Abstract
Background.
Chlamydia trachomatis causes pelvic inflammatory disease (PID) and tubal infertility. Plasmid gene protein 3 antibody (Pgp3Ab) detects prior chlamydial infections. We evaluated for an association of high chlamydial seropositivity with sequelae using a Pgp3Ab multiplex bead array (Pgp3AbMBA).
Methods.
We performed chlamydia Pgp3AbMBA on sera from women 18–39 years old participating in the 2013–2016 National Health and Nutrition Examination Survey (NHANES) with urine chlamydia nucleic acid amplification test results. High chlamydial seropositivity was defined as a median fluorescence intensity (MFI ≥ 50 000; low-positive was MFI > 551–<50 000. Weighted US population high-positive, low-positive, and negative Pgp3Ab chlamydia seroprevalence and 95% confidence intervals (CI) were compared for women with chlamydial infection, self-reported PID, and infertility.
Results.
Of 2339 women aged 18–39 years, 1725 (73.7%) had sera, and 1425 were sexually experienced. Overall, 104 women had high positive Pgp3Ab (5.4% [95% CI 4.0–7.0] of US women); 407 had lowpositive Pgp3Ab (25.1% [95% CI 21.5–29.0]), and 914 had negative Pgp3Ab (69.5% [95% CI 65.5–73.4]). Among women with high Pgp3Ab, infertility prevalence was 2.0 (95% CI 1.1–3.7) times higher than among Pgp3Ab-negative women (19.6% [95% CI 10.5–31.7] versus 9.9% [95% CI 7.7–12.4]). For women with low Pgp3Ab, PID prevalence was 7.9% (95% CI 4.6–12.6) compared to 2.3% (95% CI 1.4–3.6) in negative Pgp3Ab.
Conclusions.
High chlamydial Pgp3Ab seropositivity was associated with infertility although small sample size limited evaluation of an association of high seropositivity with PID. In infertile women, Pgp3Ab may be a marker of prior chlamydial infection.
Keywords: chlamydia serology, reproductive sequelae, seroprevalence, sexually transmitted infection
Prior to the coronavirus disease 2019 (COVID-19) pandemic, chlamydial infections had consistently been the most commonly reported infectious disease in the United States, with nearly 1.8 million cases reported to the Centers for Disease Control and Prevention (CDC) in 2018 [1]. About 30% of US women have serologic evidence of Chlamydia trachomatis infection [2]. The highest prevalence of chlamydial infection occurs in young women with 4% of women 14–24 years old chlamydia positive by urine nucleic acid amplification test (NAAT) [1]. Following a cervical infection, C. trachomatis and other sexually transmitted infections can ascend in the female genital tract and cause reproductive sequelae, including pelvic inflammatory disease (PID), ectopic pregnancy, and tubal factor infertility (TFI). Approximately 10% of untreated chlamydial infections may progress to PID within a year [3], and PID may cause TFI about 11% of the time [4], although currently available diagnostic tests cannot identify women with lower tract disease at risk for progressing to sequelae. Chlamydia NAAT tests can measure acute cervical infection that may lead to sequelae; however, they cannot measure prior infections.
Unlike chlamydial NAATs, chlamydial serologic assays may be used to measure antibodies indicating prior chlamydial infection that may lead to PID and infertility [5]. Using a variety of chlamydial serologic assays, studies have evaluated the association between current and prior chlamydial infection and PID. Although some have found an increased risk of PID, other studies have not found a statistically significant association [6–9]. Estimates of the percentage of tubal factor infertility attributable to chlamydia using different serologic assays range from 10% to 50% [10–12]. Although chlamydia is known to cause PID and infertility, existing knowledge is incomplete about the proportions of PID and infertility caused by chlamydia, and which women with chlamydia are at elevated risk for upper genital tract sequelae primarily due to the poor sensitivity of existing commercially available chlamydial serologic assays [5].
Serological assays can detect antibodies against C. trachomatis plasmid gene protein 3 (Pgp3) and may provide further insights on the association between Pgp3 antibody (Pgp3Ab) level and chlamydial sequelae. Detection of Pgp3Abs has shown good (92% at 6 months or less post-chlamydial infection) sensitivity for chlamydia compared to NAAT tests [5]. Additionally, the Pgp3Ab multiplex bead array (Pgp3AbMBA) has shown similar [13], or greater [14] ability to detect prior chlamydial infection than the Pgp3 ELISA [2]. Pgp3 may have a role in the inflammatory sequelae of chlamydia. Mice data suggest that Pgp3 may influence Chlamydia muridarum’s upper tract ascension with less upper genitourinary tract chlamydial infection when Pgp3 antigen is absent [15]. Immunization with Pgp3 also leads to lower C. trachomatis in mouse fallopian tubes [16].
Evidence suggests that higher chlamydia antibody levels are related to increased risk of developing TFI [17, 18]. An assay that could distinguish chlamydial sequelae from uncomplicated chlamydial infection could be used to identify women at risk for developing upper tract sequelae and expand the public health use of chlamydia serology [19]. We took advantage of the wide dynamic range of the multiplex bead array (MBA) assay and used sera from a nationally representative sample of women 18–39 years old to evaluate for associations between a high level of anti-chlamydial Pgp3Ab response, and the reproductive health sequelae of PID and infertility.
METHODS
Study Design/Population
We used data and sera from women 18–39 years old with available urine C. trachomatis NAAT results who participated in the 2013–2016 cycles of NHANES. NHANES is a nationally representative survey that has been conducted by the National Center for Health Statistics (NCHS) in the US resident, civilian, noninstitutionalized population since 1971 [20, 21]. Participants in this survey have undergone a survey interview, physical examination, and were asked to consent to a blood draw and urine specimen collection. Women with unknown or unavailable laboratory results were excluded. We performed Pgp3AbMBA on the sera as outlined below.
