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Randomized clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal fibronectin–positive women
ORIGINAL RESEARCH
Randomized Clinical Trial of Metronidazole Plus Erythromycin to Prevent Spontaneous Preterm Delivery in Fetal Fibronectin–Positive Women William W. Andrews, PhD, MD, Baha M. Sibai, MD, Elizabeth A. Thom, PhD, Donald Dudley, MD, J. M. Ernest, MD, Donald McNellis, MD, Kenneth J. Leveno, MD, Ronald Wapner, MD, Atef Moawad, MD, Mary J. O’Sullivan, MD, Steve N. Caritis, MD, Jay D. Iams, MD, Oded Langer, MD, Menachem Miodovnik, MD, and Mitchell Dombrowski, MD, for the National Institute of Child Health & Human Development Maternal–Fetal Medicine Units Network* OBJECTIVE: To estimate whether antibiotic treatment of asymptomatic women with a positive cervical or vaginal fetal fibronectin test in the second trimester would reduce the risk of spontaneous preterm delivery. METHODS: Women were screened between 21 weeks 0 days and 25 weeks 6 days of gestation with cervical or vaginal swabs for fetal fibronectin. Women with a positive test (50 ng/mL or more) were randomized to receive metronidazole (250 mg orally three times per day) and erythromycin (250 mg orally four times per day) or identical placebo pills for 10 days. The primary outcome was spontaneous delivFrom the Department of Obstetrics and Gynecology, Center for Research in Women’s Health, University of Alabama at Birmingham, Birmingham, Alabama; Department of Obstetrics and Gynecology, University of Tennessee, Memphis, Tennessee; The Biostatistics Center, George Washington University, Rockville, Maryland; Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah; Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina; The National Institute of Child Health and Human Development, Bethesda, Maryland; Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Obstetrics and Gynecology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois; Department of Obstetrics and Gynecology, University of Miami, Miami, Florida; University of Pittsburgh/Magee-Women’s Hospital, Pittsburgh, Pennsylvania; Department of Obstetrics and Gynecology, Ohio State University, Columbus, Ohio; Department of Obstetrics and Gynecology, University of Texas at San Antonio, San Antonio, Texas; Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, Ohio; and Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan. Supported by grants from the National Institute of Child Health and Human Development (U10-HD27869, U10-HD21414, U10-HD36801, U10HD34208, U10-HD27860, U10-HD34116, U10-HD34136, U10HD27861, U10-HD34122, U10-HD21410, U10-HD27915, U10HD34210, U10-HD27905, and U10-HD27917). Fetal fibronectin assays were performed at no cost to the project by Adeza Biomedical, Sunnyvale, California. *For other members of the Network, see the Appendix.
ery before 37 weeks’ gestation after preterm labor or premature membrane rupture. RESULTS: A total of 16,317 women were screened for fetal fibronectin, and 6.6% had a positive test; 715 fetal fibronectin test–positive women consented to randomization. Outcome data were available for 703 women: 347 in the antibiotic group and 356 in the placebo group. The antibiotic and placebo groups were not significantly different for maternal age (P ⴝ .051), ethnicity (P ⴝ .849), marital status (P ⴝ .127), education (P ⴝ .244), and bacterial vaginosis (P ⴝ .236). No difference was observed in spontaneous preterm birth before 37 weeks’ (odds ratio [OR] 1.17, 95% confidence interval [CI] 0.80, 1.70), less than 35 weeks’ (OR 0.92, 95% CI 0.54, 1.56), or less than 32 weeks’ (OR 1.94, 95% CI 0.83, 4.52) gestation in antibiotic- compared with placebo-treated women. Among women with a prior spontaneous preterm delivery, the rate of repeat spontaneous preterm delivery at less than 37 weeks’ gestation was significantly higher in the active drug compared with the placebo group (46.7% versus 23.9%, P ⴝ .039). CONCLUSION: Treatment with metronidazole plus erythromycin of asymptomatic women with a positive cervical or vaginal fetal fibronectin test in the late second trimester does not decrease the incidence of spontaneous preterm delivery. (Obstet Gynecol 2003;101:847–55. © 2003 by The American College of Obstetricians and Gynecologists.)
Preterm birth complicates 11% of all pregnancies and remains the primary cause of perinatal mortality and long-term neurologic morbidity.1,2 Published literature has strongly linked clinically silent upper genital tract bacterial infection and/or inflammation with preterm birth and adverse pregnancy outcomes.3–7 Although randomized trials of systemic antibiotics to reduce pre-
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term birth in women with altered vaginal flora have yielded mixed results,6,8 –12 genital tract infections represent a potentially treatable cause of spontaneous preterm delivery. Fetal fibronectin is a placental and membrane protein that is a unique epitope of the fibronectins. When detected in asymptomatic women (those without signs or symptoms of vaginal infection or preterm labor) as early as 23–24 weeks’ gestation, a positive fetal fibronectin test is associated with a 59-fold increased risk of spontaneous preterm delivery at less than 28 weeks’ gestation.13 One hypothesis holds that intrauterine infection causes disruption of the extracellular choriodecidual basement membrane, causing leakage of fetal fibronectin into cervical or vaginal secretions, in which it can then be detected.14 –16 Our objective in this study was to estimate whether treatment with metronidazole plus erythromycin of asymptomatic women with a positive cervical or vaginal fetal fibronectin test before 26 weeks’ gestation would reduce the risk of spontaneous preterm delivery. MATERIALS AND METHODS Women undergoing routine prenatal care at each of 13 participating centers were screened between 21 weeks 0 days and 25 weeks 6 days of gestation for cervical and vaginal fetal fibronectin. Separate Dacron swab specimens were collected from the exocervix and posterior vaginal fornix with a vaginal speculum without a lubricant and before collection of other specimens. These specimens were immediately stored at 2– 8C and shipped overnight to a central laboratory (Adeza Biomedical, Sunnyvale, CA), where fetal fibronectin was determined by an enzyme-linked immunosorbent assay. Based on previously published data,17 a positive test was defined as a concentration of 50 ng/mL or more in either the cervical or the vaginal swab. Other details of the specimen collection, handling, and assay have been previously published.13,14 Vaginal smears obtained at screening were evaluated (with Nugent criteria18) in a central laboratory for the presence of bacterial vaginosis. Women were not selected based on the presence or absence of any specific risk factor (other than a positive fetal fibronectin test) for a spontaneous preterm birth. Exclusion criteria included the following: fetal death, major fetal anomalies, multiple gestation, allergy to study medication, antibiotic use at randomization, use of topical antifungals within 24 hours of screening, vaginal symptoms (unelicited, spontaneously reported vaginal symptoms, including itching, burning, or malodor indicating need for specific treatment), vaginal bleeding (defined as active bleeding at screening, not spotting and not
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bleeding due to a friable cervix), ethanol abuse, preterm labor, rupture of membranes, tocolytic use, cerclage, preeclampsia, hypertension requiring medication, placenta previa, uterine anomaly, insulin-requiring diabetes mellitus, renal insufficiency, collagen vascular disease, isoimmunization, acquired immunodeficiency syndrome– defining illness, and anticipated prenatal care or delivery at a nonparticipating center. The study was approved by the institutional review boards at each clinical site, and all women gave written, informed consent before enrollment in the study. Eligible women with a positive fetal fibronectin test were randomized (double-masked) between 21 weeks 0 days and 25 weeks 6 days of gestation to receive either metronidazole 250 mg three times daily plus erythromycin 250 mg four times daily or identical placebo capsules orally for 10 days. The simple urn method of randomization19 with stratification according to clinical center was used to create a computer-generated random sequence, and study drugs were packaged accordingly in vials for distribution to the participants. Subjects were instructed to take one metronidazole capsule (or identical placebo) three times daily with meals and one erythromycin capsule (or placebo) four times daily (at each meal and at bedtime) for 10 days. Medication was begun on the day of randomization. One follow-up visit was scheduled 14 days after randomization, at which fetal fibronectin and bacterial vaginosis status were reassessed. Medication compliance was estimated at this visit by examining the pill containers for remaining capsules. Subjects who failed to return the pill container were asked whether any capsules remained. If unconsumed capsules remained, the cervical and vaginal specimens were still obtained, and the women were encouraged to take the remainder of the study medication. Establishment of the gestational age at randomization was determined by the date of the last menstrual period and by ultrasound results with a previously published scheme.11,12 Preterm birth was defined as delivery before 37 completed weeks’ gestation (259 days), and spontaneous preterm birth was defined as preterm delivery due to the spontaneous onset of preterm labor or spontaneous preterm premature rupture of membranes. The primary outcome was spontaneous delivery before 37 weeks’ gestation after preterm labor or premature membrane rupture. Usual prenatal care was provided at the respective institutions, but enrollment continued until pregnancy outcomes were assessed. The target sample size of 700 women was calculated assuming a 30% rate of spontaneous preterm delivery before 37 weeks’ gestation in the placebo group and an estimated effect size of a one third reduction of this
OBSTETRICS & GYNECOLOGY
Figure 1. Summary of screening for fetal fibronectin and randomization to active drugs or placebo. Andrews. Fetal Fibronectin and Prematurity. Obstet Gynecol 2003.
