Combination antibiotics and indomethacin in idiopathic preterm labor: A randomized double-blind clinical trial

Combination antibiotics and indomethacin in idiopathic preterm labor: A randomized double-blind clinical trial Edward R. Newton, MD, Laurence Shields, MD, Louis E. Ridgway III, MD, Michael D. Berkus, MD, and Byron D. Elliott, MD San Antonio, Texas Subclinical infection may playa role in the failure of magnesium sulfate tocolysis. Using a double-blind randomized study design, we administered a combination of ampicillin-sulbactam and indomethacin or corresponding placebos to patients in preterm labor who were receiving intravenous magnesium sulfate tocolysis. The mean gestational age at enroliment was 30.1 weeks, and mean cervical dilatation was 2.15 cm. No differences were noted between placebo (n = 43) and study patients (n = 43) in gestational age at delivery, term deliveries, days gained, or neonatal outcome. Preterm delivery «36 weeks) occurred in 61% of the total population. The likelihood of a ~ error was 0.07 to 0.23 on the basis of outcome analysis. In our population adjunctive ampiciliin-sulbactam with indomethacin did not improve the success of magnesium sulfate tocolysis. (AM J OBSTET GVNECOL 1991 ;165:1753-9.)

Key words: PreteI'm labor, antibiotics, indomethacin The m~ority of neonatal deaths, morbidity, and perinatal health care costs are associated with birth at <36 weeks. The ability of tocolytics to prevent preterm birth varies by site and study design rather than agent. In comparative trials the likelihood of tocolytic failure ranges from 28% to 81 % for ritodrine,l-o 39% to 61 % for magnesium sulfate,'-7 and 20% to 55% for terbutaline. 2 - 4 • K These high failure rates underline the need for better tocolytic regimens. In the past IS years, a wide body of epidemiologic, biochemical, and clinical evidence has supported the role of subclinical infection in preterm birth. 9 Bacterial species differ in the strength of their association with preterm birth. However, genital tract anaerobes have been associated consistently with preteI'm birth by different authors and different institutions. 10-13 If subclinical infection plays a role in preterm birth, then antibiotic therapy that eradicates anaerobes should prevent preterm birth in that subgroup of patients. Tocolytic failure is associated with positive amniotic fluid cultures or an elevated C-reactive protein level. Ten to twenty percent of amniotic fluid cultures are positive in patients with idiopathic preterm labor. , 4- 17 With the exception of Duff and Kopelman,'6 most authors have associated positive amniotic fluid cultures with tocolytic failure. Potkul ct al. '" showed that 23 of From the Department of Obstetrics and Gynecology, The University of Texas H ealth Science Center at San Ai!tonio. Presented in part at the Thirty-eighth Annual Meeting of the Society for Gynecologic Investigation, San Antonio, Texas, March 20-23 ,

1991.

Reprint requests: Edward R. Newton, MD , Department of Obstetrics and Gynecology, 7703 Floyd Curl Dr. , San Antonio, TX 782847836.

6/6/33015

24 patients (96%) with normal C-reactive protein levels had successful tocolysis, whereas 10 of 16 patients (62 %) with elevated C-reactive protein levels had tocolytic failure. Similarly, Handwerker et al. 19 showed that 33 of 35 (94%) had tocolytic success with normal C-reactive protein levels and 11 of 15 (73%) had tocolytic failure with elevated C-reactive protein levels. Given these observations, the addition of antibiotic therapy to standard tocolytic therapy may reduce the likelihood of tocolytic failure. The use of antibiotics has a potential to increase uterine activity transiently. The lysis of bacteria releases endotoxin from the cell walls. Subsequently, endotoxin will stimulate the macrophages to release cytokines or enzymes, which initiates prostaglandin synthesis. 20 As macrophage-like cells are numerous in the decidua, the surge of endotoxin-induced prostaglandins may counteract the benefits of adjunctive antibiotics. Therefore a short course of a prostaglandin inhibitor may enhance the benefits of adjunctive antibiotic therapy. McGregor et aI."' in 1986 reported the first controlled trial of antibiotics in patients with active preterm labor. With subsequent support by Morales et al. 22 and Winkler et al!' in 1988, adjunctive antibiotics seemed to reduce the incidence of preterm birth in a subgroup of patients with cervical dilatation 2: 1 em. In contrast to the latter studies, we reported in 198924 that the combination of ampicillin plus erythromycin used in conjunction with standard tocolytics failed to improve outcome. I fwe assume subclinical infection to be a m~or cause of tocolytic failure, our discrepant results have been due to differences in study design, population differences in genital tract flora, inadequate anaerobic cov-

