Infertility and vaginal infections

Urogenital infections in reproductive medicine

Urogenital infections, be it with Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, or Escherichia coli, are commonly seen in women in the reproductive age-group.¹   Infections with C. trachomatis constitute the most prevalent sexually-transmitted bacterial diseases.²

All these infections can alter important human functions, including reproduction. Bacteria, fungi, viruses and parasites have the potential to interfere with the reproductive function in both sexes.³   Urogenital infections have frequently been associated with infertility. In women, chronic salpingitis has been associated with subsequent tubal infertility and ectopic pregnancies.²   Tubo-peritoneal damage appears to be the principal way in which microorganisms interfere with human fertility.³

The burden of urogenital infections appears to be high in women belonging to the reproductive age. Madhivanan et al⁴   evaluated the burden of T. vaginalis infection among young reproductive age women in Mysore, India. Nearly 8.5% of the women belonging to the 15-30 years age group had T. vaginalis infection. Risk factors independently associated with T. vaginalis infection included early age at first intercourse, concurrent bacterial vaginosis (BV), vaginal candidiasis and herpes simplex virus type-2 infection. Bhalla and colleagues⁵   evaluated the prevalence of bacterial vaginosis in urban and rural communities in Delhi. About 32.8% of the studied subjects had BV. Highest prevalence of the infection was seen in urban slum (38.6%), followed by rural (28.8%) and urban middle class community (25.4%) (Figure 1). All women with vaginal trichomoniasis appeared to have BV while 50% of subjects having syphilis also had BV.

A study conducted in Poland investigating 161 women, including 101 women treated for infertility and 60 fertile women who had already given birth to healthy children reported infection with U. urealyticum in 9% of the infertile women and in 8% of controls. M. hominis was detected only in infertile women (4%) and C. trachomatis only in controls (3%). N. gonorrhoeae and M. genitalium were not found in any of the subjects. The frequency of aerobic vaginitis in both groups appeared to be 12%. There were 7% BV cases in the study group, and none in the control group.⁶

A cohort of 853 young, sexually active women was evaluated in Mysore, India for BV and Trichomonas vaginalis (TV) at baseline, and at 3- and 6-month visit. Participants with abnormal vaginal flora at 2 consecutive visits had 9-fold higher risk of TV at the latter visit, in comparison to those with persistently normal flora. An increased risk of TV was also evident in participants whose flora status changed from normal to abnormal and from abnormal to normal.⁷

Bacterial vaginosis: A cause of infertility

Bacterial vaginosis (BV) is a common disorder in women. The condition is characterized by changes in the normal acidic lactobacilli-predominant vaginal ecosystem to an environment dominated by Gardnerella vaginalis, Mycoplasma species and anaerobes, with an increase in pH.⁸   BV is significantly associated with infertility and appears to be an underestimated cause of unexplained infertility.⁹

Bacterial vaginosis: Pathogenesis

Bacterial vaginosis signifies a complex change in the vaginal flora that is characterized by a reduction in concentration of the normally dominant hydrogen-peroxide producing lactobacilli associated with an increase in concentration of other organisms, especially anaerobic gram negative rods.^10-13      Although the mechanism by which the floral imbalance occurs and the role of sexual activity in the pathogenesis of BV still needs to be clearly elucidated, formation of an epithelial biofilm containing G. vaginalis appears to play a significant role.^14-16

Hydrogen-peroxide producing lactobacilli have a pivotal role in preventing the overgrowth of the anaerobes normally present in the vaginal flora. As a person looses these lactobacilli, pH rises and massive overgrowth of vaginal anaerobes ensues. As a result, large amounts of proteolytic carboxylase enzymes are produced that break down vaginal peptides into volatile, malodorous amines. The rise in pH favors adherence of G. vaginalis to the exfoliating epithelial cells.

