Genital chlamydial infections: Epidemiology and reproductive sequelae

Genital chlamydial infections: Epidemiology and reproductive sequelae Willard Cates, Jr., MD, MPH, and Judith N. Wasserheit, MD, MPH Atlanta, Georgia, and Bethesda, Maryland Genital chlamydial infection is increasing and is now more common than gonorrhea. A sizable percentage of chlamydial infections of the lower genital tract in women progress to endometritis and salpingitis. Tubal infertility and ectopic pregnancy are important sequelae. Failure to control chlamydial infections reflects the following four factors: (1) Many cases are mild or asymptomatic; (2) diagnostic tests are expensive and technically demanding; (3) at least 7 days of multiple-dose therapy are currently required; and (4) partner notification is not routinely performed. Thus early identification of infected persons and compliance with curative therapy are less likely than with other sexually transmitted bacterial diseases. (AM J OBSTET GVNECOL 1991 ;164:1771-81.)

Key words: Pelvic inflammatory disease, endometritis, salpingitis, ectopic pregnancy, nonspecific urethritis

During the past two decades, genital chlamydial infections have surpassed gonorrhea as the number one sexually transmitted bacterial infection in the United States.! About 4 million chlamydial infections occur each year at an estimated cost of $2.2 billion for 1990} As with gonorrhea, the most important implications of genital chlamydia are the reproductive health sequelae of upper genital tract infections in women. In addition, chlamydia causes genital tract complications in men. Chlamydia apparently produces less severe symptoms than gonorrhea, but it generally seems to smolder with a minimum of patient awareness until secondary or tertiary problems arise. This review describes the epidemiology and reproductive sequelae of genital chlamydial infections and will concentrate on pelvic inflammatory disease (PID) and the complications of tubal infertility and ectopic pregnancy. The article that follows will elaborate on the effects of chlamydia on pregnancy.; j

"

Epidemiology

Although genital chlamydial infection is not reportable in all 50 states, national trends can be estimated through physician surveys and sentinel surveillance projects. Using the syndrome of nonspecific urethritis (NSU) in men as a proxy for chlamydial infections, incidence levels have remained high in the 1970s and From the DWlSion of STDI HIV PreventIOn, Center for PreventIOn Sennces. Centers for Disease Control, and the STD Branch, Microbiology and InfectIOUS DISeases Program, NatIOnal Institute ofAllergy and Infectious DISeases, NatIOnal Institutes of Health. Reprint requests: Wzllard Cates. Jr.• MD. MPH, Director. DlvlSlon of STDI HIV Prevention, Technical InformatIOn SenJlces (£06), Centers For Dzsease Control. Atlanta. GA 30333.

610129703

1980s. In the United States, the number of visits to private physicians' offices for the diagnosis ofNSU surpassed gonorrhea in 1972 (Fig. 1). The gap has widened in recent years, with NSU now twice as common as gonococcal urethritis in men. This elevated level of NSU is more remarkable when juxtaposed against the pattern of decreasing visits for all conditions to private physicians. Thus the percentage of NSU visits has actually been increasing. A similar picture is found in Great Britain." The British use the term nongonococcal urethritis (NGU) to estimate chlamydial infections. During the 1970s and 1980s, the incidence of NGU reported to British authorities more than doubled. In England and Wales, NGU now accounts for nearly three times as many infections in men as gonorrhea. Another estimate of the annual incidence of genital chlamydial infections was derived from a model that used a ratio of chlamydial to gonococcal infections. 7 The ratio was based on data provided by sentinel sites during the mid-1980s and on a literature review of selected prevalence studies. In 1986 chlamydia was estimated to cause more than 4 million infections in the United States-approximately 2.6 million infections occurred in women, 1.8 million in men, and 250,000 in infants. The ratio of Chlamydia trachomatis to Neisseria gononhoeae infections was influenced by at least five variables besides age and sex. These included race, pregnancy status, choice of contraception, the proportion of infection without symptoms, and sexual preference. Considerably higher chlamydia to gonorrhea ratios were found among whites, pregnant women, oral contraceptive users, and persons without symptoms; lower ratios were found among homosexual men. 1771

1772

Cates and Wasserheit

June 1991 Am J Obstet Gynecol

Consultations (in thousands) 900 800 700

..... :. -

Urethritis

:;.

600

.....

500

."......

400 300

...... ........ ',.

200

'-"'..

......."......., .. ...... .......

....

Gonorrhea

100 0

1966

1970

1975

1980

1985

1989

Fig. 1. Total consultations for nonspecific urethritis and gonorrhea among men in the United States from 1966 to 1989. Source: National Disease and Therapeutic Index (IMS America).

Data from many North American metropolitan areas have also documented the predominance of chlamydial compared with gonococcal infections. For example, in Seattle, a provider-based survey of urethritis in the 1970s found markedly higher rates for NSU than for gonococcal infection." The Seattle NSU to gonorrhea ratio was higher in men seen by private practitioners than in those treated in health department clinics. In Denver the incidence of NGU rose rapidly in the late 1970s and 1980s, and it became the most prevalent sexually transmitted disease in this area by the early 1980s." Chlamydia also is prevalent outside of urban areas. In a rural province in Southern Quebec (Canada), prospective surveillance of genital infections found that C. trachornatls was three times more frequent than N. gonorrhoeae. fIO In Colorado Springs, Col., similar distributions occurred. II Chlamydia is apparently more difficult to transmit than gonorrhea. 12 Based on extrapolations from partner notification programs, within couples with discordant infection status, men will transmit C. trachornatis to their female partners 40% of the time, whereas women will transmit the infection to their male partner 32% of the time. Because these infection risks are based on the average frequency of intercourse for each couple, the transmission probability from a single coital episode is probably much lower. During the past 5 years, a plethora of articles have been published on the prevalence and characteristics of chlamydial infections in women. These have sharpened the epidemiologic focus regarding the magnitude of infection and the consistency of risk factors. Depending on the population of women screened, the