1753

1754

Newton et al.

erage, or an increase in uterine activity that was precipitated by a surge of endotoxin-induced prostaglandins from the lysis of bacteria. In the current study we examined the last two possibilities. Our study hypothesis was that the combination of antibiotics with anaerobic coverage (ampicillin-sulbactam) with a prostaglandin inhibitor (indomethacin) will reduce the incidence of tocolytic (magnesium sulfate) failure. Material and methods

Subjects were selected from hospitalized patients at Medical Center Hospital in San Antonio. The Medical Center serves an indigent, predominantly MexicanAmerican population, who are cared for by the residents and full-time faculty at The University of Texas Health Science Center at San Antonio. The protocol was a pproved by the Institutional Review Board of the Health Science Center. We used the following criteria to select eligible patients: (1) preterm gestation between 24 weeks and 33 weeks 6 days or an estimated fetal weight between 750 and 2200 gm by ultrasonographic measurement and (2) premature labor diagnosed by three contractions in 20 minutes and observed cervical effacement or dilatation or cervical dilatation of ~2 em and 50% effacement at initial examination. Upper-level residents in obstetrics and gynecology, under the supervision of maternal-fetal medicine faculty, made the diagnosis of preterm labor, on the basis of cervical examination and contraction monitoring. Gestational age was determined from menstrual dating, date of pregnancy test, serial fundal height measurement, and previous obstetric ultrasonographic examination. In addition, every patient had a detailed ultrasonographic evaluation of the fetus on admission. When menstrual data were considered unreliable, a mean gestational age was determined by biparietal diameter, head circumference, femur length, and abdominal circumference. The exclusion criteria were premature rupture of membranes, suspected intrauterine growth retardation (estimated fetal weight < 10th percentile for gestational age), hypertension, known uterine anomalies, incompetent cervix, third-trimester bleeding, oligohydramnios, abnormal fetal testing, liver disease, asthma, known allergies to indomethacin or ampicillin-sulbactam, or clinical evidence of maternal infection. The study design is depicted in Fig. I .Tocolytic therapy was the same for both groups. We chose magnesium sulfate because it is our standard tocolytic. Preterm patients with at least three contractions in 20 minutes, with or without cervical dilatation, were hospitalized and received hydration and sedation. Only patients with contractions in spite of the latter therapy were given parenteral intravenous magnesium sulfate: a

December 1991 Am J Dbstet Gynewl

4 gm loading dose followed by 2 gm/hr and adjusted every 30 minutes to maintain uterine quiescence (fewer than one contraction in 15 minutes) or a magnesium sulfate level of 6 to 8 mEq/dl. Of these, only patients with a cervical change or cervical dilatation ~2 em and ~50 % effacement who met selection criteria were enrolled. Before the administration of study medications, we obtained blood for serum chemistry tests, complete and differential blood cell counts, C-reactive protein level, and an erythrocyte sedimentation rate. Vaginal Gram's stain was performed to detect bacterial vaginosis (bacterial vaginosis score ~ 7). Vaginal cultures for aerobes and genital mycoplasmas were performed, and organisms were isolated and identified with standard techniques . A cervical sample was obtained for cultures (Neisseria gonorrhoeae) and an antigen test for Chlamydia trachomatis (Microtrak) was performed . Patients in whom group B streptococcus or C. trachomatis were identified were not treated until delivery was unavoidable. The study medications were assigned randomly in a I : I ratio by the pharmacy and administered in a double-blind fashion. Patients received intravenous ampicillin (2 gm)-sulbactam (1 gm) every 6 hours for 12 doses plus concomitant oral indomethacin (50 mg loading dose, followed by 25 mg every 6 hours for seven doses) or corresponding placebos. Indomethacin was chosen as a prostaglandin ' synthetase inhibitor because of its clinical experience in obstetrics in the treatment of preterm labor and the lack of neonatal effects when it is used as a tocolytic. 25 Fetal echocardiography was performed on each fetus at 24 and 48 hours after enrollment to monitor changes in cardiac dimensions that may be related to premature closure of the ductus arteriosus. The results of the cardiac biometry were not reported to the clinicians and did not change clinical management. The findings are the subject of a separate report. After successful therapy with parenteral tocolytics patients were treated with oral magnesium oxide (400 mg every 3 to 4 hours) or oral terbutaline sulfate (2.5 to 5 mg every 3 to 4 hours). The patients were hospitalized as long as was clinically appropriate, usually 3 to 4 days. Undelivered patients had vaginal cultures and vaginal Gram's stain repeated between 2 and 14 days after therapy. If preterm labor necessitating intravenous magnesium sulfate recurred and in those patients whose contractions did not stop with a serum magnesium level of 6 to 8 mEq/dl, amniotic fluid was obtained by amniocentesis for Gram's stain, aerobic and anaerobic culture, and fetal lung maturity studies. If the amniotic fluid Gram's stain demonstrated bacteria or fetal lung maturity study results were positive , tocolysis was discon-

