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Home , Bacterial vaginosis, Cervicitis, Dyspareunia, Endometritis, Tubal factor infertility, Vaginal discharge

The new england journal of medicine

Review Article

Edward W. Campion, M.D., Editor Pelvic Inflammatory

Robert C. Brunham, M.D., Sami L. Gottlieb, M.D., M.S.P.H., and Jorma Paavonen, M.D.​

elvic inflammatory disease is an -induced From the Department of Medicine, Uni- of the female upper reproductive tract (the , fallopian tubes, versity of British Columbia, Vancouver, 1 Canada (R.C.B.); the Department of Re- , or pelvic peritoneum); it has a wide range of clinical manifestations. productive Health and Research, World P Health Organization, Geneva (S.L.G.); Inflammation spreads from the or to the upper genital tract, with as an intermediate stage in the pathogenesis of disease.2 The hall- and the Department of and Gynecology, University of Helsinki, Hel- mark of the diagnosis is pelvic tenderness combined with inflammation of the sinki (J.P.). Address reprint requests to lower genital tract; women with pelvic inflammatory disease often have very subtle Dr. Brunham at the Department of Medi- symptoms and signs.3 Many women have clinically silent spread of infection to the cine, University of British Columbia, 655 1,4 West 12th Ave., Vancouver, BC V5Z 4R4, upper genital tract, which results in subclinical pelvic inflammatory disease. Canada, or at robert­ .​ brunham@­ bccdc​­ .​ ca.­ Pelvic inflammatory disease is a major concern because it can result in long- N Engl J Med 2015;372:2039-48. term reproductive disability, including , ectopic , and chronic DOI: 10.1056/NEJMra1411426 . After the introduction of laparoscopy in the 1960s, research on pelvic in- Copyright © 2015 Massachusetts Medical Society. flammatory disease proliferated through the 1970s, 1980s, and 1990s, leading to major breakthroughs in the understanding of the microbial causes of the disease and its relationship to reproductive disability, as well as enabling the standardization of antimicrobial treatment. According to a national estimate, in 2001 more than 750,000 cases of pelvic inflammatory disease occurred in the United States.5 Over the past two decades, the rates and severity of pelvic inflammatory disease have declined in North America and western Europe.6-9 These declines have occurred in association with public health efforts to control trachomatis and infection.6,10,11 Despite progress, however, pelvic inflammatory disease remains a problem because reproductive outcomes among treated patients are still suboptimal, subclinical pelvic inflammatory disease remains poorly controlled, and programs aimed at the prevention of pelvic inflammatory disease are not feasible in much of the developing world.

Pathophysiology and Microbial Causes Acute (≤30 days’ duration), clinically diagnosed pelvic inflammatory disease is caused by spontaneous ascension of microbes from the cervix or vagina to the en- dometrium, fallopian tubes, and adjacent structures. More than 85% of are due to sexually transmitted cervical or –associated microbes, and approximately 15% are due to respiratory or enteric organisms that have colonized the lower genital tract (Table 1). Subclinical pelvic inflammatory disease has causes similar to those of acute pelvic inflammatory disease and may be twice as common.1,12 Chronic (>30 days’ duration) pelvic inflammatory disease is defined as chronic infection due to Mycobacterium or actinomyces spe- cies rather than as chronic recurrent pelvic pain, which remains common after the treatment of acute pelvic inflammatory disease. This review focuses on acute and subclinical pelvic inflammatory disease.

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Table 1. Clinical Classification of Pelvic Inflammatory Disease and Likely Microbial Causes.

Clinical Syndrome Causes Acute pelvic inflammatory disease Cervical pathogens (Neisseria gonorrhoeae, , and (≤30 days’ duration) genitalium) Bacterial vaginosis pathogens (peptostreptococcus species, species, atopobium species, leptotrichia species, M. hominis, , and clostridia species) Respiratory pathogens (, , group A streptococci, and ) Enteric pathogens (Escherichia coli, Bacteroides fragilis, group B streptococci, and campylobacter species) Subclinical pelvic inflammatory C. trachomatis and N. gonorrhoeae disease Chronic pelvic inflammatory dis- Mycobacterium tuberculosis and actinomyces species ease (>30 days’ duration)

