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Trichomonas vaginalisAssociated With Low Birth Weight and Preterm Delivery

COTCH, MARY FRANCES PhD*; PASTOREK, JOSEPH G. II MD; NUGENT, ROBERT P. PhD; HILLIER, SHARON L. PhD§; GIBBS, RONALD S. MD; MARTIN, DAVID H. MD; ESCHENBACH, DAVID A. MD§; EDELMAN, ROBERT MD*; CAREY, CHRISTOPHER J. MD; REGAN, JOAN A. MD**; KROHN, MARIJANE A. PhD§; KLEBANOFF, MARK A. MD, MPH; RAO, VIJAYA A. PhD††; RHOADS, GEORGE G. MD, MPHTHE VAGINAL INFECTIONS AND PREMATURITY STUDY GROUP

Sexually Transmitted Diseases: July 1997 - Volume 24 - Issue 6 - p 353–360
Original Article
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Background: Several studies have suggested that pregnant women infected withTrichomonas vaginalismay be at increased risk of an adverse outcome.

Goal: To evaluate prospectively the association betweenT. vaginalisand risk of adverse pregnancy outcome in a large cohort of ethnically diverse women.

Study Design: At University-affiliated hospitals and antepartum clinics in five United States cities, 13,816 women (5,241 black, 4,226 Hispanic, and 4,349 white women) were enrolled at mid-gestation, tested forT. vaginalisby culture, and followed up until delivery.

Results: The prevalence ofT. vaginalisinfection at enrollment was 12.6%. Race-specific prevalence rates were 22.8% for black, 6.6% for Hispanic, and 6.1% for white women. After multivariate analysis, vaginal infection withT. vaginalisat mid-gestation was significantly associated with low birth weight (odds ratio 1.3; 95% confidence interval 1.1 to 1.5), preterm delivery (odds ratio 1.3; 95% confidence interval 1.1 to 1.4), and preterm delivery of a low birth weight infant (odds ratio 1.4; 95% confidence interval 1.1 to 1.6). The attributable risk ofT. vaginalisinfection associated with low birth weight in blacks was 11% compared with 1.6% in Hispanics and 1.5% in whites.

Conclusions: After considering other recognized risk factors including co-infections, pregnant women infected withT. vaginalisat mid-gestation were statistically significantly more likely to have a low birth weight infant, to deliver preterm, and to have a preterm low birth weight infant. Compared with whites and Hispanics,T. vaginalisinfection accounts for a disproportionately larger share of the low birth weight rate in blacks.

*From the National Institute of Allergy and Infectious Diseases, Bethesda, Maryland (M.F.C. now at the National Eye Institute, Bethesda, MD; R.E. now at the University of Maryland, Baltimore, Maryland); the Medical Center of Louisiana at New Orleans (formerly Charity Hospital), New Orleans, Louisiana; the National Institute of Child Health and Human Development, Bethesda, MD (G.G.R. now at the University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey); §University of Washington, Seattle, Washington (S.L.H. and M.A.K. (now at the University of Pittsburgh, Pittsburgh, Pennsylvania); University of Texas Health Science Center, San Antonio, Texas (R.S.G. now at the University of Colorado); University of Oklahoma, Oklahoma City, Oklahoma; **Columbia University, New York, New York; and ††Research Triangle Institute, Research Triangle Park, North Carolina.

The authors thank Dr. Shiriki Kumanyika for her helpful comments on an earlier draft of this paper, to the numerous study personnel for their diligence, and to the many women for volunteering their participation in this study.

Other members of the Vaginal Infections and Prematurity Study Group include: Sumner J. Yaffe, MD, Charlotte S. Catz, MD, Donald McNellis, MD, and Heinz W. Berendes, MD, MHS, from the National Institute of Child Health and Human Development, Bethesda, MD; William C. Blackwelder, PhD, Richard A. Kaslow, MD, MPH (now at the University of Alabama, Birmingham, AL), and George F. Reed, PhD, from the National Institute of Allergy and Infectious Diseases, Bethesda, MD; Ellen M. Greenberg, MS, from Columbia University, New York, NY; Sterling Williams, MD, from Harlem Hospital Center, New York, NY; and Philip J. Rettig, MD, from the University of Oklahoma, Oklahoma City, OK. Supported in part by contracts HD-3–2832 through HD-3–2836 and AI-4–2532 from the National Institutes of Health.