Data Sources and Methods
Laboratory Methods
Prior to testing serum specimens with the Pgp3AbMBA, the positivity cutoff was determined using a receiver operator characteristic (ROC) curve based on a panel of 85 serum samples previously tested by enzyme-linked immunosorbent assay (ELISA), MBA, and lateral flow assay [13]. The overall positivity cutoff for the Pgp3AbMBA was set at a median fluorescence intensity (MFI) of >551. Beads were coupled to Pgp3 antigen as previously described [22]. All reagents, specimens, and plates were brought up to room temperature before testing. Serum was diluted 1:400 in Buffer B (1X phosphate buffered saline [PBS], 0.5% casein, 0.5% polyvinyl alcohol, 0.8% polyvinylpyrrolidone, 0.02% NaN3, 0.3% Tween 20 and 3 μg/mL of Escherichia coli cell extract) and 50 μL of the diluted serum was incubated with Pgp3-coupled beads (1250 per well) for 1.5 hours. Beads were then washed 3 times with PBST (1X PBS + 0.05% Tween-20) and incubated with 50 ng biotinylated mouse anti-human immunoglobulin G (IgG) Fc (Southern Biotech, Birmingham, Alabama) and 20 ng biotinylated mouse anti-human IgG4 (Southern Biotech, Birmingham, Alabama) for 45 minutes. After this incubation, beads were again washed 3 times with PBST and incubated with 250 ng streptavidin phycoerythrin (SA-PE) for 30 minutes, washed 3 times with PBST and incubated in Buffer A (1X PBS, 0.5% bovine serum albumin [BSA], 0.05% Tween-20 and 0.02% sodium azide) for 30 minutes, washed once more with PBST, and suspended in 100 μl 1X PBS [14]. Beads with antibodies from participant sera were read on the Luminex MAGPIX instrument with the background subtracted.
Variables and Definitions
Speculating that the strongest association would be found with the highest level of Pgp3Ab and (a) self-reported PID, and/or (b) self-reported infertility, we categorized the Pgp3Ab MFI values into three categories: MFI values of ≥50 000 were classified as high-positive (high seropositivity) based on expert opinion, MFI values of >551 to 49 999 were classified as low-positive (low seropositivity), and values ≤551 were considered seronegative. We also performed a secondary analysis that used an alternate definition for a high positivity based on selecting the median value between the 551 cutoff and the highest positive value. With this alternate definition, high seropositivity at the median of the positive values was an MFI of 25 048 or higher, and low seropositivity was defined as an MFI value of 551 to <25 048.
We limited our study sample to women who reported ever having had any type of sex including vaginal, oral, or anal sex (sexually experienced). Women with a positive urine chlamydia NAAT at the time of the NHANES exam were classified as having current chlamydia; women who self-reported having been told of a chlamydia diagnosis in the 12 month-period before the NHANES exam were classified as having recent chlamydia although this did not necessarily include women who had current chlamydia or a positive NAAT test at the time of the NHANES exam. PID was defined as a woman reporting ever having been treated for PID. Infertility was defined as a woman reporting an inability to get pregnant over a one-year period despite attempting to get pregnant.
Analytic Methods
Sample weights were used to generate US national estimates by multiplying each included participant by the frequency of US women represented by the included participant. Weighted seroprevalences of high-positive, low-positive, and negative results along with 95% confidence intervals (CIs) were calculated overall and by various characteristics by applying Clopper Pearson CIs. We also calculated weighted prevalence ratios for chlamydia sequelae. Median MFI with interquartile ranges (IQR) were calculated for each outcome category. Weighted prevalence or prevalence ratio estimates were suppressed where data presentation criteria were not met for the effective sample size, prevalence, or confidence intervals per NHANES guidance [23]. Statistical analyses for weighted data were conducted using SAS 9.4 per NHANES guidance [24].
Ethical and IRB Review
NHANES respondents provided consent for their specimens to be used in future research during the specimen collection process. Our study protocol was reviewed and approved by the National Center for Health Statistics Ethics Review Board and in accordance with the Helsinki Declaration.
RESULTS
In the 2013–2016 cycles of the NHANES survey, the initial survey response rate ranged from 61–79% among all 16–39 year old women who were approached for inclusion [25]. Of the 10 251 women of all ages with information participating in the survey there were 2339 women 18–39 years old. Among these 2339 women, 2195 (93.8%) had available chlamydia NAAT results. We limited our analysis to the 1425 (80.6%) women that had serology results among 1768 women with chlamydia NAAT results who reported sexual experience (Figure 1). In comparing women with and without available Pgp3 serology results from our sample, women with serology results were older, differed in their racial/ethnic distribution (with a higher percentage of non-Hispanic Black women not having serology results), had higher income, more often reported a history of anal sex, and less often had recent chlamydia (data not shown).
Figure 1.
Women included in final sample of 1425 women aged 18–39 years with available chlamydia nucleic acid amplification test result, reported sexual experience, and available chlamydia serology result, National Health and Nutrition Examination Survey 2013–2016.
High Seropositivity, Low Seropositivity, and Seronegativity
Among the 1425 sexually experienced women 18–39 years old, the weighted prevalence of high-positive Pgp3 MFI (high seropositivity) was 5.4% (95% CI 4.0–7.0), of low-positive Pgp3 MFI (low seropositivity) was 25.1% (95% CI 21.5–29.0), and of seronegative Pgp3 was 69.5% (95% CI 65.5–73.4) (Table 1). Using our alternate definition of high-positive Pgp3 MFI, the prevalence of high-positive seropositivity was 13.9% (95% CI 11.3–16.8), whereas low-positive seropositivity was 16.6% (95% CI 13.8–19.7) (Table 2).
Table 1.