Ascending infection from the cervix is often of the fallopian tubes and ovaries, which leads to due to sexually acquired infections with N. gonor- scarring, adhesions, and possibly partial or total rhoeae or C. trachomatis. Sexually transmitted My- obstruction of the fallopian tubes. The adaptive coplasma genitalium has been identified as a likely immune response plays a role in the - cause of , endometritis, , and esis of pelvic inflammatory disease because re- infertility, but the evidence has been inconsis- infection substantially increases the risk of tubal- tent.13-15 The factors determining which cervical factor infertility (i.e., the inability to conceive infections ascend to the upper genital tract have because of structural or functional damage to the not been completely elucidated, but data from fallopian tubes). Infection-induced selective loss prospective studies suggest that about 15% of of ciliated epithelial cells along the untreated chlamydial infections progress to clini- can cause impaired ovum transport, cally diagnosed pelvic inflammatory disease.16-18 resulting in tubal-factor infertility or ectopic preg- The risk of pelvic inflammatory disease after nancy (Fig. 1).28 Peritoneal adhesions along the gonococcal infection may be even higher. Sexual fallopian tubes may prevent pregnancy, and adhe- intercourse and retrograde may be sions within the are related to pelvic pain. particularly important in the movement of organ- 1 isms from the lower to the upper genital tract. Clinical Manifestations and Anaerobic and facultative that are Diagnosis found in have been isolated alone or with N. gonorrhoeae and C. trachomatis infection in Pelvic inflammatory disease is particularly com- the fallopian tubes of women with acute pelvic mon among sexually active young and adoles- inflammatory disease (Table 1).1,19-23 These or- cent women, who are most often treated in am- ganisms occur in greater concentrations in asso- bulatory clinics, physician offices, or emergency ciation with bacterial vaginosis, a polymicrobial departments.9,29-31 The abrupt onset of severe lower dysbiosis characterized by a reduction in normal during or shortly after menses vaginal lactobacilli and overgrowth of a much has been the classic symptom used to identify more complex anaerobic -associated mi- acute pelvic inflammatory disease, although it is crobiome.24 Bacterial vaginosis is associated with now well recognized that both the onset and se- local production of enzymes that degrade cervical verity of symptoms can be more ill-defined and mucus and associated antimicrobial peptides.3,25,26 subtle. Atypical, milder clinical manifestations This degradation may impair the cervical barrier have become more common as rates of N. gonor- to ascending infection and facilitate the spread rhoeae infection have fallen.32,33 The symptoms of microorganisms to the upper genital tract.27 associated with acute pelvic inflammatory disease Infection results in fibrinous or suppurative include pelvic or lower abdominal pain of vary- inflammatory damage along the epithelial surface ing severity, abnormal , inter- of the fallopian tubes and the peritoneal surface menstrual or , , and

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.34 can occur, but systemic manifes- the diagnosis.41 Figure S1 in the Supplementary tations are not a prominent feature of pelvic in- Appendix, available with the full text of this ar- flammatory disease. Occasionally, right-upper- ticle at NEJM.org, shows a simplified algorithm quadrant pain suggestive of inflammation and for guiding the clinical diagnosis of pelvic inflam- formation in the liver capsule (peri- matory disease. hepatitis or the Fitz-Hugh–Curtis syndrome) can Unfortunately, the clinical diagnosis of pelvic accompany pelvic inflammatory disease. inflammatory disease is imprecise. Only about A large body of evidence suggests that infec- tion and inflammation in the upper genital tract can occur and lead to long-term reproductive com- A plications in the absence of symptoms, a condi- tion often called subclinical pelvic inflammatory disease.1,4,12 Asymptomatic infections of the up- per genital tract have been well documented,35 and most women with tubal-factor infertility do not have a history of clinically diagnosed pelvic inflammatory disease, as has been observed in studies showing strong associations between in- fertility and serologic evidence of previous C. tra- chomatis or N. gonorrhoeae infection.36,37 Among women with tubal-factor infertility, biopsy spec- imens show similar pathologic tubal damage in women who have a history of pelvic inflamma- tory disease and those who do not.28 However, of note, in one study involving infertile women without a history of diagnosed pelvic inflamma- B tory disease, 60% of the women with tubal-factor infertility, as compared with only 19% of those without tubal-factor infertility, reported health care visits for abdominal pain38; this suggests that many cases of pelvic inflammatory disease are missed and that clinicians should have a low threshold for considering the diagnosis. The clinical diagnosis of pelvic inflammatory disease is based on the finding of pelvic organ tenderness, as indicated by cervical motion ten- derness, adnexal tenderness, or uterine compres- sion tenderness on bimanual examination, in conjunction with signs of lower genital tract in- flammation. Signs of lower genital tract inflam- mation include cervical mucopus, which is visible as an exudate from the endocervix or as yellow or green mucus on a cotton-tipped swab placed Figure 1. Pathologic Changes in the Epithelial Surface of the Fallopian Tube after Pelvic Inflammatory gently into the cervical os (positive “swab test”); Disease. cervical friability (easily induced columnar epi- Scanning electron micrographs show normal human thelial bleeding); or increased numbers of white fallopian tube epithelia (Panel A) and the epithelial cells observed on saline microscopic examina- surface after pelvic inflammatory disease (Panel B). tion of vaginal secretions (wet mount) (Fig. 2).39,40 Pelvic inflammatory disease causes a selective loss of Pelvic tenderness of any kind has high sensitiv- ciliated epithelial cells, which interferes with intratubal ovum transport, resulting in infertility or ectopic preg- ity (>95%) for pelvic inflammatory disease, but nancy. Images courtesy of Dorothy L. Patton, Universi- it has poor specificity. Findings of lower genital ty of Washington, Seattle. tract inflammation increase the specificity of

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A B

C D

Figure 2. Diagnosis of Pelvic Inflammatory Disease. The clinical diagnosis of pelvic inflammatory disease is based on the findings of pelvic tenderness on bimanual vag- inal examination and of lower genital tract inflammation on speculum examination. Panel A shows mucopurulent endocervical discharge as seen on speculum examination. An area of endocervical columnar epithelium (ectopy) is seen on the face of the cervix. The epithelium is edematous and erythematous and bleeds easily when touched (fri- ability). Panel B shows mucopurulent endocervical discharge as a yellow–green exudate on the tip of a Dacron swab (a positive swab test).38 Panels C and D show high-power microscopic examination of vaginal fluid, with clue cells typical of bacterial vaginosis (Panel C) and increased numbers of white cells (≥1 per vaginal epithelial cell) (Panel D).

