Published in IJCP August 2019
Clinical Study
Comparative Study of Clinical Efficacy of Placental Extract and Azithromycin in Pelvic Inflammatory Disease
August 16, 2019 | Madhuri S, Kavya D Sharma, Prameela Hj
     


Abstract

Pelvic inflammatory disease (PID), an infection and inflammation of upper genital tract organs typically involving fallopian tubes, ovaries and surrounding structures, is one of the most frequent infections seen in reproductive age group. Therapeutic goal in management of PID is to prevent chronic residual disease. Failure of antibiotic therapy to prevent sequelae of salpingitis reflects the need for additional therapy along with antibiotics. Therefore, there is a need of a therapeutic agent with comprehensive anti-inflammatory action, debridement action to clear up the necrosed tissue and debris and also collagenase activity to break the bands and adhesions formed by earlier episodes of infection. A drug derived from an extract of fresh term, healthy, human placenta has multi-pronged anti-inflammatory action, debridement action, causes tissue regeneration and remodeling, promotes wound healing, has significant immunotropic action involving both humoral and cellular immunity. An open randomized prospective clinical trial was conducted at the Dept. of Obstetrics and Gynecology, MMC&RI, Mysuru from December 2013 to May 2015 to find the efficacy of the placental extract in comparison with azithromycin for the treatment of PID.

Keywords: Pelvic inflammatory disease, placental extract, azithromycin, Chlamydia trachomatis

Pelvic inflammatory disease (PID) is one of the most frequent infections seen in reproductive age group and is associated with major clinical and pelvic health problems. It is infection and inflammation of upper genital tract organs typically involving fallopian tubes, ovaries and surrounding structures. PID is polymicrobial in nature and is associated with different etiological agents. Clinical presentations may vary from mild-to-severe. No specific signs and symptoms are pathognomic of PID. Laboratory tests are also poor predictors of PID. There may be subclinical symptoms and patient later may present with infertility.

The Centers for Disease Control and Prevention (CDC) recommends treatment for even mild cases of PID. Therapeutic goal in management of PID is to prevent chronic residual disease. Failure of antibiotic therapy to prevent sequelae of salpingitis reflects the need for additional therapy along with antibiotics.

Studies from India have revealed the prevalence of Chlamydia trachomatis infection to be 23% in gynecology outpatient department (OPD) and 19.9% in sexually transmitted disease (STD) patients. It has been recovered from 30% to 60% cases of salpingitis and PID in India, while seroprevalence is shown to be higher in at least one study.

Many Indian women suffer from PID. Only 40% seem to present with overt symptoms, of which 4% are severe and 36% present with mild-to-moderate symptoms. Rest 60% of the rising PID cases in India present as subclinical or asymptomatic. There has been a change in the epidemiology of PID cases in India, where there is a shift from inpatient to outpatient PID cases. Infection with C. trachomatis seems to be on the rise and at present outnumbering gonococcus infections (Fig. 1).

Figure 1. Case rates for C. trachomatis infection, PID and EP, in British Columbia, Canada, 1992-2009.

PID = Pelvic inflammatory disease; EP = Ectopic pregnancy.

The sequelae of PID also differs widely. Management of sequelae includes periodic courses of antibiotics, steroids and surgery. Treatment is mainly aimed at alleviating symptoms, and preventing the disabling squealae like infertility, etc. Antimicrobial therapy improves prognosis for fertility but actual fertility results are not satisfactory. Antibiotics alone cannot prevent sequelae of PID. Antibiotics alone can neither prevent sequelae of salpingitis nor reverse the damage that has already set in. Therefore, there is a need of a therapeutic agent with comprehensive anti-inflammatory action, debridement action to clear up the necrosed tissue and debris and also collagenase activity to break the bands and adhesions formed by earlier episodes of infection and inflammation and that the drug can be continued for long without much adverse effects.

A drug derived from placental extract contains peptides  (FNP-III, Ubiquitin, CRF), nucleotides (PDRN) and glutamate. It is derived from an extract of fresh term, healthy, human placenta. It has significant anti-inflammatory effect involving chemical mediators of immunological response. Effect of the drug is well-documented in wound healing and in treatment of burns and radiation effects.

The primary modes of action of placental extract in PID are:

Anti-inflammatory action

The drug exerts comprehensive anti-inflammatory action thus offering better control of PID due to the presence of polydeoxyribonucleotides (PDRNs), which inhibit the proinflammatory cytokines possibly acting via adenosine receptors.

