Chlamydial Pgp3 Seropositivity and Population-Attributable Fraction Among Women With Tubal Factor Infertility.

BACKGROUND: Chlamydial infection is associated with tubal factor infertility (TFI); however, assessment of prior chlamydial infection and TFI is imperfect. We previously evaluated a combination of serological assays for association with TFI. We now describe the chlamydial contribution to TFI using a newer Chlamydia trachomatis Pgp3-enhanced serological (Pgp3) assay. METHODS: In our case-control study of women 19 to 42 years old with hysterosalpingogram-diagnosed TFI (cases) and non-TFI (controls) in 2 US infertility clinics, we assessed possible associations and effect modifiers between Pgp3 seropositivity and TFI using adjusted odds ratios with 95% confidence intervals (CIs) stratified by race. We then estimated the adjusted chlamydia population-attributable fraction with 95% CI of TFI. RESULTS: All Black (n = 107) and 618 of 620 non-Black women had Pgp3 results. Pgp3 seropositivity was 25.9% (95% CI, 19.3%-33.8%) for non-Black cases, 15.2% (95% CI, 12.3%-18.7%) for non-Black controls, 66.0% (95% CI, 51.7%-77.8%) for Black cases, and 71.7% (95% CI, 59.2%-81.5%) for Black controls. Among 476 non-Black women without endometriosis (n = 476), Pgp3 was associated with TFI (adjusted odds ratio, 2.6 [95% CI, 1.5-4.4]), adjusting for clinic, age, and income; chlamydia TFI-adjusted population-attributable fraction was 19.8% (95% CI, 7.7%-32.2%) in these women. Pgp3 positivity was not associated with TFI among non-Black women with endometriosis or among Black women (regardless of endometriosis). CONCLUSIONS: Among non-Black infertile women without endometriosis in these clinics, 20% of TFI was attributed to chlamydia. Better biomarkers are needed to estimate chlamydia TFI PAF, especially in Black women.

Host Genetic Risk Factors for Chlamydia trachomatis-Related Infertility in Women.

BACKGROUND: Chlamydia trachomatis (Ct) infection ascending to the upper genital tract can cause infertility. Direct association of genetic variants as contributors is challenging because infertility may not be diagnosed until years after infection. Investigating the intermediate trait of ascension bridges this gap. METHODS: We identified infertility genome-wide association study (GWAS) loci using deoxyribonucleic acid from Ct-seropositive cisgender women in a tubal factor infertility study and Ct-infected cisgender women from a longitudinal pelvic inflammatory disease cohort with known fertility status. Deoxyribonucleic acid and blood messenger ribonucleic acid from 2 additional female cohorts with active Ct infection and known endometrial infection status were used to investigate the impact of infertility single-nucleotide polymorphisms (SNPs) on Ct ascension. A statistical mediation test examined whether multiple infertility SNPs jointly influenced ascension risk by modulating expression of mediator genes. RESULTS: We identified 112 candidate infertility GWAS loci, and 31 associated with Ct ascension. The SNPs altered chlamydial ascension by modulating expression of 40 mediator genes. Mediator genes identified are involved in innate immune responses including type I interferon production, T-cell function, fibrosis, female reproductive tract health, and protein synthesis and degradation. CONCLUSIONS: We identified Ct-related infertility loci and their potential functional effects on Ct ascension.

Tubal Factor Infertility, In Vitro Fertilization, and Racial Disparities: A Retrospective Cohort in Two US Clinics.

BACKGROUND: Nearly 14% of US women report any lifetime infertility which is associated with health care costs and psychosocial consequences. Tubal factor infertility (TFI) often occurs as a result of sexually transmitted diseases and subsequent pelvic inflammatory disease. We sought to evaluate for and describe potential racial disparities in TFI and in vitro fertilization (IVF) prevalence. METHODS: Records of women aged 19 to 42 years in our retrospective cohort from 2 US infertility clinics were reviewed. We calculated TFI prevalence, IVF initiation prevalence, and prevalence ratios (PRs), with 95% confidence intervals (CIs) for each estimate, overall and by race. RESULTS: Among 660 infertile women, 110 (16.7%; 95% CI, 13.8-19.5%) had TFI which was higher in Black compared with White women (30.3% [33/109] vs 13.9% [68/489]; PR, 2.2 [95% CI, 1.5-3.1]). For women with TFI, IVF was offered to similar proportions of women by race (51.5% [17/33] vs 52.9% [36/68] for Black vs White women); however, fewer Black than White women with TFI started IVF (6.7% [1/15] vs 31.0% [9/29]; PR, 0.2 [95% CI, 0-1.0]), although the difference was not statistically different. CONCLUSIONS: Tubal factor infertility prevalence was 2-fold higher among Black than White women seeking care for infertility. Among women with TFI, data suggested a lower likelihood of Black women starting IVF than White women. Improved sexually transmitted disease prevention and treatment might ameliorate disparities in TFI.

Population-attributable fraction of tubal factor infertility associated with chlamydia.

