16, 2023.  https://www.cdc.gov/std/statistics/2021/overview.htm#Chlamydia

3. Curry A, Williams T, Penny ML. Pelvic inflammatory disease: diagnosis, management, and prevention. Am Fam Physician. 2019;100(6):357-364

4. Horner PJ, Anyalechi GE, Geisler WM. What can serology tell us about the burden of infertility in women caused by chlamydia? J Infect Dis. 2021;224(12 Suppl 2):S80-S85. doi:10.1093/infdis/jiab047

5. Sexually transmitted infections treatment guidelines, 2021: chlamydial infections. Centers for Disease Control and Prevention. Updated July 22, 2021. Accessed May 16, 2023. https://www.cdc.gov/std/treatment-guidelines/chlamydia.htm

6. Hanson MA, Dumesic DA. Initial evaluation and treatment of infertility in a primary-care setting. Mayo Clin Proc. 1998;73(7):681-685. doi:10.1016/S0025-6196(11)64894-64895.

7. Dreyer K, Out R, Hompes PG, Mijatovic V. Hysterosalpingo-foam sonography, a less painful procedure for tubal patency testing during fertility workup compared with (serial) hysterosalpingography: a randomized controlled trial. Fertil Steril. 2014;102(3):821-825. doi:10.1016/j.fertnstert.2014.05.042

8. van Welie N, van Rijswijk J, Dreyer K, et al. Can hysterosalpingo-foam sonography replace hysterosalpingography as first-choice tubal patency test? A randomized non-inferiority trial. Hum Reprod. 2022;37(5):969-979. doi:10.1093/humrep/deac034

9. Tiberio F, Exacoustos C, Szabolcs B, et al. OP22.08: Hysterosalpingo-foam sonography (HyFoSy) with tubal flushing increase chances of spontaneous pregnancy. Ultrasound Ob Gyn. 2016;48(S1):124-124. doi:https://doi.org/10.1002/uog.16373