Prevalence of Cervico-vaginal Infection by Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum and Beta-hemolytic Streptococcus B in Pregnant Women
J.C. Vázquez Niebla
Some of the most frequent microorganisms associated with premature rupture of membranes (PROM) and preterm labor are Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum and beta-haemolytic group B Streptococcus (GBS). A possible pathophysiologic explanation is that the microorganisms are able to ascend from the cervix through the internal ostium and colonize the fetal membranes. They as well as neutrophils and lymphocytes produce an inflammatory response, that may destroy or weaken the fetal membranes. It is demonstrated that microorganisms produce mucinase that may hydrolyse protective cervical mucine as well as immunoglobulin A (IgA) protease, which can destroy mucosal membrane IgA, an important element of the reproductive tract immune system. Bacteria may also produce an increase of arachidonic acid and prostaglandins, increasing the frequency of non-labor uterine contractions. Vaginal, cervical and fetal membrane infection is associated with maternal sepsis, uterine contractility disorders and cesarean section. In fetus and neonate PROM it is associated with late decelerations, fetal distress, hyaline membrane disease, prematurity, sepsis and admission to Neonatal Intensive Care Units (NICU). It is our proposal to carry out an observational study in order to know the prevalence of vaginal and cervical infection by Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum and beta-haemolytic group B Streptococcus in pregnant women. We will study 600 pregnant women coming to "America Arias" Hospital for routine ultrasound, with gestational age between 20 and 26 weeks and living in Centro Habana or Habana Vieja municipalities. Four laboratory samples will be taken to know the prevalence of Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum and beta-haemolytic group B Streptococcus. Four forms will be filled with data from interviews and clinical records: consent, inclusion criteria, treatment, and final outcomes. Patients having a positive culture for Chlamydia trachomatis will receive a single dosage of azithromycin (1 g orally), together with their partners. This treatment will be administered on an outpatient basis.
Inclusion criteria : gestational age between 20 and 26 weeks and consent to participate.
Exclusion criteria : gestational age less than 20 or more than 26 weeks; do not agree to participate in the study; have a history of adverse reaction to macrolides (e.g. erythromycin); multiple pregnancy, suspected or confirmed fetal congenital malformation by ultrasound, liver disease and/or concurrent intake of hepatotoxic medicines or other antibiotics. Women will be exluded from the study if it is requested by them, PROM or delivery occurs or if they do not continue the follow-up.
Data will be coded, monitored and verified by means of Data Base and EPI-INFO programs.
Analysis will be made by means of frequency tables.The study will last two years and it will be conducted with the collaboration of the Microbiology Department of "America Arias" Hospital.
The main problem anticipated is to retrieve the patients with positive sample for Chlamydia trachomatis in order to administer them and their partners the antibiotic. It will be solved collaborating with primary attention clinics and personal visits of the principal investigator and collaborating personnel. The expected main objective is to know the prevalence of cervical and vaginal infections in pregnant women. In our country there is no existing data available..
Description of the project
Some of the most frequent microorganisms associated with premature rupture of membranes (PROM) and preterm labour are Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum and beta-haemolytic group B Streptococcus (GBS). Some information may lead to conclude that the presence of bacterial vaginosis may be responsible for the occurrence of PROM and subsequent preterm delivery in a significant number of pregnant women. Premature rupture of membranes (PROM) is still an important perinatal problem. It is defined as the rupture of the fetal membranes at least one hour before labor starts at any time during pregnancy. In our hospital it occurs in approximately 20% of all births.With regard to the mother, PROM is associated to:
Prolonged PROM (latency greater than 24 hours) increases morbidity/mortality and preterm labor risk.
PROM is associated with infectious and non-infectious factors. Non-infectious factors are mechanical (vaginal examination, coitus, amniocentesis, intra amniotic catheters), cervical incompetence, ascorbic acid, zinc and copper deficiency, preterm labor and increased intraamniotic pressure (polyhydramnios, multiple gestation). These factors may act synergistic with abnormal microbial flora of the reproductive tract, which is perhaps more important than non-microbial factors in the occurrence of PROM.