Characteristics of Sexually Experienced Women 18–39 Years With Available Chlamydia trachomatis Serology Data, by Category of Serological Pgp3 Multiplex Bead Array Fluorescence Intensity Result (Negative, Low-positive [551–49 999], and High-positive [≥50 000]), National Health and Nutrition Examination Survey (NHANES), 2013–2016
| Total | Negative Sample N | Weighted Negative Prevalence (95% CI) | Low-positive Sample N | Weighted Low- positive Prevalence (95% CI) | High- positive Sample N | Weighted High- positive Prevalence (95% CI) | |
|---|---|---|---|---|---|---|---|
| Overall | 1425 | 914 | 69.5 (65.5–73.4) | 407 | 25.1 (21.5–29.0) | 104 | 5.4 (4.0–70) |
| Age group, years | |||||||
| 18–24 | 458 | 297 | 68.6 (62.8–74.0) | 122 | 24.8 (20.1–30.0) | 39 | 6.6 (4.3–9.6) |
| 25–31 | 452 | 299 | 71.8 (65.9–773) | 120 | 23.1 (18.2–28.6) | 33 | 5.1 (3.1–79) |
| 32–39 | 515 | 318 | 68.1 (61.4–74.2) | 165 | 272 (21.3–33.8) | 32 | 4.7 (2.5–79) |
| Race/ethnicity | |||||||
| Non-Hispanic White | 506 | 378 | 773 (72.7–81.5) | 117 | 20.5 (16.1–25.5) | 11 | 2.1 (.9–4.2) |
| Non-Hispanic Black | 259 | 79 | 29.8 (22.2–38.3) | 135 | 53.0 (44.6–61.3) | 45 | 172 (11.7–24.0) |
| Hispanic | 442 | 295 | 66.5 (61.9–70.9) | 117 | 26.8 (22.7–31.2) | 30 | 6.7 (4.5–9.6) |
| Non-Hispanic Asian | 138 | 115 | 83.1 (75.8–88.9) | 19 | 14.0 (79–22.2) | 4 | a |
| Other/multiracial | 80 | 47 | 64.4 (48.7–78.1) | 19 | 20.8 (10.8–34.4) | 14 | a |
| Recent chlamydia | |||||||
| No | 1390 | 907 | 70.5 (66.6–74.3) | 383 | 24.1 (20.6–279) | 100 | 5.3 (3.9–71) |
| Yes | 33 | 6 | 23 | 4 | a | ||
| Recent gonorrhea | |||||||
| No | 1417 | 912 | 69.6 (65.6–73.5) | 401 | 24.9 (21.3–28.8) | 104 | 5.4 (4.1–71) |
| Yes | 6 | 1 | 5 | 0 | a | ||
| Recent sexually transmitted disease | |||||||
| No | 1193 | 799 | 72.0 (677–76.0) | 311 | 22.9 (19.0–271) | 83 | 5.1 (3.6–6.9) |
| Yes | 230 | 114 | 58.9 (51.4–66.0) | 95 | 34.4 (28.3–40.9) | 21 | 6.7 (3.9–10.8) |
| PID | |||||||
| No | 1354 | 886 | 70.8 (66.8–74.5) | 372 | 23.9 (20.4–278) | 96 | 5.3 (3.9–6.9) |
| Yes | 59 | 22 | 32 | 5 | a | ||
| Infertility | |||||||
| No | 1280 | 837 | 70.1 (66.0–74.0) | 358 | 25.0 (21.5–28.8) | 85 | 4.9 (3.5–6.5) |
| Yes | 144 | 76 | 64.2 (53.3–74.1) | 49 | 25.9 (16.8–36.9) | 19 | a |
| Current chlamydia | |||||||
| Negative | 1389 | 909 | 70.5 (66.3–74.4) | 389 | 24.6 (21.0–28.6) | 91 | 4.9 (3.6–6.5) |
| Positive | 36 | 5 | 18 | 13 | a | ||
| Income to poverty ratio | |||||||
| <1.5 | 577 | 308 | 572 (51.3–62.9) | 206 | 33.0 (278–38.6) | 63 | 9.8 (71–13.1) |
| 1.5–<3 | 362 | 240 | 69.6 (61.1–772) | 97 | 25.7 (19.6–32.7) | 25 | 4.7 (2.3–8.3) |
| ≥3 | 413 | 321 | 80.8 (76.2–84.9) | 79 | 16.9 (13.1–21.2) | 13 | 2.4 (.9–4.9) |
| Marital status | |||||||
| Never married | 433 | 247 | 63.9 (58.9–68.6) | 141 | 28.3 (24.1–32.8) | 45 | 78 (5.2–11.2) |
| Married/living with partner | 721 | 501 | 74.1 (68.9–78.8) | 184 | 22.3 (175–276) | 36 | 3.6 (2.3–5.5) |
| Divorced/widowed/separated | 113 | 56 | 54.5 (42.9–65.8) | 47 | 38.2 (28.2–49.1) | 10 | a |
| Education | |||||||
| <High school | 190 | 100 | 53.3 (45.4–61.1) | 74 | 39.4 (31.5–478) | 16 | 73 (4.0–12.0) |
| High school graduate/general education diploma | 240 | 133 | 59.7 (50.7–68.3) | 86 | 34.3 (26.4–43.0) | 21 | 5.9 (3.3–9.7) |
| Some college/associates degree | 498 | 299 | 66.3 (61.2–71.1) | 153 | 26.2 (21.5–31.4) | 46 | 75 (4.7–11.1) |
| ≥College gradúate | 339 | 272 | 84.0 (78.0–88.9) | 59 | 14.7 (10.4–19.9) | 8 | 1.3 (.3–3.7) |
| Health insurance coverage | |||||||
| No | 345 | 205 | 60.6 (53.7–672) | 108 | 31.6 (25.6–38.1) | 32 | 78 (5.1–11.3) |