prevalence of genital chlamydia appears to range from 8% to 40%, with a typical median of 15%.13-15 Demographic risk markers for chlamydia have been remarkably uniform-young age, unmarried status, and lower socioeconomic conditions predict higher rates. Other risk factors for cervical chlamydia in women are anatomic (ectopy), behavioral (number of sexual partners), microbiologic (concurrent gonorrhea), and hormonal (use of oral contraception). Because of the consistency of these risk markers and factors and the financial and technical constraints on routine testing for C. trachomatis, attempts have been made to generate a sensitive set of predictors of chlamydial infection on the basis of nonlaboratory data from patient histories or physical examinations. For example, among patients attending a sexually transmitted disease clinic in Denver, multiple logistic regression was used to define sets of risk markers and factors that would identify patients with chlamydial infections. lfi In heterosexual men with urethral discharge, among whom 27% were infected with C. trachomatis, Gram's stain evidence of nongonococcal urethritis, young age, history of urethral discharge for more than a week, and absence of dysuria were factors that identified subgroups with a prevalence as high as 64%. In women, among whom the overall prevalence of infection was 17%, young age, unmarried status or a contact with gonorrhea, presence of cervical erythema or mucopus, evidence of PID, and absence of recent antibiotic use identified subgroups with a prevalence up to 61 %. On the basis of these data, the investigators suggested a strategy of empiric therapy for women with four or more of these factors, laboratory testing for women with two or three of the factors, and neither testing nor

Reproductive sequelae of chlamydial infection

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1773

Table I. Detection of C. trachomatis and N. gonoTThoeae among women with acute PID: Selected studies C. tr(U;hOTnatts

Study (yr) Europe Adler et al.50 (1982) Moller et al.46 (l 981) Eilard et aI. 58 (l976) Paavonen et al."·" (1979, 1980, 1981) Ripa et al." (\980) Mardh et al!'·48 (1977, 1981) Henry-Suchet et al. 45 (1980) Moss et al. 56 (1986) Stacey et al. 57 (1987) Gjonnaess et al. 49 (1982) Osser et al. 52 (1982) North America Sweet et al.G' (1981) Hemsell et al. 65 (1988) Thompson et al. 62 (1980) Brunham et al. 66 (1988) Eschenbach et al. 60 (1975) Sweet et al. 6'.... (1977, 1980) Cromer et al. 6' (1987) Bowie et aI. 59 (1981)

CerV1X

5% 22% 27% 32% 33% 38% 38% 41% 44% 46% 47% 5% 7% 10% 14% 20% 27% 39% 51%

I

Tubes

9% 30% 24%

I

N. gonorrhoeae

Antzbody

Ceroix

31% 20%

18% 5% 32% 26% 19% 17% 0% 9% 27% 8% 20%

26% 46% 37%

16%

40% 51%

0%

23%

10% 8% 2%

40% 20%

46% 56%* 80% 42% 44% 40% 27% 35%

I

Tubes

5% 7% 25% 0% 23% 33% 18% 13%

Modified from Cates W Jr, Rolfs RT, Aral SO. Sexually transmitted diseases, pelvic inflammatory disease, and infertility: an epidemiologic update. Epidemiol Rev 1990;12:199-220, by permission. *Endometrial specimens. treatment for the remainder. In their population this would result in antibiotic coverage of 98% of infected women while testing only 68% of clinic patients and unnecessarily treating only 9%. Such analyses are useful primarily for local purposes to determine the actual yield of particular screening approaches. Other recent attempts to design such algorithms l7 .• ! have varied depending on the population to which they are applied. Thus the use of specific demographic markers, medical histories, and physical examination results to exclude persons from screening must be carefully tailored to the type of facility, characteristics of the patients, and availability of resources. Natural history

The natural history of the chlamydial infections of the lower genital tract is uncertain. Many chlamydial infections are asymptomatic or not easily recognized on clinical grounds alone. Asymptomatic carriage in both men and women may be prolonged, further increasing the potential for transmission. 22 As many as 25% of men identified with urethral infections caused by C. trachomatis have no signs or symptoms of infection.'"2. These asymptomatic men may be an important source of infection to women unless identified through screening tests and appropriately treated!' As many as 70% of women with cervical infection caused by C. trachomatis may be essentially without symptoms;6 although mild symptoms of vaginal discharge, bleeding, lower abdominal pain, or dysuria may be present. 26. 2' Asymptomatic infection of the urethra

and rectum caused by C. trachomatis can accompany infection of the cervix!8.29 In some women, C. trachomatis infection of the urethra results in symptomatic urethritis with dysuria and pyuria. 30 Furthermore, asymptomatic chlamydial infection may lead to epidemiologic patterns that differ substantially from those of gonococcal infection. A recent study in Baltimore characterized chlamydial infections as "prevalent" infections because, in contrast to the "incident" pattern of gonococcal disease, chlamydia rates did not vary significantly by reason for clinic visit, number of sexual partners, or classification of partners as new, regular, or casual." The percentage of untreated chlamydia of the lower genital tract that ascends may be quite high. One study estimated that approximately 8% of untreated chlamydial infections progress to salpingitis3., however, among women treated for gonorrhea with penicillin whose subsequent culture showed simultaneous cervical chlamydia, 40% had developed signs of upper genital tract infection during the 7-day follow-up interval." Other studies have shown that cervical chlamydia treated only with f3-lactam antibiotics tends to hibernate in the endometrium." Finally, douching may playa role in producing upper genital tract infection in women with chlamydia of the lower genital tract. 35 Oral contraceptives appear to promote acquisition of chlamydial infection of the lower genital tract. 3b· 37 For example, in a recent randomized prospective study that controlled for differences in demographic factors, sexual behavior, and cervical ectopy, oral contraceptive

