European Journal of Obstetrics Elsevier
EUROBS
& Gynecology and Reproductive
103
Biology, 38 (1990) 103-108
01032
Vaginal infections, cervical ripening and preterm delivery S. Chambers
i, J.C. Pons 2, A. Richard
2, M. Chiesa 2, J. Bouyer
3 and E. Papiemik
2
’ University of Oklahoma Medical Center, Departement of Obstetrics and Gynecology, Oklahoma, OK, U.S.A., and ’ INSERM, 187, Physiologic et Psychologie de la Reproduction Humaine, UniversitC Paris&d, Unite 170, Epidemiologic et Statistique sur I’Environment Accepted
for publication
13 February
Unite H6pital Antoine BeWre, Clamart and -’INSERM, et la Sante. Villejuif; France 1990
A prospective study is presented which addresses the relative effect of cervicovaginal infection and precocious maturation of the uterine cervix on preterm delivery. From April 1981 through December 1983, a total of 5758 pregnant women were checked by means of a vaginal examination at every prenatal visit and a research for bacterial cervicovaginal infection whenever abnormal signs were observed. The study reveals that vaginal infection has no measurable effect when observed during the second trimester of pregnancy, and a small effect during the third trimester. This means that infection of the vagina or/and the cervix may be demonstrated as a risk factor only when the cervix is short before 28 weeks or open before 37 weeks. Vagina,
infection;
Cervix, ripening;
Delivery,
preterm
Introduction
It has long been thought that a closed uterine cervix during pregnancy serves as a natural barrier between the endometrium and chorioamniotic membranes from infection and its consequences, predomantly, preterm birth [11,12,14]. More specifically, the normal cervix possesses both a local secretory immune system [19,25] composed of secretory cells and IgA - containing plasma cells which multiply during pregnancy. Preterm birth rates for women with chorioamnionitis have been observed to be significantly
Correspondence: Dr. J.C. Pons, Department of Obstetrics and Gynecology. Antoine B&l&e Hospital, 92141 Clamart Cedex France.
0028-2243/90/$03.50
Q 1990 Elsevier Science Publishers
higher than the norm by Creadick et al. in 1920 [7], Emig et al. in 1961 [ll], and Naeye et al. 1971 [20]. In addition, the infants of these mothers often have symptoms of morbidity and mortality [20,8]. An infection of the cervix or vagina which then ascends is the suggested origin of chorioamnionitis [2,4,17,21]. This pathway evaluated by Hawkinson and Schulman [14] by means of a prospective study examining women for clinical signs of vaginitis or cervicitis (‘dirty cervix’). Those women with the signs had a significantly higher preterm birth rate when compared with a control population. This correlation has been observed not only with bacterial infections but also with Trichomonas vaginitis [12] and, more recently, with ureaplasma urealyticum [18]. What appears to be of great importance, as shown by Creatsos [lo], is the relationship between identified endocervical
B.V. (Biomedical
Division)
104
bacterial infection and subsequent chorioamnionitis, and the frequency of premature membrane rupture. The mechanism explaining the relationship between infection and preterm birth was suggested by Bejar [5] to be induced by bacterial phospholipase A on the fetal membranes by releasing increased amounts of arachidonic acid and, thus, increasing protaglandins production. Chorion and decidua in vitro cultures have been shown to be sites of prostaglandin synthesis [l]. As prostaglandins are substances known to increase uterine contractibility and to cause cervical maturation [15], the additive effect produced by the bacterial phospholipase would hasten/ stimulate this process, and then lead to preterm labor and delivery. Premature shortening and dilation of the uterine cervix are more frequently observed during routine vaginal examinations in women who will later undergo preterm labor [3,22,26]. The predictive value of these signs and the value of clinically identifying them in successful programs have been documented [9,16,22,23]. It must be remembered, however, that cervicovaginal infections are frequently observed during pregnancy in women who deliver at full term. For example, positive cultures of group Beta Streptococcus have been found in large percentages of pregnant women, 14.8% during the second trimester and 25.4% in the third trimester [4]. Furthermore, a prospective study by Harrison et al. [13], revealed that antepartum Chlamydia trachomatis and Mycoplasma cervical infections were not predictive of preterm birth. It thus appears that the relationship, between cervicovaginal infection and preterm delivery is hardly simplistic. Moreover, there have been no previous studies which examined the combination of both preterm birth risk predictors (cervix maturation signs and cervicovaginal infection) and their affect on preterm birth rates. This study addresses the relationship between precocious cervical maturation (shortened and dilated cervix), cervicovaginal infections, and preterm birth rates. There is .a great need for an investigation on those specificities that allow infection to affect gestational length. Furthermore, whether infections and precocious cervical changes
