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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynaecology, Northwick Park and St. Mark’s Hospital, London; Imperial College School of Medicine, London; Department of Obstetrics and Gynaecology, Jessops Hospital for Women, Sheffield; and Manchester Centre for Sexual Health, Manchester Royal Infirmary, Manchester, United Kingdom.
Address reprint requests to: Ronald F. Lamont, DM, FRCOG, Northwick Park and St. Mark’s Hospital, Department of Obstetrics & Gynaecology, Watford Road, Harrow, Middlesex, London, HA1 3UJ, United Kingdom; E-mail: pauline.mills{at}nwlh.nhs.uk.
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ABSTRACT |
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METHODS: This was a randomized, double-blind, placebo-controlled, tricenter study. A total of 409 women with abnormal genital tract flora on Gram stain of vaginal secretions at 13–20 weeks’ gestation were randomized to receive a 3-day course of clindamycin vaginal cream or placebo. Those women who still had abnormal vaginal flora 3 weeks later received a 7-day course of the original study drug (ie, either clindamycin vaginal cream or placebo as per original randomization). The primary outcome measure was the incidence of preterm birth.
RESULTS: There was a statistically significant reduction in the incidence of preterm birth in the clindamycin vaginal cream group (4%) compared with placebo (10%) (P < .03). Significantly more babies born preterm (63%) required admission to the neonatal intensive care unit compared with term infants (4%) (P < .001).
CONCLUSION: A 2% clindamycin vaginal cream, when compared with placebo administered to women with abnormal genital tract flora before 20 weeks’ gestation, can reduce the incidence of preterm birth by 60% and hence the need for neonatal intensive care.
Preterm delivery (less than 37 completed weeks of gestation) is the major cause of perinatal mortality and morbidity in the developed world.1 The etiology of preterm labor is multifactorial, but there is evidence that infection is an important cause2–5 and may account for up to 40% of all cases of spontaneous preterm birth.6 By the time a woman is admitted in preterm labor there may be irreversible changes in the cervix that render attempts to inhibit the process unsuccessful. As a result, attention has focused on the possibility of predicting preterm birth by the detection of abnormal genital tract colonization in early pregnancy. A number of studies have shown that abnormal genital tract flora, either in the form of bacterial vaginosis or in the detection of bacterial vaginosis–related organisms, such as anaerobes, Mycoplasma hominis or Gardnerella vaginalis, is associated with preterm birth.7 The purpose of this study was to assess whether intervention and treatment of abnormal genital tract flora using intravaginal antibiotics in the second trimester of pregnancy could reduce the incidence of preterm birth.
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MATERIALS AND METHODS |
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Women were required to self-administer 5 g of 2% clindamycin intravaginal cream (equivalent to 100 mg of clindamycin) or placebo each night for 3 consecutive nights before retiring and were assigned using a computerized, randomized block procedure with a block size of ten, using a computer-generated random code list. The investigational drug and the placebo cream were of identical composition except for the active drug, which accounted for a small amount of the overall formulation. Active and placebo creams were packaged identically and labeled only with protocol number, patient number, abbreviated instructions for use, and an instruction to return the part used or empty tube. The full blind treatment code was located in the pharmacology department of the study site in the form of the random code list, whereas individual subject code envelopes were attached to the rear inside cover of the case report form.
For the purpose of this intervention study, clinical evaluation took place at baseline (first antenatal visit at 13–20 weeks’ gestation), visit 2 (20–24 days after baseline visit), and a final report 24–48 hours postdelivery. At baseline visit, following eligibility checklist and informed consent, demographic, medical, and obstetric examination were obtained. A sterile speculum was used to sample upper vaginal secretions, which were smeared on a glass slide, sealed with acetone and dried in air, and examined using Gram stain. All women were screened for syphilis. A high vaginal swab for Neisseria gonorrhoeae and Trichomonas vaginalis and an endocervical swab for Chlamydia trachomatis were taken to exclude the possibility of sexually transmitted disease, using standard techniques. The Gram stain was graded according to Nugent criteria8: grade I, normal (predominantly lactobacillus species); grade II, intermediate (reduced lactobacilli mixed with other bacterial morphotypes); or grade III, bacterial vaginosis (few or no lactobacillus morphotypes and greatly increased numbers of other morphotypes). If the woman had grade II or grade III on Gram stain (ie, abnormal genital tract flora), the woman was randomized to receive either clindamycin vaginal cream or placebo. The outcome of pregnancy according to treatment group was determined for all women with abnormal genital tract flora. At visit 2, the Gram stain was repeated, and if the woman had a positive Gram stain she was given a 7-day course of clindamycin vaginal cream or placebo, as per original randomization.