75% of women who have received a clinical di- findings of increased numbers of plasma cells and agnosis of pelvic inflammatory disease that is is more commonly used to confirm based on symptoms of pelvic tenderness and in- the diagnosis of pelvic inflammatory disease, and flammation of the lower genital tract have lapa- these findings are often seen in association with roscopic confirmation of salpingitis (visualiza- laparoscopically confirmed salpingitis.2 However, tion of tubal and uterine inflammation, exudate, is somewhat invasive, re- adhesions, or abscess).42 Although laparoscopy quires skill for the pathological interpretation of has been considered the standard for the diag- the sample, and results in a delayed diagnosis.45 nosis of pelvic inflammatory disease, it has high Transvaginal ultrasonography and magnetic res- interobserver variability43 and might not detect onance imaging (MRI) revealing thickened, fluid- endometritis or early tubal inflammation.44 In filled tubes are available during the diagnostic addition, it is an invasive surgical procedure that workup and are highly specific for salpingitis.46,47 is not readily available in many settings and is However, the sensitivity of ultrasonography is not routinely performed, especially in women only fair, and although MRI has high sensitivity, with mild-to-moderate symptoms. Transcervical it is expensive and not typically available in re- endometrial aspiration with histopathological source-poor settings. Power Doppler studies show-

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Table 2. First-Line Antimicrobial Treatment Recommended by the Centers for Disease Control and Prevention (CDC) for Pelvic Inflammatory Disease.*

Outpatient regimen for mild-to-moderate pelvic inflammatory disease (100 mg orally twice daily for 2 wk) with or without (500 mg orally twice daily for 2 wk), plus one of the following: Ceftriaxone (250 mg intramuscularly in a single dose) (2 g intramuscularly) with probenicid (1 g orally) concurrently in a single dose Other parenteral third-generation cephalosporin (cefotaxime or ceftizoxime) Inpatient regimen for moderate-to-severe pelvic inflammatory disease with or without tubo-ovarian abscess† One of the following: Cefotetan (2 g intravenously every 12 hr) plus doxycycline (100 mg orally or intravenously every 12 hr) Cefoxitin (2 g intravenously every 6 hr) plus doxycycline (100 mg orally or intravenously every 12 hr) (900 mg intravenously every 8 hr) plus (3 to 5 mg per kilogram of body weight intrave- nously once daily)

* Complete treatment information, including alternative regimens and additional considerations, is available at the CDC website.33 † Transition to oral therapy can usually be initiated within 24 to 48 hours after clinical improvement, and oral therapy should be continued to complete 2 weeks of therapy.

ing increased fallopian-tube blood flow are high- mentation rate or C-reactive protein level can ly suggestive of infection.46,48 Imaging studies increase the specificity of a pelvic inflammatory may also be useful in making an alternative disease diagnosis.41 diagnosis, such as , , ectopic pregnancy, or acute appendicitis; these Treatment conditions can be found in 10 to 25% of women who are thought to have acute pelvic inflamma- Guidelines for the treatment of pelvic inflamma- tory disease. tory disease have been developed by the Centers All patients with suspected pelvic inflamma- for Disease Control and Prevention (CDC) on the tory disease should undergo cervical or vaginal basis of the results of clinical trials and the con- nucleic amplification tests for N. gonorrhoeae sensus recommendations of expert clinicians and C. trachomatis infection; if the results are (Table 2).33 The treatment of pelvic inflammatory positive, the probability that pelvic inflamma- disease is empirical and involves the use of broad- tory disease is present increases substantially.41 spectrum combination regimens of antimicrobial Molecular tests for M. genitalium are not yet com- agents to cover likely pathogens. Treatment should mercially available. Vaginal fluid should be evalu- cover the principal pathogens, N. gonorrhoeae and ated for increased numbers of white cells (more C. trachomatis, regardless of the results of testing. than one per epithelial cell) and signs The need to cover anaerobes has not been defi- of bacterial vaginosis, including vaginal epithe- nitely established in randomized clinical trials, but lial cells that have their cell margins obscured because bacterial vaginosis is commonly found by attached bacteria (i.e., clue cells), an elevated in women with pelvic inflammatory disease and pH, and an amine odor on addition of potassium anaerobes are often recovered from upper geni- hydroxide (positive “whiff” test).40 Normally, tal tract samples, antimicrobials with anaerobic bacterial vaginosis is a noninflammatory condi- coverage are recommended. Reliable coverage of tion, and if white cells accompany clue cells, this M. genitalium is problematic, because the majority suggests pelvic inflammatory disease. A preg- of strains are resistant to doxycycline. Moxifloxa- nancy test should be routinely requested to help cin reliably eradicates M. genitalium13; however, rule out ectopic pregnancy. Serologic testing for N. gonorrhoeae has acquired quinolone resistance, human immunodeficiency (HIV) should be and quinolone monotherapy for pelvic inflamma- performed; HIV increases the risk of a tubo- tory disease is no longer routinely recommend- ovarian abscess.49 An elevated erythrocyte sedi- ed.50 Substitution of azithromycin for doxycycline