Bacterial vaginosis and infertility: Clinical evidence

A study assessed whether BV is associated with reproductive complications in women. Of the 510 women that were analyzed, 14.1% had BV. Statistical analysis between the BV negative and positive population demonstrated a significant association with infertility. Multiple infections such as Candida, Chlamydia and Human papilloma virus were noted in 4.2%, 15.3% and 8.3% of BV-infected women, respectively. ⁸   A more recent study determined the prevalence of BV in infertile women and evaluated the impact of treatment of BV on pregnancy rate in patients with polycystic ovarian disease (PCOD) and unexplained infertility.⁹   The prevalence of BV was significantly higher in infertile than fertile women (45.5% vs. 15.4%; Figure 2). The highest prevalence was found in patients with PCOD (60.1%) and unexplained infertility (37.4%). The cumulative pregnancy rate in patients with PCOD and unexplained infertility was significantly higher in those who were treated for BV. Of note, BV was a significant factor interfering with pregnancy.⁹

Gaudoin and colleagues¹⁷   estimated the incidence of active vaginal infection in women undergoing in vitro fertilization (IVF), related it to the cause of infertility, and evaluated the relation with the outcome of fresh ET. Seropositivity for Chlamydia species and the presence of BV were strongly and independently associated with tubal disease.

Bacteriological agents playing a role in the development of infertility

Infertility is known to affect approximately 10-15% of all couples. The infections that appear to be commonly related to infertility include gonorrhea, chlamydia, and PID. Tuberculosis is another common cause of infertility. Neisseria gonorrhoeae and Chlamydia trachomatis are the primary causes of PID. Polymicrobial infections with other organisms including anaerobes or facultative aerobes may be caused by gonorrhea, chlamydia, or both.¹⁸

Literature suggests that infections mainly caused by C. trachomatis or N. gonorrhoeae represent the greatest risk for human reproduction.¹⁹     Available data indicate that nearly 20.1% of infertility patients may be positive for U. urealyticum, 1.3% for M. hominis, 2.2% for C. trachomatis, and 0.4% for N. gonorrhoeae (Figure 3).²⁰

C. trachomatis is closely implicated in the development of infertility among the reproductive age-group women. There is ample evidence suggesting that C. trachomatis has a major role in vaginal infections, and eventually in female infertility. A study conducted in Aligarh, India reported C. trachomatis positivity in 28.1% of the infertile women and in 3.3% in the control group (Figure 4). Chlamydial positivity was apparent in 27% women with primary infertility and in 30.6% with secondary infertility. Among the 58 asymptomatic women, 36.2% had chlamydia infection while among the 52 symptomatic cases 19.2% were detected with the infection. Approximately 38% women with chlamydial infection also had tubal occlusion.²¹

It is thus clearly evident that C. trachomatis infection is highly prevalent in women with infertility.

Role of parasites and fungi in secondary infertility

Parasites and fungi have frequently been witnessed to cause infertility. Evidence suggests that some protozoa, helminths and fungi can potentially impair women’s reproductive capacity, causing deformities of genital tract, rendering conception impossible. If conception does occur, normal implantation and development of placenta are impossible. Schistosoma hematobium causes vulvar papule, swelling, tumors, irregular vaginal hemorrhage, tubular infertility and ectopic pregnancies. Schistosomiasis itself can lead to tubular infertility. Chronic Entamoeba histolytica infection causes pelvic pain and dyspareunia in some patients. Trichomonas vaginalis is a common cause of tubal inflammation. In enterobiosis, presence of adult worms and eggs in fallopian tube causes chronic salpingitis and tubal occlusion. Also in ascariosis, presence of adult forms and eggs can lead to acute colpitis. Candida albicans causes a fungal infection that leads to colpitis and endometritis resulting in infertility.²²

Research has suggested that the motility pattern of T. vaginalis within the vagina is a vertical zigzag configuration leading to a circular whirling. Its whirling movement possibly disrupts normal sperm movement and potentially results in difficulty in fertilization.²³   Toxoplasmosis is another important parasitic disease that has been associated with certain psychiatric disorders and sterility.²⁴   Schistosomiasis is a frequently neglected tropical disease. Recent literature suggests that the impact of schistosomiasis on infertility may be underestimated.²⁵

Vaginal candidiasis

Evidence suggests that the prevalence of vaginal candidiasis is consistently increasing.²⁶   Candidiasis as a correlate of primary infertility was noted in 30.8% of the young women, reported a study.²⁷