A total of 409 women were recruited to the study and were analyzed on an intent-to-treat analysis, with 208 in the clindamycin vaginal cream group and 201 in the placebo group. The majority of women returned for visit 2: 178 (86%) in the clindamycin vaginal cream group and 190 (95%) in the placebo group. Demographic data at study entry showed that there was no difference between the groups with respect to age, weight, height, gestational age at baseline, and history of smoking, alcohol, or substance abuse. Similarly, there was no difference between the groups with respect to medical history, gravidity, parity, history of sexually transmitted disease, or obstetric history. The size of the sample was calculated to detect a reduction in the number of adverse effects, such as preterm birth (delivery before 37 completed weeks of gestation), preterm rupture of the membranes, second trimester miscarriage, or intrauterine fetal death, from 20% in the placebo group to 10% in the clindamycin vaginal cream group. With a 5% significance level and 80% power, 219 subjects per group were required, and approximately this number was recruited.
The background differences between the two treatment groups were examined initially. T tests were used to examine the differences in age, weight, and height, whereas Fisher exact test was used to study differences in race, smoking status, and alcohol consumption. Weight was found to have a skewed distribution and was given a log transformation. Univariate analyses were performed to assess the effect of treatment and gestational age at administration of the drug upon the occurrence of preterm birth and other outcome measures. Gestational age was measured on a continuous scale. Fisher exact test was used to investigate the effect of treatment on preterm birth, low birth weight (less than 2500 g), very low birth weight (less than 1500 g), and the occurrence of stillborn fetus. A t test was used to compare the differences in birth weight and occurrence of stillborn fetus, whereas linear regression was used to examine the effect on birth weight. Multivariable analyses were subsequently performed to examine the effect of treatment on the outcome variables, adjusted for the effects of gestational age at administration of study drug. Multiple linear regression was used for birth weight, and multiple logistic regression for all other outcomes. Logistic regression and Fisher exact test were used to examine the effect of treatment, gestational age at administration, and all the previous outcome variables on the need for admission to the neonatal intensive care unit. All statistical analyses were performed using Stata 6.0 (Stata Corp., College Station, TX). For gestational age at delivery, the data were skewed because of a few very early gestations. Accordingly, the median value was used, and the Mann-Whitney test was used to compare the two groups.
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RESULTS |
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). Similarly, there were no differences between the groups at study entry with respect to gravidity, parity, or previous number of live births, preterm deliveries, low birth weight babies born at term, or previous numbers of spontaneous or therapeutic abortions (Table 1). There was a significant difference in the number of babies born as a result of spontaneous preterm labor between the two treatment groups (P = .03). There was a significantly lower occurrence of spontaneous preterm labor and preterm birth in the clindamycin vaginal cream group (4%) than in the placebo group (10%). The incidence of iatrogenic preterm birth was the same in both groups but too small to be analyzed statistically. The gestational age at delivery was statistically significantly lower in women in the placebo group. There were no statistically significant differences between the two groups with respect to low birth weight, very low birth weight, or number of stillborn fetuses (Table 2). There was no effect of gestational age at administration of study drug on the occurrence of preterm birth, stillborn fetus, birth weight, low birth weight or very low birth weight (Table 3). The results of the multivariable analysis indicated that after adjusting for gestational age at administration there was still a significant difference in the number of preterm births in the two treatment groups (odds ratio clindamycin vaginal cream: placebo 0.38; 95% confidence interval 0.16, 0.90; P < .03). After adjusting for gestational age, there was no significant effect of treatment on the other outcome variables. There was a significant effect of preterm birth upon the number of babies admitted to the neonatal intensive care unit (P < .001). Of the 27 preterm births, 17 (63%) were admitted into the neonatal intensive care unit, whereas only 13 of 363 (4%) born at term were admitted.