BACKGROUND: Chlamydia trachomatis infection is highly prevalent among young women in the United States. Prevention of long-term sequelae of infection, including tubal factor infertility, is a primary goal of chlamydia screening and treatment activities. However, the population-attributable fraction of tubal factor infertility associated with chlamydia is unclear, and optimal measures for assessing tubal factor infertility and prior chlamydia in epidemiological studies have not been established. Black women have increased rates of chlamydia and tubal factor infertility compared with White women but have been underrepresented in prior studies of the association of chlamydia and tubal factor infertility. OBJECTIVES: The objectives of the study were to estimate the population-attributable fraction of tubal factor infertility associated with Chlamydia trachomatis infection by race (Black, non-Black) and assess how different definitions of Chlamydia trachomatis seropositivity and tubal factor infertility affect population-attributable fraction estimates. STUDY DESIGN: We conducted a case-control study, enrolling infertile women attending infertility practices in Birmingham, AL, and Pittsburgh, PA, during October 2012 through June 2015. Tubal factor infertility case status was primarily defined by unilateral or bilateral fallopian tube occlusion (cases) or bilateral fallopian tube patency (controls) on hysterosalpingogram. Alternate tubal factor infertility definitions incorporated history suggestive of tubal damage or were based on laparoscopic evidence of tubal damage. We aimed to enroll all eligible women, with an expected ratio of 1 and 3 controls per case for Black and non-Black women, respectively. We assessed Chlamydia trachomatis seropositivity with a commercial assay and a more sensitive research assay; our primary measure of seropositivity was defined as positivity on either assay. We estimated Chlamydia trachomatis seropositivity and calculated Chlamydia trachomatis-tubal factor infertility odds ratios and population-attributable fraction, stratified by race. RESULTS: We enrolled 107 Black women (47 cases, 60 controls) and 620 non-Black women (140 cases, 480 controls). Chlamydia trachomatis seropositivity by either assay was 81% (95% confidence interval, 73-89%) among Black and 31% (95% confidence interval, 28-35%) among non-Black participants (P < .001). Using the primary Chlamydia trachomatis seropositivity and tubal factor infertility definitions, no significant association was detected between chlamydia and tubal factor infertility among Blacks (odds ratio, 1.22, 95% confidence interval, 0.45-3.28) or non-Blacks (odds ratio, 1.41, 95% confidence interval, 0.95-2.09), and the estimated population-attributable fraction was 15% (95% confidence interval, -97% to 68%) among Blacks and 11% (95% confidence interval, -3% to 23%) among non-Blacks. Use of alternate serological measures and tubal factor infertility definitions had an impact on the magnitude of the chlamydia-tubal factor infertility association and resulted in a significant association among non-Blacks. CONCLUSION: Low population-attributable fraction estimates suggest factors in addition to chlamydia contribute to tubal factor infertility in the study population. However, high background Chlamydia trachomatis seropositivity among controls, most striking among Black participants, could have obscured an association with tubal factor infertility and resulted in a population-attributable fraction that underestimates the true etiological role of chlamydia. Choice of chlamydia and tubal factor infertility definitions also has an impact on the odds ratio and population-attributable fraction estimates.

Gestational hypothyroidism: development of mild hypothyroidism in early pregnancy in previously euthyroid women.

OBJECTIVE: To determine the proportion of euthyroid women attending a fertility practice who develop hypothyroidism in very early pregnancy (gestational hypothyroidism [GHT]), and to examine the association of GHT with exogenous gonadotropin treatment. DESIGN: Retrospective cohort study. SETTING: A private reproductive medicine practice. PATIENT(S): All healthy women (N = 94) with infertility or recurrent pregnancy loss, TSH level <2.5 mIU/L, negative thyroid peroxidase antibodies at initial evaluation, and not taking thyroid medication, who conceived during an 18-month period. INTERVENTION(S): Usual fertility care; 30 women who had received exogenous gonadotropins. MAIN OUTCOME MEASURE(S): Serum TSH level at the time of pregnancy detection. RESULT(S): Gestational hypothyroidism (TSH ≥ 2.5 mIU/L) developed in 23 of 94 women (24%). The mean increase in serum TSH level from initial evaluation to early pregnancy was 0.45 ± 0.08 [SE] mIU/L. There was a trend toward the association of GHT with use of exogenous gonadotropins. Gestational hypothyroidism was positively associated with initial prepregnancy TSH level. CONCLUSION(S): Euthyroid women may develop mild hypothyroidism in early pregnancy, especially after exogenous gonadotropin treatment. Appropriate vigilance will allow for timely levothyroxine treatment.

Effect of spontaneous pregnancy reduction on obstetric outcome.