| Yes | 1078 | 708 | 71.7 (66.7–76.4) | 298 | 23.5 (19.1–28.3) | 72 | 4.8 (3.4–6.7) |
| Place for routine healthcare | |||||||
| No | 285 | 188 | 69.4 (62.3–75.8) | 74 | 25.4 (19.4–32.2) | 23 | 5.2 (3.0–8.5) |
| Yes | 1140 | 726 | 69.6 (65.2–73.7) | 333 | 25.0 (21.0–29.4) | 81 | 5.4 (3.9–73) |
| Type of place for routine healthcare | |||||||
| Has office-based provider | 1070 | 695 | 70.7 (66.6–74.6) | 302 | 24.0 (20.1–28.1) | 73 | 5.3 (3.8–72) |
| Hospital emergency room | 66 | 27 | 42.0 (28.0–56.9) | 31 | 49.2 (35.1–63.3) | 8 | a |
| HIV status | |||||||
| Negative | 1422 | 913 | 69.6 (65.5–73.4) | 405 | 25.0 (21.4–28.9) | 104 | 5.4 (4.1–70) |
| Positive | 1 | 0 | 0 | 1 | 100 | 0 | 0 |
| Currently pregnant | |||||||
| No | 1168 | 754 | 70.1 (65.9–74.0) | 335 | 25.0 (21.3–28.9) | 79 | 5.0 (3.6–6.6) |
| Yes | 81 | 44 | 63.2 (50.0–75.0) | 27 | 28.1 (18.1–40.0) | 10 | a |
| Ever pregnant | |||||||
| No | 382 | 302 | 82.0 (76.6–86.6) | 64 | 15.4 (11.7–19.8) | 16 | 2.6 (1.1–5.3) |
| Yes | 883 | 500 | 62.8 (56.9–68.4) | 308 | 30.6 (25.4–36.2) | 75 | 6.6 (4.6–9.1) |
| Age at first sex, years | |||||||
| <15 | 235 | 97 | 48.2 (40.0–56.4) | 92 | 35.7 (272–45.0) | 46 | 16.1 (11.1–22.3) |
| 15–17 | 647 | 370 | 63.0 (58.0–678) | 226 | 31.2 (26.7–36.0) | 51 | 5.8 (4.0–8.0) |
| 18–19 | 297 | 228 | 80.4 (73.5–86.2) | 64 | 18.4 (12.6–25.3) | 5 | 1.2 (.3–3.3) |
| ≥20 | 246 | 219 | 91.2 (85.0–95.4) | 25 | 8.3 (4.3–14.1) | 2 | .5 (0–2.5) |
| Lifetime no. of sex partners | |||||||
| 1–4 | 705 | 560 | 84.8 (80.4–88.5) | 121 | 12.7 (9.1–170) | 24 | 2.5 (1.4–4.1) |
| 5–9 | 359 | 169 | 55.7 (48.2–63.0) | 152 | 371 (30.3–44.3) | 38 | 72 (4.6–10.6) |
| ≥10 | 360 | 185 | 574 (50.6–64.1) | 134 | 34.3 (28.5–40.5) | 41 | 8.2 (5.6–11.6) |
| New recent sex partner | |||||||
| No | 1059 | 690 | 70.5 (65.9–74.8) | 300 | 24.7 (20.5–29.3) | 69 | 4.8 (3.3–6.7) |
| Yes | 294 | 174 | 65.1 (58.4–71.5) | 88 | 26.8 (21.8–32.2) | 32 | 8.1 (4.7–12.7) |
| Sex with a woman | |||||||
| No | 1207 | 797 | 71.6 (677–75.2) | 337 | 24.0 (20.4–279) | 73 | 4.4 (3.0–6.1) |
| Yes | 218 | 117 | 58.9 (50.6–66.9) | 70 | 30.6 (24.0–378) | 31 | 10.5 (6.8–15.3) |
| Sexual identity | |||||||
| Straight | 1226 | 783 | 69.3 (65.2–73.1) | 356 | 25.4 (21.6–29.5) | 87 | 5.4 (3.9–72) |
| Lesbian/Gay | 25 | 15 | a | 9 | a | 1 | a |
| Bisexual | 128 | 86 | 73.8 (63.5–82.4) | 30 | 20.8 (12.7–30.9) | 12 | a |
| Other | 42 | 28 | a | 10 | a | 4 | a |
| Oral sex | |||||||
| No | 192 | 125 | 70.7 (61.3–79.0) | 56 | 25.2 (179–33.8) | 11 | a |
| Yes | 1232 | 788 | 69.3 (65.3–73.1) | 351 | 25.1 (21.5–29.0) | 93 | 5.6 (4.1–73) |
| Anal sex ever | |||||||
| No | 816 | 544 | 73.4 (68.0–78.4) | 218 | 22.1 (177–26.9) | 54 | 4.5 (2.9–6.7) |
| Yes | 609 | 370 | 65.0 (60.2–69.7) | 189 | 28.6 (24.2–33.2) | 50 | 6.4 (4.6–8.6) |
| Condomless sex in last year | |||||||
| Never | 273 | 181 | 69.8 (61.9–76.9) | 65 | 22.5 (15.8–30.3) | 27 | 77 (4.0–13.2) |
| <50% | 234 | 154 | 70.1 (63.6–76.1) | 60 | 22.4 (16.9–28.6) | 20 | 75 (3.8–13.1) |
| ≥50% and <100% | 252 | 150 | 65.5 (58.6–71.9) | 85 | 29.3 (22.7–36.7) | 17 | 5.2 (2.8–8.7) |
| Always | 561 | 357 | 70.2 (64.6–75.4) | 166 | 25.3 (20.2–30.9) | 38 | 4.5 (2.9–6.5) |
| Ever had genitourinary cancer | |||||||
| No | 1248 | 797 | 69.7 (65.3–73.8) | 361 | 25.0 (21.4–29.0) | 90 | 5.3 (3.8–71) |
| Yes | 19 | 7 | a | 11 | a | 1 | a |
Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; Pgp3, plasmid gene protein 3; PID, pelvic inflammatory disease.
Denotes estimates with wide confidence intervals per NHANES guidance; thus, estimates are suppressed.
Table 2.