Verghese and colleagues evaluated 326 high vaginal swabs from infertile women. Candida species was isolated from 12.88% patients. The most common isolates included Candida albicans (40.47%) and Candida glabrata (38.09%). Other species included Candida tropicalis (14.28%) and Candida krusei (7.14%) (Figure 5).²⁶

Mixed vaginal infections

Vaginitis may be caused by single or mixed infections. Nearly 30% of all cases of vaginitis are caused by simultaneous infections with at least two or more pathogens, for instance presence of bacterial vaginosis in patients of vulvovaginal candidiasis.²⁸   A study evaluated the prevalence of BV, candida sp, mixed infections (Bacterial Vaginosis + Candida sp), Trichomonas vaginalis, Actinomyces sp in Ankara, Turkey. The prevalence of BV, Candida sp, mixed infections, Trichomonas vaginalis, Actinomyces sp was 7.76%, 2.81%, 0.32%, 0.13%, and 0.27%, respectively.²⁹   The prevalence of BV and concomitant lower genital tract infections among asymptomatic pregnant women is quite high. A study conducted among women in a developing community reported the prevalence of mixed vaginal infections of BV and trichomoniasis to be 14%.³⁰

Use of clotrimazole for vaginal fungal infections

Vaginal candidiasis is one of the commonest infections in females. A wide range of antifungal drugs are used for treatment. Around 75% of all women are estimated to experience at least one episode of vulvovaginal candidiasis (VVC) in their lifetime.³¹

Imidazoles are potential agents that block fungal ergosterol biosynthesis and are effective against vaginal candidiasis. Clotrimazole is one of the most commonly used imidazoles for the treatment of VVC. The agent has been noted to persist at inhibitory levels in vaginal secretions for up to 3 days following a single treatment.³¹

A retrospective clinical study of patients with positive vaginal cultures for the presence of pathogenic yeast species reported the highest prevalence of VVC was found in women aged between 20 and 30 years. Candida albicans was the most commonly identified species of pathogenic yeasts (87.4%). C. glabrata and C. krusei were the other prevalent species. A minimal number of resistant yeast isolates was observed for econazole, clotrimazole and nystatin. On the contrary, a relatively high number of resistant strains was observed for other azole antifungals including miconazole, ketoconazole, itraconazole, and fluconazole.³²   Clotrimazole appears to be one of the most effective antifungals against most isolates of Candida.³³

Khan and Bagai³⁴     reported clotrimazole to be more effective than fluconazole and nystatin against vaginal candidiasis in females of childbearing age. In vitro antifungal activity indicated clotrimazole to be effective against 70% of Candida spp, fluconazole effective against 36.2%, and nystatin against 63.5% isolates (Figure 6).

Furthermore, clotrimazole has also been noted to reduce the rate of preterm births. Data suggest that vaginal clotrimazole reduces the proportion of preterm births because of the effective treatment of genital infections caused by candidiasis in pregnant women.^35,36   A comparative study evaluating fluconazole and clotrimazole in the treatment of VVC reported mycological cure rates 1 week after treatment to be 79.2% in the fluconazole group and 80.0% in the clotrimazole group. Approximately 4 weeks after treatment, these rates were 60.4% and 66.0%, respectively.³⁷

Clindamycin for vaginal infections

BV seems to be the most frequently found condition of the female genital tract. Intravaginal clindamycin is a preferred therapeutic agent in vaginal infections. The agent can be particularly used in those with allergy or intolerance to metronidazole.³⁸   Additionally, clindamycin has superior activity against M. hominis, Mobiluncus spp, and G. vaginalis than metronidazole.³⁹

Vaginal Group B Streptococcus (GBS) colony counts appear to fall rapidly after intrapartum clindamycin administration.⁴⁰   Nyirjesy et al⁴¹   compared the effects of treatment with vaginal clindamycin and metronidazole for BV on vaginal Mobiluncus morphotypes. More patients in the clindamycin group than in the metronidazole group achieved microbiologic (57.5% vs. 26.7%), clinical (57.5% vs. 26.7%), and therapeutic cures of BV (45.0% vs. 20.0%; Figure 7). Clindamycin also reduces the risk of preterm birth and late miscarriage.⁴²