1774 Cates and Wasserhelt

June 1991 Am J Obstet Gynecol

Symptoms of PIO

PIO Without Visual Salpingitis

No PIO Symptoms

Fig. 2. Schematic representation of symptomatic and asymptomatic PID.

users developed 70% more chlamydial and gonococcal infections than women relying on intrauterine devices and tuballigation. 38 Cervical ectopy appeared partially to explain the increased risk of chlamydial infection but did not contribute to the higher gonorrhea rates. A study in guinea pigs inoculated intravaginally supports these human data. 39 Oral contraceptive-treated guinea pigs were more likely than control animals to have prolonged chlamydial infection of the lower tract, with higher nu~bers of organisms and delayed appearance of local antibodies. Whether the increase in cervical chlamydial infection associated with oral contraception affects the risk of endometrial or tubal infection is unclear.'6 In Seattle, women with cervical chlamydia who used oral contraception were less likely to develop symptoms of upper genital tract infection than those using no contraceptives"o Whether oral contraceptives truly reduced tubal infection or possibly suppressed inflammatory symptoms could not be resolved by this study. In addition, these data are inconsistent with results from animal models 4l and analytic studies of tubal factor infertility.42 Finally, chlamydial cervicitis may alter the natural history of cervical atypia. Recent preliminary data from Finland indicate that women with persistent koilocytotic atypia were almost three times as likely to have chlamydial infection (alone or together with gonorrhea) as were women in whom koilocytosis resolved. Although the association did not reach statistical significance, it is consistent with other data linking chlamydial infections to an increased risk of cervical neoplasia." Sequelae: PID

Both microbiologic and serologic measures have established C. trachomatis as an important sexually transmitted organism leading to upper genital tract infec-

tion." However, the rate at which chlamydial and gonococcal organisms have been recovered in patients with symptoms of PID varies widely. This variation is probably from differences among the populations studied, in the time period during which the investigations took place, in methods used to recover the organisms, and in the severity of infection. In both Europe and North America, more recent investigations4 '.67 have generally found a higher proportion of C. trachomatis than N. gonol'l'hoeae in women with symptoms of PID (Table I). In Scandinavia, between one quarter and one half of PID was associated with culture, serologic evidence, or both of C. trachomatis infection. Chlamydia has also been isolated in as many as 51 % of some North American populations.'" In nearly all studies of women with symptoms of PID in whom abdominal cultures were taken, chlamydia was isolated at a lower rate from tubal than from cervical specimens (Table I). This is not unexpected, since extraluminal swabs may not be as efficient in obtaining organisms as endocervical techniques and smaller numbers of organisms may reach the tubes than reach the cervix. Moreover, local neutralizing antibodies may limit culture sensitivity at the intratubal level. Detection of chlamydia antibodies, indicative of either present or past infection, was usually more frequent than isolation of organisms from the cervix or tubes. Based on our evolving knowledge of PID, asymptomatic ("silent") or "atypical" syndromes have assumed a greater importance (Fig. 2). Because of its smoldering nature, chlamydial infection plays a key role in this problem. Chronic, subacute, or latent endometrial and tubal infection is probably present in a large number of women, but a consensus definition of these clinically subtle infections is lacking. 58 Moreover, the magnitude of the problem is unknown. Endometritis has been

Reproductive sequelae of chlamydial infection

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1775

Table II. Case-control studies of previous C. trachomatls infection and subsequent tubal infertility Ftndlllgs of antIbody posltwe / tubal occlusIOn

C trachomatls

Study populatIOns

Study/ location (yr)

antIbody level

Punnonen et al.,75 Turku, Finland (1979) Henry-Suchet et al.,45 Paris, France (1980) Ballard et al.,'6 Johannesburg, South Africa (1981) Jones et al.,77 Indianapolis, Ind. (1982) Moore et a1. 7" Seattie, Wash. (1982) Gump et al.,'9 Burlington, Vt. (1983) Cevenini et al.,80 Bologna, Italy (1982) Padjen et al.,81 Leyden, The Netherlands (1984) Conway et al.,82 Bristol, England (1984) Kane et al.," London, England Battin et aI., 84 Los Angeles, Calif. (1984) Brunham et al.,85 Winnipeg, Canada (1985) Moller et al.,"6 Aarhus, Denmark (1985) Kelver et al.,"7 Galveston, Texas (1989) Hawes et al.,88 Melbourne, Australia (1986) Guderian et al.,'9 Los Gatos, Calif. (1986) Quinn et al.,90 Toronto, Canada (1987) Anestad et al.,91 Oslo, Norway (1987) Reniers et al.,92 Franceville, Gabon (1989) Sellors et aI.,93 Hamilton, Canada (1988) Minassian et al.,94 Philadelphia, Pa. (1990)

MIF 2: 1: 16

Infertile women with abnormal HSG Infertile women with normal HSG

91 51

MIF 2::64

Infertile women with tubal obstruction Infertile women without tubal obstruction

26 4

MIF2:1:8

Infertile women with tubal disease Pregnant women

87 38

MIF 2:1 : 8

Infertile women with chlamydia antibody Infertile women without chlamydia antibody