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covers M. genitalium and simplifies dosing. How- Infertility (i.e., an inability to conceive after 1 year ever, in a recent trial of treatment for nongono- of attempting to become pregnant) developed, coccal ,51 azithromycin was found to be overall, in 16% of the women with laparoscopi- less reliable than doxycycline for the eradication cally confirmed salpingitis, as compared with 2.7% of C. trachomatis, so it remains an alternative of the women with clinically suspected pelvic regimen. inflammatory disease but no salpingitis. In ad- The Pelvic Inflammatory Disease Evaluation dition, 9% of women with salpingitis had a sub- and Clinical Health (PEACH) study showed that sequent ectopic pregnancy. The PEACH study among women with mild-to-moderate pelvic in- provides more modern-day estimates of the risk flammatory disease, the efficacy of cefoxitin– of reproductive sequelae among 831 urban Amer- doxycycline therapy, with respect to both short- ican women treated with cefoxitin and doxycycline term and long-term complications, was similar for mild-to-moderate, clinically diagnosed pelvic in inpatient and outpatient settings.52 The same inflammatory disease between 1996 and 1999.52 held true for adolescents. The reasons for hospi- After 3 years of follow-up, approximately 18% of talization for pelvic inflammatory disease cur- the women reported infertility, 0.6% had an rently include pregnancy, an inability to rule out ectopic pregnancy, and 29% had chronic pelvic competing diagnoses, severe illness combined pain (pain reported at two or more consecutive with an inability to take oral , or tubal visits 3 to 4 months apart during a period of 2 to abscess. 5 years); 15% of the women had recurrent pelvic Most patients are successfully treated as inflammatory disease.55 Both of these studies outpatients with single-dose intramuscular cef- indicate that repeated episodes of pelvic inflam- triaxone, cefoxitin plus probenicid, or another matory disease markedly worsen the reproduc- third-generation cephalosporin (cefotaxime or tive outcomes. Of note, delayed care for pelvic ceftizoxime), followed by oral doxycycline with inflammatory disease has also been strongly or without metronidazole for 2 weeks (Table 2). associated with worse long-term outcomes.56 It For hospitalized patients, therapy with cefotetan remains unclear why the long-term outcome of or cefoxitin (administered parenterally until 24 to treated pelvic inflammatory disease remains so 48 hours after clinical improvement) together dismal, given the high rates of clinical response. with doxycycline and followed by doxycycline with Perhaps infection-induced damage to the fallopian or without metronidazole to complete 2 weeks of tubes has occurred by the time treatment is first treatment is recommended. A regimen of clindamy- given. This observation, together with the frequent cin and an aminoglycoside may be particularly occurrence of subclinical pelvic inflammatory dis- appropriate for patients with a tubo-ovarian ab- ease, have highlighted the importance of recog- scess. Adjunctive nonsteroidal anti-inflammato- nizing prevention of pelvic inflammatory disease ry drugs do not improve the clinical outcome.53 as a major public heath priority. Removal of an (IUD) does not hasten clinical resolution (and may delay it), and Prevention in most cases the IUD is left in place.54 The most important public health measure for Long-Term Reproductive the prevention of pelvic inflammatory disease is Outcomes the prevention and control of sexually transmitted infections with C. trachomatis or N. gonorrhoeae. Although more than 90% of patients with pelvic Many high-income countries have implemented inflammatory disease will have a clinical response programs to screen and treat women for asymp- to CDC-recommended treatment, the long-term tomatic C. trachomatis infection, on the basis of outcome of treatment is still suboptimal. In clas- evidence from randomized controlled trials indi- sic studies conducted between 1960 and 1984, cating that screening for and treating cervical Westrom and colleagues followed 2501 Swedish C. trachomatis infection can reduce a woman’s risk women for several years after the women under- of pelvic inflammatory disease by approximately went laparoscopy and treatment for clinically 30 to 50% over 1 year.17,57,58 The U.S. Preventive suspected pelvic inflammatory disease; 1844 of Services Task Force, CDC, and other professional the women (74%) had confirmed salpingitis.42 organizations recommend annual C. trachomatis

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screening for all sexually active women younger ease and can be used to track the response to than 25 years of age and older women at in- therapy.63,64 Further study is needed before these creased risk for infection (e.g., women with mul- assays are adopted into clinical practice. Immu- tiple or new sex partners).33,59 These groups also nohistochemical analysis and flow cytometry recommend testing for N. gonorrhoeae among are being used to define specific cellular infil- women at increased risk for infection (e.g., wom- trate patterns from endometrial biopsy specimens en with or previous gonor- that correlate with infection.65 Several studies that rhea infection and women living in communities have assessed diagnostic imaging have shown with a high prevalence of disease). the potential of MRI, transvaginal ultrasonogra- Comprehensive , promotion of phy, and power Doppler imaging to improve the the use of , and provision of condoms diagnosis of pelvic inflammatory disease,47 but are cornerstones of the prevention of sexually larger follow-up studies are needed to better transmitted infection globally and also have ben- define the role of these techniques in the treat- efits for the prevention of pelvic inflammatory ment of symptomatic women and asymptomatic disease. Data from the PEACH study showed women with lower genital tract infection. that persistent use during follow-up was In recent studies in high-income populations, associated with reduced risks of recurrent pelvic less than half the women with pelvic inflamma- inflammatory disease, chronic pelvic pain, and tory disease have had evidence of C. trachomatis infertility.60 In women with pelvic inflammatory or N. gonorrhoeae infection, and the exact micro- disease due to N. gonorrhoeae or C. trachomatis, biologic cause of inflammation remains unclear.66 reinfection and repeat pelvic inflammatory dis- M. genitalium and bacterial vaginosis–associated ease are common. Thus, prompt evaluation and microbes have been implicated as potential empirical treatment of male sex partners of causes. Confirmatory studies are necessary to women with pelvic inflammatory disease or cer- define the independent role of M. genitalium in vical infection are essential. If sex partners can- causing pelvic inflammatory disease and long- not be linked to care, expedited treatment of the term sequelae.13 The results of an ongoing clinical partner (e.g., providing prescriptions or medica- trial (ClinicalTrials.gov number, NCT01160640) tions to a patient to take to her partner, without evaluating the addition of metronidazole therapy the clinician examining the partner) is a useful to pelvic inflammatory disease regimens are approach and has been shown to reduce the risk expected in 2015 and should help clarify the role of reinfection.61 that organisms that cause bacterial vaginosis play in the pathogenesis of pelvic inflammatory dis- Unanswered Questions and ease. Anaerobic culture and deep sequencing Unaddressed Needs methods are being used to identify specific bac- terial vaginosis–associated organisms that may be The National Institutes of Health recently con- more likely to cause pelvic inflammatory disease. vened a workshop to identify research needs for For financial and logistic reasons, pelvic in- the improvement of the diagnosis, treatment, and flammatory disease prevention programs that prevention of pelvic inflammatory disease (Ta- are based on screening are simply unavailable in ble 3).62 One of the most important needs for most low-income and middle-income countries, research regarding pelvic inflammatory disease where the burden of pelvic inflammatory dis- and clinical care of women with the disease is ease may be greatest. The global epidemiologic the development of an accurate noninvasive or profile of pelvic inflammatory disease has not minimally invasive test to confirm infection of been well defined. However, because an estimat- the fallopian tubes or inflammatory changes ed 95.5 million C. trachomatis and N. gonorrhoeae that predict long-term reproductive tract disease. infections occur globally among women each Biomarkers of the immune response to C. tracho- year67 and approximately 15% of untreated infec- matis can predict tubal-factor infertility due to tions lead to pelvic inflammatory disease,18 the subclinical pelvic inflammatory disease.36,37 How- global burden of pelvic inflammatory disease is ever, additional biomarkers are needed. Levels of probably substantial. The proportion of infertil- CA-125 and E-cadherin in serum correlate with ity that is tubal-factor infertility — and thus the diagnosis of acute pelvic inflammatory dis- caused primarily by scarring from genital infec-