Preterm delivery is defined as delivery that occurs before the 37th week of pregnancy. It is also an important perinatal problem. Its world incidence is difficult to know because of the subregisters in developing countries. In our hospital it is about 4% of all births. Because of the great contribution of preterm delivery to perinatal morbidity/mortality rates, several studies have been carried out in order to identify the possible causes and associated risk factors and to decrease its incidence. In Cuba, two vaginal samples, (first and third trimester), are taken from pregnant women to identify the presence of C albicans, T vaginalis and G vaginalis. Treatment is given when samples are positive. It consists of vaginal tablets of nystatin (100 000 I.U. twice per day) for C albicans, and vaginal tablets of metronidazole (500 mg three times per day) for T vaginalis and G vaginalis. The main objective of this project is to study the prevalence of Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum and beta-haemolytic GBS because of their possible role in the occurrence of PROM and preterm labor.
To know the prevalence of Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum and beta-haemolytic GBS infection in pregnant Cuban women.
Much recent information suggests that abnormal reproductive tract host-microbial relationships may be responsible for the occurrence of PROM and subsequent preterm delivery in a significant number of pregnant women. Some of the most frequent microorganisms associated with premature rupture of membranes (PROM) and preterm labor are Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum and beta-haemolytic GBS.
We performed a review from MEDLINE database in order to know the prevalence of these microorganisms in the different countries in the last two years. We found that prevalence has a great variation according to authors and countries. Chlamydia trachomatis is detected in about 10% of pregnant women, with a range between 3-25% in low risk/asymptomatic women, which may be higher in high risk or symptomatic women. With regard to Group B Streptococcus, frequency is about 15%, with a range between 5-30%. Ureaplasma urealyticum has been isolated in about 40% of screened populations (range 6-55%). Mycoplasma hominis has been found in about 10% of pregnant women, although in high risk population, the reported prevalence is 40%.
A possible pathophysiologic explanation is that the microorganisms are able to ascend from the cervix through the internal ostium and colonize the fetal membranes. Bacteria as well as neutrophils and lymphocytes produce an inflammatory response that may destroy or weaken collagen that constitutes the connective tissue framework, which gives both strength and elasticity to fetal membranes. It is demonstrated that microorganisms produce mucinases that may hydrolyse protective cervical mucin as well as immunoglobulin A (IgA) protease, which can destroy mucosal membrane IgA, an important element of the reproductive tract immune response.Other bacteria-associated factors may also mediate PROM and preterm labor. They are:
Prostaglandins (Pg) E2 and F2 Alfa play a role in cervical softening, the formation of myometrial gap junctions and in the increase in myometrial free calcium content, which stimulates uterine tone and contractions.
Arachidonic acid serves as a limiting substrate for Pg production. Its product of degradation is leucotriene B4.
Lipopolysaccharides (LPS) are produced by bacteries and stimulate macrophages and decidual cells to release a variety of cytokynes such as Tumor Necrosis Factor alfa (TNF); Interleukin 1, 6 and 8, and Macrophage Colony Stimulating Factor. They stimulate Pg production from Arachidonic acid.
Platelet-activating Factor (PAF) may be released by LPS action on macrophages or decidua or through platelet aggregation caused by inflammatory endothelial changes.
Some trials have been conducted in order to prevent preterm labor using antibiotics. Morales et al. and Newton et al. used erythromycin and found no association between the use of antibiotic and the occurrence of delivery after 14 days of starting treatment. They found a protective effect on the occurrence of the delivery after 37 weeks of pregnancy (O.R.= 0.49; 95% C.I.: 0.28-0.85).
Kirschbaum carried out a review of prospective, randomized trials using antibiotics for the prevention of PROM and preterm labor. He found the following results :
In a placebo controlled trial Mc Cormack used erythromycin and clindamycin in pregnant women between 22 and 32 weeks with vaginal swab culture positive for M hominis or U urealyticum. There were no differences between the groups regarding the incidence of preterm labor, PROM or perinatal mortality.
Eschenbach used erythromycin in pregnant women between 23 and 26 weeks having positive vaginal culture for U Urealyticum, beta-haemolytic Streptococcus serogroup B and C trachomatis. There were no differences between the groups regarding the incidence of PROM or perinatal mortality.
Mc Gregor used erythromycin in pregnant women between 26 and 30 weeks. PROM occurred less frequently in treated (6%) than untreated women (16%, p<0.01). Preterm PROM, birth weight, preterm labor and perinatal mortality rates were unchanged.