75 28

MIF 2:1 :32

Infertile women With adhesions Infertile women Infertile women Infertile women

75 21 0 64 28

MIF 2:1: 16

with tubal occlusion without tubal conditions with abnormal HSG with normal HSG

(%)

MIF 2:1:8

Infertile women with salpingitis Infertile women without salpingitis

90 27

EIA

Infertile women with inflammatory tubal abnormalities Infertile women without tubal abnormalities

83 16

MIF2:1:32

Infertile women with tubal damage Infertile women without tubal damage

75 31

MIF 2:1: 8

Infertile women with hydrosalpinx Infertile women with normal tubes

41 12

MIF 2:1 : 32

Infertile women with tubal disease Infertile women without tubal disease

94 86

MIF 2:1: 32

Infertile women with tubal damage Infertile women without tubal damage

72 9

MIF 2:1 :32

Infertile women with abnormal HSG Infertile women with normal HSG

33 13

MIF 2:1: 16

Infertile women with posItive chlamydia serology Infertile women with negative chlamydia serology

35

MIF 2:1: 160

Infertile women with tubal damage Infertile women for other reasons Pregnant women

67 7 10

MIF 2:1 :32

Infertile women with tubal disease Infertile women with normal tubes

83 16

MIF 2:1: 32

Infertile women with tubal occlusion Infertile women with ovulation defects Normal women Infertile women with tubal occlusion Infertile women with normal tubes Pregnant women Infertile women with tubal obstruction Infertile women with normal tubes Pregnant women Infertile women undergoing tuboplasty Women with tubal ligation Women having hysterectomy Infertile women with chlamydia antibody Infertile women without chlamydia antibody

71 19 16 91

MIF2:1:8 MIF 2:1 :64 EIA EIA

MIF, Microimmunofluorescence; HSG, hysterosalpingogram; EIA, enzyme immunoassay; NA, not available.

77

55

47 N/A 81 37 33 87 14

1776 Cates and Wasserheit

June 1991 Am J Obstet Gynecol

Table III. Studies comparing both chlamydial and gonococcal antibodies associated with tubal infertility Chlamydial antibodies Study/ locatIOn (yr)

Mabey et al.,YS The Gambia (1985) Tjiam et al.,"" The Netherlands (1985)

Robertson et al.,97 Bristol, England (1987)

Miettmen et al.,"s Tampere, Finland (1990) WHO Multicenter99 (unpublished) (1990)

DeMuylder et al.,IOO Gweru, Zimbabwe (1990)

Study populatIOns

%

Tubal infertility Pregnant women Tubal infertility Infertile-normal tubes Blood donors Tubal infertility Infertile-normal tubes Barrier contraceptives Sterilization Tubal infertility Infertile-normal tubes Tubal infertilIty Infertile-normal tubes Pregnant women Tubal infertility Infertile-normal tubes Pregnant women

I

Gonococcal antibodzes

I

RelatIVe risk

%

68 35 21 0

1.9 (1.2-3.1) 1.0

68 27 61 25

0 73 34

1.0 1.9 (1.3-2.9) 0.9 (0.5-1.5)

4 2 3

1.0

25

0.7 (0.4-1.2)

4

NS

38 46 7

1.0 11.1 (3.1-40.3) 1.0

5 14 0

1.0

55 30

3.9 (2.1-7.3) 1.4 (0.8-2.3)

44 17

3.7 (1.3-10.5) 1.0 (0.3-2.6)

24 39 5

1.0 8.7 (3.6-22.2) 0.9 (0.4-3.3)

18 52 25

1.0 20.7 (7.5-61.7) 8.3 (2.6-29.6)

7

1.0

5

1.0

0:

1.0

Relative nsk 2.4 (1.4-4.1) 1.0 P < 0.1

WHO, World Health Organization; NS, not significant.

found in 40% of women with cervicitis who had no symptoms of PID at the time of referral."Y Conversely, in three of nine women with symptoms of PID but normal external tubal serosa at laparoscopy, endometrial biopsy specimens revealed plasma cell endometritis; moreover, several weeks later the endometrial infection eventually led to salpingitis. 70 Thus PID, which both causes symptoms and also produces visually detectable salpingitis, probably accounts for less than half of the total cases. After a decade of using the term "acute salpingitis" to provide specific diagnoses, clinical evidence now appears to favor a more sensitive definition of PID. Not only does the upper genital tract infection affect more than just the fallopian tubes but also the tubes themselves can be involved without visual evidence of salpingitis. Future efforts to identify women with smoldering upper genital tract infection will have to rely on atypical symptoms (e.g., abnormal or increased bleeding) or biochemical markers (e.g., tumor-associated trypsin inhibitor and Creactive protein). Sequelae: Tubal infertility

Acute salpingitis, whether related to C. trachomatis, N. gonorrhoeae, both organisms, or neither, is causally related to tubal infertility.71 However, silent salpingitis accounts for a sizable proportion of tubal infertility, probably the majority. Nearly all investigations have found that more than half of the women with documented tubal occlusion report no history of previous