Reprint requests: Robert P. Nugent, PAMA, CRMC, NICHD, Executive Building, Room 4B11J, 6100 Executive Boulevard, MSC 7510, Bethesda, MD 20892–7510.

Received for publication July 29, 1996, revised October 11, 1996, accepted October 17, 1996.

PRETERM delivery and low birth weight remain significant public health problems in the United States, particularly among nonwhite populations, although their cause remains elusive.1,2 Seven studies have suggested that pregnant women infected with the protozoan, Trichomonas vaginalis, may be at increased risk of having an adverse pregnancy outcome.3–9 In five cohort studies, an association of T. vaginalis was reported with premature membrane rupture,5 preterm delivery,7,9 low birth weight among women with spontaneous membrane rupture,3 and low birth weight and preterm delivery.4 In two other studies, data from treatment trials support a positive but not statistically significant association between T. vaginalis infection and preterm delivery.6,8 All of these studies are limited by small sample size, select patient populations, suboptimal T. vaginalis detection methods, or failure to consider simultaneously other possible explanatory factors.

To evaluate more definitively the association between infection with T. vaginalis and adverse pregnancy outcome, a large enough sample is needed to consider the combined influence of demographic and behavioral characteristics, such as race, marital status, and cigarette smoking, which are both associated with T. vaginalis carriage9,10 and related to adverse pregnancy outcome.1,2 In addition, one must consider co-infection of the genital tract with other sexually transmitted disease organisms, such as Chlamydia trachomatis and Neisseria gonorrhoeae, as well as with the condition bacterial vaginosis, because of their reported coexistence with T. vaginalis infection and their role in adverse pregnancy outcome.4,11 In the Vaginal Infections and Prematurity Study, a large, prospective, multicenter study, genital specimens were analyzed using culture methods for T. vaginalis. The relationship was evaluated between T. vaginalis and measures of adverse pregnancy outcome while simultaneously taking into account numerous demographic, behavioral, and other microbiologic factors.

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Methods

Patient Population

The Vaginal Infections and Prematurity (VIP) Study, a multicenter prospective study of genital infections and pregnancy outcome, enrolled women from these antepartum clinics: Columbia University and Harlem Hospital Center, New York; University of Washington, Seattle; University of Oklahoma Health Science Center, Oklahoma City; University of Texas Health Science Center, San Antonio; and Charity Hospital, New Orleans. Between 1984 and 1989, women who met the eligibility criteria and who agreed to participate were enrolled at 23 to 26 completed weeks of gestation and followed up until delivery, as described in detail elsewhere.10–12 All women gave written informed consent approved by each local Institutional Review Board before enrollment.

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Data Collection

Women were enrolled at a routine prenatal visit occurring between 23 and 26 completed weeks of gestation, at which time demographic, medical, behavioral, and sexual information was collected by interview. A pelvic examination was performed using a clean, nonlubricated speculum, and genital specimens were collected and processed as described previously.11,12 Data were collected on paper forms and sent to the independent Data Coordinating Center, Research Triangle Institute, where they were computerized. Data requiring editing were identified by quality control procedures and sent back to the centers for correction.

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Microbiologic Procedures

Specimens used for the detection of T. vaginalis were collected from the posterior vaginal fornix using a sterile, cotton swab and were inoculated directly into a tube of modified Diamond's medium.13 Cultures were incubated at 37 °C in room air. At 2- to 3-day intervals, aliquots of media were drawn from the bottom of the tube using a Pasteur pipette and examined microscopically under 400x power for the presence of motile, oval flagellated protozoa. Specimens showing no organisms after incubation for 5 days were considered negative for T. vaginalis. To ascertain the reproducibility of the culture results, duplicate cultures were performed on specimens obtained from a sample of 670 women, resulting in 97.2% agreement. A determination of bacterial vaginosis was made based on a Gram's stain scoring method in combination with a vaginal pH above 4.5.11 All other microorganisms were detected using culture methods as described previously.11,12 Laboratory work was performed at each institution using a common protocol and without awareness of the patient's clinical assessment.

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Outcome Definitions

The primary outcomes of interest were delivery before 37 completed weeks of gestation (preterm delivery) and/or delivery of an infant weighing less than 2,500 g at birth (low birth weight). Secondary outcomes that were considered included rupture of fetal membranes before onset of labor (PROM), PROM before 37 completed weeks of gestation (preterm PROM), postpartum endometritis, stillbirth, and neonatal death. Gestational age was estimated from the date of a woman's last menstrual period supplemented by clinical examination and ultrasound information, when available.

