Prevalence of Cervico-vaginal Infection by Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum and Beta-hemolytic Streptococcus B in Pregnant Women
J.C. Vázquez Niebla
Research Department "America Arias" Hospital, Director: Dr Ubaldo Farnot
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:
- Sepsis (endometritis and parametritis)
- Irregularities in uterine contractility
- Induced labour
- Cesarean section
- Preterm delivery
- Late decelerations
- Fetal distress
- Breech presentation
- Caput succedaneum and cephalhaematoma
- Hyaline membrane disease
- Umbilical cord prolaps
- Admission to Neonatal Intensive Care Units (NICU)
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:
- Polyamines such as putrescine
- Short chain fatty acid salts such as butyrate and propionate
- Succinate reduces polymorphonuclear cell chemotaxis and may impair host responses to microorganisms.
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:
- Consent to participate
- Gestational age between 20 and 26 weeks (in order to guarantee the accomplishment of the treatment before the delivery)
- No consent to participate
- Gestational age less than 20 and more than 26 weeks
- Referred allergies to macrolides
- Multiple pregnancy
- Suspected or confirmed fetal congenital malformation by ultrasound
- Referred liver disease
- Current intake of hepatotoxic medicines
- Current intake of other antibiotics
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:
- Obstetric history
- Gestational age (by day of last menstrual period and ultrasound)
- Marital status
- Family income
- Number of persons living with the patient
- Number of rooms in the house
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:
- Data of personal identification
- Isolated microorganisms
- Data of personal identification
- Isolated microorganisms
- Date treatment started
- Gestational age when the treatment started
- Adverse effects of the treatment
- Date of completion of treatment
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:
- It is requested by the patient
- PROM or delivery
- Patient does not attend the follow-up
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:
- Number of subjects who accepted to enter the study
- Number of subjects who refused to enter
- Number of subjects with positive samples
- Number of subjects with negative samples
- Number of patients who completed the treatment
- Number of patients who abandoned the treatment
- Number of patients who delivered
- Number of patients lost to follow-up
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:
- Date of delivery
- Birth weight
- Gestational age at delivery
- Occurrence of PROM
- PROM latency
- Neonatal sepsis
- Admission to NICU
- Days of admission to NICU
- Newborn status at hospital discharge
- Newborn age at death
- Occurrence of maternal sepsis
- Days of maternal hospitalisation
- Other antibiotics used
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.
1- Abdul-Karim RW, Beydoun SN. Parto prematuro. In: Iffy L, Kaminetzki HA (eds) Obstericia y Perinatología. Principios y práctica. Buenos Aires, Médica Panamericana 1986, T II, Cap 82: 1461-1472
2- Abele- Horn M,Wolff C, Dressel P, Pfaff F, Zimmermann A. Association of Ureaplasma urealyticum biovars with clinical outcome for neonates, obstetric patients, and gynecological patients with pelvic inflamatory disease. J Clin Microbiol 1997, 35: 1199-1202
3- Alkalay Al, Brunell PA, Greenspon JS, Pomerance JJ. Management of neonates born to mothers with group B streptococcus colonization. J Perinatol 1996, 16: 470-477
4- Amin JD, Zaria LT, el-Nafaty AU, Mai AM. Genital Chlamydia trachomatis infection in women in a Nigerian hospital. Genitourin Med 1997, 73: 146-147
5- Andreu Domingo A, Salcedo Abizanda S, Heredia Prim F, Gonzalez Morlan J, Bartolome Comas RM, Cabero Roura L. Characteristics of group B streptococcus vertical transmission. An Pediatr 1997, 46: 383-388
6- Andrews WW, Lee HH, Roden WJ, Mott CW. Detection of genitourinary tract Chlamydia trachomatis infection in pregnant women by ligase chain reaction assay. Obstet Gynecol 1997, 89: 556-560