Ampicillin-sulbactam, indomethacin, and preterm labor

Volume 165 Number 6, Part I

I

Contractions

j

I

••

Hydration and Sedation

I Cervical Change and Admission

I

1755

I

•

Preterm Labor Treated with Intravenous MgS04

+

J No

1 Inclusion/Exclusion Criteria

I·

~

Out

Yes

I

No

Informed consent

~

Out

Yes

..

Randomized by Pharmacy Ampicillin 3 g/Sulbactam 1 9 Q6° x 12 doses plus Indomethacin 50 mg then 25 mg Q6°x 7 doses

Placebo

Fig. 1. Flow chart.

tinued. If the amniotic fluid study results were negative, tocolytic therapy was changed to ritodrine hydrochloride. Tocolytic failure was defined as labor with cervical dilation ~6 cm, clinical infection, rupture of the membranes, or fetal distress and subsequent pre term birth. Birth weight and gestational age at delivery were considered the most important outcome variables. A sample size was determined with these variables. Clinically significant increases in mean birth weight and gestational age at delivery were estimated to be 250 gm and 7 days, respectively. The variances in birth weight and gestational age at delivery were estimated to be 500 gm and 14 days, respectively. Assuming an (X-error threshold of 0.05 and a power of 0.8, we determined that a sample size of 49 in each arm would be sufficient to determine significance. Univariate analyses were performed with the Student t test and analysis of variance for continuous data. N onparametric tests (Mann-Whitney U test) were used to confirm the validity of parametric testing and to determine the probability of differences between the groups in variables with nonnormal distributions. Cat-

egoric data were analyzed with X2 and Fisher's exact tests. Product limit survival analysis 26 was used to describe differences in days gained in placebo and study groups. Probabilities <0.05 were considered significant. Results

Between July 1989 and January 1991, we identified 298 laboring women who met the gestational age criteria (24 weeks to 33 weeks 6 days), who had cervical change or cervical dilatation >2 cm and cervical effacement > 50% and who were being treated with parenteral magnesium sulfate. Thirty-four (14%) met the criteria but were delivered before informed consent was obtained. Most of these patients were admitted at cervical dilatations of 4 to 5 cm and were delivered shortly thereafter. Thirty-seven (15%) eligible patients either refused participation or were not identified. The remaining 88 (35%) met the exclusion criteria, including 21 (8%) with abnormal fetal test results, 15 (6%) with third-trimester bleeding, and 13 (5%) with concurrent antibiotic use. The mean birth weight of those

1756 Newton et al.

December 1991 Am J Obstet Gynecol

Table I. Population characteristics at enrollment Placebo Parameter

(n = 43)

Ampicillin-sulbactam plus indomethacin (n = 43)

Age (yr, mean ± SD) Nulliparity (No.) Gestational age (wk, mean ± SD) Estimated fetal weight (gm, mean ± SD) Cervix (em, mean ± SD) Elevated C-reactive protein level (No.) White blood cell count 2e: 12,000 cells/mm' (No.)

23.8 ± 5.0 16 30.3 ± 5.0 1601 ± 422 2.13 ± 0.93 28 31

23.8 ± 5.5 11 29.8 ± 2.7 1624 ± 533 2.1 ± 0.95 24 28

Table II. Microbiologic composition of vagina Placebo (n Enrollment (n = 45) Organism

No.