PDRN components act by entering the microbes and interfere with their replication thus also exerting both bacteriostatic and fungistatic activities in vitro. In vitro tests show growth inhibition of Escherichia coli, Staphylococcus aureus and fungi including Saccharomyces cerevisiae, Kluyveromyces fragilis and Candida albicans. They also prevent growth of clinically isolated bacteria like E. coli from urine and blood culture and S. aureus from pus. Drug-resistant strains e.g., E. coli DHSoc and Pseudomonas aeruginosa Cam R have also been significantly inhibited by the extract with a dose-dependent response.

These activities possibly help in treatment of bacterial infections, and eliminate bacteria in PID, which are persistent or resistant to antibiotics. PDRN also stimulate growth factors like fibroblast growth factor (FGF), placental growth factor (PIGF) and transforming growth factor (TGF)-b that help in tissue repair and healing.

Preliminary studies indicate that the drug disrupts the biofilm in bacterial infection. This property can aid in antibiotic action where it can reduce the duration of therapy and also decrease the chance of recurrence or resistance. Most of the recent clinical studies are indicative of this. Corticotropin-releasing factor like peptide in the drug suppresses the production of prostaglandins and leukotrienes through endogenous steroids production.

The anti-inflammatory and platelet anti-aggregatory activity of the drug are demonstrated in suitable animal models and in in vitro study, respectively.

Debridement action

Component containing fibronectin like peptide identified in the drug exerts debridement action by stabilizing the local trypsin or trypsin-like serine proteases (broad-spectrum proteases). Proteolytic enzymes improve blood flow by increasing the flexibility of red blood cells, inhibiting the aggregation of platelets and help to prevent abnormal blood clotting. Enzyme activity also helps to support the cleansing of the tissues and promotes better circulation as well as stimulating formation of new, healthy tissue. They make the blood less viscous. This helps to bring proper circulation to the inflamed tissue. This particularly helps in opening of fallopian tubes blocked by inflammation, necrosed tissue and debris. Reduction in inflammation, increase in proper blood formation, increase in proper circulation hinders scar tissue and adhesion formation, while reducing pain.

Collagenase action

Excess and faulty collagen formations lead to scar tissue formation and adhesion causing fertility issues. Ubiquitin is known to destroy faulty collagen tissue. Placenta derived ubiquitin-like peptide softens and breaks up adhesions, scar tissues in fallopian tubes and penetrates directly to the pelvic region to clear any debris or mucus plugs formed during chronic inflammation leading to recurrent attacks of PID. This helps in maintaining the patency of the fallopian tubes, thus bringing down the chances of infertility or ectopic pregnancy. Thus the placental extract has multi-pronged anti-inflammatory action, debridement action, causes tissue regeneration and remodeling, promotes wound healing, has significant immunotropic action involving both humoral and cellular immunity.

This is conspicuous in clinical studies where it significantly relieved the cervical motion tenderness and adnexal tenderness. The drug has been recommended for prescription in PID but there is not much data in literature regarding the efficacy alone in PID. So, we conducted a trial to find efficacy of the drug in comparison with azithromycin for the treatment of PID.

MATERIAL AND METHODS

An open randomized prospective clinical trial was conducted at the Dept. of Obstetrics and Gynecology, MMC&RI, Mysuru from December 2013 to May 2015 after obtaining ethical clearance.

A total of 100 patients of PID within reproductive age group of 20-45 years were recruited. Diagnosis of PID was made on the basis of clinical history and examination.

Inclusion Criteria

  • Female subjects of childbearing age.
  • Patients diagnosed to have PID in the last 6-12 months.
  • Patients with primary or secondary infertility with diagnosis of PID.
  • Patients with persistent PID despite antibiotic treatment within past 6 weeks.
  • Willingness to receive intramuscular (IM) injections for 14 days.

Exclusion Criteria

  • Postmenopausal women or women outside reproductive age group.
  • Subjects who were pregnant or breastfeeding.
  • Subjects on active treatment or with evidence of active tuberculosis/STD.
  • Subjects with endometriosis.
  • History of more than 3 episodes of documented PID/bacterial STD.
  • Any hepatic or renal impairment.