7- Baker CJ. Group B streptococcal infections. Clin Perinatol 1997, 24: 59-70
8- Belady PH, Farkouh LJ, Gibss RS. Intraamniotic infection and premature rupture of membranes. Clin Perinatol 1997, 24: 43-57
9- Bihari A. Screening of sexually transmitted diseases (Myco- plasma hominis, Ureaplasma urealyticum and Chlamydia trachomatis) in young women. Orv Hetil 1997, 138: 799-803
10- Blaszczak I, Barlowska Z, Lubera K, Rzeszutek K. Chlamydia trachomatis in inminent premature deliveries. Pol Merkuriusz Lek 1997, 3: 234-235
11- Calleri L, Porcelli A, Gallello D, Tacanni C, Surico N. Bacterial vaginosis and premature membrane rupture: an open study. Preliminary data. Minerva Ginecol 1997, 49: 19-23
12- Chaisilwattana P, Chuachoowong R, Siriwasin W, Bhadrakom C, Mangclaviraj Y, Young NL, Chearskul S, Chotpitayasunondh T, Mastro TD, Shaffer N. Chlamydial and gonococcal cervicitis in HIV-seropositive and HIV sero-negative pregnant women in Bangkok: prevalence, risk factors, and relation to perinatal HIV transmission. Sex Transm Dis 1997, 24: 495-502
13- Cheon-Lee E, Amstey MS. Compliance with the Centers for Disease Control and Prevention antenatal care culture protocol for preventing group B streptococcal neonatal sepsis. Am J Obstet Gynecol 1998, 179: 77-79
14- Chlamydia trachomatis genital infections--United States 1995. MMWR Morb Mortal Wkly Rep 1997, 46: 193-198
15- Chokephaibulkit K, Patamasucon P, List M, Moore B, Rodriguez H. Genital Chamydia trachomatis infection in pregnant adolescentes in east Tennessee: a 7-year case-control study. J Pediatr Adolesc Gynecol 1997, 10: 95-100
16- Clarithromycin. In: Advice for the patient. Drug information and lay language. Maryland, USPDI 1995
17- Clavero-Núñez JA. Corioamnionitis. Acta Ginecol 1987, XLIV: 99-104
18- Clyde WA Jr, Kenny GF, Schachter J. Cumitech 19: Laboratory diagnosis of chlamydial and mycoplasmal infection. Diew WL (ed). American Society of Microbiology 1984, Washington DC
19- Crowley P. Antibiotics for preterm prelabour rupture of membranes. In: Chalmers I (ed) Oxford Database of Perinatal Trials. Version 1.3, Disk Issue 7, Spring 1992. Record 4391
20- de Cueto M, Sanchez MJ, Sampedro A, Miranda JA, Herruzo AJ, Rosa-Fraile M. Timing of intrapartum ampicillin and prevention of vertical transmission of group B streptococcus. Obstet Gynecol 1998, 91: 112-114
21- Deak J, Nagy E, Vereb I, Meszaros G, Kocacs L, Nyari T, Berbik I. Prevalence of Chlamydia trachomatis infection in a low-risk population in Hungary. Sex Transm Dis 1997, 24: 538-542
22- Danforth DN. Otras alteraciones y complicaciones del embarazo. In: Danforth DN (ed) Tratado de Obstetricia y Ginecología. Mexico DF, Interamericana 1987, Cap 26: 466-469
23- Diaz-Barreiro G, Diaz Lopez E, Servin-Ramirez JF. Frequency of Chlamydia trachomatis in the cervix of pregnant women during prenatal examination. Ginecol Obstet Mex 1997, 65: 48-51
24- Dong ZW, Li Y, Zhang LY, Liu RM. Detection of Chlamydia trachomatis intrauterine infection using polymerase chain reaction on chorionic villi. Int J Gynaecol Obstet 1998, 61: 29-32
25- Dowe G, King SD, Smikle MF, Wynter HH, Chout R, Klaskala W. Prevalence of viral and bacterial sexually transmitted pathogens in Jamaican pregnant women. West Indian Med J 1998, 47: 23-25
26- Driscol SG. Importancia de la corioamnionitis aguda. Clín Obstetr Ginecol 1979, 2: 321-327
27- Fu YL, Huang Y, Zhang WS. Risk factor score model of STD for pregnant women in antenatal clinic. Chung Hua I Hsueh Tsa Chih 1997, 77: 87-90
28- Gibbs RS. Corioamnionitis y patología infecciosa relacionada con la monitorización intrauterina. In: Monif GRG (ed) Enfermedades infecciosas en Obstetricia y Ginecología. La Habana, Científico-Técnica 1985, Cap 14: 353-365
29- Glantz JC, Kedley KE. Concepts and controversies in the management of group B streptococcus during pregnancy. Birth 1998, 25: 45-53
30- Goldenberg RL, Andrews WW, Yuan AC, Trent Mc Kay H, St Louis ME. Sexually transmitted diseases and adverse outcomes of pregnancy. Clin Pernatol 1997, 24: 23-41