Ryan et al. used erythromycin in pregnant women with vaginal culture positive for C trachomatis. The treated group had a lower incidence of PROM (2.9% vs 5.9%) and a lesser incidence of low birth weight (11% vs 19.6%). Lower perinatal mortality rates were also seen in this group (0.6% vs 2.4%).
Mc Gregor et al. critically reviewed obstetric, epidemiologic, microbiologic and pathophysiologic information regarding the possible causal relationship of bacterial vaginosis (BV) and PROM.
Gravett et al. found that BV was significantly associated with the occurrence of preterm PROM (O.R.= 2.0; 95% C.I.: 1.1-3.7), preterm labour (O.R.= 2.0; 95% C.I. 1.1-3.5) and amniotic fluid infection (O.R.= 2.7; 95% C.I.: 1.1-6.1). Cervical infection for C trachomatis was also independently associated with these events.
Kurki et al. demonstrated a 7.3 fold-risk (95% C.I.: 1.8-29.4) for preterm PROM for women with BV.
Hillier et al. demonstrated a strong correlation between preterm birth (<37 weeks) and BV (R.R.= 3.2; 95% C.I.: 1.1-6.6). PROM was the only obstetric factor associated with preterm deliveries in these patients.
Cohen et al. found that the incidence of PROM and preterm labor was reduced when erythromycin was used in pregnant women with vaginal culture positive for C trachomatis.
Minkoff et al. found BV in 40% of patients with PROM compared with 28% of control subjects who delivered at term. Bacteroids and M hominis were recovered from the vagina. T vaginalis was also associated with PROM.
Gravett et al. found a strong association between BV and preterm labour (43% for study patients vs 14% of control patients; p= 0.02; R.R.= 3.8). PROM occurred in many of these patients.
Martius et al. had similar findings. BV was significantly associated with preterm labour (O.R.= 2.3). 70% of women in preterm labor had PROM.
French et al. found ethnical differences in the presence of BV and the occurrence of preterm PROM: BV was associated with preterm PROM among nonwhites (BV 17.2%, non-BV 1%), but not among white women (BV 4.4%, non-BV 3.2%).
Controlled clinical trials
Thomson et al found that penicillin treatment for group B streptococcus bacteriaemia or urinary tract infection during pregnancy was associated with reduced risk of PROM and preterm birth.
Mc Gregor et al. used erythromycin in a placebo controlled study and demonstrated reduced occurrence of PROM (p<= 0.01) and preterm PROM (p= 0.02).
Design and Methodology
An observational study will be carried out in order to know the prevalence of cervical and vaginal infections in pregnant women between 20 and 26 weeks coming to the hospital for routine ultrasound (which is performed on all pregnant women in order to detect genetic malformations). Four laboratory samples will be taken from 600 patients in order to know the prevalence of Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum and beta-haemolytic GBS. Four forms will be filled during personal interviews and from clinical records: consent, inclusion, treatment and final outcomes.
Pregnant women testing positive for Chlamydia trachomatis will be treated, together with their partners, with azithromycin, 1 g orally, single dose.
It will be an observational study as for ethical reasons it would not be acceptable to withhold antibiotic treatment from a woman with positive diagnosis of cervical and vaginal infection. Thus, it is not possible to carry out a placebo-controlled clinical trial.
The treatment will be administered to the patients and their partners on an outpatient basis.
Criteria for the selection of subjectsSubjects will be selected from pregnant women coming to "America Arias" Hospital from Centro Habana and Habana Vieja municipalities for routine ultrasound, with the following characteristics:
Antibiotic treatment will be administered to patients with a positive sample for Chlamydia trachomatis, as well as to their partners, considering C trachomatis as a high risk factor for PROM and preterm labor.
Patients testing positive for Chlamydia trachomatis will have an appointment at the hospital's outpatient service for prescription of the treatment.
Description of drugs and devices to be studied
240 complete doses of azithromycin ( 4 tablets for 250 mg, 1 g orally, once a day, single dosage) will be necessary in order to treat all possible patients and her partners. It will be administered by the principal investigator, because this drug is not available in Cuban pharmacies.