Patients were randomly assigned to two groups. Group 1 (50 patients) was given injection of the placental extract 2 mL IM daily for 14 days; Group 2 (50 patients) were given tablet azithromycin 1,000 mg stat and repeated the same dose after 1 week.

Patients were followed up at 2, 4 and 12 weeks after starting the treatment; the first follow-up at 2 weeks after initiation of the therapy was to assess the immediate relief of symptoms while on therapy; the 2nd follow-up at 4 weeks was to assess persistence of relief and the 3rd follow-up at 12 weeks was to assess recurrence of symptoms. History suggestive of PID included lower abdomen pain, discharge per vagina, menstrual irregularity, dysmenorrhea and dyspareunia. Clinical signs consisted of presence of discharge, uterine tenderness, restricted mobility of uterus and adnexal tenderness (Table 1). The responses of treatment were made based on history and examination.

Table 1. Symptomatology and Signs

 

Group 1

Group 2

 

Initial (50)

2 weeks (50)

4 weeks (46)

12 weeks (46)

Initial
(50)

2 weeks (46)

4 weeks (40)

12 weeks (40)

Symptomatology

               

Lower abdominal pain

46 (92%)

24 (48%)

20 (43.5%)

20 (43.5%)

44 (88%)

32 (69.6%)

28 (70%)

28 (70%)

Backache

32 (64%)

12 (24%)

10 (21.7%)

8 (17.4%)

34 (68%)

14 (30.4%)

16 (40%)

16 (40%)

Menstrual irregularities

16 (32%)

8 (16%)

6 (13%)

6 (13%)

18 (36%)

10 (21.7%)

12 (30%)

14 (35%)

Dysmenorrhea

32 (64%)

14 (28%)

12 (26.1%)

12 (26.1%)

22 (44%)

16 (34.8%)

14 (35%)

12 (30%)

Dyspareunia

18 (36%)

8 (16%)

6 (13%)

6 (13%)

12 (24%)

8 (17.4%)

6 (15%)

6 (15%)

Signs

               

Discharge per vagina

30 (60%)

18 (36%)

16 (34.8%)

10 (21.7%)

28 (56%)

10 (21.7%)

16 (40%)

16 (40%)

Uterine tenderness

32 (64%)

20 (40%)

18 (39.1%)

14 (30.4%)

32 (64%)

12 (26.1%)

22 (55%)

18 (45%)

Restricted uterine mobility

16 (32%)

6 (12%)

4 (8.7%)

4 (8.7%)

18 (36%)

12 (26.1%)

10 (25%)

10 (25%)

Fornix tenderness

38 (76%)

10 (20%)

20 (43.5%)

24 (52.2%)

40 (80%)

30 (65.2%)

20 (50%)

18 (45%)

Cervical erosion

8 (16%)

2 (4%)

4 (8.7%)

4 (8.7%)

6 (12%)

4 (8.7%)

4 (10%)

4 (10%)

RESULTS AND DISCUSSION

Total 100 cases of PID were recruited, 50 in Group 1 and 50 in Group 2; mean age of patients was 30.36 years in Group 1 and 31.1 in Group 2. Most  of them were P2L2. Four cases in Group 1 and 10 cases in Group 2 were lost out of follow-up. There were no major or minor side effects in both the groups except mild gastric upset seen in 2 cases in Group 2. No patients had allergic reaction, fever or pain at injection site in Group 1.

Pelvic inflammatory disease is a frequent infection seen in reproductive aged women. Despite availability of antibiotics, treatment of PID is still not satisfactory. In our study, we have evaluated efficacy of a placental extract injection with azithromycin in curing PID.

On analyzing the results for each symptom and sign, we found that the lower abdominal pain markedly reduced in Group 1; 48.5% versus 18% in Group 2, which was significant statistically (p ≤ 0.01).