PID despite serologic evidence of past chlamydial infection. 72 . 73 Moreover, morphologic and physical analyses of tubal epithelium from women with distal tubal obstruction found extensive ultrastructural damage, even in those without knowledge of previous PID. 74 A large number of investigations from 14 countries (Table II) have examined the relationship between serologic evidence of past chlamydiaI infection and tubal infertility.74-94 Despite wide variations in design, these studies have uniformly found a significant association between tubal occlusion and serologic evidence of prior chlamydial infection. In addition, five of the six additional studies,9S-loo which included both chlamydial and gonococcal antibodies (Table III), implied independent etiologic associations between the infections and tubal infertility. Only one study in Bristol, England, found no relation to previous gonococcal infection. Cohort studies verify the link between sexually transmitted diseases, PID, and tubal infertility. In Lund, Sweden, among wome~ with symptoms of laparoscopically verified salpingitis, similar levels of tubal occlusion occurred regardless of whether gonorrhea, chlamydia, both organisms, or neither was isolated from the cervix. lol 102 In Winnipeg further evidence of PID sequelae was confirmed in a study of 50 women with laparoscopically verified acute salpingitis. 66 Of the 50 women, 23 attempted to become pregnant and had a subsequent evaluation to determine their fertility status. Seven of 13 women with nongonococcal infection had an adverse reproductive outcome compared

Reproductive sequelae of chlamydial infection

Volume 164 t"umber 6, Part 2

1777

Table IV. Case-control studies of previous C. trachomatzs infections and subsequent ectopic pregnancy Study/locatwn (yr)

Svenson et al.,'" Lund, Sweden (1985) Brunham et al.,'" Winnipeg, Canada (1986) Hartford et al.,"5 Los Angeles, Calif. (1987) Robertson et al., 116 Southampton, England (1988) Walters et al., 117 San Antonio, Texas (1988) Chaim et al.,'" Beer Sheva, Israel (1989) Miettinen et al., 9' Tampere, Finland (1990) Chow et al.,"'l Los Angeles, Calif. (1990) Sherman et al.,'2~ Seattle, Wash. (1990) DeMuylder et al., 100 Gweru, Zimbabwe (1990)

PopulatlOlI

Chlamvdw antibodv . (%) .

Relatzve rISk crude/adjusted

56 84 44 21

3.1

56 18 22

2.5

112 Women with EP 56 Postsalpingitis 56 Other 86 Pregnant women 50 Women with EP 36 Without risk factors 14 With IUD/TL 49 Pregnant women 24 Women with EP 10 Tubal disease 14 No tubal disease 50 Women with EP 50 Pregnant women

50 0 32 4

7.9 1.0

60 Women with EP 60 Pregnant women

66 20

6.6 (adjusted) 1.0

35 Women with EP 294 Healthy women 20 Infertile women with EP history 28 Infertile women with normal tubes 306 Women with EP 266 Pregnant women 135 Women with EP 192 Random women in prepaid health plan 60 Women with EP 39 Abnormal tubes 21 Normal tubes 104 Pregnant women

32 8 40 7 71 39

4.9 1.0 5.7 1.0 2.4 (adjusted) 1.0 2.1 (adjusted) 1.0

26 5 7

4.8 0.9 1.0

1.0

1.0 a

EP, Ectopic pregnancy; UD/TL, intrauterine device/tubal ligation.

with none of 10 women with gonococcal infection (P = 0.007). Two factors were associated with adverse reproductive outcome: four of the seven infertile women had initial tubal abscesses, and three had evidence of C. trachomatis. Chlamydia apparently causes more severe subclinical tubal inflammation and, ultimately, tubal damage than other agents despite its more benign-appearing symptoms and signs. IO:l· lo5 Colonization of the fallopian tube by C. trachomatis has been found in infertile women without symptoms in the absence of laparoscopic signs of active pelvic infection. lO(' The severity of tubal damage despite mild clinical symptoms is probably because chlamydial salpingitis is more chronic than salpingitis caused by other organisms. This hypothesis is supported by the low prevalence of immunoglobulin M antibody to chlamydia among women with acute salpingitis. I" The mechanism that accounts for tubal occlusion after chlamydial infection is unknown. An indirect and long-term process may be responsible. Animal studies have demonstrated that single chlamydial infections have been self-limiting with little residual damage; however, repeated chlamydial infection eventually produces tubal occlusion and infertility.lo7 Serial inoculations of chlamydia directly into the fallopian tube of pig-tailed monkeys result in intratubal adhesions and

distal tubal obstruction. lOS Similar histopathologic findings occurred after tubal challenge that followed repeated chlamydial cervical infection. lOY Whether this represents immune-mediated tubal destruction or exacerbation of chronic, active chlamydial infection is not clear." o 'Y- Interferon may also be involved with chlamydial mechanisms of pathogenesis. I " Untreated chlamydial salpingitis may show symptoms of resolution in the face of progressive damage. Moreover, in mice, treatment with tetracycline had to be started early in the course of tubal infection to have any influence in reducing infertility. "~ Sequelae: Ectopic pregnancy

Ectopic pregnancy is also associated with prior chlamydial PID. Several case-control studies""""O have demonstrated an association between chlamydial infection and ectopic pregnancy, with adjusted relative risks ranging between 2.4 and 7.9 (Table IV). The cohort study of salpingitis in Lund, Sweden, provides the strongest etiologic evidence of an association between PID and ectopic pregnancy.'"' Of 544 women with acute salpingitis proved at laparoscopy, 7o/c of the first pregnancies in these women were ectopic. Among control women with no acute salpingitis, less than lo/c of the subsequent pregnancies were ectopic. 10" Case-control studies of ectopic pregnancy that in-