outcome in the active drug group. A type I error (twosided) of 5% and a power of 80% was chosen, and an adjustment for a dropout rate of 5% was made. Continuous variables were compared using the Wilcoxon rank-sum test, and categoric variables were compared using 2 and Fisher exact tests. Before the study was started, the group sequential method of Lan and DeMets with the modified O’Brian-Fleming spending function was chosen for adjustment of the significance
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level in interim analyses.20 An independent data and safety-monitoring committee reviewed the interim results. RESULTS A total of 26,203 women were evaluated for a screening examination between July 1996 and May 2000 (Figure 1). Of these, 9886 were either ineligible or refused con-
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Table 1. Baseline Characteristics of the Study Subjects Characteristic Marital status Married Divorced Never married Ethnicity Black White Hispanic Asian Other/unknown Medical funding source Government Private None Smoked during this pregnancy Alcohol during this pregnancy Illicit drugs this pregnancy Nulliparous Prior spontaneous preterm delivery Infection during this pregnancy Syphilis Gonorrhea Chlamydia Trichomonas Bacterial vaginosis at screening Human immunodeficiency virus Maternal age (y) Gestational age at randomization (wk) Educational level (y) Prepregnancy weight (kg)
Active drug group (n ⫽ 353)
Placebo group (n ⫽ 362)
P
49.6 3.1 47.3
42.5 4.7 52.8
.127
49.6 16.1 31.7 0.8 1.7
52.8 16.3 29.3 0.6 1.1
.849
73.1 10.2 16.7 14.7 6.8 4.2 39.7 8.5 28.6 0 4.2 3.4 5.4 27.4 0.6 24.2 ⫾ 5.4 23.7 ⫾ 1.1 11.2 ⫾ 2.6 65 ⫾ 15.9
75.7 11.3 13.0 16.6 6.9 4.1 44.2 13.3 31.2 0.8 2.2 4.4 3.6 31.7 0.3 23.4 ⫾ 5.1 23.7 ⫾ 1.1 11.1 ⫾ 2.4 64.5 ⫾ 16.4
.359 .498 .955 .944 .219 .041 .447 .249 .141 .565 .280 .236 .620 .051 .689 .244 .781
Data are presented as % or mean ⫾ standard deviation.
sent. Thus, 16,317 women agreed to a screening pelvic examination; 1079 of them were determined to be fetal fibronectin positive. A total of 715 women were randomized to either the active drug (353) or placebo (362) groups (Figure 1). Only 15 women (2%) were lost to follow-up. The treatment groups were similar with respect to demographics and socioeconomic indicators (Table 1). A history of a previous spontaneous preterm delivery was significantly more common among placebo-treated compared with antibiotic-treated women (Table 1). Outcome data were available for 703 of the 715 randomized women. Among the 15 women lost to followup, the gestational age at which the subject was last known to be pregnant was greater than 37 weeks’ gestation for three. Therefore, these three women were included as term births in the analysis. No significant differences were observed between the treatment groups for spontaneous preterm delivery or preterm delivery due to any reason before 37, 35, or 32 weeks’ gestation (Table 2). Likewise, the mean gestational age at delivery (38.1 ⫾ 3.0 versus 38.1 ⫾ 2.8 weeks, P ⫽ .954) and the
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frequency of infant birth weights less than 2500 g and less than 1500 g were no different between the two treatment groups (Table 2). Because a history of a previous spontaneous preterm delivery was significantly more common among placebo-treated compared with antibiotic-treated women, a regression analysis including prior preterm birth history was performed. This regression model revealed no significant association between treatment group and spontaneous preterm birth at less than 37 weeks’ gestation (odds ratio 1.3, 95% confidence interval 0.82, 2.05). No statistically significant difference in spontaneous preterm delivery before 37 weeks’ gestation was observed between the two groups among women in terms of race, a low body mass index, or the presence of bacterial vaginosis at screening (Table 3). Among women with a history of a spontaneous preterm delivery in a previous pregnancy, the frequency of spontaneous preterm delivery before 37 weeks’ gestational age was nearly twice as high in the antibiotic- compared with the placebo-treated group (46.7% versus 23.9%, P ⫽ .039; Table 3). Although not statistically significant among
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Table 2. Pregnancy Outcomes According to Treatment Group Outcome
Active drug group (%) (n ⫽ 347)
Placebo group (%) (n ⫽ 356)
Relative risk (95% CI)
14.4 6.9 4.3
12.4 7.5 2.2
1.17 (0.80, 1.70) 0.92 (0.54, 1.56) 1.94 (0.83, 4.52)
16.4 8.1 4.9
16.6 9.5 3.1
0.99 (0.71, 1.38) 0.85 (0.53, 1.37) 1.60 (0.76, 3.36)
12.7 3.5
14.3 3.2
0.88 (0.60, 1.29) 1.12 (0.50, 2.50)
Spontaneous* preterm delivery Before 37 wk Before 35 wk Before 32 wk Preterm delivery Before 37 wk Before 35 wk Before 32 wk Birth weight Less than 2500 g Less than 1500 g
CI ⫽ confidence interval * Due to spontaneous onset of preterm labor or spontaneous preterm premature rupture of membranes.
women with a prior spontaneous preterm delivery, a higher risk of repeat spontaneous preterm birth in the antibiotic- compared with the placebo-treated women was observed for delivery before 35 weeks’ gestation (23.3% versus 14.6%, P ⫽ .327) and before 32 weeks’ gestation (16.7% versus 8.3%, P ⫽ .294).