Relief in backache was better with Group 1; 46.6% versus 28% in Group 2 and was found to be statistically significant (p ≤ 0.01). As far as menstrual irregularity is concerned, it was observed that it was marginally better but not statistically significant (p ≤ 0.263). A small study has shown improvement in menstrual irregularities. Dysmenorrhea improved to some extent in both the groups but it was not statistically significant (p ≤ 0.11). Relief of dyspareunia did not show significant improvement in both the groups (p ≤ 0.128). A small study showed that relief of dyspareunia was better with placental extract treatment. Response to vaginal discharge was present in both the groups with marginal benefit in Group 1 (p ≤ 0.50) but it was not statistically significant. Uterine tenderness improved more in Group 1 - 33.6% versus 19% in Group 2, but it was not statistically significant. Uterine mobility improved in both groups but was not statistically significant. Fornix tenderness showed improvement in both the groups but was statistically better in Group 1 (p ≤ 0.02). There was no improvement in cervical erosion in both the groups. Efficacy of placental extract in cervical erosion has been reported but with local application of placental extract gel. Thus overall, Group 1 had better and sustained effect of therapy in relieving lower abdominal pain, backache, fornix tenderness, which was statistically significant. In other symptoms, there was marginal improvement when compared with Group 2.

Complete remission with treatment at 2 weeks occurred in 24 cases (48%) in Group 1 versus 16 (32%) cases in Group 2 (Table 2 and Fig. 2). Complete remission at 12 weeks follow-up was seen in 34 cases (68%) in Group 1 versus 10 (20%) cases in Group 2 (Fig. 3). Lack of response to treatment at 2 weeks was seen in 10 (20%) in Group 1 versus 18 cases (36%) in Group 2. Recurrence at 12 weeks was seen in 8 (16%) cases in Group 1 compared to 18 (36%) in Group 2 (Fig. 4). As regards overall patient satisfaction, it was better in Group 1 36% versus 16% in Group 2 (Fig. 5).

Table 2. Overall Efficacy

Parameter

Group 1

Group 2

Complete remission on Rx at 2 weeks

24 (48%)

16 (32%)

Complete remission on Rx at 12 weeks

34 (68%)

10 (20%)

Lack of response at 2 weeks

10 (20%)

18 (36%)

Recurrence at 12 weeks

8 (16%)

18 (36%)

Patient's satisfaction of more than 75% on therapy

18 (36%)

8 (16%)

Figure 2. Complete remission on Rx at 2 weeks.

Figure 3. Complete remission on Rx at 12 weeks.

Figure 4. Recurrence at 12 weeks.

Figure 5. Patient's satisfaction of more than 75% on therapy.

CONCLUSION

Pelvic inflammatory disease is one of the most frequent infections encountered in gynecology. Conventional antibiotic therapy does not provide adequate relief of symptoms and its sequelae. Conventional anti-inflammatory and proteolytic enzymes leave a therapeutic gap. Placental extract injection is expected to fill up the gaps adequately. It leads to marked relief in symptoms as compared with antibiotic therapy alone. As placental extract decreases adnexal inflammation to significant level, it can be a good option especially to reduce symptoms and sequelae of PID.

SUGGESTED READING

  1. Agarwal N, Kulshrestha V, Kriplani A. Clinical efficacy of placentrex injection in pelvic inflammatory disease.
    J Indian Med Assoc. 2010;108(2):117-8, 122.
  2. Garg R, Zahra F, Chandra JA, Vatsal P. A comparative study of injection placentrex and conventional therapy in treatment of pelvic inflammatory disease. J Indian Med Assoc. 2008;106(7):463, 467.
  3. Dahiya P, Paul A. A randomised study to evaluate the efficacy and safety of placentrex injection in patients suffering from pelvic inflammatory disease. J Indian Med Assoc. 2013;111(5):352-3.
  4. Sarkar B, Kishore N, Mookherjee J, Nagrath A. Effect of Placentrex on tubal blockage and menstrual irregularities. J Obstet Gynaecol India. 1976;26(5):757-61, iii-v.
  5. Sen and Bhargava et al (ADL Data on file).
  6. Purandare BN, Purandare CB, Hirlekar V. Placental extract injection therapy in tubal block. The Clinician. 1970;XXXIV(1):45-8.
  7. Chandanwale A, Langade D, Mohod V, Sinha S, Ramteke A, Bakhshi GD, et al. Comparative evaluation of human placental extract for its healing potential in surgical wounds after orthopaedic surgery: an open, randomised, comparative study. J Indian Med Assoc. 2008;106(6):405-8.
  8. Kaul R, Chaudhary V, Mukhopadhayay P. To evaluate the effect of local placentrex therapy in reducing side effects of radiation in patients of cervical carcinoma. Antiseptic. 2001;98(4):131-2.
  9. Chandravati et al. Placentrex gel with electrocauterization in the treatment of cervical erosion. Obstet Gynaecol 2004;12:823-7.