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Statistical Analysis

Associations between T. vaginalis and measures of adverse pregnancy outcome were first identified in a univariate fashion using chi-square statistics for categorical outcome measures and t-test values for continuous outcome measures using the SPSS package for personal computers (SPSS, Inc., Chicago, IL). Bivariate analyses were conducted using Mantel-Haenszel statistics. Multiple logistic regression analysis was performed to determine whether T. vaginalis remained associated with a primary outcome after adjusting for potential confounders. Factors considered as possible covariates included enrolling institution, race, age group (< 20 years; 20 to 24 years; 25 to 29 years; and 30 years and over), smoking during pregnancy, marital status, education, household income, gravidity, prepregnancy weight (by quartile), previous adverse pregnancy outcome, other coflora including Candida spp., N. gonorrhoeae, Mycoplasma hominis, Ureaplasma urealyticum, anaerobic gram-negative rods, Chlamydia trachomatis, bacterial vaginosis, and intercurrent metronidazole use. Adjusted odds ratios from logistic regression analysis with corresponding 95% confidence intervals14 and attributable risks (composite measures reflecting the level of risk associated with T. vaginalis infection and the prevalence of T. vaginalis infection in this cohort)15 were calculated.

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Results

Of the 13,914 women enrolled in the VIP study, 13,816 (99.3%) were tested for T. vaginalis at 23 to 26 weeks of gestation, and 1,736 women (12.6%) had a positive culture (Table 1). As reported on this population previously, women infected with T. vaginalis were more likely to be black, never married, less educated, economically disadvantaged, and cigarette smokers.10 It is noteworthy that these same demographic subgroups of women also experienced higher rates of preterm delivery and low birth weight infants (Table 1).

TABLE 1

TABLE 1

Of the women with T. vaginalis, 11.5% had a low birth weight infant compared with 7.1% of uninfected women (Table 2). Women infected with T. vaginalis were also significantly more likely to deliver preterm, deliver a low birth weight infant preterm, have preterm premature rupture of fetal membranes, and have postpartum endometritis compared with women without T. vaginalis. Infected women were almost twice as likely to have a stillbirth or a neonatal death compared with uninfected women. There was no association between T. vaginalis colonization and premature membrane rupture. Infants born to infected mothers had significantly lower mean gestational ages at birth and mean birth weights. Even when preterm delivery was redefined to be delivery before 34 weeks of gestation, infected women were at significantly greater risk compared with uninfected women (6.4% vs. 4.6%, p < .002).

TABLE 2

TABLE 2

Bivariate associations between T. vaginalis and a variety of potentially confounding factors were examined to evaluate the consistency of the univariate associations across subgroups of women. The increased risk of preterm delivery and low birth weight among women infected with T. vaginalis was consistent across enrolling institutions and by race. Infected women were significantly more likely to have an adverse pregnancy outcome regardless of their smoking status. The association between infection and adverse pregnancy outcome was also independent of the presence or absence of bacterial vaginosis, group B streptococci, or other sexually transmitted diseases.

The rates of low birth weight, preterm delivery, and preterm delivery of a low birth weight infant in women infected or co-infected with T. vaginalis and bacterial vaginosis are displayed graphically in Figure 1. Compared with uninfected women, women with bacterial vaginosis but not T. vaginalis had a 39% increased risk of delivering a low birth weight infant. Conversely, women infected with T. vaginalis but not bacterial vaginosis had a 68% increased risk, whereas women with bacterial vaginosis who also were infected with T. vaginalis had a 103%, or twofold, increased risk compared with uninfected women and a higher risk compared with women with either infection alone. Similarly, compared with uninfected women, these three other subgroups of women, respectively, had a 11%, 33%, and 60% increased risk of delivering preterm and a 40%, 57%, and 120% increased risk of preterm delivery of a low birth weight infant. There was no statistically significant interaction in risk among women having both bacterial vaginosis and T. vaginalis infection, beyond additivity of the combined independent effects associated with having either condition.

Figure 1

Figure 1

In order to allow for the simultaneous adjustment of multiple epidemiologic characteristics and co-infections reported to be associated with T. vaginalis carriage and with having an adverse pregnancy outcome, logistic regression analysis was performed. The unadjusted and adjusted odds ratios and their corresponding 95% confidence limits are presented in Table 3. After considering multiple possible covariates, women infected with T. vaginalis were 30% more likely than uninfected women to deliver preterm or to have a low birth weight infant and 40% more likely to both have an infant who was delivered preterm and at a low birth weight.