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Table 3. Research Needs Identified by Clinicians, Public Health Professionals, and Researchers at a 2011 National Institutes of Health Workshop.*

Characterize pathophysiological aspects of disease Determine whether M. genitalium and bacterial vaginosis–associated organisms play a causal role in pelvic inflamma- tory disease and its sequelae Determine whether histopathological endometritis correlates with subclinical pelvic inflammatory disease and its se- quelae Identify biomarkers Identify immune and other biomarkers that correlate with pelvic inflammatory disease and its sequelae, as well as non- invasive tests to detect and measure them Improve disease detection Develop polymicrobial tests for lower genital tract infection Evaluate patient-administered diagnostic tests to improve case finding Determine the individual and combined predictive values of C. trachomatis and N. gonorrhoeae detection, endometrial biopsy, and imaging (MRI and ultrasonography) for the detection of pelvic inflammatory disease Determine most effective treatment Determine benefits of antimicrobial coverage for anaerobes and mycoplasma species Improve oral outpatient regimens Determine benefits of immune-modulating agents Prevent reinfection Improve mechanisms of partner treatment

* The table is adapted from Darville.62

tion — varies widely by setting. In the United addition, the specter of cephalosporin-resistant States, tubal-factor infertility affects 14% of N. gonorrhoeae looms on the horizon. Thus, the couples seeking assisted reproductive technolo- World Health Organization has concluded that gy for infertility68; in sub-Saharan Africa, tubal- the development of vaccines against C. trachoma- factor infertility may be present in 65 to 85% of tis and N. gonorrhoeae is a critical priority for the women who seek infertility care.69,70 prevention of pelvic inflammatory disease and Most clinicians in low-income and middle- its long-term sequelae globally.72 Progress is income settings rely on syndromic management most advanced for C. trachomatis, for which sub- (i.e., the use of genital-symptom algorithms to unit, live, and inactivated vaccines have emerged guide treatment) without diagnostic tests. Be- from basic research for further clinical develop- cause most C. trachomatis and N. gonorrhoeae infec- ment.73 Vaccines and other strategies to prevent tions in women are asymptomatic, the majority pelvic inflammatory disease lie at the heart of of infections are missed. In addition, syndromic efforts to improve women’s diagnosis of vaginal discharge is a poor predic- globally. tor of N. gonorrhoeae and C. trachomatis cervical Dr. Brunham reports holding pending patents (WO/2013/044398; infection. Inexpensive, point-of-care diagnostic US 0027793, and PCT WO/2010/085896, CAN, US, EU, AU) re- tests for C. trachomatis and N. gonorrhoeae that are lated to chlamydia-specific proteins that may compose a Chla- easy to use in low-resource settings are urgently mydia trachomatis vaccine. No other potential conflict of interest 71 relevant to this article was reported. needed. However, the costs and complexities of Disclosure forms provided by the authors are available with screening programs may still be prohibitive. In the full text of this article at NEJM.org.

References 1. Paavonen J, Westrom L, Eschenbach ogy in patients with culture-proved upper Amortegui AJ, Sweet RL. Subclinical pel- D. Pelvic inflammatory disease. In:​ genital tract infection and laparoscopi- vic inflammatory disease and infertility. Holmes KK, Sparling PF, Stamm WE, et cally diagnosed acute salpingitis. Am J Obstet Gynecol 2012;​120:​37-43. al., eds. Sexually transmitted . Surg Pathol 1990;​14:​167-75. 5. Sutton MY, Sternberg M, Zaidi A, St 4th ed. New York:​ McGraw-Hill, 2008. 3. Soper DE. Pelvic inflammatory dis- Louis ME, Markowitz LE. Trends in pelvic 2. Kiviat NB, Wølner-Hanssen P, Eschen- ease. Obstet Gynecol 2010;​116:​419-28. inflammatory disease hospital discharg- bach DA, et al. Endometrial histopathol- 4. Wiesenfeld HC, Hillier SL, Meyn LA, es and ambulatory visits, United States,

