Adjunctive erythromycin treatment for idiopathic preterm labor: Results of a randomized, double-blinded, placebo-controlled trial

doi:10.1016/0002-9378(86)90401-1

American Journal of Obstetrics and Gynecology

Volume 154, Issue 1, January 1986, Pages 98-103

https://doi.org/10.1016/0002-9378(86)90401-1 Get rights and content

Abstract

Pathogenesis and optimal treatment of prevention of preterm labor remain incompletely understood. Entry of cervical/vaginal microorganisms into lower uterine tissues has been implicated in preterm labor and may be amenable to specific therapy. Fifty-eight women with <34 completed weeks of gestation and without other obstetric complications, who were receiving intravenous tocolytics because of uterine contractions and who had cervical alteration (<5 cm dilated), were enrolled in a prospective randomized, double-blinded evaluation of 7 days of adjunctive therapy with enteric-coated erythomycin base (333 mg three times daily by mouth) versus placebo. Microbiologic examination included cultures for Neisseria gonorrhoeae, Chlamydia trachomatis, and group B streptococcus. Fifty-eight women with singleton pregnancies (29 erythomycin; 29 placebo) completed the protocol. Among women with cervical dilatation ≥1 cm at the beginning of treatment, mean time until delivery was 32.5 days with erythromycin and 22.4 days with placebo treatment (p = 0.027). Of the erythromycin-treated women, seven of eight were delivered at ≥37 weeks and only three of nine placebo-treated women were delivered at ≥37 weeks (p − 0.035). Orally administered enteric-coated erythromycin as adjunctive treatment of pregnant women in labor ≤34 weeks is well tolerated. Adjunctive erythromycin given to women treated for preterm labor ≤34 weeks is associated with prolongation of pregnancy and delivery at 37 weeks only in women with cervical dilatation at the beginning of treatment.

References (29)

RH Paul et al.
Obstetric factors influencing outcome in infants weighing from 1,001 to 1,500 grams
Am J Obstet Gynecol
(1979)
G Chamberlain
Epidemiology and aetiology of the preterm baby
Clin Obstet Gynecol
(1984)
JA Washington et al.
Erythromycin: a microbial and clinical perspective after 30 years of clinical use (first of two parts)
JA Regan et al.
Premature rupture of membranes, preterm delivery, and group B streptococcal colonization of mothers
Am J Obstet Gynecol
(1981)
B Gustavii
Sweeping of the fetal membranes by a physiologic saline solution: effect on decidual cells
Am J Obstet Gynecol
(1974)
HA Elder et al.
The natural history of asymptomatic bacteriuria during pregnancy: the effect of tetracycline on the clinical course and outcome of pregnancy
Am J Obstet Gynecol
(1971)
Incidence of low birth weight
MMWR
(1984)
World Health Organization
World Health Stat Q
(1980)
BF Dolk
Infectious processes and preterm birth
H Minkoff
Prematurity: infection as an etiologic factor
Obstet Gynecol
(1983)

W Ledger

Premature ruptured membranes and in utero fetal infection

Clin Obstet Gynecol

(1979)

R Bejar et al.

Premature labor. II. Bacterial sources of phospholipase

Obstet Gynecol

(1981)

WM McCormack et al.

Hepatotoxicity of erythromycin estolate during pregnancy

Antimicrob Agents Chemother

(1977)

AM Shibl et al.

Antibiotic inhibition of protease production by Pseudomonas aeruginosa

J Med Microbiol

(1980)

Cited by (117)