exert an independent or combined effect on preterm birth risk remains unclear. Thus, we will try to investigate the relative effect of both predictors, cervicovaginal infection and precocious cervical changes, either alone or in combined, on preterm birth. Patients and Methods
The hospital Antoine B&&e (located in a Paris suburb) is a local public hospital as well as a university-associated teaching institution. Its maternity unit has applied the innovative program for the prevention of preterm births proposed by Papiernik in 1969 [22], since its opening in 1973. This program includes a careful, uniform screening for risk factors of preterm labor and delivery, and most of the prenatal care is delivered in the outpatient clinic of the maternity unit. Specifically, routine evaluation of the uterine cervix is performed on all follow-up pregnant women in order to detect precocious cervix maturation. Cervical changes are described according to the guidelines of Bishop [6], and any signs of cervical maturation (shortening and dilation) are prospectively recorded. The entire prevention program practised by the maternity hospital is described elsewhere with both its applications and its results v41.
All data from each prenatal visit, examination and laboratory result are collected on charts in a prospective fashion, and a summary of the data is filed into a computerized information system after delivery. A vaginal swab is made followed by a standard culture if indicated by the following: the presence of abnormal discharge, vulva1 or vaginal pruritis, cervical ulceration, light bleeding or spotting. The cervicovaginal secretions are immediately examined under a microscope (wet prep and gram stain) in order to screen for quantities of epithelial cells, polynuclear cells (normal or abnormal), vaginal flora, abnormal bacteria, Trichomonas and Monilla. The results are reported on a semi-quantitative scale. A culture is subsequently performed if this first examination, the results of which are available in 24-48 h, shows abnormal signs. Those cases which showed evidence of numerous polynuclear cells, disap-
105
pearance of normal vaginal flora, and the presence of dominating abnormal bacterial in culture were considered as an incidence of infection. Most cases were treated with antibiotics or antiseptic, antifungal medications adapted to the observed flora. In the cases in which the direct examination revealed great numbers of polymorphonuclearcytes and a diminished number of local flora (‘Doderlein’) but yet the culture was negative, the follow-up examinations were performed with particular care. Cervicovaginal infections, when filed into the data system as mentioned, were separated according to the trimester in which they occurred; however, first trimester infections were not included in our study. The gestational age was carefully checked. Most of the pregnant women (80%) will have an ultrasound scan before 15 weeks; all women have a scan if they have abnormal cycles, discordant uterine size, or unknown last menstrual period (LMP). This study includes only those women who are followed-up early (two or more clinic visits before the 28th week) and women having their deliveries between April 1, 1981 and December 31, 1983 with a total of 5758 pregnancies being studied. Preterm birth is defined as less than 37 completed weeks from the first day of the LMP (or corrected by ultrasound scans). Preterm birth rates will be compared by groups of pregnant women with or without the following findings: TABLE
(1) Shortened cervix: defined as a length of 1 cm or less, recorded on the chart whenever it was found, and collected in the data system if it occurred before 28 weeks gestation, the time at which a shortened cervix is demonstrated to be predictive of an increased risk for preterm birth. (2) Open cervix: defined as a dilatation of the internal cervical OS for at least 1 cm if it occurred before 37 weeks gestation (the time at which it was demonstrated to be predictive of an increased risk for preterm delivery. Results