Aerobic gram-negative rods

11

Mycoplasma hominis Ureaplasma urealyticum Gardnerella vaginalis

16 24 28 2 21 0 5 17

Group B streptococcus

Lactobacillus sp. N. gonorrhoeae C. trachomatis

Bacterial vaginosis

/

% 24 36 53 62 4 47 38t

Ampicillin-sulbactam plus indomethacin (n = 43)

= 43) Follow-up (n = 15) No.

6 5 5 8 2 5 0 0 6

/

Enrollment (n = 43)

%

No.

40 33 33 53 13 33

11 16 20 12 7 27 0 4 7

40

/

Follow-up (n = 15)

%

No.

24 37 46

9 2 6 2 0 2 0 4 1

16 63 16

I

% 60* 13 40 13* 13* 7

*Change in vaginal flora at follow-up, p < 0.05. tPlacebo versus antibiotic group at enrollment, p < 0.05.

not included in the study was 1620 ± 749 gm. Ninetyone patients (31 %) met the selection criteria and were enrolled. Subsequent to enrollment, five patients were dropped from analysis, one because of delivery before study drug administration, one as a result of concurrent antibiotic therapy for a urinary tract infection at entry, and three patients who had successful tocolysis but were lost to follow-up after discharge and before 36 weeks. Forty-three placebo and 43 study drug patients were used in the analysis of outcome data. The enrollment was halted early (91 enrolled vs 98 projected patients) for administrative reasons. Tables I and II describe the population characteristics at enrollment. Our selection criteria and randomization process created similar populations in the placebo and study drug groups except for the presence of bacterial vaginosis. The presence of more bacterial vaginosis in the placebo group than in the treatment group (38% vs 16%, P < 0.05) would bias against the placebo group and decrease an antibiotic effect. Antibiotics increased the likelihood of aerobic gram-negative rods, decreased Lactobacillus sp. and C. vaginalis at follow-up. Twelve (14%) patients underwent amniocentesis; none had an intraamniotic infection. The median times from admission to administration of study

drugs or placebo were 8 and 7 hours, respectively. This delay was not correlated with birth weight (r = 0.1, p, not significant). Table III describes maternal outcome. There were no differences in gestational age at delivery, deliveries at >35 weeks, days gained from enrollment in the study, number of patients with recurrent pre term labor, or maternal infection (intra amniotic infection or endometritis). Fig. 2 describes the cumulative deliveries by weeks after enrollment. The curves are similar visually and statistically. Of note, 80% in both groups were undelivered at I week after enrollment. Table IV depicts the neonatal outcome. Six sets of twins were enrolled (two placebo, four study drug). As a result, neonatal outcome was analyzed in 45 placebo and 47 study drug infants. There was no difference in perinatal mortality and morbidity. The net gain in fetal weight (birth weight minus estimated fetal weight) was 789 ± 674 gm in study drug patients and 645 ± 649 gm in placebo patients (p = not significant). One case of group B streptococcal disease was noted in a 2330 gm infant who was delivered 25 days after enrollment. The mother received placebo, and the culture for group B streptococcus was negative at enrollment. The infant did well. Another neonate, weighing 694 gm,

Ampicillin-sulbactam, indomethacin, and preterm labor

Volume 165 Number 6, Part 1

1757

Fig. 2. Graph of days gained.

Table III. Maternal outcome Placebo Parameter

(n = 43)

Gestational age (wk, mean ± SD) Delivery 2:36 wk No.

33.5 ± 4.0

%

Days gained Median Range Recurrent pre term labor (No.) Maternal infection (No.)

was born on the third day of ampicillin-sulbactam plus indomethacin therapy. On the seventh day of life, the neonate had a clinical course consisting of sepsis and death but cultures were negative. The other perinatal death was an intrapartum death of a 750 gm, previable (25-week) fetus on the third day of ampicillin-sulbactam plus indomethacin therapy. Chorioamnionitis developed, and the fetus died during a complicated breech extraction. No autopsy was performed. We stratified the population to identify a subgroup where antibiotics plus prostaglandin inhibitors might be of benefit. No improvement in outcome was noted in singleton gestations (n = 82), in patients at <31 weeks (n = 35), elevated C-reactive protein levels (n = 52), enrollment white blood cell count> 12,000 cells/mm 3 (n = 59), abnormal vaginal flora (positive group B streptococcus or bacterial vaginosis) (n = 33), or the presence of U. urealyticum at enrollment (n = 44).