1778 Cates and Wasserhelt

corporated serologic tests for chlamydial infection have also shown strong associations (Table IV). The relationship between chlamydial serologic findings and ectopic pregnancy was particularly high among women who did not use intrauterine devices at conception. In England, chlamydial antibodies were more than two times more frequent than gonococcal antibodies among women with ectopic pregnancy.116 However, evidence of previous infection with both these organisms was significantly higher in women with ectopic pregnancy than in the those with intrauterine pregnancies. In addition, an independent association between C. lraehorTUltis and ectopic pregnancy was found in a recent study from the United States that controlled for douching as a risk behavior. 119 Moreover, "silent" salpingitis may also be related to ectopic pregnancy. m Among 27 women who had an ectopic pregnancy after attending an infertility clinic, previous laparoscopy had indicated "normal" tubal morphologic findings in 12 (44%). Eight fallopian tubes were available from these 12 women for histologic examination after the ectopic pregnancy. All eight had evidence of ongoing, low-grade salpingitis. These findings suggest that laparoscopy cannot exclude smoldering intraluminal tubal disease in some women with normal serosal findings. Conclusion

Genital chlamydial infections remain an important cause of preventable reproductive morbidity in the United States. During the past two decades, we have learned much about the factors related to infection with C. traehomatis and the insidious sequelae that eventually result. Failure to control chlamydial infections is a reflection of the following four factors: (I) Both symptoms and signs of chlamydial infection are often either extremely mild or totally absent; (2) tests for C. lraehorTUltis are expensive and technically demanding; (3) at least 7 days of multiple-dose therapy are necessary to eradicate the organism; and (4) partner notification is not routinely performed for patients with chlamydial syndromes. Together these factors mean that early identification of infected individuals and compliance with curative therapy are less likely to occur with chlamydial infection than with other bacterial sexually transmitted diseases. However, when aggressive programs to control chlamydia are undertaken by communities, a measurable impact on lowering these smoldering genital infections can result. I" 121

June 1991 Am J Obstet Gynecol

3.

4. 5. 6.

7.

8. 9. 10. II. 12.

13. 14. 15. 16.

17.

18.

19.

20. 21.

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23. Stamm WE, Koutsky LA, Benedetti JK, Jourden JL, Brunham RC, Holmes KK. Chlamvdw trachomatis urethral infections in men. Prevalence, risk factors, and clinical manifestations. Ann Intern Med 1984;100:47-51. 24. Stamm WE, Cole B. Asymptomatic Chlamvdla trachomatis urethritis in men. Sex Transm Dis 1986;13:163-5. 25. Stamm WE. Diagnosis of Chlam.vdza trachomatl5 genitourinary infections. Ann Intern Med 1988;108:710-17. 26. Schachter J, Stoner E, Moncada J. Screenmg for chlamydial infections in women attending family planning clinics. WestJ Med 1983;138:375-9. 27. Brunham RC, Paavonen J, Stevens CE, et al. Mucopurulent cervicitis-the ignored counterpart in women of urethritis in men. N Engl J Med 1984;311: 1-6. 28. Jones RB, Rabinovitch RA, Katz BP, et al. Chlamvdla trachomatis in the pharynx and rectum of heterosexual patients at risk for genital infection. Ann Intern Med 1985;102:757-62. 29. Jones RB, Katz BP, van der Pol B, Caine VA, Batteiger BE, Newhall WJ. Effect of blind passage and multiple sampling on recovery of Chlamydia trachomat15 from urogenital specimens. J Clin Microbiol 1986;24: 1029-33. 30. Stamm WE, Wagner KF, Amsel R, et al. Causes of the acute urethral syndrome in women. N Engl J Med 1980;303:409-15. 31. Hook EW, Reichart CA, Ray P. et al. Comparative epidemiology of gonococcal and chlamydial infections in Baltimore STD clinic patients. In: Bowie WR, Caldwell HD, Jones RB, et aI., eds Chlamydial infections. New York: Cambridge University Press. 1990: 580-3. 32. Westrom L. Chlamydial and gonococcal infections in a defined population of women. In: Mardh P-A, ed. Chlamydw trachomat15 in genital and related infections. Stockholm, Sweden: Almquist and Wiksell. 1981:152-7. 33. Stamm WE, Guinan ME, Johnson C, Starcher T, Holmes KK, McCormack WM. Effect of treatment regimens for N. gonorrhoeae on simultaneous infection with C. trachomat15. N Engl J Med 1984;310:545-9. 34. Sweet RL, Schachter J, Robbie MO. Failure of r3-lactam antibiotics to eradicate Chlamydia trachomat15 in the endometrium despite apparent clinical cure of acute salpingitis. JAMA 1983;250:2641-5. 35. Wolner-Hanssen P, Eschenbach DA, Paavonen J, et al. Association between vaginal douching and acute pelvic inflammatory disease. J AMA 1990;263: 1936-41. 36. Washington AE, Gove S, Schachter J, Sweet RL. Oral contraceptives, Chlamydw trachomatl5 infection, and pelvic inflammatory disease: a word of caution about protection. JAMA 1985;253:2246-50. 37. Cates W Jr, Washington AE, Rubin GL, Peterson HB. The pill, chlamydia, and PID. Fam Plann Perspect 1985; 17: 175-6. 38. Louv WC, Austin H. Perlman J, Alexander WJ. Oral contraceptive use and the risk of chlamydial and gonococcal infections. AM J OBSTET GYNECOL 1989; 160:396402. 39. Rank RG, Barron AL. Specific effects of estradiol on genital mucosal antibody response in chlamydial ocular and genital infections. Infect Immunol 1987;55:2317-9. 40. Wolner-Hanssen P, Eschenbach DA, Paavonen J. et al. Decreased risk of symptomatic chlamydial pelvic inflammatory disease associated with oral contraceptive use. JAMA 1990;263:54-9. 41. Barron AL, Pasley IN, Rank RG, et al. Chlamydial salpingitis in female guinea pigs receiving oral contraceptives. Sex Transm Dis 1988;15:169-73. 42. Cramer DW, Goldman MB, Schiff I. et al. The relationship of tubal infertility to barrier method and oral contraceptive use. JAMA 1987;257:2446-50. 43. Yia-Outinen A, Lehtinen M, Romparrien U, et al. Chlam.vdza trachomat15: a risk factor of persistent koilocytotic atypia. In: Bowie WR, Caldwell HD, Jones RB. et aI.,