The data from Table I shows that women with proven antepartum cervicovaginal infections in the second or third trimesters have significantly higher rates of preterm births than women without infection. Using the relative risk for the ‘no infection’ category as a value of 1, the presence of infection in the second trimester increases the relative risk to 2.03 (P < O.OOl), and infection in the third trimester increases the relative risk to 2.27 (P < 0.001). However, there is no additional increase in preterm birth risk for those women with infection in both the second and third trimester (relative risk value of 2.00 with P c 0.05). Table II demonstrates that women with precocious cervical changes (premature shortening of the cervix before 28 weeks or with open cervix before 37 weeks) have more preterm deliveries
I
Infection
status
Infection
status
and the relative
risk of preterm
Total deliveries
delivery Preterm
deliveries
Relative risk
P value
N
%
4628
153
3.3
1
only
447
30
6.7
2.03
C 0.001
Infection in 3rd trimester only
531
40
7.5
2.27
-z 0.001
Infection in 2nd and 3rd trimester
152
10
6.6
2.00
-z 0.05
No infection Infection in 2nd trimester
106 TABLE II Cervical status and the relative risk of preterm delivery Cervical status
Total deliveries
Neither short nor open cervix
Preterm deliveries N
%
Relative risk
P value
4155
109
2.5
1
Short cervix only (before 28 weeks)
516
29
5.6
2.15
< 0.001
Open cervix only (before 37 weeks)
911
65
7.1
2.73
< 0.001
Both short and open cervix
176
30
17.0
6.54
< 0.001
than women who do not show these early changes. The relative risk for the presence of a short cervix is 2.15 (P -CO.OOl), while that for the presence of an open cervix is 2.73 (P < 0.001). Furthermore, the risk is greatest in those women who show both precocious cervical maturation changes with a relative risk value of 6.54 (P < 0.001). The specific role (Table III) of cervicovaginal infection and precocious cervical maturation was tested by performing a logistic regression analysis. We obtained values for the relative risk of each factor alone or in combination with another factor, after adjusting for other factors with standardized values. The results indicate that when the
TABLE III Adjusted relative risks value of relative risk and P value No
Infection Infection Infection infec- 2nd trimes- 3rd trimes- 2nd and tion ter only ter only 3rd trimester
Neither short 1 nor open cervix
1.9 n.s.
2.1 0.05
Short cervix only
2.3 0.001
4.3 0.001
4.9 0.001
3.9 0.001
Open cervix only
2.9 0.001
5.4 0.001
0.2 0.001
5.0 0.001
Both short and open cervix
12.3 6.6 0.001 0.001
14.0 0.001
11.4 0.001
ns., not significant.
1.7 ns.
cervix is neither open nor short, infection in the second trimester does not significantly raise the rate of preterm birth during the second trimester; however, a third trimester infection does increase the risk (P -C0.05). An infection in both the second and third trimester results in only a slightly increased rate of preterm birth. Table III also shows that in the presence of precocious cervical maturation (shortening and/or dilation), infection either in the second or third trimester significantly increases the preterm delivery rate. With a shortened cervix, the relative risk of preterm delivery with second trimester infection is 4.3, compared to the relative risk for a shortened cervix before 28 weeks [2,3]. The greatest increase in preterm birth risk occurs when there are both signs of precocious cervix maturational and is infection in the third trimester (14.0, P -c0.001). Discussion
When examining the multifaceted problem of preterm birth, new insights may be gained by considering the interactions of factors. The results indicate that while both infection and precocious cervical maturation by themselves are predictors of increases preterm birth risk, their co-existence has an even greater predictive value. When adjusting the relative risk of each factor in relation to the others (Table III), we found that the presence of an infection when there are no signs of cervix maturation adds no significant adjusted relative
107
risk in the second trimester, and only a slight effect in third trimester. The various combinations of the existence of an infection and its timing and the occurrence of one or both of the cervix maturational signs reveal that the adjusted relative risks are always significantly larger when both infection and cervix changes coexist. We realize that our study was limited by the fact that there was no systematic screening for infection for all pregnant women. The decision to perform a cervicovaginal culture was taken whenever the observations at a prenatal visit indicated the possible presence of infection. However, the search for infection was not directly related to preterm labor. From the results obtained, the presence of an infection, especially when coexistant with a cervix maturational sign, can be predictive of an increased