OBJECTIVE: To determine if obstetric outcome is compromised in pregnancies in which a spontaneous pregnancy reduction (SPR) occurred in the first trimester. STUDY DESIGN: Case-control study. RESULTS: First-trimester SPR was diagnosed in 29 (27.8%) of 104 twin pregnancies, 14 (28.6%) of 49 triplet pregnancies and 10 (28.6%) of 35 quadruplet pregnancies. Of these 53 patients, 15 were excluded from the analysis. In the remaining 38 women with SPR, vaginal bleeding occurred in 2 (5.3%) as compared to 7 (8.3%) of the controls. Pregnancy-induced hypertension occurred in 4 (10.5%) of SPR pregnancies as compared to 9 (10.7%) of control pregnancies. When compared to respective controls, there were no significant differences in the birth weights or gestational age at delivery of pregnancies spontaneously reduced to singletons (SPR, 38.5 weeks; controls, 38.2 weeks), twins (SPR, 36.2 weeks; controls, 34.4 weeks) or triplets (SPR, 31.0 weeks; controls, 32.0 weeks). CONCLUSION: SPR can be recognized in >25% of multiple pregnancies diagnosed in the early first trimester. Our data suggests that SPR is not associated with decreased gestational age at delivery, reduced birth weight or increased incidence of pregnancy-induced hypertension.

Effect of obesity on recombinant follicle-stimulating hormone absorption: subcutaneous versus intramuscular administration.

OBJECTIVE: To determine whether recombinant follicle-stimulating hormone (rFSH) should be administered intramuscularly (i.m.) or subcutaneously (s.c.) to obese women. DESIGN: Randomized, single-center, two-way crossover study. SETTING: Academic clinical research center. SUBJECT(S): Nineteen healthy women of reproductive age with body mass indices of 19.9 kg/m(2)-42.8 kg/m(2). INTERVENTION(S): Leuprolide acetate 3.75 mg i.m. to achieve pituitary down-regulation as determined by serum E(2) levels. Subjects were then given a single dose of 300 IU rFSH either i.m. or s.c.. Multiple blood sampling was performed over the next two weeks, and after retreatment with leuprolide, a second 300 IU rFSH dose was given via the other administration route. MAIN OUTCOME MEASURE(S): Serum samples were analyzed in duplicate for follicle-stimulating hormone (FSH) using a standard radioimmunoassay in a single run. Maximum concentrations (C(max)), times to C(max) (T(max)), and extent of absorption (area under curve [AUC]) with i.m. vs. s.c. administration were compared using paired analysis. RESULT(S): Maximal concentrations were achieved within 24 hours with both s.c. and i.m. routes. No significant differences were found in C(max), T(max), or AUC with s.c. vs. i.m. administration. A decline of AUC occurred among subjects of higher body mass index (BMI) with rFSH given either s.c. or i.m.. Subcutaneous administration achieved AUCs comparable to i.m. administration in both normal-weight and obese subjects. CONCLUSION(S): Our data indicate that the s.c. administration of rFSH is appropriate for women regardless of body mass.

Partner characteristics, intensity of the intercourse, and semen exposure during use of the female condom.

The objective of this study was to assess how characteristics of the intercourse and the couple relate to semen exposure during use of the female condom. From 1996 to 1998, 210 women in Birmingham, Alabama, were trained to use the female condom and follow study procedures during a group session and individually practiced inserting the device. The outcome was semen exposure as defined by comparing pre- and postcoital prostate-specific antigen levels in vaginal fluid. Women who had high income levels had lower rates of semen exposure (odds ratio (OR) = 0.3, 95% confidence interval (CI): 0.2, 0.7), while those in a relationship of less than 2 years were at greater risk (OR = 2.4, 95% CI: 1.3, 4.1). Couples with a large disparity in vaginal fundus size and penis size were at increased risk of semen exposure (OR = 2.7, 95% CI: 1.2, 6.0). Engaging in very active intercourse also increased the risk (OR = 1.7, 95% CI: 1.1, 2.6). Thus, the protective effect of the female condom appears to be a function of user- and intercourse-specific characteristics. Future studies of male condom efficacy should focus on collecting detailed data about the users and characteristics of intercourse to predict failure accurately.

Efficacy of the female condom as a barrier to semen during intercourse.

In 1996-1998, the authors measured prostate-specific antigen (PSA) in vaginal fluid to assess the frequency of female condom failure and to evaluate the association of self-reported failure with semen exposure. Women at low risk of sexually transmitted diseases (n = 210) were recruited in Birmingham, Alabama. They were trained to use the female condom, sample vaginal fluid before and after condom use, and complete forms to report problems during each use. Semen exposure was assessed by comparing pre- and postcoital PSA levels in vaginal fluid. A total of 175 women used 2,232 condoms. The rate of semen exposure ranged from 7% to 21% of condom uses, depending on the exposure criterion. Exposure was more likely (21-34%) and more intense (mean postcoital PSA, 24.7 ng/ml) if participants reported a mechanical problem versus other problems or no problems (exposure rate, 5-20% in both instances; mean postcoital PSA, 9.6 and 7.8 ng/ml, respectively). In logistic regression analyses for repeated measurements, user-reported problems accounted for less than 59% of the instances of semen exposure. The female condom prevented semen exposure in 79-93% of condom uses. Exposure was associated with user-reported problems but also occurred in their absence. Reported problems and semen exposure decreased with user experience.