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1985-2001. Sex Transm Dis 2005;​32:​778- kusi EA, Totten PA. Detection of novel publications/Publications/​ 201206​ 84. organisms associated with salpingitis, by -Sexually-Transmitted-Infections 6. Bender N, Herrmann B, Andersen B, use of 16S rDNA polymerase chain reac- -Europe-2010.pdf).​ et al. Chlamydia infection, pelvic inflam- tion. J Infect Dis 2004;​190:​2109-20. 33. Centers for Disease Control and Pre- matory disease, ectopic pregnancy and 20. Eschenbach DA, Buchanan TM, Pol- vention. Pelvic inflammatory disease: infertility: cross-national study. Sex lock HM, et al. Polymicrobial etiology of STD treatment guidelines. Atlanta: ​De- Transm Infect 2011;​87:​601-8. acute pelvic inflammatory disease. partment of Health and Human Services, 7. Bohm MK, Newman L, Satterwhite N Engl J Med 1975;​293:​166-71. 2010 (http://www​.cdc​.gov/​std/​treatment/​ CL, Tao G, Weinstock HS. Pelvic inflam- 21. Wasserheit JN, Bell TA, Kiviat NB, et 2010/​pid​.htm). matory disease among privately insured al. Microbial causes of proven pelvic in- 34. Eschenbach DA, Wölner-Hanssen P, women, United States, 2001-2005. Sex flammatory disease and efficacy of Hawes SE, Pavletic A, Paavonen J, Holmes Transm Dis 2010;37:​ 131-6.​ clindamycin and tobramycin. Ann Intern KK. Acute pelvic inflammatory disease: 8. French CE, Hughes G, Nicholson A, et Med 1986;​104:​187-93. associations of clinical and laboratory al. Estimation of the rate of pelvic inflam- 22. Brunham RC, Binns B, Guijon F, et al. findings with laparoscopic findings. Ob- matory disease diagnoses: trends in Eng- Etiology and outcome of acute pelvic in- stet Gynecol 1997;​89:​184-92. land, 2000-2008. Sex Transm Dis 2011;​38:​ flammatory disease. J Infect Dis 1988;​ 35. Wiesenfeld HC, Sweet RL, Ness RB, 158-62. 158:510-7.​ Krohn MA, Amortegui AJ, Hillier SL. 9. Rekart ML, Gilbert M, Meza R, et al. 23. Soper DE, Brockwell NJ, Dalton HP, Comparison of acute and subclinical pel- Chlamydia public health programs and Johnson D. Observations concerning the vic inflammatory disease. Sex Transm Dis the epidemiology of pelvic inflammatory microbial etiology of acute salpingitis. 2005;​32:​400-5. disease and ectopic pregnancy. J Infect Am J Obstet Gynecol 1994;​170:​1008-14. 36. Brunham RC, Maclean IW, Binns B, Dis 2013;​207:​30-8. 24. Brotman RM. Vaginal microbiome Peeling RW. Chlamydia trachomatis: its 10. Anschuetz GL, Asbel L, Spain CV, et and sexually transmitted infections: an role in tubal infertility. J Infect Dis 1985;​ al. Association between enhanced screen- epidemiologic perspective. J Clin Invest 152:​1275-82. ing for Chlamydia trachomatis and Neis- 2011;121:​ 4610-7.​ 37. Robertson JN, Ward ME, Conway D, seria gonorrhoeae and reductions in se- 25. McGregor JA, French JI, Jones W, et al. Caul EO. Chlamydial and gonococcal an- quelae among women. J Adolesc Health Bacterial vaginosis is associated with pre- tibodies in sera of infertile women with 2012;​51:​80-5. maturity and vaginal fluid mucinase and tubal obstruction. J Clin Pathol 1987;​40:​ 11. Ross JD, Hughes G. Why is the inci- sialidase: results of a controlled trial of 377-83. dence of pelvic inflammatory disease fall- topical clindamycin cream. Am J Obstet 38. Wølner-Hanssen P. Silent pelvic in- ing? BMJ 2014;348:​ g1538.​ Gynecol 1994;​170:​1048-59. flammatory disease: is it overstated? Ob- 12. Wiesenfeld H, Cates WJ. Sexually 26. Draper DL, Landers DV, Krohn MA, stet Gynecol 1995;86:​ 321-5.​ transmitted diseases and infertility. In:​ Hillier SL, Wiesenfeld HC, Heine RP. Lev- 39. Brunham RC, Paavonen J, Stevens CE, Holmes KK, Sparling PF, Stamm WE, et els of vaginal secretory leukocyte protease et al. Mucopurulent cervicitis — the ig- al., eds. Sexually transmitted diseases. inhibitor are decreased in women with nored counterpart in women of urethritis 4th ed. New York:​ McGraw-Hill, 2008. lower reproductive tract infections. Am J in men. N Engl J Med 1984;​311:​1-6. 