After the ultrasound a cervical and vaginal swab sample will be taken from patients who accepted to participate in the study. Four gentle samples will be taken in order to screen the presence of one or more than one germ.The followng baseline data will be recorded:
The administration of the antibiotic will start once the patient with one positive sample for Chlamydia trachomatis arrives at the hospital's outpatient department, and it will be a personal responsibility of the Principal Investigator.
Follow-up procedureThe principal investigator will be informed by the microbiologist about the results of the sample and the following data will be recorded:
After the treatment patients will continue to attend their primary antenatal care physician or return to the hospital if any problems occur.
Criteria for discontinuationSubjects will be excluded from the study if one of the following events occur:
Laboratory and other investigations
The following microbials will be screened for in each patient: Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum and beta-haemolytic GBS. In order to achieve reliable results, appropriate samples must be taken as follows:
Collection, transportation and preparation of samples for microbiological analysis
The patient will take gynecological position and the speculum will be placed in the vagina. The speculum will be moistened with warm water since the lubricants contain antibacterial agents. After cervix visualization, the mucus will be removed by gentle rubbing of the area with a cotton ball and a special nontoxic dracon swab will be used for sampling.
For C trachomatis detection, the swab will be inserted into the cervix, rotated and moved from side to side for 30 seconds before it is removed. The swab will be placed in 1 ml working strength transport medium in a heat resistant vial (IDEIA Specimen Collection kit). The sample will be stored at 4°C and transported to the laboratory as soon as possible. Once in the laboratory, the vial will be shaken by using vortex and treated as it is indicated for the detection of Chlamydia antigens by using commercial ELISA tests (IDEIA Chlamydia kit, DAKO, Denmark).
For M hominis and U urealyticum samples will be taken from the upper part of the vagina. The swabs must be placed in trypticase soy broth with 0.5% albumin and 400 u/ml of penicillin. Culture methods for both germs will be applied according to previously published papers (Clyde et al 1984 and Mardh 1984).
For GBS the sample will also be taken from the upper part of the vagina. The swab will be placed in a Stuart transport medium and should arrive at the laboratory within two hours. The samples will be inoculated on Columbia blood agar base with 5% CO2 for at least a week. Identification of the streptococcus should be done by careful examination of colony morphology and hemolytic patterns. Final identification will be done by coagglutination (Phadebact, Boule Diagnostic)
Data about date and time of enrolment, treatment allocation and time of delivery will be recorded. Data will be coded in order to be processed later with a personal computer.
MonitoringA monthly report will be performed in order to be up to date about the recruitment status (see Appendix II). It will include:
A program to verify the data entry will be done with EPI-INFO system in order to detect range and consistence errors During the study 10% of all the subjects (60 patients) will be selected at random and data filling will be repeated and compared.
Data analysis will be done by means of EPI-INFO program with a personal computer.
Frequency tables will give information about the prevalence of cervical and vaginal infections and patients' socio-demographic characteristicsThe following outcome measures will be recorded:
Data will be analyzed according to the different socio-economic levels of the women.
Sample size and statistical power:
The following formula was used to determine the sample size:
n= N x Z2 x p x q / N x d2 + Z2 x p x q
N = Size of the population in study (3000 births per year)
d = Precision of the estimator (0.05)
p = Theoretical prevalence (0.10). This is the Chlamydia trachomatis' mean prevalence in asymptomatic pregnant women estimated from reports in other countries, since it is unknown in Cuba.
q = 1 - p Z = 2
549 subjects are necessary to carry out the project. Taking into account the possible loss to follow-up, it will be necessary to recruit 600 subjects.
Duration of the project
The estimated time to complete for the study is two years.
Overall responsibility for the project:
Dr Juan Carlos Vázquez (design, implementation, co-ordination, monitoring, interpretation, writing)
Main anticipated problems
The main problem anticipated is the allocation and appointment of patients testing positive for Chlamydia trachomatis in order to administer them and their partners the antibiotic. It will be solved by collaborating with primary care clinics and visits of the principal investigator and collaborating personnel.
Expected outcome of the study
It is expected to know the prevalence of infection by Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum and beta-haemolytic GBS in pregnant women.
The findings of this study will be disseminated by means of national and international medical journals.
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