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laparoscopy: what is the appropriate site to sample? AM j OBSTET GYNECOL 1980;138:985-9. Hemsell DL, Nobles Bj, Heard MC, et al. Upper and lower reproductive tract bacteria in 126 women with acute pelvic inflammatory disease: microbial susceptibility and clinical response to four therapeutic regimens. j Reprod Med 1988;33:799-805. Brunham Re, Binns B, Guijon F, et al. Etiology and outcome of acute pelvic inflammatory disease. j Infect Dis 1988;158:510-7. Cromer EA, Heald FP. Pelvic inflammatory disease associated with Neisseria gonorrlweae and Chlamydia trachomatlS: clinical correlates. Sex Transm Dis 1987;14: 125-9. Wolner-Hanssen PW, Kiviat NB, Holmes KK. Atypical pelvic inflammatory disease: subacute, chronic, or subclinical upper genital tract infection in women. In: Holmes KK, Mardh P-A, Sparling PF, et aI., eds. Sexually transmitted diseases. 2nd ed. New York: McGraw-Hili, 1990:615-20. Paavonen j, Kiviat NB, Brunham RC, et al. Prevalence and manifestations of endometritis among women with cervicitis.· AM j OBSTET GYNECOL 1985;152:280-4. Paavonen j, Aine R, Teisala K, et al. Comparison of endometrial biopsy and peritoneal fluid cytologic testing with laparoscopy in the diagnosis of acute pelvic inflammatory disease. AM j OBSTET GYNECOL 1985;151:64550. Westrom L. Pelvic inflammatory disease: bacteriology and sequelae. Contraception 1987;36:111-28. Moore DE, Cates W Jr. Sexually transmitted diseases and infertility. In: Holmes KK, Mardh P-A, Sparling PF, et aI., eds. Sexually transmitted diseases. 2nd ed. New York: McGraw-Hill, 1990:763-9. Cates W jr. Sexually transmitted organisms and infertility: the proof of the pudding. Sex Transm Dis 1984; 11: 113-6. Patton DL, Moore DE, Spadoni LR, et al. A comparison of the fallopian tube's response to overt and silent salpingitis. Obstet Gynecol 1989;73:622-30. Punnonen R, Terho P, Nikkanen V, et al. Chlamydial serology in infertile women by immunofluorescence. Fertil Steril 1979;31 :656-9. Ballard RC, Fehler HG, Duncan MO, et aI. Urethritis and associated infections in johannesburg-the role of Chlamydia trachomatlS. Afr j Sex Transm Dis 1981; I: 24-6. jones RB, Ardery BR, Hui SL, et aI. Correlation between serum antichlamydial antibodies and tubal factor as a cause of infertility. Fertil Steril 1982;38:553-8. Moore DE, Sapdoni LR, Foy HM, et al. Increased frequency of serum antibodies to Chlamydia traclwmatlS in infertility due to distal tube disease. Lancet 1982;ii: 574-7. Gump DW, Gibson M, Ashikaga T. Evidence of prior pelvic inflammatory disease and its relationship to Chlamydia trachomatis antibody and intrauterine contraceptive device use in infertile women. AM j OBSTET GYNECOL 1983;146:153-9. Cevenini R, Possati G, LaPlaca M. Chlamydia trachomatlS infection in infertile women. In: Mardh P-A, Holmes KK, Oriel Dj, et aI., eds. Chlamydial infections. Amsterdam, The Netherlands: Elsevier Biomedical Press, 1982:189-92. Padjen A, Nash LD, Fiscelli T. The relationship between chlamydia antibodies and involuntary infertility. Fertil Steril 1984;41:97S-8S. Conway D, Glazener CMA, Caul EO, et aI. Chlamydial serology in fertile and infertile women. Lancet 1984;i: 191-3. Kane jL, Woodland RM, Forsey T, et al. Evidence of chlamydial infection in infertile women with and without fallopian tube obstruction. Fertil Steril 1984;42:832-8.