TABLE 3

TABLE 3

Overall, in this study, 3.6% of low birth weight was attributed solely to infection with T. vaginalis. Although the risk of low birth weight among infected women was not significantly different for black, Hispanic, and white women, there were striking differences in prevalence rates of T. vaginalis, and the risks of low birth weight attributable to T. vaginalis infection were estimated to be 11.0% in black, 1.6% in Hispanic, and 1.5% in white women. The attributable risks of T. vaginalis on preterm delivery were estimated to be 8.0% in black, 1.6% in Hispanic, and 0.6% in white women.

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Discussion

In this large cohort study, T. vaginalis was associated with a 40% increase in preterm low birth weight and a 30% increase in low birth weight and preterm birth as separate outcomes after adjustment for a variety of possible explanatory factors. The effect of T. vaginalis on pregnancy outcome was independent of bacterial vaginosis, another infection highly associated with preterm low birth weight in this cohort.11 It is noteworthy that cocaine use (as detected by serum analysis) in this population was uncommon (2.3%) and unrelated to preterm delivery and low birth weight as has been reported previously.16

There have been other published accounts of adverse pregnancy outcomes associated with T. vaginalis.3–9 Grice3 observed in 8,128 public patients a statistically significant association between T. vaginalis infection diagnosed using Papanicolaou smears at the first prenatal visit and spontaneous membrane rupture resulting in the delivery of an infant weighing 1,000 to 2,500 g (crude relative risk, 2.6, 95% confidence interval 1.5 to 4.5). Using second trimester culture results from 188 predominately black women of low socioeconomic status, Mink-off and colleagues5 found that infected women were significantly more likely to have premature membrane rupture (crude relative risk, 1.4; p < 0.03). Among 115 randomly selected pregnant teenagers of low socioeconomic status in inner-city Baltimore, Hardy and coworkers4 found that the rate of low birth weight infants born to the 39 adolescents infected with T. vaginalis as detected in third trimester cultures was significantly higher than the low birth weight rate in teenagers without T. vaginalis (18.0% versus 6.7%). The mean gestational ages at delivery were also lower in T. vaginalis-infected adolescents (38.2 ± 2.7 weeks vs. 39.5 ± 2.1 weeks).

In Denver, McGregor and colleagues enrolled 1,260 women into a two-phased prospective treatment trial designed to evaluate and reduce the risk of adverse pregnancy outcomes among women infected with common genital tract microorganisms.8 They found that untreated women with both bacterial vaginosis and T. vaginalis infection had a significant increase in preterm delivery (relative risk, 3.3, 95% confidence interval 1.0 to 10.7). After multivariate analysis, women with T. vaginalis remained at increased risk of a preterm birth, although the finding was not statistically significant (odds ratio, 1.5, 95% confidence interval 0.8 to 2.7).

Based on a multicenter cohort of 2,929 women, Meis and colleagues reported the odds ratios of spontaneous preterm birth at less than 35 weeks gestation among patients with T. vaginalis positive wet mount results at 24 weeks' gestation to be 1.5 (95% confidence interval, 0.1 to 1.8) and at 28 weeks' gestation to be 0.9 (95% confidence interval, 0.2 to 3.6).9 Riduan and coworkers7 also reported an increased risk of preterm delivery among T. vaginalis infected mothers compared with mothers without T. vaginalis infection (23.1% vs. 12.7%), although the numbers of infected women were too small for the association to be statistically significant.

Given the modest 30% to 40% increased risk of adverse pregnancy outcome observed in this study, it is not surprising that more studies have not been able to show a statistically significant relationship between T. vaginalis and adverse pregnancy outcome, although an elevated risk was observed.6–8 The present study was able to detect an association because of its large sample size and resultant greater statistical power, its use of culture as a more sensitive diagnostic method, and its ability to consider simultaneously multiple infections. Absent of these study design features, the independent effect of T. vaginalis infection as a risk factor for adverse pregnancy outcome may have been obscured in previous studies.