13. Manhart LE, Broad JM, Golden MR. Obstet Gynecol 2000;183:​ 1243-8.​ 40. Amsel R, Totten PA, Spiegel CA, Chen : should we treat 27. Ness RB, Kip KE, Hillier SL, et al. A KC, Eschenbach D, Holmes KK. Nonspe- and how? Clin Infect Dis 2011;​53:​Suppl 3:​ cluster analysis of bacterial vaginosis-as- cific : diagnostic criteria and mi- S129-S142. sociated microflora and pelvic inflamma- crobial and epidemiologic associations. 14. Bjartling C, Osser S, Persson K. Myco- tory disease. Am J Epidemiol 2005;​162:​ Am J Med 1983;​74:​14-22. plasma genitalium in cervicitis and pelvic 585-90. 41. Peipert JF, Boardman L, Hogan JW, inflammatory disease among women at a 28. Patton DL, Moore DE, Spadoni LR, Sung J, Mayer KH. Laboratory evaluation gynecologic outpatient service. Am J Ob- Soules MR, Halbert SA, Wang SP. A com- of acute upper genital tract infection. Ob- stet Gynecol 2012;​206(6):​476.e1-476.e8. parison of the fallopian tube’s response stet Gynecol 1996;87:​ 730-6.​ 15. Bjartling C, Osser S, Persson K. The to overt and silent salpingitis. Obstet Gy- 42. Weström L, Joesoef R, Reynolds G, association between Mycoplasma genita- necol 1989;73:​ 622-30.​ Hagdu A, Thompson SE. Pelvic inflam- lium and pelvic inflammatory disease af- 29. Schappert SM, Rechtsteiner EA. Am- matory disease and fertility: a cohort ter termination of pregnancy. BJOG 2010;​ bulatory medical care utilization esti- study of 1,844 women with laparoscopi- 117:361-4.​ mates for 2006. National Health Statistics cally verified disease and 657 control 16. Haggerty CL, Gottlieb SL, Taylor BD, Reports No. 8. Hyattsville, MD:​ National women with normal laparoscopic results. Low N, Xu F, Ness RB. Risk of sequelae Center for Health Statistics, 2008:​1-29 Sex Transm Dis 1992;​19:​185-92. after Chlamydia trachomatis genital in- (http://www​.cdc​.gov/​nchs/​data/​nhsr/​ 43. Molander P, Finne P, Sjöberg J, Sellors fection in women. J Infect Dis 2010;​201:​ nhsr008​.pdf). J, Paavonen J. Observer agreement with Suppl 2:S134-S155.​ 30. Goyal M, Hersh A, Luan X, Localio R, laparoscopic diagnosis of pelvic inflam- 17. Oakeshott P, Kerry S, Aghaizu A, et al. Trent M, Zaoutis T. National trends in matory disease using photographs. Ob- Randomised controlled trial of screening pelvic inflammatory disease among ado- stet Gynecol 2003;101:​ 875-80.​ for Chlamydia trachomatis to prevent pel- lescents in the emergency department. 44. Sellors J, Mahony J, Goldsmith C, et vic inflammatory disease: the POPI (Pre- J Adolesc Health 2013;​53:​249-52. al. The accuracy of clinical findings and vention of Pelvic Infection) trial. BMJ 31. Centers for Disease Control and Pre- laparoscopy in pelvic inflammatory dis- 2010;​340:​c1642. vention. Sexually transmitted disease sur- ease. Am J Obstet Gynecol 1991;​164:​113- 18. Price MJ, Ades AE, De Angelis D, et al. veillance 2012. Atlanta:​ Department of 20. Risk of pelvic inflammatory disease fol- Health and Human Services, 2013 (http:// 45. Vicetti Miguel RD, Chivukula M, lowing Chlamydia trachomatis infection: www.cdc​ .gov/​ std/​ stats12/​ surv2012​ .pdf)​ Krishnamurti U, et al. Limitations of the analysis of prospective studies with a 32. Sexually transmitted infections in criteria used to diagnose histologic endo- multistate model. Am J Epidemiol 2013;​ Europe 1990-2010. Stockholm:​ European metritis in epidemiologic pelvic inflam- 178:​484-92. Center for Disease Prevention and Con- matory disease research. Pathol Res Pract 19. Hebb JK, Cohen CR, Astete SG, Bu- trol, 2013 (http://ecdc​.europa​.eu/​en/​ 2011;​207:​680-5.

