The success of treatment for PID is generally gauged by short-term clinical improvement and/or microbiologic cure. Our results show that these short-term markers (tenderness at 5 and 30 days; gonococcal/chlamydial cervicitis at 30 days; endometritis at 30 days) are not strongly predictive of the long-term sequelae from PID that treatment is trying to prevent. Although persistent tenderness significantly increased the occurrence of chronic pelvic pain and recurrent PID, positive predictive values were too low to make short-term tenderness a clinically meaningful intermediate for predicting these long-term outcomes. Moreover, cervicitis and endometritis were not significantly associated with chronic pelvic pain or PID, and none of the short-term measures were predictive of the ability to achieve pregnancy.
We considered several explanations for our findings. First, cervical infection status may not adequately represent upper genital tract inflammation such as fallopian tube infection.5,22,29
Cervical infection often exists in the absence of endometrial infection/inflammation resulting in a short-term marker that is a false positive. The converse is also true: in two studies, 3.7% to 10% of women were documented with positive upper genital tract chlamydial cultures, despite negative cervical culture at baseline.5,22
This has also been documented post-treatment for PID, where four of 16 women had positive endometrial cultures for chlamydia despite negative endocervical cultures after second and third generation cephalosporin treatment.29
Thus, despite a negative test for thirty day cervical infection, women may have experienced a persistent infection in their upper genital tract that contributed to long-term sequelae.
Second, women who delay seeking treatment for PID for three days or more are at nearly a three fold increase in risk for impaired fertility,30
suggesting that early treatment administration may be necessary to halt a complete mounting of the inflammatory response. Because the majority of women in the PEACH study presented with three or more days of pelvic pain (71%),22
they may have been at increased risk for long-term sequelae regardless of short-term treatment response.
Third, women may have had prior subclinical (silent) PID that resulted in tubal damage preceding the baseline episode. Prior PID may have contributed, independent of the short-term markers from the index diagnosis of PID, to adverse reproductive sequelae. In a macaque monkey model, repeated exposure to chlamydial infections produced a Th-1 type cytokine response that was associated with the progression to fibrosis and infertility.31–33
In a study by Soper et al., second look laparoscopy revealed that previous disease was strongly predictive of subsequent tubal damage.34
One test of cervical infection at thirty-days might not capture the women who had repeated exposures sufficient to produce fibrosis and scarring. We did not find any statistically significant interaction between prior PID and the short-term markers in predicting outcomes of recurrent PID or lack of pregnancy. For the outcome of chronic pelvic pain, our results are counterintuitive and might represent the inclusion of women with diagnoses other than PID in the outcome of chronic pelvic pain.
Fourth, PID has a polymicrobial etiology and several non-chlamydial, non-gonococcal pathogens have been implicated, including Mycoplasma hominis
, Ureaplasma urealyticum
, bacterial vaginosis (independent of gonorrhoea or chlamydia), and Mycoplasma genitalium
Some of these pathogens (M. hominis
and U. urealyticum
) are largely resistant to tetracyclines, and may have persisted following PID treatment.37
In a previous PEACH analysis, women with nongonococcal bacteria in the endometrium were more likely to have reproductive morbidity compared to women with endometrial gonococcal infection (infertility rates were: N. gonorrhoeae
13%, C. trachomatis
19%, anaerobic bacteria 22%, U. urealyticum
41% and M. hominis
Further, Brunham and colleagues demonstrated over a five to seven month follow-up, 54% of women with non-gonococcal infections had adverse reproductive outcomes, compared to none of the women with gonococcal PID.5
Thus, women in the study may have had non-gonococcal, non-chlamydial pathogens that resulted in long-term sequelae. Our data suggest that commonly-used short-term markers do not adequately reflect the underlying pathophysiology that leads some women to have adverse long-term outcomes while others do not.
We had previously shown that endometritis and upper genital tract infection were not associated with reduced pregnancy, recurrent PID, infertility, or chronic pelvic pain after one year of follow-up in the PEACH Study.38
This analysis extends that finding to examine the associations between several short-term markers and sequelae related to PID after a mean of six years of follow-up. The study has several strengths. First, the prospective design allowed actual measurements of all outcomes. Second, the PEACH study had a long-follow up duration (average follow-up length 84 months) and a sizeable rate of retention (69.1%).22
Third, the study was generalizable, as it enrolled women with mild-to-moderate PID who comprise 90% of women with PID.39
Fourth, standardized laboratory procedures minimized bias and misclassification.
One notable weakness is the diminution in sample size between the five and thirty day visit, with 713 women (out of 831) with complete five day return visit data, and only 298 women with complete covariate and marker data at thirty days. Lack of significant findings may have resulted from a lack of power, particularly for the assessment of cervical infection at 30 days. The women who did not return for the thirty day visit were more likely to be 25 or older, and of race other than African American or white. There were no significant differences in educational status, history of PID, parity and baseline gonococcal/chlamydial status. A second weakness was the reliance on self-report to determine recurrent PID. However, as previously noted, we found 76% confirmation of recurrent PID in verified medical records.22
A final weakness was that only about half of participants had endometritis and/or upper genital tract infection (indicators of salpingitis); in women without the true condition, short-term markers would likely not correlate with long-term outcomes. However, as the cohort represents patients that are typically treated for PID, the lack of predictiveness of short-term markers remains generalizable to women seen in usual clinical practice.
Short-term intermediate endpoints are frequently used to determine clinical or microbiologic cure for PID. However, our results suggest that such markers are generally unrelated to long-term reproductive morbidity and even when significant associations exist, the accompanying positive and negative predictive values are less than optimal. When conducting treatment trials, and when counseling women about their long-term health risks, we can recommend no currently-accepted short-term marker to predict the occurrence of PID-related reproductive morbidity.