risk for preterm birth. Whereas infection was treated in the majority of the cases, we did not try to evaluate the effect of this therapeutic scheme, and no controlled trial was proposed. Thus, this question of the effect of treatment for cervicovaginal infections on the prevention of preterm birth cannot be answered here. In previous studies, the prophylactic treatment of women did not affect preterm birth rates [14]. We still do not know whether there is a causal relationship between cervicovaginal infection and precocious maturation of the cervix and the increased risk of preterm birth. For instance, we do not know whether the opening of the cervix induces infection to enter, or whether infection enables the cervix to open. We do know that if an open cervix weakens the physiological protection against bacterial proliferation, the cervical mucous and its content with local immunoglobulins is no longer effective. It is clear, however, that any action or preventative measure taken against preterm birth cannot be limited to prevent infection. We see from Table III that the adjusted relative risk of infection is only significant in the third trimester. Some prevention programs are built upon the idea that the treatment of bacterial infections will be enough to prevent delivery. This type of prevention must be questioned. However, we have chosen a different strategy for the prevention of preterm birth. This policy has had positive results in reducing the preterm birth rate [24]. The
best hypothesis to interpret the observed facts would be that infection is a secondary risk factor, only effective in inducing preterm delivery if the cervix is previously modified: shortened before 28 weeks or opened before 37 weeks. Thus, we see the importance of investigating both the state of the uterine cervix and the presence of a cervicovaginal infection for the prediction of a preterm birth risk, during the prenatal visits. References
9 10
11
12
13
14
15
Acker G, Pesty A, Bianchi A, Chasseray J, Papiemik E. In vitro influence of steroids, histamine, adrenaline and oxytocin secretion of prostaglandins PG, and PGF,, by human fetal membranes. Dev Pharmacol Ther (suppl) 1984;1:67. Amiel-Tison C, Pilla Brossi S, Henrion R. Infection bacterienne neo-natale par contamination matemo-foetale. J Gynecol Obstet Biol Reprod 1980;9:479. Anderson ABM, Tumbull AC. Relationship between length of gestation and cervical dilatation: uterine contractability and other factors during pregnancy. Am J Obstet Gynecol 1969;105:1207. Baker CJ, Barrett FF, Yow MD. The influence of advancing gestation on group B streptococcal colonization in pregnant women. Am J Obstet Gynecol 1975;122:820. Bejar R, Curbelow V. David C, Gluck L. Premature Labor. II. Bacteria1 sources of phospholipase. Obstet Gynecol 1981;75:479. Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266. Creadick AN. The frequency and significance of omphalitis. Surg Gynecol Obstet 1920;30:278. Creasy RK. Mead Johnson Symposium on Perinatal development: preterm Labor. June, 1979. Creasy RK. System for predicting spontaneous preterm birth. Obstet Gynecol. 1980;55:695. Creatsos G. Pavlatos M et al. Bacterial contamination of the cervix and premature rupture of membranes. Am J Obstet Gynecol 1981;139:522. Emig 0. Napier JV, Brazie JV. Inflammation of the placenta: correlation with prematurity and perinatal death. Obstet Gynecol 1961;17:743. Grice AC. Vaginal infection causing spontaneous rupture of the membranes and premature delivery. Aust NZ J Obstet Gynecol 1966:94:898. Harrison HR, Alexander ER, et al. Cervical Chlamydia trachomatis and Mycoplasmal infections in pregnancy. JAMA 1983;250:1721. Hawkinson JA, Schulman H. Prematurity associated with cervicitis and vaginityis during pregnancy. Am J Obstet Gynecol 1966;94: 898. Huszar G. Biology and biochemistry of myometrial con-
108
16
17 18
19
20
21
tractability and cervical maturation. Sem Perinatol Series 1981;5:216. Kaminski M, Papiemik E. Multifactorial study of the risk of prematurity at 32 weeks of gestation. II. Comparison between an empirical prediction and a discriminant analysis. J Pet-mat Med 1974,2:31. Kass EH. Infectious disease and perinatal morbidity. Yale J Biol Med 1982;55:231. Kundsin RB, Driscoll SB, Shirley et al. Association of Ureaplasma urealyticum in the placenta with perinatal morbidity and mortality. N Engl J Med 1984;310:941. Murdoch AJM, Buckley CH, Fox H. Hormonal control of the secretory immune system of the uterine cervix. J Reprod Immunol 1982;4:23. Naeye RL, Dellinger WS, Blane WA. Fetal and maternal geatures of antenatal bacterial inections. Pediatrics 1971;79:733. Neaye RL, Peters EC. Causes and consequences of premature rupture of fetal membranes. Lancet 198O;i:192.