Because black women are known to be at increased risk for spontaneous preterm delivery and also have a higher prevalence of bacterial vaginosis, a consistent risk factor for preterm birth,7 a subanalysis within this ethnic group was performed. Among black women, no difference in the frequency of spontaneous preterm delivery
Table 3. Spontaneous Preterm Delivery* Stratified by Selected Risk Clinical Factors Outcome Previous spontaneous preterm delivery Yes No Ethnicity Black Hispanic White/other Body mass index (kg/m2) ⬍19.8† ⱖ19.8 Bacterial vaginosis at screening examination Negative Positive Timing of FFN test (gestational wk) 20–22 23–24 ⱖ25 Recent intercourse‡ No Yes Screening to randomization interval (d) 0–7 8–14 15–21 ⱖ22
Active drug group (n, %)
Placebo group (n, %)
Relative risk (95% CI)
14/30 (46.7) 36/317 (11.4)
11/46 (23.9) 33/310 (10.7)
1.95 (1.03, 3.71) 1.07 (0.68, 1.67)
30/172 (17.4) 7/109 (6.4) 13/66 (19.7)
25/187 (13.4) 6/104 (5.8) 13/65 (20.0)
1.30 (0.80, 2.13) 1.11 (0.39, 3.20) 0.98 (0.49, 1.96)
9/60 (15.0) 40/268 (14.9)
13/71 (18.3) 30/269 (11.2)
0.82 (0.38, 1.78) 1.34 (0.86, 2.08)
30/229 (13.1) 11/86 (12.8)
23/217 (10.6) 15/99 (15.2)
1.24 (0.74, 2.06) 0.84 (0.41, 1.74)
28/205 (13.7) 17/127 (13.4) 5/15 (33.3)
23/212 (10.9) 19/124 (15.3) 2/20 (10.0)
1.26 (0.75, 2.11) 0.87 (0.48, 1.60) 3.33 (0.75, 14.9)
21/94 (22.3) 3/61 (4.9)
18/115 (15.7) 7/63 (11.1)
1.43 (0.81, 2.52) 0.44 (0.12, 1.63)
32/176 (18.2) 11/108 (10.2) 5/43 (11.6) 2/20 (10.0)
22/176 (12.5) 16/121 (13.2) 5/42 (11.9) 1/17 (5.9)
1.45 (0.88, 2.40) 0.77 (0.37, 1.59) 0.98 (0.30, 3.13) 1.70 (0.17, 17.2)
FFN ⫽ Fetal Fibronectin; other abbreviation as in Table 2. * Less than 37 weeks’ gestational age. † Less than the tenth percentile. ‡ Within 24 hours.
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Table 4. Selected Neonatal Outcomes According to Treatment Group Outcome
Active drug group (n ⫽ 347)
Placebo group (n ⫽ 356)
P
Congenital malformations 1-min Apgar score ⬍5 5-min Apgar score ⬍7 Umbilical artery pH Transient tachypnea Persistent pulmonary hypertension Culture-proven sepsis Pneumonia Necrotizing enterocolitis Grade III or IV intraventricular hemorrhage Respiratory distress syndrome Days of ventilator support Days of supplemental oxygen Bronchopulmonary dysplasia Patent ductus arteriosus Seizures Retinopathy of prematurity Fetal death Infant death
1.5 5.9 2.4 7.3 ⫾ 0.1 3.0 0.3 1.5 1.2 0.9 0.6 3.8 0.3 ⫾ 2.7 0.8 ⫾ 5.0 0.9 0.6 0.3 0.9 0.8 0.6
1.4 2.9 1.2 7.3 ⫾ 0.1 3.8 0.0 1.4 1.2 0.0 0.3 3.8 0.2 ⫾ 1.6 0.5 ⫾ 3.1 0.3 0.6 0.3 0.0 0.3 0.6
⬎.999 .056 .234 .601 .558 .495 ⬎.999 ⬎.999 .121 .621 .958 .797 .407 .369 ⬎.999 ⬎.999 .122 .369 ⬎.999
Data are presented as % or mean ⫾ standard deviation.
before 37 weeks’ gestation was observed between the antibiotic- and placebo-treated groups, regardless of whether bacterial vaginosis was present (13.2% versus 19.3%, P ⫽ .388) or absent (17.5% versus 10.4%, P ⫽ .138) at randomization. Stratification by other clinical factors, including the gestational timing of the fetal fibronectin test, intercourse within 24 hours of the fetal fibronectin test, and the interval between obtaining the fetal fibronectin screening test and subsequent randomization, revealed no statistically significant difference in spontaneous preterm delivery before 37 weeks’ gestation between the antibiotictreated and placebo-treated groups (Table 3). No significant differences in spontaneous preterm delivery between the two groups were observed when the outcomes were stratified by clinical center (data not shown). The antibiotic- and placebo-treated groups did not differ significantly with respect to the number of admissions to the hospital for preterm labor or premature rupture of membranes (16.3% versus 13.4%, P ⫽ .291), use of tocolytic drugs (6.4% versus 6.0%, P ⫽ .821), frequency of antepartum bleeding (0.9% versus 1.1%, P ⫽ 1.00), occurrence of preeclampsia or gestational hypertension (7.9% versus 8.3%, P ⫽ .842), oligohydramnios (5.0% versus 5.2%, P ⫽ .911), need for cesarean delivery (15.4% versus 15.9%, P ⫽ .868), presence of meconium in labor (20.9% versus 16.4%, P ⫽ .134), placental abnormalities (2.3% versus 1.7%, P ⫽ .567), or gestational diabetes (3.8% versus 2.6%, P ⫽ .360). The number of women who developed vaginal infections requiring treatment during the pregnancy (14.7%
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versus 21.3%, P ⫽ .025), postpartum endometritis (2.1% versus 5.2%, P ⫽ .028), and clinical chorioamnionitis (3.8% versus 6.6%, P ⫽ .099) was lower in the antibioticthan in the placebo-treated group. Selected neonatal outcomes were also similar in the group treated with active drugs compared with the group treated with placebo (Table 4). Of particular importance in this antibiotic-intervention study, neonatal infection– related morbidities were similar in the antibiotic- and placebo-treated groups, including culture-proven sepsis, pneumonia, and necrotizing enterocolitis (Table 4). A full course of treatment consisted of 70 capsules, including three metronidazole plus four erythromycin (or respective placebo) capsules daily for 10 days. Compliance data were available for 666 women. Overall, 68.4% (n ⫽ 489) of the women completed more than 1 week of treatment (56 –70 capsules), and 53.1% consumed all 70 capsules. There were no statistically significant differences between the active drug and placebo groups regarding the percentage of women who completed 8 or more days of treatment (67.4% versus 69.3%, P ⫽ 0.582) or all 10 days of treatment (50.7% versus 55.5%, P ⫽ 0.197). The primary reason reported for not completing the treatment course was the occurrence of one or more adverse effects; 44.3% and 36.7% of those who did not complete treatment were in the active drug and placebo groups, respectively (P ⫽ .157). Commonly reported adverse effects in the active drug and placebo groups, respectively, included any adverse effect (40.0% versus 29.7%, P ⫽ .005), nausea (28.6% versus 19.8%, P ⫽ .008), vomiting (15.1% versus 7.9%, P ⫽ .003), diar-
OBSTETRICS & GYNECOLOGY
rhea (6.8% versus 3.8%, P ⫽ .084), abdominal pain (5.5% versus 2.6%, P ⫽ .056), and loss of appetite (4.0% versus 4.1%, P ⫽ .957). Also, women in both treatment groups who did not complete their treatment reported that they often simply forgot to take their fourth (bedtime) dose of erythromycin or placebo (active drug versus placebo: 28.7% versus 30.6%, P ⫽ .695). Overall, 29.5% of women were determined to have bacterial vaginosis at the randomization visit, and no difference in the frequency of this condition was observed between the active drug and placebo groups (27.4% versus 31.7%, P ⫽ .236). Bacterial vaginosis was significantly lower in the active drug group than in the placebo group at the follow-up visit (9.9% versus 27.3%, P ⬍ .001). By design, all women were positive for fetal fibronectin at the randomization visit. The frequency of a positive result for fetal fibronectin overall was substantially lower at the follow-up visit (19.5%). The frequency of a positive fetal fibronectin test at the follow-up visit was significantly higher in the active drug group than in the placebo group (22.9% versus 16.2%, P ⫽ .040). DISCUSSION In this randomized, clinical trial, treatment of asymptomatic women with a positive cervical or vaginal fetal fibronectin test between 21 and 25 weeks’ gestational age with metronidazole plus erythromycin did not decrease the risk of spontaneous delivery and did not result in improved neonatal