The new england journal of medicine Review Article Edward W. Campion, M.D., Editor Pelvic Inflammatory Disease Robert C. Brunham, M.D., Sami L. Gottlieb, M.D., M.S.P.H., and Jorma Paavonen, M.D. elvic inflammatory disease is an infection-induced inflammation From the Department of Medicine, Uni- of the female upper reproductive tract (the endometrium, fallopian tubes, versity of British Columbia, Vancouver, 1 Canada (R.C.B.); the Department of Re- ovaries, 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 vagina or cervix to the upper genital tract, with endometritis as an intermediate stage in the pathogenesis of disease.2 The hall- and the Department of Obstetrics 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 infertility, ectopic pregnancy, and chronic DOI: 10.1056/NEJMra1411426 pelvic pain. 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 Chlamydia trachomatis and Neisseria gonorrhoeae 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 infections are due to sexually transmitted cervical pathogens or bacterial vaginosis–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 tuberculosis 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. n engl j med 372;21 nejm.org May 21, 2015 2039 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. The new england journal of medicine Table 1. Clinical Classification of Pelvic Inflammatory Disease and Likely Microbial Causes. Clinical Syndrome Causes Acute pelvic inflammatory disease Cervical pathogens (Neisseria gonorrhoeae, Chlamydia trachomatis, and (≤30 days’ duration) Mycoplasma genitalium) Bacterial vaginosis pathogens (peptostreptococcus species, bacteroides species, atopobium species, leptotrichia species, M. hominis, Ureaplasma urealyticum, and clostridia species) Respiratory pathogens (Haemophilus influenzae, Streptococcus pneumoniae, group A streptococci, and Staphylococcus aureus) 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 pathogen- cause of cervicitis, endometritis, salpingitis, 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 fallopian tube untreated chlamydial infections progress to clini- epithelium 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 menstruation may be sions within the pelvis 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 bacteria that are Diagnosis found in vaginal flora 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 abdominal pain during or shortly after menses vaginal lactobacilli and overgrowth of a much has been the classic symptom used to identify more complex anaerobic biofilm-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 vaginal discharge, inter- of the fallopian tubes and the peritoneal surface menstrual or postcoital bleeding, dyspareunia, and 2040 n engl j med 372;21 nejm.org May 21, 2015 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 dysuria.34 Fever 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- adhesion 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