22 Papiemik E. Le coefficient de risque d’accouchement premature. Presse MM 1969;77:793. 23 Papiemik E. Proposals for a programmed prevention policy of preterm birth. Clin Obstet Gynecol 1984;27:614. 24 Papiemik E, Keith LG, Bouyer J, Dreyfus J, Lazar Ph. Effective prevention of preterm birth: the French experience measured at Haguenau. March of dimes defects foundation. White plains, New York, U.S.A. - birth defects: original article Series, vol 25, Nl, 1989. 25 Rebello R, Green FHY, Fox H. A study of the secretory immune system of the female genital tract. Br J Obstet Gynecol 1975;82:812. 26 Wood C, Barmerman EHO, Booth RT, Pinkerton JHM. The predictions of premature labor by observation of the cervix and external tocography. Am J Obstet Gynecol 1965:91:385.
EUROBS
& Gynecology and Reproductive
103
Biology, 38 (1990) 103-108
01032
Vaginal infections, cervical ripening and preterm delivery S. Chambers
i, J.C. Pons 2, A. Richard
2, M. Chiesa 2, J. Bouyer
3 and E. Papiemik
2
’ University of Oklahoma Medical Center, Departement of Obstetrics and Gynecology, Oklahoma, OK, U.S.A., and ’ INSERM, 187, Physiologic et Psychologie de la Reproduction Humaine, UniversitC Paris&d, Unite 170, Epidemiologic et Statistique sur I’Environment Accepted
for publication
13 February
Unite H6pital Antoine BeWre, Clamart and -’INSERM, et la Sante. Villejuif; France 1990
A prospective study is presented which addresses the relative effect of cervicovaginal infection and precocious maturation of the uterine cervix on preterm delivery. From April 1981 through December 1983, a total of 5758 pregnant women were checked by means of a vaginal examination at every prenatal visit and a research for bacterial cervicovaginal infection whenever abnormal signs were observed. The study reveals that vaginal infection has no measurable effect when observed during the second trimester of pregnancy, and a small effect during the third trimester. This means that infection of the vagina or/and the cervix may be demonstrated as a risk factor only when the cervix is short before 28 weeks or open before 37 weeks. Vagina,
infection;
Cervix, ripening;
Delivery,
preterm
Introduction
It has long been thought that a closed uterine cervix during pregnancy serves as a natural barrier between the endometrium and chorioamniotic membranes from infection and its consequences, predomantly, preterm birth [11,12,14]. More specifically, the normal cervix possesses both a local secretory immune system [19,25] composed of secretory cells and IgA - containing plasma cells which multiply during pregnancy. Preterm birth rates for women with chorioamnionitis have been observed to be significantly
Correspondence: Dr. J.C. Pons, Department of Obstetrics and Gynecology. Antoine B&l&e Hospital, 92141 Clamart Cedex France.