outcomes. The ineffectiveness of the intervention was observed despite the use of a prolonged course of broad-spectrum combination antibiotics. Rationale for this treatment regimen was derived from a prior study, in which treatment of more than a week with this same combination of antibiotics was associated with a lower rate of spontaneous preterm birth among highrisk women with asymptomatic bacterial vaginosis.9 Additionally, the combination of both metronidazole and erythromycin seemed best suited to cover the major organisms typically isolated from the upper genital tract among women with a spontaneous preterm delivery.5 Compliance with the study medication was good according to verbal reports by participants and capsule counts conducted by study personnel. One objective measure of compliance was the frequency of bacterial vaginosis detected at the follow-up visit, which was observed to be significantly lower in the women who took active drugs (including metronidazole) compared with those given placebo capsules. Some adverse effects were more commonly reported by women taking active drug compared with placebo-treated women. Also, the primary reason given by subjects for not completing the treatment course was the occurrence of one or more
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adverse effects. However, the percentage of women who completed 7 or more days of treatment was almost identical in both groups. Therefore, noncompliance in the groups assigned to metronidazole plus erythromycin compared with the group assigned to placebo did not explain the failure of the active intervention to reduce spontaneous preterm delivery. The assumptions used to calculate the sample size for this investigation were based on extensive data collected during the Preterm Prediction Study, an observational study of 2929 pregnant women previously conducted by the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network.13 Based on this study, we assumed that an approximate 30% rate of spontaneous preterm delivery before 37 weeks’ gestation would occur in the placebo group.13 Instead, we observed a much lower incidence of spontaneous preterm delivery, 13.7% overall. Therefore, it could be argued that this study lacked sufficient statistical power and that a significantly lower incidence of spontaneous preterm birth might have been observed if the sample size had been larger. However, given the almost identical percentage of spontaneous preterm delivery observed in the active drug and placebo groups (14.4% and 12.4%, respectively) providing no suggestion of even a trend toward a lower incidence of the primary outcome in either group, this seems highly unlikely. Nevertheless, explanation for the lower incidence of spontaneous delivery before 37 weeks’ gestation observed in this investigation compared with that observed in the Preterm Prediction Study remains speculative. Although the frequency of a positive fetal fibronectin test at the follow-up visit was significantly higher in the active drug group than in the placebo group, the magnitude of this difference does not likely explain the failure to observe a benefit to antibiotic treatment. It is difficult to speculate as to whether or not the antibiotic treatment actually increased choriodecidual matrix disruption, leading to higher rate of fetal fibronectin leakage from the upper to the lower genital tract. Notably, the fetal fibronectin test was negative in 80% of the women at the follow-up visit. An intriguing finding was the nearly two-fold higher risk of spontaneous preterm delivery observed in the active drug group compared with the placebo group among women with a history of a spontaneous preterm delivery in a previous pregnancy. Interpretation of this observation must be guided by caution because this is a secondary analysis of data, and the explanation remains a subject of speculation. It is unclear whether antibiotic treatment actually increased the risk of preterm delivery in this subset of women by altering the vaginal flora or by some other mechanism. However, this observation is
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consistent with an increased risk of preterm delivery in certain subgroups of women treated with antibiotics during pregnancy (Hauth JC, Cliver SP, Hodgkins P, Andrews WW, Schwebke JR, Hooke EW, et al. Midtrimester metronidazole and azithromycin did not prevent preterm birth in women at increased risk: A doubleblind trial [abstract]. Am J Obstet Gynecol 2001;185: S86).6,9,12 Such data underscore the need for clinical caution and argue against the indiscriminate use of antibiotics to prevent preterm birth. Although vaginal infections and postpartum endometritis were less common in the active drug group compared with the placebo group, these observations are secondary outcomes of this study and do not, in our view, warrant a recommendation for second trimester fetal fibronectin screening and antibiotic treatment solely to reduce the risk of these outcomes. Despite the previously reported performance of the fetal fibronectin test to identify women at increased risk for subsequent spontaneous preterm delivery,13,14 based on the results of this trial, we discourage the practice of cervical or vaginal fetal fibronectin screening to direct an antibiotic intervention for preterm birth prevention.
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19. 20.
metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med 1995;333:1732–6. McDonald HM, O’Loughlin JA, Vigneswaran R, Jolley PT, Harvey JA, Bof A, et al. Impact of metronidazole therapy on preterm birth in women with bacterial vaginosis flora (Gardnerella vaginalis): A randomized, placebo controlled trial. Br J Obstet Gynaecol 1997;104: 1391–7. Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 2000;342:534–40. Klebanoff MA, Carey JC, Hauth JC, Hillier SL, Nugent RO, Thom EA, et al. Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl J Med 2001;345: 487–93. Goldenberg RL, Mercer BM, Meis PJ, Copper RL, Das A, McNellis D. The Preterm Prediction Study: Fetal fibronectin testing and spontaneous preterm birth. Obstet Gynecol 1996;87:643–8. Lockwood CJ, Senyei AE, Dische MR, Casal D, Shah KD, Thung SN, et al. Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. N Engl J Med 1991;325:669–74. Feinberg RF, Kliman HJ, Lockwood CJ. Is oncofetal fibronectin a trophoblast glue for human implantation? Am J Pathol 1991;138:537–43. Goldenberg RL, Thom E, Moawad AH, Johnson F, Roberts J, Caritus SN, et al. The Preterm Prediction Study: Fetal fibronectin, bacterial vaginosis and peripartum infection. Obstet Gynecol 1996;87:656–60. Goepfert AR, Goldenberg RL, Andrews WW, Hauth JC, Mercer B, Iams J, et al. The Preterm Prediction Study: Quantitative fetal fibronectin values and the prediction of spontaneous preterm birth. Am J Obstet Gynecol 2000; 183:1480–3. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis by a standardized method of Gram stain interpretation. J Clin Microbiol 1991;29: 297–301. Wei LJ, Lachin JM. Properties of the urn randomization in clinical trials. Control Clin Trials 1988;9:345–64. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659–63.
Address reprint requests to: William W. Andrews, PhD, MD, University of Alabama at Birmingham, Department of Obstetrics and Gynecology, 619 19th Street South—OHB 458,Birmingham, AL 35249-7333; E-mail: [email protected]. Received January 21, 2003. Received in revised form February 7, 2003. Accepted February 13, 2003.