Characteristics of Sexually Experienced Women 18–39 Years With Available Chlamydia trachomatis Serology Data, by Category of Serological Pgp3 Multiplex Bead Array Fluorescence Intensity Result (Negative, Low-positive [551-median of Positive Results], and High-positive [Greater Than or Equal to the Median Positive Results]), National Health and Nutrition Examination Survey (NHANES), 2013–2016
| Total | Negative Sample N | Weighted Negative Prevalence (95% CI) | Low- positive Sample N | Weighted Low- positive Prevalence (95% CI) | High- positive Sample N | Weighted High- positive Prevalence (95% CI) | |
|---|---|---|---|---|---|---|---|
| Overall | 1425 | 914 | 69.5 (65.5–73.4) | 255 | 16.6 (13.8–19.7) | 256 | 13.9 (11.3–16.8) |
| Age group, years | |||||||
| 18–24 | 458 | 297 | 68.6 (62.8–74.0) | 67 | 14.4 (10.7–18.9) | 94 | 170 (13.4–21.2) |
| 25–31 | 452 | 299 | 71.8 (65.9–77.3) | 77 | 15.9 (11.6–21.2) | 76 | 12.2 (8.7–16.5) |
| 32–39 | 515 | 318 | 68.1 (61.4–74.2) | 111 | 19.0 (13.4–25.7) | 86 | 12.9 (9.6–16.9) |
| Race/ethnicity | |||||||
| Non-Hispanic White | 506 | 378 | 773 (72.7–81.5) | 86 | 15.3 (12.1–19.0) | 42 | 73 (5.0–10.3) |
| Non-Hispanic Black | 259 | 79 | 29.8 (22.2–38.3) | 66 | 25.6 (176–35.0) | 114 | 44.6 (36.1–53.5) |
| Hispanic | 442 | 295 | 66.5 (61.9–70.9) | 81 | 19.0 (14.7–23.9) | 66 | 14.5 (11.0–18.7) |
| Non-Hispanic Asian | 138 | 115 | 83.1 (75.8–88.9) | 12 | 9.0 (4.5–15.6) | 11 | 79 (4.0–13.7) |
| Other/multiracial | 80 | 47 | 64.4 (48.7–78.1) | 10 | a | 23 | 26.4 (14.1–42.2) |
| Recent chlamydia | |||||||
| No | 1390 | 907 | 70.5 (66.6–74.3) | 247 | 16.4 (13.6–19.5) | 236 | 13.1 (10.6–15.9) |
| Yes | 33 | 6 | a | 7 | a | 20 | a |
| Recent gonorrhea | |||||||
| No | 1417 | 912 | 69.6 (65.6–73.5) | 253 | 16.6 (13.8–19.7) | 252 | 13.7 (11.2–16.6) |
| Yes | 6 | 1 | a | 1 | a | 4 | a |
| Recent STD | |||||||
| No | 1193 | 799 | 72.0 (677–76.0) | 203 | 15.6 (12.7–18.9) | 191 | 12.4 (10.2–14.9) |
| Yes | 230 | 114 | 58.9 (51.4–66.0) | 51 | 20.9 (15.0–278) | 65 | 20.3 (14.1–277) |
| PID | |||||||
| No | 1354 | 886 | 70.8 (66.8–74.5) | 236 | 16.0 (13.4–18.9) | 232 | 13.2 (10.6–16.2) |
| Yes | 59 | 22 | a | 16 | 28.7 (14.1–475) | 21 | a |
| Infertility | |||||||
| No | 1280 | 837 | 70.1 (66.0–74.0) | 226 | 16.6 (13.9–19.5) | 217 | 13.3 (10.5–16.5) |
| Yes | 144 | 76 | 64.2 (53.3–74.1) | 29 | 170 (10.1–26.0) | 39 | 18.9 (11.7–28.0) |
| Current chlamydia | |||||||
| Negative | 1389 | 909 | 70.5 (66.3–74.4) | 247 | 16.5 (13.6–19.7) | 233 | 13.1 (10.5–16.0) |
| Positive | 36 | 5 | a | 8 | a | 23 | a |
| Income to poverty ratio | |||||||
| <1.5 | 577 | 308 | 572 (51.3–62.9) | 126 | 21.5 (16.8–26.9) | 143 | 21.3 (16.7–26.5) |
| 1.5–<3 | 362 | 240 | 69.6 (61.1–772) | 58 | 16.4 (12.0–21.7) | 64 | 14.0 (9.4–19.6) |
| ≥3 | 413 | 321 | 80.8 (76.2–84.9) | 57 | 12.3 (9.2–6.0) | 35 | 6.9 (4.1–10.8) |
| Marital status | |||||||
| Never married | 433 | 247 | 63.9 (58.9–68.6) | 71 | 14.6 (11.4–18.3) | 115 | 21.5 (173–26.2) |
| Married/living with partner | 721 | 501 | 74.1 (68.9–78.8) | 132 | 16.7 (13.1–20.9) | 88 | 9.2 (6.5–12.5) |
| Divorced/widowed/ separated | 113 | 56 | 54.5 (42.9–65.8) | 31 | 271 (18.0–379) | 26 | 18.4 (10.0–29.7) |
| Education | |||||||
| <High school | 190 | 100 | 53.3 (45.4–61.1) | 55 | 30.3 (23.6–376) | 35 | 16.5 (10.6–23.8) |
| High school graduate/general education diploma | 240 | 133 | 59.7 (50.7–68.3) | 45 | 19.8 (13.0–28.3) | 62 | 20.4 (14.3–277) |
| Some college/associates degree | 498 | 299 | 66.3 (61.2–71.1) | 97 | 178 (14.2–21.8) | 102 | 15.9 (11.8–20.8) |
| ≥College gradúate | 339 | 272 | 84.0 (78.0–88.9) | 37 | 9.5 (5.7–14.5) | 30 | 6.5 (4.0–10.0) |
| Health insurance coverage | |||||||
| No | 345 | 205 | 60.6 (53.7–672) | 75 | 23.3 (18.0–29.4) | 65 | 16.0 (11.6–21.3) |
| Yes | 1078 | 708 | 71.7 (66.7–76.4) | 179 | 14.9 (11.7–18.7) | 191 | 13.4 (10.5–16.6) |
| Place for routine healthcare | |||||||
| No | 285 | 188 | 69.4 (62.3–75.8) | 45 | 16.1 (10.4–23.3) | 52 | 14.5 (10.0–20.1) |
| Yes | 1140 | 726 | 69.6 (65.2–73.7) | 210 | 16.7(14.0–19.8) | 204 | 13.7 (11.0–16.8) |
| Type of place for routine healthcare | |||||||
| Has office-based provider | 1070 | 695 | 70.7 (66.6–74.6) | 192 | 16.2 (13.5–19.1) | 183 | 13.1 (10.3–16.3) |
| Hospital emergency room | 66 | 27 | 42.0 (28.0–56.9) | 18 | 29.9 (18.6–43.3) | 21 | 28.2 (175–41.0) |
| HIV status | |||||||
| Negative | 1422 | 913 | 69.6 (65.5–73.4) | 254 | 16.6 (13.9–19.6) | 255 | 13.8 (11.2–16.7) |
| Positive | 1 | 0 | 0 | 1 | 100.0 | 0 | 0 |
| Currently pregnant | |||||||
| No | 1168 | 754 | 70.1 (65.9–74.0) | 211 | 16.7 (13.8–20.0) | 203 | 13.2 (10.6–16.2) |