0028-2243/90/$03.50
Q 1990 Elsevier Science Publishers
higher than the norm by Creadick et al. in 1920 [7], Emig et al. in 1961 [ll], and Naeye et al. 1971 [20]. In addition, the infants of these mothers often have symptoms of morbidity and mortality [20,8]. An infection of the cervix or vagina which then ascends is the suggested origin of chorioamnionitis [2,4,17,21]. This pathway evaluated by Hawkinson and Schulman [14] by means of a prospective study examining women for clinical signs of vaginitis or cervicitis (‘dirty cervix’). Those women with the signs had a significantly higher preterm birth rate when compared with a control population. This correlation has been observed not only with bacterial infections but also with Trichomonas vaginitis [12] and, more recently, with ureaplasma urealyticum [18]. What appears to be of great importance, as shown by Creatsos [lo], is the relationship between identified endocervical
B.V. (Biomedical
Division)
104
bacterial infection and subsequent chorioamnionitis, and the frequency of premature membrane rupture. The mechanism explaining the relationship between infection and preterm birth was suggested by Bejar [5] to be induced by bacterial phospholipase A on the fetal membranes by releasing increased amounts of arachidonic acid and, thus, increasing protaglandins production. Chorion and decidua in vitro cultures have been shown to be sites of prostaglandin synthesis [l]. As prostaglandins are substances known to increase uterine contractibility and to cause cervical maturation [15], the additive effect produced by the bacterial phospholipase would hasten/ stimulate this process, and then lead to preterm labor and delivery. Premature shortening and dilation of the uterine cervix are more frequently observed during routine vaginal examinations in women who will later undergo preterm labor [3,22,26]. The predictive value of these signs and the value of clinically identifying them in successful programs have been documented [9,16,22,23]. It must be remembered, however, that cervicovaginal infections are frequently observed during pregnancy in women who deliver at full term. For example, positive cultures of group Beta Streptococcus have been found in large percentages of pregnant women, 14.8% during the second trimester and 25.4% in the third trimester [4]. Furthermore, a prospective study by Harrison et al. [13], revealed that antepartum Chlamydia trachomatis and Mycoplasma cervical infections were not predictive of preterm birth. It thus appears that the relationship, between cervicovaginal infection and preterm delivery is hardly simplistic. Moreover, there have been no previous studies which examined the combination of both preterm birth risk predictors (cervix maturation signs and cervicovaginal infection) and their affect on preterm birth rates. This study addresses the relationship between precocious cervical maturation (shortened and dilated cervix), cervicovaginal infections, and preterm birth rates. There is .a great need for an investigation on those specificities that allow infection to affect gestational length. Furthermore, whether infections and precocious cervical changes
exert an independent or combined effect on preterm birth risk remains unclear. Thus, we will try to investigate the relative effect of both predictors, cervicovaginal infection and precocious cervical changes, either alone or in combined, on preterm birth. Patients and Methods
The hospital Antoine B&&e (located in a Paris suburb) is a local public hospital as well as a university-associated teaching institution. Its maternity unit has applied the innovative program for the prevention of preterm births proposed by Papiernik in 1969 [22], since its opening in 1973. This program includes a careful, uniform screening for risk factors of preterm labor and delivery, and most of the prenatal care is delivered in the outpatient clinic of the maternity unit. Specifically, routine evaluation of the uterine cervix is performed on all follow-up pregnant women in order to detect precocious cervix maturation. Cervical changes are described according to the guidelines of Bishop [6], and any signs of cervical maturation (shortening and dilation) are prospectively recorded. The entire prevention program practised by the maternity hospital is described elsewhere with both its applications and its results v41.