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APPENDIX Other members of the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network are as follows: University of Alabama at Birmingham, R. Goldenberg, A. Northen, R. Cooper, C. Morgan; University of Tennessee at Memphis, R. Ramsey; George Washington University Biostatistics Center, L. Leuchtenburg, A. Das, M. Fisher; University of Utah, E. Taggart; Wake Forest University, M. Swain, A. Luper; National Institute of Child Health and Human Development, M. Klebanoff, C. Spong; University of
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Texas Southwestern Medical Center, J. McCampbell, M. L. Sherman; Thomas Jefferson University, M. DiVito, A. Sciscione; University of Chicago, P. Jones, G. Mallet, D. Scott, M. R. Brinson, M. Brown; University of Miami, S. Beydoun, C. Alfonso, F. Doyle, R. Washington, G. Diaz; University of Pittsburgh/Magee-Women’s Hospital, M. Cotroneo, T. Kamon, E. Daugherty, P. Heine; Ohio State University, M. Landon, C. Latimer, S. Meadows, F. Johnson; University of Texas San Antonio, S. Nicholson, S. Barker, D. Skiver; University of Cincinnati, H. How; Wayne State University, Y. Sorokin, G. Norman.
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Randomized Clinical Trial of Metronidazole Plus Erythromycin to Prevent Spontaneous Preterm Delivery in Fetal Fibronectin–Positive Women William W. Andrews, PhD, MD, Baha M. Sibai, MD, Elizabeth A. Thom, PhD, Donald Dudley, MD, J. M. Ernest, MD, Donald McNellis, MD, Kenneth J. Leveno, MD, Ronald Wapner, MD, Atef Moawad, MD, Mary J. O’Sullivan, MD, Steve N. Caritis, MD, Jay D. Iams, MD, Oded Langer, MD, Menachem Miodovnik, MD, and Mitchell Dombrowski, MD, for the National Institute of Child Health & Human Development Maternal–Fetal Medicine Units Network* OBJECTIVE: To estimate whether antibiotic treatment of asymptomatic women with a positive cervical or vaginal fetal fibronectin test in the second trimester would reduce the risk of spontaneous preterm delivery. METHODS: Women were screened between 21 weeks 0 days and 25 weeks 6 days of gestation with cervical or vaginal swabs for fetal fibronectin. Women with a positive test (50 ng/mL or more) were randomized to receive metronidazole (250 mg orally three times per day) and erythromycin (250 mg orally four times per day) or identical placebo pills for 10 days. The primary outcome was spontaneous delivFrom the Department of Obstetrics and Gynecology, Center for Research in Women’s Health, University of Alabama at Birmingham, Birmingham, Alabama; Department of Obstetrics and Gynecology, University of Tennessee, Memphis, Tennessee; The Biostatistics Center, George Washington University, Rockville, Maryland; Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah; Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina; The National Institute of Child Health and Human Development, Bethesda, Maryland; Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Obstetrics and Gynecology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois; Department of Obstetrics and Gynecology, University of Miami, Miami, Florida; University of Pittsburgh/Magee-Women’s Hospital, Pittsburgh, Pennsylvania; Department of Obstetrics and Gynecology, Ohio State University, Columbus, Ohio; Department of Obstetrics and Gynecology, University of Texas at San Antonio, San Antonio, Texas; Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, Ohio; and Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan. Supported by grants from the National Institute of Child Health and Human Development (U10-HD27869, U10-HD21414, U10-HD36801, U10HD34208, U10-HD27860, U10-HD34116, U10-HD34136, U10HD27861, U10-HD34122, U10-HD21410, U10-HD27915, U10HD34210, U10-HD27905, and U10-HD27917). Fetal fibronectin assays were performed at no cost to the project by Adeza Biomedical, Sunnyvale, California. *For other members of the Network, see the Appendix.
ery before 37 weeks’ gestation after preterm labor or premature membrane rupture. RESULTS: A total of 16,317 women were screened for fetal fibronectin, and 6.6% had a positive test; 715 fetal fibronectin test–positive women consented to randomization. Outcome data were available for 703 women: 347 in the antibiotic group and 356 in the placebo group. The antibiotic and placebo groups were not significantly different for maternal age (P ⴝ .051), ethnicity (P ⴝ .849), marital status (P ⴝ .127), education (P ⴝ .244), and bacterial vaginosis (P ⴝ .236). No difference was observed in spontaneous preterm birth before 37 weeks’ (odds ratio [OR] 1.17, 95% confidence interval [CI] 0.80, 1.70), less than 35 weeks’ (OR 0.92, 95% CI 0.54, 1.56), or less than 32 weeks’ (OR 1.94, 95% CI 0.83, 4.52) gestation in antibiotic- compared with placebo-treated women. Among women with a prior spontaneous preterm delivery, the rate of repeat spontaneous preterm delivery at less than 37 weeks’ gestation was significantly higher in the active drug compared with the placebo group (46.7% versus 23.9%, P ⴝ .039). CONCLUSION: Treatment with metronidazole plus erythromycin of asymptomatic women with a positive cervical or vaginal fetal fibronectin test in the late second trimester does not decrease the incidence of spontaneous preterm delivery. (Obstet Gynecol 2003;101:847–55. © 2003 by The American College of Obstetricians and Gynecologists.)
Preterm birth complicates 11% of all pregnancies and remains the primary cause of perinatal mortality and long-term neurologic morbidity.1,2 Published literature has strongly linked clinically silent upper genital tract bacterial infection and/or inflammation with preterm birth and adverse pregnancy outcomes.3–7 Although randomized trials of systemic antibiotics to reduce pre-
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term birth in women with altered vaginal flora have yielded mixed results,6,8 –12 genital tract infections represent a potentially treatable cause of spontaneous preterm delivery. Fetal fibronectin is a placental and membrane protein that is a unique epitope of the fibronectins. When detected in asymptomatic women (those without signs or symptoms of vaginal infection or preterm labor) as early as 23–24 weeks’ gestation, a positive fetal fibronectin test is associated with a 59-fold increased risk of spontaneous preterm delivery at less than 28 weeks’ gestation.13 One hypothesis holds that intrauterine infection causes disruption of the extracellular choriodecidual basement membrane, causing leakage of fetal fibronectin into cervical or vaginal secretions, in which it can then be detected.14 –16 Our objective in this study was to estimate whether treatment with metronidazole plus erythromycin of asymptomatic women with a positive cervical or vaginal fetal fibronectin test before 26 weeks’ gestation would reduce the risk of spontaneous preterm delivery. MATERIALS AND METHODS Women undergoing routine prenatal care at each of 13 participating centers were screened between 21 weeks 0 days and 25 weeks 6 days of gestation for cervical and vaginal fetal fibronectin. Separate Dacron swab specimens were collected from the exocervix and posterior vaginal fornix with a vaginal speculum without a lubricant and before collection of other specimens. These specimens were immediately stored at 2– 8C and shipped overnight to a central laboratory (Adeza Biomedical, Sunnyvale, CA), where fetal fibronectin was determined by an enzyme-linked immunosorbent assay. Based on previously published data,17 a positive test was defined as a concentration of 50 ng/mL or more in either the cervical or the vaginal swab. Other details of the specimen collection, handling, and assay have been previously published.13,14 Vaginal smears obtained at screening were evaluated (with Nugent criteria18) in a central laboratory for the presence of bacterial vaginosis. Women were not selected based on the presence or absence of any specific risk factor (other than a positive fetal fibronectin test) for a spontaneous preterm birth. Exclusion criteria included the following: fetal death, major fetal anomalies, multiple gestation, allergy to study medication, antibiotic use at randomization, use of topical antifungals within 24 hours of screening, vaginal symptoms (unelicited, spontaneously reported vaginal symptoms, including itching, burning, or malodor indicating need for specific treatment), vaginal bleeding (defined as active bleeding at screening, not spotting and not