31- Grable IA, Garcia PM, Perry D, Socol ML. Group B Streptococcus and preterm premature rupture of membranes: a randomized, double-blind clinical trial of antepartum ampicillin. Am J Obstet Gynecol 1996, 175: 1036-1042
32- Greatrex B. A review of beta-haemolytic streptococcal infection in babies. Br J Nurs 1997, 6: 486
33- Hanna ME, Ohlsson A, Wang EEL. Maternal colonization with group B streptococcus and prelabour rupture of membranes at term: the role of the induction of labour. Am J Obstet Gynecol 1997, 177: 780-785
34- Hoshina K. Minimization of the number of pregnant women to be treated with preventive procedure against GBS infection by means of antibody measurement. GBS Infection Group. Acta Paediatr Jpn 1997, 546-549
35- Iams JD, Johnson FF. Prevención del parto pre-término. Clín Obstetr Ginecol 1988, 3: 579-594
36- Jensen IP, Thorsen P, Moller BR. Sensitivity of ligase chain reaction assay of urine from pregnant women for Chlamydia trachomatis. Lancet 1997, 349: 329-330
37- Keirse MJNC. Antibiotics in preterm labour with intact membranes. In: Chalmers I (ed) Oxford Database of Perinatal Trials. Version 1.3, Disk Issue 7, Spring 1992. Record 5531
38- Keski- Nisula L, Kirkinen P, Katila ML, Ollikainen M, Suonio S, Saarikoski S. Amniotic fluid U. Urealyticum colonization: significance for maternal peripartal infections at term. Am J Perinatol 1997, 14: 151-156
39- Kieran E, Matheson M, Mann AG, Efstratiou AA, Buttler K, Gorman W. Group B streptococcus (GBS) colonisation among expectant Irish mothers. Ir Med J 1998, 91: 21-22
40- Kirschbaum T. Antibiotics in the treatment of preterm labour. Am J Obstet Gynecol 1993, 168: 1239-1246
41- Knox CL, Cave DG, Farrell DJ, Eastmen HT, Timms P. The role of Ureaplasma urealyticum in adverse pregnancy outcome. Aust N Z J Obstet Gynecol 1997, 37: 45-51
42- Ledger WJ. Infecciones bacterianas que complican el embarazo. Clín Obstetr Ginecol 1978, 2: 487-508
43- Lim CT, Thong MK, Parasakthi N, Ngeow YF. Group B streptococcus: maternal carriage rate and early neonatal septicaemia. Am Acad Med Singapore 1997, 26: 421-425
44- Macrolides. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW (eds) Goodman and Gilman's. The pharmacological basis of therapeutics. New York, Mc Graw-Hill 1996: 1135-1140
45- Main DM. Epidemiología del parto pre-término. Clín Obstetr Ginecol 1988, 3: 507-517
46- Mardh PA. Laboratory diagnosis of sexually transmitted diseases. In: Holmes KK, Mardh PA, Sparling PF, Wiesner PJ (eds). Sexually transmitted diseases. Mc Graw-Hill Book Co 1984, New York
47- McGregor JA, French JI, Reller LB, Todd JK, Makowski EL. Adjunctive erythromycin treatment for idiopathic preterm labour: results of a randomized, double-blinded, placebo-controlled trial. Am J Obstet Gynecol 1988, 154: 98-103
48- Mc Gregor JA, French JI, Richter R, Vuchetich M, Bachus V, Franco-Buff A, Hillier S, Todd JK. Prospective, double-blinded, randomized, placebo-controlled trial of short-course erythromycin (E) base in women at high risk for preterm birth. Proceedings of Annual Program of the Society for Gynecologic Investigation. 1988
49- Mc Gregor JA, French JI, Seo K. Premature rupture of membranes and bacterial vaginosis. Am J Obstet Gynecol 1993, 169: 463-466
50- McCormack WM. Infecciones genitales de importancia perinatal. Clín Obstetr Ginecol 1979, 2: 321-327
51- Meda N, Sangare L, Lankoande S, Sanou PT, Compaore PI, Catraye J, Cartoux M, Soudre RB. Pattern of sexual transmitted diseases among pregnant women in Burkina Faso, west Africa: potential for a clinical management based on simple approaches. Genotourin Med 1997, 73: 188-193
52- Mei S, Wang Y. Infection of Ureaplasma urealyticum btween parents and their newbors. Chung Hua Fu Chan Ko Tsa Chih 1997, 32: 302-304
53- Morales WJ, Angel JL, O'Brien WF, Knuppel RA, Finazzo M. A randomized study of antibiotic therapy in idiopathic preterm labour. Obstet Gynecol 1988, 72: 829-833
54- Newton ER, Dinsmoor MJ, Gibbs RS. A randomized, blinded, placebo-controlled trial of antibiotic in idiopathic preterm labour. Obstet Gynecol 1989, 74: 562-566