A study conducted in Denmark compared 199 pregnant women with BV who received vaginal clindamycin for three days with 205 women treated with placebo. At the second visit, 71% in the clindamycin group were cured/improved, compared with 12% in the placebo group. At the third visit, nearly 90% who responded to initial clindamycin treatment were still cured/improved. Among those who initially failed to respond to clindamycin and were given an additional seven-day course, 33% were cured/improved by the third visit, compared with 15% who failed to respond to placebo initially and were given a further seven-day course. By the fourth visit, about 50% of the women in the clindamycin group who received additional treatment remained cured/improved, compared with 26% who had additional placebo. In the clindamycin group, a change from abnormal flora to normal rose from 71% (visit 2) to 76% (visit 3) and 79% (visit 4). A similar trend was noted for the placebo group too; however, the proportions were significantly lower (12%, 24% and 33%, respectively).⁴³

Clindamycin-clotrimazole combination therapy for vaginal infections

Signs and symptoms of vaginitis often overlap between bacterial and fungal infection. Co-infection/mixed infection often coexists. Use of one antimicrobial agent only might miss the other pathogen in a large number of patients. Moreover, antibiotic therapy against bacterial infections leads to secondary vaginal candidiasis. This calls for another treatment with a different medication. Thus, treatment with an antibacterial-antifungal combination, like clindamycin-clotrimazole combination, does away with the chances of secondary infection with candida.

The combination of a broad spectrum antibiotic with an antifungal agent, like clindamycin-clotrimazole combination, is particularly effective in treating mixed infections. The combination therapy has several benefits that include broader coverage against mixed infections, decreased rate of relapse, no chance of secondary infection, and complete elimination of vaginal infections within 7 days. Elimination of infection in 7 days is particularly significant prior to gynecological or IVF procedures that require a pathogen-free vagina. In such situations, a 7-day course of the combination is better and more effective than a 3-day course.

Gupta and colleagues⁴⁴   conducted a study to evaluate the role of screening for and treatment of abnormal vaginal flora in early pregnancy, and its correlation with pregnancy outcome. Eight hundred asymptomatic women were screened for abnormal vaginal flora at 12-24^th week of gestation. Two hundred and forty-two women with abnormal vaginal flora were randomized to receive either treatment with vaginal clindamycin and clotrimazole, or no treatment. Intervention in women with abnormal vaginal flora lead to a decrease in the rate of preterm delivery (30.3% in control group vs. 18.6% in intervention group).

Mucoadhesive vaginal drug-delivery system

Vaginal drug delivery has several benefits on account of increased permeability, a large surface area and rich blood supply.⁴⁵   The bioadhesive drug delivery system has been developed with the aim to prolong the drug’s stay in the vaginal cavity, and has both bioadhesive and sustained release properties.⁴⁶

Conventional vaginal formulations have limited efficacy owing to the lesser residence time on vaginal epithelium due to the self-cleansing action of vagina. Mucoadhesive polymers have overcome this problem resulting in an extended and intimate contact with vaginal mucosa. The binding capacity of mucoadhesive polymers to mucosal tissues for considerable period of time augments the retention time of different formulations on mucosal tissues.⁴⁷   Clotrimazole-containing vaginal mucoadhesive thermosensitive gel appears safe, convenient, and effective for treatment of vaginal infections with reduced dosing interval.⁴⁸

The availability of a mucoadhesive vaginal drug delivery system of a combination of clindamycin and clotrimazole has made it possible to completely eliminate the causative pathogens.

Summing up…

Urogenital infections are commonly seen in women in the reproductive age-group, with infections with C. trachomatis constituting the most prevalent sexually-transmitted bacterial diseases. Bacteria, fungi, viruses and parasites have the potential to interfere with the reproductive function in both sexes. Vaginal clotrimazole-clindamycin therapy is highly effective in treating vaginal infections. Mucoadhesive vaginal drug-delivery system has done away with several of the shortcomings of conventional vaginal drug-delivery systems by enhancing the binding capacity and retention of mucoadhesive polymers to mucosal tissues for considerable period of time.

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