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bleeding due to a friable cervix), ethanol abuse, preterm labor, rupture of membranes, tocolytic use, cerclage, preeclampsia, hypertension requiring medication, placenta previa, uterine anomaly, insulin-requiring diabetes mellitus, renal insufficiency, collagen vascular disease, isoimmunization, acquired immunodeficiency syndrome– defining illness, and anticipated prenatal care or delivery at a nonparticipating center. The study was approved by the institutional review boards at each clinical site, and all women gave written, informed consent before enrollment in the study. Eligible women with a positive fetal fibronectin test were randomized (double-masked) between 21 weeks 0 days and 25 weeks 6 days of gestation to receive either metronidazole 250 mg three times daily plus erythromycin 250 mg four times daily or identical placebo capsules orally for 10 days. The simple urn method of randomization19 with stratification according to clinical center was used to create a computer-generated random sequence, and study drugs were packaged accordingly in vials for distribution to the participants. Subjects were instructed to take one metronidazole capsule (or identical placebo) three times daily with meals and one erythromycin capsule (or placebo) four times daily (at each meal and at bedtime) for 10 days. Medication was begun on the day of randomization. One follow-up visit was scheduled 14 days after randomization, at which fetal fibronectin and bacterial vaginosis status were reassessed. Medication compliance was estimated at this visit by examining the pill containers for remaining capsules. Subjects who failed to return the pill container were asked whether any capsules remained. If unconsumed capsules remained, the cervical and vaginal specimens were still obtained, and the women were encouraged to take the remainder of the study medication. Establishment of the gestational age at randomization was determined by the date of the last menstrual period and by ultrasound results with a previously published scheme.11,12 Preterm birth was defined as delivery before 37 completed weeks’ gestation (259 days), and spontaneous preterm birth was defined as preterm delivery due to the spontaneous onset of preterm labor or spontaneous preterm premature rupture of membranes. The primary outcome was spontaneous delivery before 37 weeks’ gestation after preterm labor or premature membrane rupture. Usual prenatal care was provided at the respective institutions, but enrollment continued until pregnancy outcomes were assessed. The target sample size of 700 women was calculated assuming a 30% rate of spontaneous preterm delivery before 37 weeks’ gestation in the placebo group and an estimated effect size of a one third reduction of this
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Figure 1. Summary of screening for fetal fibronectin and randomization to active drugs or placebo. Andrews. Fetal Fibronectin and Prematurity. Obstet Gynecol 2003.
outcome in the active drug group. A type I error (twosided) of 5% and a power of 80% was chosen, and an adjustment for a dropout rate of 5% was made. Continuous variables were compared using the Wilcoxon rank-sum test, and categoric variables were compared using 2 and Fisher exact tests. Before the study was started, the group sequential method of Lan and DeMets with the modified O’Brian-Fleming spending function was chosen for adjustment of the significance
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level in interim analyses.20 An independent data and safety-monitoring committee reviewed the interim results. RESULTS A total of 26,203 women were evaluated for a screening examination between July 1996 and May 2000 (Figure 1). Of these, 9886 were either ineligible or refused con-
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Table 1. Baseline Characteristics of the Study Subjects Characteristic Marital status Married Divorced Never married Ethnicity Black White Hispanic Asian Other/unknown Medical funding source Government Private None Smoked during this pregnancy Alcohol during this pregnancy Illicit drugs this pregnancy Nulliparous Prior spontaneous preterm delivery Infection during this pregnancy Syphilis Gonorrhea Chlamydia Trichomonas Bacterial vaginosis at screening Human immunodeficiency virus Maternal age (y) Gestational age at randomization (wk) Educational level (y) Prepregnancy weight (kg)
Active drug group (n ⫽ 353)
Placebo group (n ⫽ 362)
P
49.6 3.1 47.3
42.5 4.7 52.8
.127
49.6 16.1 31.7 0.8 1.7
52.8 16.3 29.3 0.6 1.1
.849
73.1 10.2 16.7 14.7 6.8 4.2 39.7 8.5 28.6 0 4.2 3.4 5.4 27.4 0.6 24.2 ⫾ 5.4 23.7 ⫾ 1.1 11.2 ⫾ 2.6 65 ⫾ 15.9
75.7 11.3 13.0 16.6 6.9 4.1 44.2 13.3 31.2 0.8 2.2 4.4 3.6 31.7 0.3 23.4 ⫾ 5.1 23.7 ⫾ 1.1 11.1 ⫾ 2.4 64.5 ⫾ 16.4
.359 .498 .955 .944 .219 .041 .447 .249 .141 .565 .280 .236 .620 .051 .689 .244 .781
Data are presented as % or mean ⫾ standard deviation.
sent. Thus, 16,317 women agreed to a screening pelvic examination; 1079 of them were determined to be fetal fibronectin positive. A total of 715 women were randomized to either the active drug (353) or placebo (362) groups (Figure 1). Only 15 women (2%) were lost to follow-up. The treatment groups were similar with respect to demographics and socioeconomic indicators (Table 1). A history of a previous spontaneous preterm delivery was significantly more common among placebo-treated compared with antibiotic-treated women (Table 1). Outcome data were available for 703 of the 715 randomized women. Among the 15 women lost to followup, the gestational age at which the subject was last known to be pregnant was greater than 37 weeks’ gestation for three. Therefore, these three women were included as term births in the analysis. No significant differences were observed between the treatment groups for spontaneous preterm delivery or preterm delivery due to any reason before 37, 35, or 32 weeks’ gestation (Table 2). Likewise, the mean gestational age at delivery (38.1 ⫾ 3.0 versus 38.1 ⫾ 2.8 weeks, P ⫽ .954) and the
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frequency of infant birth weights less than 2500 g and less than 1500 g were no different between the two treatment groups (Table 2). Because a history of a previous spontaneous preterm delivery was significantly more common among placebo-treated compared with antibiotic-treated women, a regression analysis including prior preterm birth history was performed. This regression model revealed no significant association between treatment group and spontaneous preterm birth at less than 37 weeks’ gestation (odds ratio 1.3, 95% confidence interval 0.82, 2.05). No statistically significant difference in spontaneous preterm delivery before 37 weeks’ gestation was observed between the two groups among women in terms of race, a low body mass index, or the presence of bacterial vaginosis at screening (Table 3). Among women with a history of a spontaneous preterm delivery in a previous pregnancy, the frequency of spontaneous preterm delivery before 37 weeks’ gestational age was nearly twice as high in the antibiotic- compared with the placebo-treated group (46.7% versus 23.9%, P ⫽ .039; Table 3). Although not statistically significant among
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Table 2. Pregnancy Outcomes According to Treatment Group Outcome
Active drug group (%) (n ⫽ 347)
Placebo group (%) (n ⫽ 356)
Relative risk (95% CI)
14.4 6.9 4.3
12.4 7.5 2.2
1.17 (0.80, 1.70) 0.92 (0.54, 1.56) 1.94 (0.83, 4.52)
16.4 8.1 4.9
16.6 9.5 3.1
0.99 (0.71, 1.38) 0.85 (0.53, 1.37) 1.60 (0.76, 3.36)
12.7 3.5
14.3 3.2
0.88 (0.60, 1.29) 1.12 (0.50, 2.50)
Spontaneous* preterm delivery Before 37 wk Before 35 wk Before 32 wk Preterm delivery Before 37 wk Before 35 wk Before 32 wk Birth weight Less than 2500 g Less than 1500 g
CI ⫽ confidence interval * Due to spontaneous onset of preterm labor or spontaneous preterm premature rupture of membranes.
women with a prior spontaneous preterm delivery, a higher risk of repeat spontaneous preterm birth in the antibiotic- compared with the placebo-treated women was observed for delivery before 35 weeks’ gestation (23.3% versus 14.6%, P ⫽ .327) and before 32 weeks’ gestation (16.7% versus 8.3%, P ⫽ .294).