55- Ogasawara KK, Goodwin TM. The efficacy of prophilactic erythromycin in preventing vertical transmission of Ureaplasma urealyticum. Am J Perinatol 1997, 14: 233-237
56- Paavonen J. Is screening for Chlamydia trachomatis infection cost effective? Genitourin Med 1997, 73: 103-104
57- Ramier K, O'Sullivan MJ. Influence of diabetes on group B Streptococcus colonization in the pregnant women. J Matern Fetal Med 1997, 6: 120-123
58- Ramos E, Gaudier FL, Hearing LR, del Valle GO, Jenkins S, Briones D. Group B streptococcus colonization in pregnant diabetic women. Obstet Gynecol 1997, 89: 257-260
59- Rapelanoro Rabenja F, Lepere P, Escarguel C, Pelissier C, Lamarque P, Malvy D. Prevalence of urogenital mycoplasma infection in women infected with HIV in Banghi. Sante 1998, 189-192
60- Ratelle S, Keno D, Gardwood M, Etkind PH. Neonatal Chlamydial infection in Massachussetts, 1992-1993. Am J Prev Med 1997, 13: 221-224
61- Ren P, Yan X, Yang Y. Detection of Chlamydia trachomatis and Ureaplasma urealyticum from aborted tissues by polimerase chain reaction technique. Chung Hua Fu Chan Ko Tsa Chih 1997, 32: 214-216
62- Rivling ME, Morrison JC, Grossman JH 3rd. Comparison of pregnancy outcome between treated and untreated women with chlamydial cervicitis. J Miss State Med Assoc 1997, 38: 404-407
63- Romero R, Mazor M. Infección y trabajo de parto pre-término. Clín Obstetr Ginecol 1988, 2: 537-565
64- el-Shourbagy M, Abd-el-Maeboud K, Diab KM, el- Ghannam A, Nabegh L, Ammar S. Genital Chlamydia trachomatis infection in Egyptian women: incidence among different clinical risk groups. J Obstet Gynaecol Res 1996, 22: 467-472
65- Skjeldestad FE, Nordbo SA, Hadgu A. Sentinel surveillance of Chlamydia trachomatis infection in women terminating pregnancy. 1997, 73: 29-32
66- Stokes T. Screening for Chlamydia in general practice: a literature review and summary of evidence. J Public Health Med 1997, 19: 222-232
67- Stoll BJ, Schuchat A. Maternal carriage of group B Streptococci in developing countries. Pediatr Infect Dis J 1998, 17: 499-503
68- Stray-Pedersen B. Is screening for genital infections in pregnancy necessary? Acta Obstet Gynecol Scand Suppl 1997, 164: 116-120
69- Sweet RL. Infecciones perinatales. In: Iffy L, Kaminetzki HA (eds) Obstericia y Perinatología. Principios y práctica. Buenos Aires, Médica Panamericana 1986, T II, Cap 59: 1050-1085
70- Thorsen P, Jensen IP, Jeune B, Ebbesen N, Arpi M, Bremmelgaard A, Moller BR. Few microorganisms associated with bacterial vaginosis may constitude the pethologic core: a population-based microbiologic study among 3596 pregnant women. Am J Obstet Gynecol 1998, 178: 580-587
71- Uh Y, Jang IH, Yoon KJ, Lee CH, Kwon JY, Kim MC. Colonization rates and serotypes of group B streprococci isolated from pregnant women in a Korean tertiary hospital. Eur L Clin Microbiol Infect Dis 1997, 16: 753-756
72- Vile Y, Carroll SG, Watts P, Ward M, Nicolaides KH. Chlamydia trachomatis infection in prelabour amniorrhexis. Br J Obstet Gynaecol 1997, 104: 1091-1093
73- Wang EEL, Matlow AG, Ohlsson A, Nelson SC. Ureaplasma urealyticum infections in the perinatal period. Clin Perinatol 1997, 24: 91-105
74- Wasti S, Ashfaq MK, Ishaq R, Hamid R. Prevalence of Chlamydia infection in females attending antenatal and family planning clinics in Karachi Pakistan. Aust N Z Obstet Gynaecol 1997, 37: 462-465
75- Yamane T. Elementary sample theory. La Habana, Revolucionaria 1970: 99-100
76- Yancey MK, Schuchat A, Brown LK, Ventura VL, Markenson GR. The accuracy of late antenatal screening cultures in predicting genital group B streptococcal colonization at delivery. Obstet Gynecol 1996, 88: 811-815
77- Yoon BH, Chang JW, Romero R. Isolation of Ureaplasma urealyticum from the amniotic cavity and adverse outcome in preterm labour. Obstet Gynecol 1998, 92: 77-82
78- Zapata MT, Ahumada F, Cuffini CG, Cordova P, Grutadauria SL. Isolation of Chlamydia trachomatis and inmune response in different populations. Medicina (B Aires) 1997, 57: 7-14