The attributable risks calculated for this study may not be directly applicable to other populations of women with different rates of infection from those reported in this study. Infection rates among pregnant women have been reported to range between 3% to 48%,4–6,8,9,17,18 depending on the composition of the study population, the detection method used, and the inclination to treat or not to treat infected women and their sexual partners. The higher infection rate among black women observed in this study is consistent with other studies in nonpregnant women.19–21

Although it is beyond the scope of this article to speculate as to the specific role T. vaginalis may play in the pathogenesis of an adverse pregnancy outcome, it can be noted that several plausible mechanisms have been reported. Extracellular proteases are produced by T. vaginalis, and these may play a role in adherence of the parasite to vaginal epithelium.22 Gonorrhea and mycoplasmas have been shown to be phagocytized by trichomonads,23,24 and viral RNA segments have been found in certain pathogenic strains of T. vaginalis.25–28 Because of its relationship with these other microbes, it is possible that this motile protozoa may serve as a vector for another pathogen.29 Finally, the inflammatory response generated by trichomonal infection in the cervix may directly or indirectly lead to inflammatory changes in the decidua or fetal membranes.30

Currently, in most clinical settings, only symptomatic women are routinely tested for T. vaginalis. It would be preferable to have a more encompassing risk assessment tool to identify women who would most benefit from screening for T. vaginalis infection. An unfortunate limitation of this study is that information was collected on clinical signs but no data was collected on symptoms, and, partly because of this, we were unable to develop a clinically useful algorithm to predict which women to screen.10 Given the high costs associated with an adverse pregnancy outcome and if treatment is found to reduce risk, it may be more cost-effective to screen all women presenting in high-risk settings.

At present, patients are usually screened for T. vaginalis using the wet mount technique. This method is not sensitive enough to identify women with low-density colonization. Although culture would be a preferred screening method, its widespread use is impractical. The largest proportion of infected women in this study were of low socioeconomic status. Therefore, if the findings of this study are generalizable, the greatest need for screening services will be in public clinics. Development of an inexpensive, rapid, sensitive, and specific diagnostic test for T. vaginalis will be necessary to meet this need. Clinics serving high-risk patients should be encouraged to use wet mount preparations and pap smears as screening tools to identify infected individuals and to seek out additional resources with which to implement more sensitive screening methods as they become available.

Because T. vaginalis is a sexually transmitted pathogen, the screening and treatment of sexual partners of infected women are warranted as a public health measure31,32 to prevent reinfection as well as to reduce the risk of morbidity in their sexual partners. The impact of this sexually transmitted pathogen on men is also important as associations have been reported between Trichomonas vaginalis and epididymitis, prostatitis,33 nongonococcal nonchlamydial urethritis,34–37 infection of the median raphe of the penis,38 and infertility.39–41 In addition to its role in adverse pregnancy outcome, T. vaginalis has been associated with endometritis, infertility, ectopic pregnancy, and non-HPV associated cervical neoplasia42–46 as well as with respiratory disease among infants delivered vaginally from infected mothers.47

Although there is some hesitancy to administer metronidazole during pregnancy, analysis of medications from a Medicaid database shows that metronidazole is being prescribed for pregnant women48 and is reported to be safe.49–50 Apart from the VIP study protocol, we were able to identify 432 women in this cohort who were prescribed metronidazole in the period between study enrollment and delivery, 176 (41%) of whom had T. vaginalis. Although we have no way of measuring compliance, no significant adverse events were reported for these women. On the other hand, because metronidazole was not randomly assigned to women in this study and the standard of care for these T. vaginalis-infected women differed by enrolling institution and by physician, there is no evidence to suggest that treatment was effective at reducing risk of an adverse outcome. Therefore, before advocating routine treatment during pregnancy, it would be prudent to conduct a randomized, placebo-controlled treatment trial to determine whether treatment reduces risk of adverse outcome in women infected with T. vaginalis. Such a trial, designed to evaluate the benefit of treating women with T. vaginalis and/or bacterial vaginosis to prevent adverse pregnancy outcome, is under way in the National Institute of Child Health and Human Development's Maternal-Fetal Medicine Units Network. If this trial demonstrates a beneficial effect of treatment on reducing the rates of infection and the frequency of preterm delivery and low birth weight, a substantial number of premature births may be preventable. The greatest benefit of treatment, if deemed efficacious, may be among black women because this population has high infection rates and a high incidence of low birth weight infants. While awaiting the results of this randomized controlled trial, the authors suggest that increased resources be directed toward the identification and treatment of nonpregnant infected women and their sexual partners.

It is important to place the results of this study in a public health context. The vast majority of premature babies are not born to mothers infected with T. vaginalis. On the other hand, this sexually transmitted pathogen is widely prevalent and trichomoniasis is amenable to simple antimicrobial treatment. More attention needs to be focused on this parasite to further clarify its risk to women and their infants.

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