Because black women are known to be at increased risk for spontaneous preterm delivery and also have a higher prevalence of bacterial vaginosis, a consistent risk factor for preterm birth,7 a subanalysis within this ethnic group was performed. Among black women, no difference in the frequency of spontaneous preterm delivery
Table 3. Spontaneous Preterm Delivery* Stratified by Selected Risk Clinical Factors Outcome Previous spontaneous preterm delivery Yes No Ethnicity Black Hispanic White/other Body mass index (kg/m2) ⬍19.8† ⱖ19.8 Bacterial vaginosis at screening examination Negative Positive Timing of FFN test (gestational wk) 20–22 23–24 ⱖ25 Recent intercourse‡ No Yes Screening to randomization interval (d) 0–7 8–14 15–21 ⱖ22
Active drug group (n, %)
Placebo group (n, %)
Relative risk (95% CI)
14/30 (46.7) 36/317 (11.4)
11/46 (23.9) 33/310 (10.7)
1.95 (1.03, 3.71) 1.07 (0.68, 1.67)
30/172 (17.4) 7/109 (6.4) 13/66 (19.7)
25/187 (13.4) 6/104 (5.8) 13/65 (20.0)
1.30 (0.80, 2.13) 1.11 (0.39, 3.20) 0.98 (0.49, 1.96)
9/60 (15.0) 40/268 (14.9)
13/71 (18.3) 30/269 (11.2)
0.82 (0.38, 1.78) 1.34 (0.86, 2.08)
30/229 (13.1) 11/86 (12.8)
23/217 (10.6) 15/99 (15.2)
1.24 (0.74, 2.06) 0.84 (0.41, 1.74)
28/205 (13.7) 17/127 (13.4) 5/15 (33.3)
23/212 (10.9) 19/124 (15.3) 2/20 (10.0)
1.26 (0.75, 2.11) 0.87 (0.48, 1.60) 3.33 (0.75, 14.9)
21/94 (22.3) 3/61 (4.9)
18/115 (15.7) 7/63 (11.1)
1.43 (0.81, 2.52) 0.44 (0.12, 1.63)
32/176 (18.2) 11/108 (10.2) 5/43 (11.6) 2/20 (10.0)
22/176 (12.5) 16/121 (13.2) 5/42 (11.9) 1/17 (5.9)
1.45 (0.88, 2.40) 0.77 (0.37, 1.59) 0.98 (0.30, 3.13) 1.70 (0.17, 17.2)
FFN ⫽ Fetal Fibronectin; other abbreviation as in Table 2. * Less than 37 weeks’ gestational age. † Less than the tenth percentile. ‡ Within 24 hours.
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Table 4. Selected Neonatal Outcomes According to Treatment Group Outcome
Active drug group (n ⫽ 347)
Placebo group (n ⫽ 356)
P
Congenital malformations 1-min Apgar score ⬍5 5-min Apgar score ⬍7 Umbilical artery pH Transient tachypnea Persistent pulmonary hypertension Culture-proven sepsis Pneumonia Necrotizing enterocolitis Grade III or IV intraventricular hemorrhage Respiratory distress syndrome Days of ventilator support Days of supplemental oxygen Bronchopulmonary dysplasia Patent ductus arteriosus Seizures Retinopathy of prematurity Fetal death Infant death
1.5 5.9 2.4 7.3 ⫾ 0.1 3.0 0.3 1.5 1.2 0.9 0.6 3.8 0.3 ⫾ 2.7 0.8 ⫾ 5.0 0.9 0.6 0.3 0.9 0.8 0.6
1.4 2.9 1.2 7.3 ⫾ 0.1 3.8 0.0 1.4 1.2 0.0 0.3 3.8 0.2 ⫾ 1.6 0.5 ⫾ 3.1 0.3 0.6 0.3 0.0 0.3 0.6
⬎.999 .056 .234 .601 .558 .495 ⬎.999 ⬎.999 .121 .621 .958 .797 .407 .369 ⬎.999 ⬎.999 .122 .369 ⬎.999
Data are presented as % or mean ⫾ standard deviation.
before 37 weeks’ gestation was observed between the antibiotic- and placebo-treated groups, regardless of whether bacterial vaginosis was present (13.2% versus 19.3%, P ⫽ .388) or absent (17.5% versus 10.4%, P ⫽ .138) at randomization. Stratification by other clinical factors, including the gestational timing of the fetal fibronectin test, intercourse within 24 hours of the fetal fibronectin test, and the interval between obtaining the fetal fibronectin screening test and subsequent randomization, revealed no statistically significant difference in spontaneous preterm delivery before 37 weeks’ gestation between the antibiotictreated and placebo-treated groups (Table 3). No significant differences in spontaneous preterm delivery between the two groups were observed when the outcomes were stratified by clinical center (data not shown). The antibiotic- and placebo-treated groups did not differ significantly with respect to the number of admissions to the hospital for preterm labor or premature rupture of membranes (16.3% versus 13.4%, P ⫽ .291), use of tocolytic drugs (6.4% versus 6.0%, P ⫽ .821), frequency of antepartum bleeding (0.9% versus 1.1%, P ⫽ 1.00), occurrence of preeclampsia or gestational hypertension (7.9% versus 8.3%, P ⫽ .842), oligohydramnios (5.0% versus 5.2%, P ⫽ .911), need for cesarean delivery (15.4% versus 15.9%, P ⫽ .868), presence of meconium in labor (20.9% versus 16.4%, P ⫽ .134), placental abnormalities (2.3% versus 1.7%, P ⫽ .567), or gestational diabetes (3.8% versus 2.6%, P ⫽ .360). The number of women who developed vaginal infections requiring treatment during the pregnancy (14.7%
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versus 21.3%, P ⫽ .025), postpartum endometritis (2.1% versus 5.2%, P ⫽ .028), and clinical chorioamnionitis (3.8% versus 6.6%, P ⫽ .099) was lower in the antibioticthan in the placebo-treated group. Selected neonatal outcomes were also similar in the group treated with active drugs compared with the group treated with placebo (Table 4). Of particular importance in this antibiotic-intervention study, neonatal infection– related morbidities were similar in the antibiotic- and placebo-treated groups, including culture-proven sepsis, pneumonia, and necrotizing enterocolitis (Table 4). A full course of treatment consisted of 70 capsules, including three metronidazole plus four erythromycin (or respective placebo) capsules daily for 10 days. Compliance data were available for 666 women. Overall, 68.4% (n ⫽ 489) of the women completed more than 1 week of treatment (56 –70 capsules), and 53.1% consumed all 70 capsules. There were no statistically significant differences between the active drug and placebo groups regarding the percentage of women who completed 8 or more days of treatment (67.4% versus 69.3%, P ⫽ 0.582) or all 10 days of treatment (50.7% versus 55.5%, P ⫽ 0.197). The primary reason reported for not completing the treatment course was the occurrence of one or more adverse effects; 44.3% and 36.7% of those who did not complete treatment were in the active drug and placebo groups, respectively (P ⫽ .157). Commonly reported adverse effects in the active drug and placebo groups, respectively, included any adverse effect (40.0% versus 29.7%, P ⫽ .005), nausea (28.6% versus 19.8%, P ⫽ .008), vomiting (15.1% versus 7.9%, P ⫽ .003), diar-
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rhea (6.8% versus 3.8%, P ⫽ .084), abdominal pain (5.5% versus 2.6%, P ⫽ .056), and loss of appetite (4.0% versus 4.1%, P ⫽ .957). Also, women in both treatment groups who did not complete their treatment reported that they often simply forgot to take their fourth (bedtime) dose of erythromycin or placebo (active drug versus placebo: 28.7% versus 30.6%, P ⫽ .695). Overall, 29.5% of women were determined to have bacterial vaginosis at the randomization visit, and no difference in the frequency of this condition was observed between the active drug and placebo groups (27.4% versus 31.7%, P ⫽ .236). Bacterial vaginosis was significantly lower in the active drug group than in the placebo group at the follow-up visit (9.9% versus 27.3%, P ⬍ .001). By design, all women were positive for fetal fibronectin at the randomization visit. The frequency of a positive result for fetal fibronectin overall was substantially lower at the follow-up visit (19.5%). The frequency of a positive fetal fibronectin test at the follow-up visit was significantly higher in the active drug group than in the placebo group (22.9% versus 16.2%, P ⫽ .040). DISCUSSION In this