n engl j med 372;21 nejm.org May 21, 2015 2047 The New England Journal of Medicine Downloaded from nejm.org at NORTHSHORE UNIVERSITY HEALTH SYSTEM on February 28, 2017. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. Pelvic Inflammatory Disease

46. Molander P, Sjoberg J, Paavonen J, of some women with pelvic inflammatory 65. Reighard SD, Sweet RL, Vicetti Miguel Cacciatore B. Transvaginal power Doppler disease: a randomized trial. Obstet Gyne- C, et al. Endometrial leukocyte subpopu- findings in laparoscopically proven acute col 2005;106:​ 573-80.​ lations associated with Chlamydia tracho- pelvic inflammatory disease. Ultrasound 56. Hillis SD, Joesoef R, Marchbanks PA, matis, Neisseria gonorrhoeae, and Tricho- Obstet Gynecol 2001;17:​ 233-8.​ Wasserheit JN, Cates W Jr, Westrom L. monas vaginalis genital tract infection. 47. Tukeva TA, Aronen HJ, Karjalainen Delayed care of pelvic inflammatory dis- Am J Obstet Gynecol 2011;​205(4):​324.e1- PT, Molander P, Paavonen T, Paavonen J. ease as a risk factor for impaired fertility. 324.e7. MR imaging in pelvic inflammatory dis- Am J Obstet Gynecol 1993;​168:​1503-9. 66. Burnett AM, Anderson CP, Zwank ease: comparison with laparoscopy and 57. Gottlieb SL, Xu F, Brunham RC. MD. Laboratory-confirmed US. Radiology 1999;​210:​209-16. Screening and treating Chlamydia tracho- and/or chlamydia rates in clinically diag- 48. Sakhel K, Benson CB, Platt LD, Gold- matis genital infection to prevent pelvic nosed pelvic inflammatory disease and stein SR, Benacerraf BR. Begin with the inflammatory disease: interpretation of cervicitis. Am J Emerg Med 2012;​30:​1114- basics: role of 3-dimensional sonography findings from randomized controlled tri- 7. as a first-line imaging technique in the als. Sex Transm Dis 2013;​40:​97-102. 67. Global incidence and prevalence of cost-effective evaluation of gynecologic 58. Scholes D, Stergachis A, Heidrich FE, selected curable sexually transmitted in- pelvic disease. J Ultrasound Med 2013;​ Andrilla H, Holmes KK, Stamm WE. Pre- fections — 2008. Geneva:​ World Health 32:​381-8. vention of pelvic inflammatory disease by Organization, 2012 (http://www​.who​.int/​ 49. Cohen CR, Sinei S, Reilly M, et al. Ef- screening for cervical chlamydial infec- reproductivehealth/publications/​ rtis/​ fect of human immunodeficiency virus tion. N Engl J Med 1996;​334:​1362-6. ​stisestimates/​en/​index​.html). type 1 infection upon acute salpingitis: a 59. Zakher B, Cantor AG, Pappas M, Dae- 68. Centers for Disease Control and Pre- laparoscopic study. J Infect Dis 1998;​178:​ gas M, Nelson HD. Screening for gonor- vention, American Society for Reproduc- 1352-8. rhea and chlamydia: a systematic review tive Medicine, Society for Assisted Repro- 50. Kirkcaldy RD, Bolan GA, Wasserheit for the U.S. Preventive Services Task ductive Technology. 2011 Assisted JN. Cephalosporin-resistant gonorrhea in Force. Ann Intern Med 2014;​161:​884-93. reproductive technology North America. JAMA 2013;​309:​185-7. 60. Ness RB, Randall H, Richter HE, et al. success rates report. Atlanta: ​Department 51. Seña AC, Lensing S, Rompalo A, et al. Condom use and the risk of recurrent pel- of Health and Human Services, 2013 Chlamydia trachomatis, Mycoplasma vic inflammatory disease, chronic pelvic (http://www.cdc​ .gov/​ art/​ pdf/​ 2011-report/​ ​ genitalium, and pain, or infertility following an episode of fertility-clinic/​art_2011_clinic_report- infections in men with nongonococcal pelvic inflammatory disease. Am J Public full​.pdf). urethritis: predictors and persistence af- Health 2004;94:​ 1327-9.​ 69. Cates W, Farley TM, Rowe PJ. World- ter therapy. J Infect Dis 2012;​206:​357-65. 61. Golden MR, Whittington WL, Hands- wide patterns of infertility: is Africa dif- 52. Ness RB, Soper DE, Holley RL, et al. field HH, et al. Effect of expedited treat- ferent? Lancet 1985;2:​ 596-8.​ Effectiveness of inpatient and outpatient ment of sex partners on recurrent or per- 70. Dhont N, van de Wijgert J, Vyankan- treatment strategies for women with pel- sistent gonorrhea or chlamydial infection. dondera J, Busasa R, Gasarabwe A, Tem- vic inflammatory disease: results from N Engl J Med 2005;​352:​676-85. merman M. Results of infertility investi- the Pelvic Inflammatory Disease Evalua- 62. Darville T. Pelvic inflammatory dis- gations and follow-up among 312 infertile tion and Clinical Health (PEACH) Ran- ease: identifying research gaps — pro- women and their partners in Kigali, domized Trial. Am J Obstet Gynecol 2002;​ ceedings of a workshop sponsored by De- Rwanda. Trop Doct 2011;​41:​96-101. 186:929-37.​ partment of Health and Human Services/ 71. Peeling RW. Applying new technolo- 53. Dhasmana D, Hathorn E, McGrath R, National Institutes of Health/National In- gies for diagnosing sexually transmitted Tariq A, Ross JD. The effectiveness of non- stitute of and Infectious Diseases, infections in resource-poor settings. Sex steroidal anti-inflammatory agents in the November 3-4, 2011. Sex Transm Dis 2013;​ Transm Infect 2011;​87:​Suppl 2:​ii28-ii30. treatment of pelvic inflammatory disease: 40:761-7.​ 72. Broutet N, Fruth U, Deal C, Gottlieb a systematic review. Syst Rev 2014;​3:​79. 63. Paavonen J, Miettinen A, Heinonen SL, Rees H. Vaccines against sexually 54. Tepper NK, Steenland MW, Gaffield PK, et al. Serum CA 125 in acute pelvic transmitted infections: the way forward. ME, Marchbanks PA, Curtis KM. Reten- inflammatory disease. Br J Obstet Gynae- Vaccine 2014;32:​ 1630-7.​ tion of intrauterine devices in women who col 1989;96:​ 574-9.​ 73. Brunham RC, Rappuoli R. Chlamydia acquire pelvic inflammatory disease: a 64. Tsai HT, Lee TH, Yang SF, Lin LY, Tee trachomatis control requires a vaccine. systematic review. Contraception 2013;​87:​ YT, Wang PH. Markedly elevated soluble Vaccine 2013;31:​ 1892-7.​ 655-60. E-cadherin in plasma of patient with pel- Copyright © 2015 Massachusetts Medical Society. 55. Ness RB, Trautmann G, Richter HE, vic inflammatory disease. Fertil Steril et al. Effectiveness of treatment strategies 2013;​99:​490-5.

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