All data from each prenatal visit, examination and laboratory result are collected on charts in a prospective fashion, and a summary of the data is filed into a computerized information system after delivery. A vaginal swab is made followed by a standard culture if indicated by the following: the presence of abnormal discharge, vulva1 or vaginal pruritis, cervical ulceration, light bleeding or spotting. The cervicovaginal secretions are immediately examined under a microscope (wet prep and gram stain) in order to screen for quantities of epithelial cells, polynuclear cells (normal or abnormal), vaginal flora, abnormal bacteria, Trichomonas and Monilla. The results are reported on a semi-quantitative scale. A culture is subsequently performed if this first examination, the results of which are available in 24-48 h, shows abnormal signs. Those cases which showed evidence of numerous polynuclear cells, disap-
105
pearance of normal vaginal flora, and the presence of dominating abnormal bacterial in culture were considered as an incidence of infection. Most cases were treated with antibiotics or antiseptic, antifungal medications adapted to the observed flora. In the cases in which the direct examination revealed great numbers of polymorphonuclearcytes and a diminished number of local flora (‘Doderlein’) but yet the culture was negative, the follow-up examinations were performed with particular care. Cervicovaginal infections, when filed into the data system as mentioned, were separated according to the trimester in which they occurred; however, first trimester infections were not included in our study. The gestational age was carefully checked. Most of the pregnant women (80%) will have an ultrasound scan before 15 weeks; all women have a scan if they have abnormal cycles, discordant uterine size, or unknown last menstrual period (LMP). This study includes only those women who are followed-up early (two or more clinic visits before the 28th week) and women having their deliveries between April 1, 1981 and December 31, 1983 with a total of 5758 pregnancies being studied. Preterm birth is defined as less than 37 completed weeks from the first day of the LMP (or corrected by ultrasound scans). Preterm birth rates will be compared by groups of pregnant women with or without the following findings: TABLE
(1) Shortened cervix: defined as a length of 1 cm or less, recorded on the chart whenever it was found, and collected in the data system if it occurred before 28 weeks gestation, the time at which a shortened cervix is demonstrated to be predictive of an increased risk for preterm birth. (2) Open cervix: defined as a dilatation of the internal cervical OS for at least 1 cm if it occurred before 37 weeks gestation (the time at which it was demonstrated to be predictive of an increased risk for preterm delivery. Results
The data from Table I shows that women with proven antepartum cervicovaginal infections in the second or third trimesters have significantly higher rates of preterm births than women without infection. Using the relative risk for the ‘no infection’ category as a value of 1, the presence of infection in the second trimester increases the relative risk to 2.03 (P < O.OOl), and infection in the third trimester increases the relative risk to 2.27 (P < 0.001). However, there is no additional increase in preterm birth risk for those women with infection in both the second and third trimester (relative risk value of 2.00 with P c 0.05). Table II demonstrates that women with precocious cervical changes (premature shortening of the cervix before 28 weeks or with open cervix before 37 weeks) have more preterm deliveries
I
Infection
status
Infection
status
and the relative
risk of preterm
Total deliveries
delivery Preterm
deliveries
Relative risk
P value
N
%
4628
153
3.3
1
only
447
30
6.7
2.03
C 0.001
Infection in 3rd trimester only
531
40
7.5
2.27
-z 0.001
Infection in 2nd and 3rd trimester
152
10
6.6
2.00
-z 0.05
No infection Infection in 2nd trimester
106 TABLE II Cervical status and the relative risk of preterm delivery Cervical status
Total deliveries
Neither short nor open cervix
Preterm deliveries N
%
Relative risk
P value
4155
109
2.5
1
Short cervix only (before 28 weeks)
516
29
5.6
2.15
< 0.001
Open cervix only (before 37 weeks)
911
65
7.1
2.73
< 0.001
Both short and open cervix
176
30
17.0
6.54
< 0.001
than women who do not show these early changes. The relative risk for the presence of a short cervix is 2.15 (P -CO.OOl), while that for the presence of an open cervix is 2.73 (P < 0.001). Furthermore, the risk is greatest in those women who show both precocious cervical maturation changes with a relative risk value of 6.54 (P < 0.001). The specific role (Table III) of cervicovaginal infection and precocious cervical maturation was tested by performing a logistic regression analysis. We obtained values for the relative risk of each factor alone or in combination with another factor, after adjusting for other factors with standardized values. The results indicate that when the
TABLE III Adjusted relative risks value of relative risk and P value No
Infection Infection Infection infec- 2nd trimes- 3rd trimes- 2nd and tion ter only ter only 3rd trimester
Neither short 1 nor open cervix
1.9 n.s.