| Yes | 81 | 44 | 63.2 (50.0–75.0) | 18 | 176 (9.5–28.5) | 19 | 19.3 (9.2–33.4) |
| Ever pregnant | |||||||
| No | 382 | 302 | 82.0 (76.6–86.6) | 40 | 10.7 (72–15.1) | 40 | 73 (4.6–10.8) |
| Yes | 883 | 500 | 62.8 (56.9–68.4) | 194 | 20.1 (16.0–24.7) | 189 | 171 (13.6–21.2) |
| Age at first sex, years | |||||||
| <15 | 235 | 97 | 48.2 (40.0–56.4) | 57 | 22.9 (15.8–31.3) | 81 | 28.9 (21.6–372) |
| 15–17 | 647 | 370 | 63.0 (58.0–678) | 138 | 20.4 (16.9–24.3) | 139 | 16.5 (12.8–20.8) |
| 18–19 | 297 | 228 | 80.4 (73.5–86.2) | 41 | 12.3 (78–18.2) | 28 | 73 (4.0–12.0) |
| ≥20 | 246 | 219 | 91.2 (85.0–95.4) | 19 | 6.5 (3.3–11.5) | 8 | 2.3 (.8–5.0) |
| Lifetime no. of sex partners | |||||||
| 1–4 | 705 | 560 | 84.8 (80.4–88.5) | 82 | 8.7 (5.9–12.3) | 63 | 6.5 (4.8–8.7) |
| 5–9 | 359 | 169 | 55.7 (48.2–63.0) | 96 | 25.1 (19.5–31.3) | 94 | 19.2 (14.6–24.5) |
| ≥10 | 360 | 185 | 574 (50.6–64.1) | 77 | 21.9 (16.9–276) | 98 | 20.7 (15.8–26.3) |
| New recent sex partner | |||||||
| No | 1059 | 690 | 70.5 (65.9–74.8) | 191 | 16.7 (13.3–20.5) | 178 | 12.8 (10.2–15.8) |
| Yes | 294 | 174 | 65.1 (58.4–71.5) | 48 | 15.6 (11.6–20.2) | 72 | 19.3 (14.0–25.6) |
| Sex with a woman | |||||||
| No | 1207 | 797 | 71.6 (677–75.2) | 212 | 15.9 (13.3–18.7) | 198 | 12.5 (10.1–15.4) |
| Yes | 218 | 117 | 58.9 (50.6–66.9) | 43 | 20.5 (14.1–28.1) | 58 | 20.6 (14.8–274) |
| Sexual identity | |||||||
| Straight | 1226 | 783 | 69.3 (65.2–73.1) | 222 | 16.8 (13.8–20.0) | 221 | 14.0 (11.4–16.8) |
| Lesbian/Gay | 25 | 15 | a | 3 | a | 7 | a |
| Bisexual | 128 | 86 | 73.8 (63.5–82.4) | 20 | 14.1 (73–23.7) | 22 | 12.1 (6.6–19.9) |
| Other | 42 | 28 | a | 9 | 23.9 (11.4–41.0) | 5 | a |
| Oral sex | |||||||
| No | 192 | 125 | 70.7 (61.3–79.0) | 36 | 16.4 (11.2–22.7) | 31 | 12.9 (8.5–18.5) |
| Yes | 1232 | 788 | 69.3 (65.3–73.1) | 219 | 16.7 (13.8–19.9) | 225 | 14.0 (11.3–170) |
| Anal sex ever | |||||||
| No | 816 | 544 | 73.4 (68.0–78.4) | 131 | 13.7 (10.2–179) | 141 | 12.9 (9.8–16.5) |
| Yes | 609 | 370 | 65.0 (60.2–69.7) | 124 | 19.9 (16.4–23.8) | 115 | 15.0 (11.6–19.0) |
| Condomless sex in last year | |||||||
| Ne ver | 273 | 181 | 69.8 (61.9–76.9) | 42 | 16.1 (9.6–24.7) | 50 | 14.1 (8.6–21.3) |
| <50% | 234 | 154 | 70.1 (63.6–76.1) | 34 | 12.3 (78–18.1) | 46 | 176 (11.3–25.6) |
| ≥50% and <100% | 252 | 150 | 65.5 (58.6–71.9) | 44 | 16.3 (11.5–22.3) | 58 | 18.2 (13.4–23.8) |
| Always | 561 | 357 | 70.2 (64.6–75.4) | 113 | 18.0 (13.8–23.0) | 91 | 11.7 (9.1–14.8) |
| Ever had genitourinary cancer | |||||||
| No | 1248 | 797 | 69.7 (65.3–73.8) | 226 | 16.5 (13.7–19.7) | 225 | 13.8 (11.0–170) |
| Yes | 19 | 7 | a | 8 | a | 4 | a |
Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; Pgp3, plasmid gene protein 3; PID, pelvic inflammatory disease; STD, sexually transmitted disease.
Denotes estimates with wide confidence intervals per NHANES guidance; thus, estimates are suppressed.
A total of 36 women had current chlamydia, 33 had recent chlamydia, 59 reported having ever been treated for PID, and 144 reported having had infertility among the 1425 women in the sample (Table 1). Among women with reported infertility, 64.2% (95% CI 53.3–74.1) were seronegative and 25.9% (95% CI 16.8–36.9) had low seropositivity. The prevalence estimate for high seropositivity among infertile women could not be reported based on NHANES guidance for reporting confidence intervals. The prevalence estimates for high seropositivity were also unstable for women with current chlamydia, recent chlamydia, and PID.
The prevalence of high seropositivity was higher for non-Hispanic black women compared to non-Hispanic white women, 17.2% (95% CI 11.7–24.0) versus 2.1% (95% CI .9–4.2); women with 5–9 lifetime sex partners, 7.2% (95% CI 4.6–10.6) or 10 or more partners, 8.2% (95% CI 5.6–11.6) compared to 1–4 partners, 2.5% (95% CI 1.4–4.1); and women ever having sex with a woman, 10.5% (95% CI 6.8–15.3) versus never having sex with a woman, 4.4% (95% CI 3.0–6.1). The prevalence of high Pgp3Ab seropositivity was lower for women with income to poverty ratio ≥3 times the federal poverty level, 2.4% (95% CI .9–4.9) compared to women with income 1.5 times or less than the federal poverty level, 9.8% (95% CI 7.1–13.1); and women college graduates at 1.3% (95% CI .3–3.7) compared to women not completing high school, 7.3% (95% CI 4.0–12.0). Women who were older at their first sexual experience also had lower high Pgp3Ab seropositivity prevalence, 0.5% (95% CI 0–2.5) for women 20 years and older, 1.2% (95% CI .3–3.3) for women 18–19 years, and 5.8% (95% CI 4.0–8.0) for women 15–17 years, compared to 16.1% (95% CI 11.1–22.3) for women younger than 15 years at first sex.