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DISCUSSION |
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Although the association between infection and preterm birth with respect to etiology and prediction is well established, the use of antibiotics for the prevention of preterm birth causes confusion. This study was conducted to assess whether the use of intravaginal antibiotics used early in gestation would reduce the incidence of preterm birth. Published studies have used different methodologies and different ways of diagnosing abnormal genital tract flora, as well as different doses of different antibiotics given by different routes to women with differing degrees of risk; as a consequence, the results have been confusing. Some studies21–26 have examined the effect of oral antibiotics, some of which showed no benefit23,24,26 and some of which showed statistically significant benefit21,22,25 but were criticized for having small numbers21 or for having found benefit only after a post hoc analysis.22 One study was a prospective, comparative trial rather than a randomized, double-blind, placebo-controlled trial.25 One study used the presence of G vaginalis and the Nugent score8 to diagnose bacterial vaginosis,23 yet 30–50% of women colonized by G vaginalis will not have bacterial vaginosis. Although there was a trend toward benefit of antibiotics, the sample size was insufficient to show statistical significance. Carey et al,24 in a large study of oral metronidazole, failed to show benefit, but there are many criticisms of the study.27 Only 22% of evaluable women were recruited to the study. Women complaining of vaginal symptoms were excluded, which means that women with symptomatic bacterial vaginosis were not studied. No woman was treated before 16 weeks’ gestation, and 50% were treated after 20 weeks’ gestation. A delay of 8 weeks was possible from diagnosis to treatment, by which time 25% of women had reverted to normal flora. Women in the placebo group had an extremely high response to placebo (47%), which is unexplained in comparison with other treatment studies. Finally, although metronidazole is active against anaerobes, it is not active against many aerobes and mycoplasmas, which may have gained access to the decidua. Only two studies have used intravaginal antibiotics.16,28 Both were randomized, double-blind, placebo-controlled studies of a 7-day course of clindamycin vaginal cream, and neither showed benefit. However, 100% of women in one study16 and 60% of the other28 were treated after 20 weeks’ gestation, by which time microorganisms may already have ascended from the vagina into the decidua, rendering them less susceptible to intravaginal antibiotics.
In our study, nearly 100% of women were at or before 20 weeks’ gestation at study entry, and 60% were at or before 16 weeks’ gestation, and this may be why we have shown benefit. We have shown that with early use of clindamycin intravaginal cream, the incidence of preterm birth can be reduced by 60%, from 10% to 4%. Of those infants born preterm, a significantly higher number (63% versus 4%) required admission to neonatal intensive care unit than those born at term, and this will have major implications on the cost–benefit analysis of screening for and treating abnormal genital tract colonization in early pregnancy. Genital tract flora varies according to degree of abnormality on Gram stain of vaginal secretions.29 In a nonprespecified subgroup analysis of this study in which the grade of bacterial vaginosis on Gram stain, whether I, II, III, or revertant (initially abnormal flora but normal on review) was available, clindamycin vaginal cream was found to be most effective when used in those women with the most florid picture of abnormal genital tract colonization.30
Recently, Kenyon et al reported a multicenter study on the effects of antibiotics in women suspected to be in preterm labor and hence at risk of preterm birth.31 Co-amoxiclav (ampicillin and clavulanic acid), used alone or in combination with erythromycin, prolonged pregnancy but had no significant benefit for the neonate. Unfortunately, the wrong antibiotics were used in the wrong patients too late in pregnancy.32 Antibiotics alone are unlikely to be helpful at that stage. The earlier an abnormal flora is detected in pregnancy, the greater is the risk of subsequent adverse pregnancy outcome. It is, therefore, logical that antibiotics used to prevent preterm birth should be given early in pregnancy. The longer abnormal colonization remains untreated, the greater is the chance of microorganisms ascending through the cervix into the decidua and initiating the inflammatory response that leads to labor. As a result of this, treatment in pregnancy may have to be early using intravaginal antibiotics or even a combination of oral and intravaginal antibiotics for better results.
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Footnotes |
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The authors thank the obstetricians at the three hospitals for allowing their patients to be admitted to the study, and Dr. F. E. Chisti, Wendy Davis, and Jill Unerman for their hard work in the recruitment to and conduct of the study.
doi:10.1016/S0029-7844(02)03054-5
Received August 31, 2002. Received in revised form September 10, 2002. Accepted September 19, 2002.
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REFERENCES |
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