Ampicillin-sulbactam plus indomethacin (n = 43)

34.5 ± 4.1

16 37

20 46

26

26

1-71 8 6

1-79 8 1

However, the likelihood of a numbers is as high as 60%.

f3 error as a result of small

Comment

The addition of ampicillin-sulbactam plus indomethacin to magnesium sulfate tocolysis did not reduce the likelihood of preterm birth subsequent to tocolytic failure in our population. The validity of our conclusion was supported by selection criteria that identified a population where 60% were delivered at <36 weeks and <2500 gm, a randomization process that created similar populations in both treatment arms (except for the presence of bacterial vaginosis) and the probability of a f3 error, the likelihood of missing a true difference, of 0.23 on the basis of number of term deliveries, 0.19 on the basis of birth weight, and 0.07 on the basis of number of infants without perinatal morbidity. The findings are consistent with our prevous study.24

1758 Newton et al.

December 1991 Am J Obstet Gynecol

Table IV. Neonatal outcome Placebo Parameter

Birth weight <2500 gm (gm, mean ± SD) No.

(n = 45)

Ampicillin-sulbactam plus indomethacin (n = 47)

2295 ± 795

2430 ± 899

%

Hyaline membrane disease (No.) Mechanical ventilation Intraventricular hemorrhage (No.) Sepsis (No.) Necrotizing enterocolitis (No.) 5 min Apgar score 5,7 (No.) Perinatal death (No.) Congenital abnormalities (No.) No perinatal morbidity No.

%

Patients enrolled in the current study were at higher risk for preterm birth than were those in the former study. The differences included cervical dilatation at entry (2.15 vs 2.0 em, p < 0.05), gestational age at enrollment (30.0 vs 3l.7 weeks, p < O.OJ), and estimated fetal weight at enrollment (1620 vs 1910 gm, p < 0.01). However, analysis of time gained (26 vs 34 days, p < 0.05), gestational age at delivery (34 vs 36.8 weeks; p < 0.01), and birth weight (2350 vs 2850 gm, p < 0.01) indicated more adverse outcomes in the current study. Our results are in contrast to those of studies reported by McGregor et al.,21 Winkler et al.,23 and Morales et aJ.2 2 Our studies differ in analysis when compared with the latter three studies, which reported beneficial results only in subgroups selected after randomization and during analysis. McGregor et al. 21 randomized 58 patients and analyzed 17 patients, Winkler et aJ.23 randomized 40 patients and analyzed 19, and Morales et al. 22 randomized 205 patients and analyzed 150 (three treatment arms). It is possible that their subgroup selection influenced the results. Differences in population characteristics, especially the presence of vaginal pathogens, may explain our discrepant results. The frequency of positive group B streptococcus (10%) and C. trachomatis (5%) was significantly lower in our population than in that reported by Morales et al. 22 (group B streptococcus 21 % and C. trachomatis 24%). However, the presence of indirect measures of decidual or parenchymal infection. i.e., elevated C-reactive protein level of elevated white blood cell count, did not improve the results of antibiotic therapy in either of our studies. Perhaps a more specific measure of subclinical decidual infection, i.e., oncofetal fibronectin, may select a population that would benefit from antibiotic therapy. It is possible that a different antibiotic combination