2.1 0.05
Short cervix only
2.3 0.001
4.3 0.001
4.9 0.001
3.9 0.001
Open cervix only
2.9 0.001
5.4 0.001
0.2 0.001
5.0 0.001
Both short and open cervix
12.3 6.6 0.001 0.001
14.0 0.001
11.4 0.001
ns., not significant.
1.7 ns.
cervix is neither open nor short, infection in the second trimester does not significantly raise the rate of preterm birth during the second trimester; however, a third trimester infection does increase the risk (P -C0.05). An infection in both the second and third trimester results in only a slightly increased rate of preterm birth. Table III also shows that in the presence of precocious cervical maturation (shortening and/or dilation), infection either in the second or third trimester significantly increases the preterm delivery rate. With a shortened cervix, the relative risk of preterm delivery with second trimester infection is 4.3, compared to the relative risk for a shortened cervix before 28 weeks [2,3]. The greatest increase in preterm birth risk occurs when there are both signs of precocious cervix maturational and is infection in the third trimester (14.0, P -c0.001). Discussion
When examining the multifaceted problem of preterm birth, new insights may be gained by considering the interactions of factors. The results indicate that while both infection and precocious cervical maturation by themselves are predictors of increases preterm birth risk, their co-existence has an even greater predictive value. When adjusting the relative risk of each factor in relation to the others (Table III), we found that the presence of an infection when there are no signs of cervix maturation adds no significant adjusted relative
107
risk in the second trimester, and only a slight effect in third trimester. The various combinations of the existence of an infection and its timing and the occurrence of one or both of the cervix maturational signs reveal that the adjusted relative risks are always significantly larger when both infection and cervix changes coexist. We realize that our study was limited by the fact that there was no systematic screening for infection for all pregnant women. The decision to perform a cervicovaginal culture was taken whenever the observations at a prenatal visit indicated the possible presence of infection. However, the search for infection was not directly related to preterm labor. From the results obtained, the presence of an infection, especially when coexistant with a cervix maturational sign, can be predictive of an increased risk for preterm birth. Whereas infection was treated in the majority of the cases, we did not try to evaluate the effect of this therapeutic scheme, and no controlled trial was proposed. Thus, this question of the effect of treatment for cervicovaginal infections on the prevention of preterm birth cannot be answered here. In previous studies, the prophylactic treatment of women did not affect preterm birth rates [14]. We still do not know whether there is a causal relationship between cervicovaginal infection and precocious maturation of the cervix and the increased risk of preterm birth. For instance, we do not know whether the opening of the cervix induces infection to enter, or whether infection enables the cervix to open. We do know that if an open cervix weakens the physiological protection against bacterial proliferation, the cervical mucous and its content with local immunoglobulins is no longer effective. It is clear, however, that any action or preventative measure taken against preterm birth cannot be limited to prevent infection. We see from Table III that the adjusted relative risk of infection is only significant in the third trimester. Some prevention programs are built upon the idea that the treatment of bacterial infections will be enough to prevent delivery. This type of prevention must be questioned. However, we have chosen a different strategy for the prevention of preterm birth. This policy has had positive results in reducing the preterm birth rate [24]. The
best hypothesis to interpret the observed facts would be that infection is a secondary risk factor, only effective in inducing preterm delivery if the cervix is previously modified: shortened before 28 weeks or opened before 37 weeks. Thus, we see the importance of investigating both the state of the uterine cervix and the presence of a cervicovaginal infection for the prediction of a preterm birth risk, during the prenatal visits. References
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