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84. Battin DA, Barnes RB, Hoffman DI, et al. Chlamydia traclwmatis is not an important cause of abnormal postcoital tests in ovulating patients. Fertil Steril 1984; 42:233-8. 85. Brunham RC, MacLean IW, Binns B, et al. Chlamydia trachomatis: its role in tubal infertility. j Infect Dis 1985; 152: 1275-82. 86. Moller BR, Taylor-Robinson D, Furr PM, Toft B, Allen j. Serological evidence that chlamydiae and mycoplasmas are involved in infertility of women. j Reprod Fertil 1985;73:237-40. 87. Kelver ME, Ngamani M. Chlamydial serology in women with tubal infertility. Int j Fertil 1989;34:42-45. 88. Hawes LA, Gilbert GL. Seroepidemiology of Chlamydia traclwmatis infection in infertile women in Melbourne. Med j Aust 1986;45:497-9. 89. Guderian AM, Trobough GE. Residues of pelvic inflammatory disease in intrauterine device users: a result of intrauterine device or Chlamydia trachomatis infection? AMj OBSTET GYNECOL 1986;154:497-503. 90. Quinn PA, Petrie M, Barkin M, et aI. Prevalence of antibody to Chlamydia trachomatis is spontaneous abortion and infertility. AMj OBSTET GYNECOL 1987;156:291-6. 91. Anestad G, Lunde 0, Moen M, et al. Infertility and chlamydial infection. Fertil Steril 1987;48:787-90. 92. Reniers j, Collet M, Frost E, et al. Chlamydial antibodies and tubal infertility. Intj Epidemiol 1989;18:261-3. 93. SellorsjW, Mahony jB, Chernesky MA, et al. Tubal factor infertility: an association with prior chlamydial infection and asymptomatic salpingitis. Fertil Steril 1988; 49:451-7. 94. Minassian SS, Wu CH, jungkind D, Gocial B, Filer RB, Glassner M. Chlamydial antibody, as determined with an enzyme-linked immunosorbent assay, in tubal factor infertility. j Reprod Med 1990;35: 141-45. 95. Mabey DCW, Ogbaselassie G, RobertsonjN, HeckelsjE, Ward ME. Tubal infertility in the Gambia: chlamydial and gonococcal serology in women with tubal occlusion compared with pregnant controls. Bull WHO 1985;63: 1107-13. 96. Tjiam KH, Zeilmaker GH, Alberda AT, et al. Prevalence of antibodies to Chlamydia trachomatis, Nrnseria gonorrhoeae, and Mycoplasma hominis in infertile women. Genitourin Med 1985;61:175-8. 97. Robertson jN, Ward ME, Conway D, Caul EO. Chlamydial and gonococcal antibodies in sera of infertile women with tubal obstruction. j Clin Pathol 1987;40: 377-83. 98. Miettinen A, Heinonen PK, Teisala K, Hakkarainen K, Punnonen R. Serologic evidence for the role of Chlamydia trachomatis, Nrnseria gonorrlweae, and Mycoplasma hommis in the etiology of tubal factor infertility and ectopic pregnancy. Sex Transm Dis 1990;17:10-4. 99. WHO Task Force on the Prevention and Management of Infertility. Project 79923: a case-control study to assess the role of certain sexually transmitted diseases in the etiology of infertility in women. Unpublished data, june 21, 1990. 100. DeMuylder X, Laga M, Tennstedt C, Van Dyck E, AleIbers GNM, Piot P. The role of Neisseria gonorrhoeae and Chlamydia trachomatis in pelvic inflammatory disease and its sequelae in Zimbabwe. j Infect Dis 1990;162:501-5. 101. Svensson L, Mardh P-A, Westrom L. Infertility after acute salpingitis with special reference to Chlamydia traclwmatlS. Fertil Steril 1985;40:322-9. 102. Westrom L, Mardh P-A. Acute pelvic inflammatory disease. In: Holmes KK, Mardh P-A, Sparling PF, et aI., eds. Sexually transmitted diseases. 2nd ed. New York: McGraw-Hill, 1990:593-613. 103. Svensson L, Westrom L, Ripa KT, et al. Differences in some clinical and laboratory parameters in acute salpingitis related to culture and serologic finding. AM j OBSTET GVNECOL 1980;138:1017-23.

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104. Toomey KE, Rafferty MP, Stamm WE. Unrecognized high prevalence of Chlamydia trachomatlS genital infection in an isolated Alaskan eskimo population. JAMA 1987;258:53-6. 105, Paavonen J, Wolner-Hanssen P. Chlamydia trachomatlS: a major threat to reproduction. Hum Reprod 1989;2: 11124. 106, Marana R, Sanna A, Lucisano A, Dell'Acqua S, Leone F, Mancuso S, High prevalence of silent chlamydia colonization of the tubal mucosa in infertile women, Ferti! Steril 1990;53:354-6. 107, Patton DL. Immunopathology and histopathology of experimental chlamydial salpingitis. Rev Infect Dis 1985;7: 746-53. 108, Patton DL, Kuo C-C, Wang SoP, et al. Distal tubal obstruction induced by repeated Chlamydia trachomatlS salpingeal infections in pig-tailed macaques. J Infect Dis 1987; 155: 1292-8. 109. Patton DL, Wolner-Hanssen P, Cosgrove SJ, et al. Histopathology of the female reproductive tract of the pigtailed macaque after tubal challenge following repeated cervical infection with Chlamydza trachomatis [Abstract]. Presented at the Eighth Meeting of the International Society of STD Research, Copenhagen, Denmark, Sept. 1I, 1989. 110. Shepard MK, Jones RB. Recovery of Chlamydia trachomatlS from endometrial and fallopian tube biopsies in women with infertility of tubal origin. Fertil Steril 1989;52 :232-8. Ill. Byrne GI, Bruggs B, Marshall TJ, et al. Gamma interferon mediated cytotoxicity related to murine Chlamydia trachomatis infection. Infect Immunol 1988;56:2023-7. 112, Swenson CE, Sung ML, Schachter J, The effect of tetracycline treatment on chlamydial salpingitis and subsequent fertility in the mouse. Sex Transm Dis 1986; 13:40-4. 113. Svenson L, Mardh P-A, Ahlgren M, Nordenskjold F. Ectopic pregnancy and antibodies to Chlamydia trachomatlS. Fertil Steril 1985;44:313-7. 114. Brunham RC, Binns B. McDowell]. Paraskevas M. Chla-

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