randomized, clinical trial, treatment of asymptomatic women with a positive cervical or vaginal fetal fibronectin test between 21 and 25 weeks’ gestational age with metronidazole plus erythromycin did not decrease the risk of spontaneous delivery and did not result in improved neonatal outcomes. The ineffectiveness of the intervention was observed despite the use of a prolonged course of broad-spectrum combination antibiotics. Rationale for this treatment regimen was derived from a prior study, in which treatment of more than a week with this same combination of antibiotics was associated with a lower rate of spontaneous preterm birth among highrisk women with asymptomatic bacterial vaginosis.9 Additionally, the combination of both metronidazole and erythromycin seemed best suited to cover the major organisms typically isolated from the upper genital tract among women with a spontaneous preterm delivery.5 Compliance with the study medication was good according to verbal reports by participants and capsule counts conducted by study personnel. One objective measure of compliance was the frequency of bacterial vaginosis detected at the follow-up visit, which was observed to be significantly lower in the women who took active drugs (including metronidazole) compared with those given placebo capsules. Some adverse effects were more commonly reported by women taking active drug compared with placebo-treated women. Also, the primary reason given by subjects for not completing the treatment course was the occurrence of one or more
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adverse effects. However, the percentage of women who completed 7 or more days of treatment was almost identical in both groups. Therefore, noncompliance in the groups assigned to metronidazole plus erythromycin compared with the group assigned to placebo did not explain the failure of the active intervention to reduce spontaneous preterm delivery. The assumptions used to calculate the sample size for this investigation were based on extensive data collected during the Preterm Prediction Study, an observational study of 2929 pregnant women previously conducted by the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network.13 Based on this study, we assumed that an approximate 30% rate of spontaneous preterm delivery before 37 weeks’ gestation would occur in the placebo group.13 Instead, we observed a much lower incidence of spontaneous preterm delivery, 13.7% overall. Therefore, it could be argued that this study lacked sufficient statistical power and that a significantly lower incidence of spontaneous preterm birth might have been observed if the sample size had been larger. However, given the almost identical percentage of spontaneous preterm delivery observed in the active drug and placebo groups (14.4% and 12.4%, respectively) providing no suggestion of even a trend toward a lower incidence of the primary outcome in either group, this seems highly unlikely. Nevertheless, explanation for the lower incidence of spontaneous delivery before 37 weeks’ gestation observed in this investigation compared with that observed in the Preterm Prediction Study remains speculative. Although the frequency of a positive fetal fibronectin test at the follow-up visit was significantly higher in the active drug group than in the placebo group, the magnitude of this difference does not likely explain the failure to observe a benefit to antibiotic treatment. It is difficult to speculate as to whether or not the antibiotic treatment actually increased choriodecidual matrix disruption, leading to higher rate of fetal fibronectin leakage from the upper to the lower genital tract. Notably, the fetal fibronectin test was negative in 80% of the women at the follow-up visit. An intriguing finding was the nearly two-fold higher risk of spontaneous preterm delivery observed in the active drug group compared with the placebo group among women with a history of a spontaneous preterm delivery in a previous pregnancy. Interpretation of this observation must be guided by caution because this is a secondary analysis of data, and the explanation remains a subject of speculation. It is unclear whether antibiotic treatment actually increased the risk of preterm delivery in this subset of women by altering the vaginal flora or by some other mechanism. However, this observation is
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consistent with an increased risk of preterm delivery in certain subgroups of women treated with antibiotics during pregnancy (Hauth JC, Cliver SP, Hodgkins P, Andrews WW, Schwebke JR, Hooke EW, et al. Midtrimester metronidazole and azithromycin did not prevent preterm birth in women at increased risk: A doubleblind trial [abstract]. Am J Obstet Gynecol 2001;185: S86).6,9,12 Such data underscore the need for clinical caution and argue against the indiscriminate use of antibiotics to prevent preterm birth. Although vaginal infections and postpartum endometritis were less common in the active drug group compared with the placebo group, these observations are secondary outcomes of this study and do not, in our view, warrant a recommendation for second trimester fetal fibronectin screening and antibiotic treatment solely to reduce the risk of these outcomes. Despite the previously reported performance of the fetal fibronectin test to identify women at increased risk for subsequent spontaneous preterm delivery,13,14 based on the results of this trial, we discourage the practice of cervical or vaginal fetal fibronectin screening to direct an antibiotic intervention for preterm birth prevention.
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Address reprint requests to: William W. Andrews, PhD, MD, University of Alabama at Birmingham, Department of Obstetrics and Gynecology, 619 19th Street South—OHB 458,Birmingham, AL 35249-7333; E-mail: [email protected]. Received January 21, 2003. Received in revised form February 7, 2003. Accepted February 13, 2003.
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APPENDIX Other members of the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network are as follows: University of Alabama at Birmingham, R. Goldenberg, A. Northen, R. Cooper, C. Morgan; University of Tennessee at Memphis, R. Ramsey; George Washington University Biostatistics Center, L. Leuchtenburg, A. Das, M. Fisher; University of Utah, E. Taggart; Wake Forest University, M. Swain, A. Luper; National Institute of Child Health and Human Development, M. Klebanoff, C. Spong; University of
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Texas Southwestern Medical Center, J. McCampbell, M. L. Sherman; Thomas Jefferson University, M. DiVito, A. Sciscione; University of Chicago, P. Jones, G. Mallet, D. Scott, M. R. Brinson, M. Brown; University of Miami, S. Beydoun, C. Alfonso, F. Doyle, R. Washington, G. Diaz; University of Pittsburgh/Magee-Women’s Hospital, M. Cotroneo, T. Kamon, E. Daugherty, P. Heine; Ohio State University, M. Landon, C. Latimer, S. Meadows, F. Johnson; University of Texas San Antonio, S. Nicholson, S. Barker, D. Skiver; University of Cincinnati, H. How; Wayne State University, Y. Sorokin, G. Norman.
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