31

69

13 11 2 1 1 5

o o

26

58

26

55 12 12

2 I I

4

2 2

29

62

or dosing schedule might improve outcome. The duration of antibiotic therapy is arbitrary. Single-dose oral therapy successfully eradicates many urogenital infections. The improvement in efficacy of 2::4 days of intravenous therapy over 3 days has not been shown. Our previous study did not show benefit with erythromycin for 7 days. In addition, ampicillin-sulbactam had a biologic affect on vaginal flora (Table II). In fact, the emergence of aerobic gram-negative rods after treatment, in spite of in vitro activity of ampicillin-sulbactam against aerobic gram-negative rods, raises the potential for clinical infection with resistant organisms. Amniocentesis was not performed before enrollment. When it was used, i.e., for recurrent or persistent pre term labor, the amniotic fluid was not infected, a result consistent with the findings of Duff and Kopelman. 16 However, amniotic fluid infection is only an indirect measure of decidual infection, and significant decidual infection may be present with negative amniotic fluid cultures. Perhaps measures of amniotic fluid cytokines may be more predictive of decidual infection. Although >60% of our patients were delivered at <36 weeks, magnesium sulfate tocolysis with or without ampicillin-sulbactam plus indomethacin delayed delivery a median of 26 days. A delay in delivery decreases neonatal morbidity and mortality. Delay in delivery by 1 to 2 weeks in 80% of patients has been observed consistently in controlled studies of magnesium tocolysis 3.7 and was observed in the current study. However, preterm delivery after successful magnesium sulfate tocolysis remains a perplexing clinical problem. The reasons for failure after successful magnesium sulfate tocolysis are not well described. Brustman et a!. 27 demonstrated that patients who are delivered prematurely have more frequent contractions in spite of doseadjusted oral tocolytic therapy. Improved agents or de-

Volume 165 Number 6, Part I

livery mechanisms may benefit this high-risk group. The role of recurrent or episodic subclinical decidual infection in this setting remains undefined.

Ampicillin-sulbactam, indomethacin, and preterm labor

14. 15.

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2.

3. 4.

5. 6. 7. 8. 9. 10.

II. 12.

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worth], Elder MG. Spontaneous early preterm labor associated with abnormal genital bacterial colonization. Br J Obstet Gynaecol 1986;93:804-10. Leigh], Garite TJ. Amniocentesis and the management of premature labor. Obstet Gynecol 1986;67:500-6. Wallace RL, Herrick CN. Amniocentesis in the evaluation of premature labor. Obstet Gynecol 1981 ;57:483-6. Duff P, Kopelman]N. Subclinical intraamniotic infection in asymptomatic patients with refractory preterm labor. Obstet Gynecol 1987;69:756-9. Wahbeh Cj, Hill GB , Eden RD , Gall SA. Intraamniotic bacterial colonization in premature labor. AM ] OBSTET GVNECOL 1984; 148:739-43. Potkul RK, Moawad AH, Ponto KL. The association of subclinical infection with preteI'm labor: the role of Creactive protein. AM] OBSTET GVNECOL 1985;153:642-5. Handwerker SM, Tejani NA, Verma UL, Archbald F. Correlation of maternal serum C-reactive protein with outcome of tocolysis. Obstet Gynecol 1984; 163:220-4. Casey ML, MacDonald PC. Decidual activation: the role of prostaglandin in labor. In: McNellis D, Challis ]RG, MacDonald PC, Nathanielsz PW, Roberts ]M, eds. The onset of labor: cellular and integrative mechanism. Ithaca, New York: Perinatal Press, 1987:141. McGregor ]A, French JI , Reller B, Todd JK, Makowski EL. Adjunctive erythromycin treatment for idiopathic premature labor. AM J OBSTET GVNECOL 1986;154:98103. Morales MJ, AngelJL, O'Brien WF, Kruppel RA, Finazzo M. A randomized study of antibiotic therapy in idiopathic preterm labor. Obstet Gynecol 1988;72:829-33. Winkler M, Baumann L, Rickhaberle KE, Schiller EM. Erythromycin therapy for subclinical interuterine / intrauterine infections in threatened preterm delivery: a preliminary report. J Perinat Med 1988; 16:253-5. Newton ER, Dinsmoor MJ , Gibbs RS. A randomized, blinded, placebo-controlled trial of antibiotics in idiopathic preterm labor. Obstet Gynecol 1989;74:562-6. Gamissans 0, Balasch J. Prostaglandin synthetase inhibitors in the treatment of preterm birth. In: Fuchs F, Stubblefield PG, eds. Preterm birth. Toronto: Macmillan, 1984:223-48. Lee ET. Statistical methods fo r survival data analysis. Belmont, California: Wadsworth, 1980:75-87. Brustman LE, Langer 0, Damus K, Anyaegbunam A, Merkatz IR. Uterine contractibility patterns after an episode of preteI'm labor. Obstet Gynecol 1990;75:346-9.