High Seropositivity, Chlamydia Status, and Sequelae of PID and Infertility
The prevalence of current chlamydia among women with high seropositivity, 10.7% (95% CI 5.4–18.6) was higher than the prevalence of current chlamydia among seronegative women, 0.4% (95% CI .1–1.3) (Table 3). Recent chlamydia prevalence was higher, 5.8% (95% CI 3.7–8.5) versus 0.7% (95% CI .1–1.9) comparing women with low seropositivity to seronegative women; as was PID prevalence, 7.9% (95% CI 4.6–12.6) versus 2.3% (95% CI 1.4–3.6); and current chlamydia prevalence, 3.5% (95% CI 1.7–6.4) versus 0.4% (95% CI .1–1.3). Using our alternate definition for high seropositivity, comparing women with high seropositivity to those seronegative, we observed a greater prevalence of PID, 8.0% (95% CI 4.0–14.2) versus 2.3% (95% CI 1.4–3.6); recent chlamydia, 7.9% (95% CI 4.7–12.2) versus 0.7% (95% CI .1–1.9); and current chlamydia, 7.2% (95% CI 4.4–11.1) versus 0.4% (95% CI .1–1.3) (Table 4). The weighted prevalence of infertility did not statistically significantly vary by level of seropositivity based on our primary and alternate high-seropositive definitions.
Table 3.
Weighted Prevalence of Pelvic Inflammatory Disease (PID), Infertility, and Chlamydia Among Women With Negative, Low-positive (551–49 999), and High-positive (≥50 000) Pgp3 Multiplex Bead Array Median Fluorescence Intensity Results Among Sexually Experienced Women 18–39 years, National Health and Nutrition Examination Survey (NHANES), 2013–2016
| Characteristic | Total Sample N | Overall Prevalence of Characteristic | Pgp3 Negative Sample N | Prevalence of Listed Characteristic Among Pgp3 Negative (95% CI) | Pgp3 Low-positive Sample N | Prevalence of Listed Characteristic Among Pgp3 Low-positive (95% CI) | Prevalence Ratio of Listed Characteristic Comparing Low-positive to Negative Pgp3 (95% CI) | Pgp3 High-positive Sample N | Prevalence of Listed Characteristic Among Pgp3 High-positive (95% CI) | Prevalence Ratio of Listed Characteristic Comparing High-positive to Negative Pgp3 (95% CI) |
|---|---|---|---|---|---|---|---|---|---|---|
| PID | 59 | 3.8 (2.7–5.2) | 22 | 2.3 (1.4–3.6) | 32 | 79 (4.6–12.6) | a | 5 | a | a |
| Infertility | 144 | 10.7 (9.0–12.5) | 76 | 9.9 (7.7–12.4) | 49 | 11.0 (75–15.5) | 1.1 (.7–1.7) | 19 | 19.6 (10.5–31.7) | 2.0 (1.1–3.7) |
| Recent chlamydia | 33 | 2.1 (1.4–3.0) | 6 | 0.7 (.1–1.9) | 23 | 5.8 (3.7–8.5) | a | 4 | a | a |
| Current chlamydia | 36 | 1.7 (1.1–2.6) | 5 | 0.4 (.1–1.3) | 18 | 3.5 (1.7–6.4) | a | 13 | 10.7 (5.4–18.6) | a |
Abbreviations: CI, confidence interval; Pgp3, plasmid gene protein 3..
Denotes estimates with wide confidence intervals per NHANES guidance; thus, estimates are suppressed.
Table 4.
Weighted Prevalence of Pelvic Inflammatory Disease (PID), Infertility, and Chlamydia Among Women With Negative, Low-positive (551-median of Positive Results), and High-positive (Greater Than or Equal to the Median of Positive Results) Pgp3 Multiplex Bead Array Median Fluorescence Intensity Results Among Sexually Experienced Women 18–39 Years, National Health and Nutrition Examination Survey (NHANES), 2013–2016
| Characteristic | Total Sample N | Overall Prevalence of Characteristic | Pgp3 Negative Sample N | Prevalence of Listed Characteristic Among Pgp3 Negative (95% CI) | Pgp3 Low-positive Sample N | Prevalence of Listed Characteristic Among Pgp3 Low-positive (95% CI) | Prevalence Ratio of Listed Characteristic Comparing Low-positive to Negative Pgp3 (95% CI) | Pgp3 High-positive Sample N | Prevalence of Listed Characteristic Among Pgp3 High-positive (95% CI) | Prevalence Ratio of Listed Characteristic Comparing High-positive to Negative Pgp3 (95% CI) |
|---|---|---|---|---|---|---|---|---|---|---|
| PID | 59 | 3.8 (2.7–5.2) | 22 | 2.3 (1.4–3.6) | 16 | a | 2.9 (1.3–6.2) | 21 | 8.0 (4.0–14.2) | a |
| Infertility | 144 | 10.7 (9.0–12.5) | 76 | 9.9 (77–12.4) | 29 | 10.9 (6.7–16.4) | 1.1 (.7–1.7) | 39 | 14.5 (9.5–20.8) | 1.5 (.9–2.5) |
| Recent chlamydia | 33 | 2.1 (1.4–3.0) | 6 | 0.7 (.1–1.9) | 7 | a | a | 20 | 79 (4.7–12.2) | a |
| Current chlamydia | 36 | 1.7 (1.1–2.6) | 5 | 0.4 (.1–1.3) | 8 | a | a | 23 | 72 (4.4–11.1) | a |
Abbreviations: CI, confidence interval; Pgp3, plasmid gene protein 3.
Denotes estimates with wide confidence intervals per NHANES; thus, estimates are suppressed.
Women with high positivity had a higher prevalence ratio (PR) of 2.0 (95% CI 1.1–3.7) for infertility comparing high seropositivity to seronegativity (Table 3). For women reporting PID or recent chlamydia, the sample size of women with these characteristics limited our ability to estimate the prevalence and PR of these characteristics comparing high seropositivity to seronegativity. Although we could not determine the weighted PR for current chlamydia with precision, the current chlamydia prevalence of 10.7% (95% CI 5.4–18.6) for women with high seropositivity was approximately 25 times higher than the current chlamydia prevalence of 0.4% (95% CI .1–1.3) for seronegative women. Using our alternate definition of high seropositivity, the prevalence ratio for infertility for women with high seropositivity was no longer significant, PR 1.5 (95% CI .9–2.5) (Table 4). With our alternate definition, the PR of PID was significantly associated with low seropositivity, 2.9 (95% CI 1.3–6.2).
Seropositivity Profiles
Overall, women with current chlamydia had a median MFI of 35 780 (IQR 7240–51 480); women with recent chlamydia had a median MFI of 31 152 (IQR 2444–49 465); women with PID had a median MFI of 2593 (IQR 37–27 156); and women with infertility had a median MFI of 43 (IQR 19–12 600) (Table 5).
Table 5.
Weighted Median and Interquartile Range (IQR) of Pgp3 Multiplex Bead Array Chlamydia Median Fluorescence Intensity for Women 18–39 Years With Various Outcomes, National Health and Nutrition Examination Survey, 2013–2016
| Weighted Median [IQR] Pgp3 Multiplex Bead Array Median Fluorescence Intensity | Chlamydia Positive | Recent Chlamydia Positive | PID Positive | Infertility Positive | Sample N |
|---|---|---|---|---|---|
| 35 780 [7240–51 480] | Yes | 36 | |||
| 31 152 [2444–49 465] | Yes | 33 | |||
| 2593 [37–27 156] | Yes | 59 | |||
| 43 [19–12 600] | Yes | 144 | |||
| 29 [18–1021] | No | No | No | No | 1166 |
Abbreviations: Pgp3, plasmid gene protein 3; PID, pelvic inflammatory disease.
DISCUSSION
In our evaluation of high-positive chlamydial Pgp3AbMBA MFI levels among a nationally representative sample of US women 18–39 years old, we found that the prevalence of infertility among women with high-positive Pgp3Ab results was twice the prevalence among women with negative Pgp3Ab results. PID prevalence also differed by seropositivity level, although our sample size limited an evaluation of an association of PID with high seropositivity. To our knowledge, our study is unique in evaluating quantitative Pgp3AbMBA levels in a nationally representative sample that includes women with infertility.
Two recent studies describe differing chlamydial Pgp3Ab levels in subfertile women compared to noninfertile women [17, 26]. Our finding of an association of infertility with high seropositivity is consistent with studies which have found an association of Pgp3Ab and other chlamydial serologic assays with infertility or TFI although this association has not been seen consistently [27] and is not completely understood [28]. Previous studies found that non-Pgp3 chlamydial antibody levels were related to the degree of tubal damage and obstruction [29–31], suggesting the possibility that a higher degree of chlamydial immune response secondary to higher chlamydial bacterial burden resulted in more reproductive pathology.
Although we observed an association of infertility and high seropositivity, the magnitude of the association was small, and the average MFI value among women with infertility was lower than the median level for all other outcome categories except for those with no occurrence of any of the chlamydial outcomes. It is possible that we did not observe higher median Pgp3Ab levels among women with infertility and PID for a few reasons. First, TFI that follows from STIs is only about 25–35% of all reported infertility [32]. Also, because infertility was self-reported and not systematically evaluated, all women with infertility may not have been identified. Finally, although Pgp3Ab can persist for up to 12 years [33], antibody levels may wane as early as weeks to months after an initial chlamydia infection [5] and have been documented to be lower 3–10 years after the initial infection [34]. Similarly for PID, not all PID is caused by chlamydia [35]; thus, we would not expect a high positive or even positive chlamydia serology in all women with PID or infertility. Additionally, PID, which can be subclinical a majority of the time, was based on participant self-report and potentially subject to recall bias and misclassification [36].
Although findings from mice studies suggest that Pgp3Abs are related to upper tract disease [15, 16], we found that high-positive Pgp3Abs were more strongly associated with current chlamydia, with higher median Pgp3Ab levels in women with current or recent chlamydia. Thus, Pgp3Ab may not be an ideal marker of chlamydial infection ascending to the upper genital tract and causing tubal damage. Rather, Pgp3Ab may better serve as a marker of previous chlamydial infection, as also suggested by Mazraani et al [26]. Unlike most chlamydial serologic assays, Pgp3 ELISA has shown good (92%) sensitivity compared to chlamydia NAAT [5] and fair (72–83%) sensitivity compared to self-report of chlamydial infection [33]. Similar to other studies, we observed higher chlamydial seropositivity in non-Hispanic black as compared to non-Hispanic white women, women with earlier onset of sexual activity, or women with a higher number of sexual partners [5, 37]. Because these characteristics also represent risk groups for chlamydial infection [38], very high Pgp3Ab serology levels in these risk-groups may again simply indicate a greater risk of having uncomplicated chlamydial infection or recurrent chlamydial infection.
The association between infertility and high Pgp3Ab seropositivity, and PID and low Pgp3Ab seropositivity should be taken in the context of our study design and other limitations beyond those already mentioned. Our study was a cross-sectional analysis in which the temporal relationships between chlamydia and PID or infertility could not be determined and did not adjust for confounders. Because women may not mount an antibody response to chlamydial infection [34], serologic tests may misclassify these women, muting our observed association. Additionally, differences in characteristics between women who did and did not have serum available limit the representativeness of our data.
Despite the limitations of our study design, we did observe an increased prevalence of infertility among women with high Pgp3Ab seropositivity. Better estimates of this association and for women with PID might be obtained by using additional cycles of data to increase sample size or by conducting cohort studies to be sure that chlamydial infection precedes sequelae. A cohort study would also allow for better characterization of the kinetics of the Pgp3Ab response. Future studies should continue the search for serologic or other biomarkers that might predict upper genital tract chlamydial ascension to broaden our understanding of women most at risk for these reproductive sequelae of STIs.
Acknowledgments.
The authors acknowledge the role of Melissa Pagaoa, MPH, in creating analytic programs for database management and Katherine Bowden, PhD, in overseeing the preparation and implementation of the Pgp3AbMBA assay.
Financial support.
This work was supported by funding from the Division of STD Prevention at the CDC.
Footnotes
Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Disclaimer. The findings in this study represent the views of the authors only and not necessarily those of the Centers for Disease Control and Prevention (CDC).
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