Antibiotic administration can eradicate intra-amniotic infection or intra-amniotic inflammation in a subset of patients with preterm labor and intact membranes
2019, American Journal of Obstetrics and Gynecology
Citation Excerpt :
However, rapid tests are now available for the diagnosis of intra-amniotic inflammation (such as amniotic fluid white blood cell count, glucose, amniotic fluid MMP-8, or interleukin-6, among others),4,19,38,53,60,126,127,167,176,177,179–184 and for the diagnosis of infection using PCR.8,23,123,140,185–188 The evidence that intra-amniotic infection is causally linked to spontaneous preterm labor and delivery coalesced in the 1980s;2,3,13,14,144,189,190 this led to the conduct of several randomized clinical trials in which patients with an episode of preterm labor were allocated to antimicrobial agents vs placebo or no treatment.73,74,77–80,82,191–194 Although the initial trials reported pregnancy prolongation75,77,191 and, in some cases, a lower frequency in the rate of preterm delivery,73,77 these findings were not supported by subsequent clinical trials78,81 or systematic reviews and meta-analyses.195-197
Intra-amniotic infection is present in 10% of patients with an episode of preterm labor, and is a risk factor for impending preterm delivery and neonatal morbidity/mortality. Intra-amniotic inflammation is often associated with intra-amniotic infection, but is sometimes present in the absence of detectable microorganisms. Antibiotic treatment of intra-amniotic infection has traditionally been considered to be ineffective. Intra-amniotic inflammation without microorganisms has a prognosis similar to that of intra-amniotic infection.
To determine whether antibiotics can eradicate intra-amniotic infection or intra-amniotic inflammation in a subset of patients with preterm labor and intact membranes.
The study population consisted of women who met the following criteria: 1) singleton gestation between 20 and 34 weeks; 2) preterm labor and intact membranes; 3) transabdominal amniocentesis performed for the evaluation of the microbiologic/inflammatory status of the amniotic cavity; 4) intra-amniotic infection and/or intra-amniotic inflammation; and 5) received antibiotic treatment that consisted of ceftriaxone, clarithromycin, and metronidazole. Follow-up amniocentesis was performed in a subset of patients. Amniotic fluid was cultured for aerobic and anaerobic bacteria and genital mycoplasmas, and polymerase chain reaction was performed for Ureaplasma spp. Intra-amniotic infection was defined as a positive amniotic fluid culture or positive polymerase chain reaction, and intra-amniotic inflammation was suspected when there was an elevated amniotic fluid white blood cell count or a positive result of a rapid test for matrix metalloproteinase-8. For this study, the final diagnosis of intra-amniotic inflammation was made by measuring the interleukin-6 concentration in stored amniotic fluid (>2.6 ng/mL). These results were not available to managing clinicians. Treatment success was defined as eradication of intra-amniotic infection and/or intra-amniotic inflammation or delivery ≥37 weeks.
Of 62 patients with intra-amniotic infection and/or intra-amniotic inflammation, 50 received the antibiotic regimen. Of those patients, 29 were undelivered for ≥7 days and 19 underwent a follow-up amniocentesis. Microorganisms were identified by culture or polymerase chain reaction of amniotic fluid obtained at admission in 21% of patients (4/19) who had a follow-up amniocentesis, and were eradicated in 3 of the 4 patients. Resolution of intra-amniotic infection/inflammation was confirmed in 79% of patients (15/19), and 1 other patient delivered at term, although resolution of intra-amniotic inflammation could not be confirmed after a follow-up amniocentesis. Thus, resolution of intra-amniotic inflammation/infection or term delivery (treatment success) occurred in 84% of patients (16/19) who had a follow-up amniocentesis. Treatment success occurred in 32% of patients (16/50) with intra-amniotic infection/inflammation who received antibiotics. The median amniocentesis-to-delivery interval was significantly longer among women who received the combination of antibiotics than among those who did not (11.4 days vs 3.1 days: P = .04).
Eradication of intra-amniotic infection/inflammation after treatment with antibiotics was confirmed in 79% of patients with preterm labor, intact membranes, and intra-amniotic infection/inflammation who had a follow-up amniocentesis. Treatment success occurred in 84% of patients who underwent a follow-up amniocentesis and in 32% of women who received the antibiotic regimen.
Determination of antibiotic concentration in meconium and its association with fetal growth and development
2019, Environment International
Citation Excerpt :
A more recent report indicated that antibiotics exposure in mid-pregnancy were associated with lower birth weight for gestational age, whereas antibiotics use in the third trimester was associated with higher cord blood leptin (a marker of fetal adiposity) (Mueller et al., 2017). Some clinical trials also have shown that antibiotic treatment during pregnancy increases birth weight (Elder et al., 1971; Gichangi et al., 1997; Kass et al., 1981; Mccormack et al., 1987; Mcgregor et al., 1986; Temmerman et al., 1995). These findings collectively suggest that the antibiotic use during pregnancy affects fetal growth and is associated with infant birth outcomes.
The association between antibiotic use during pregnancy and neonatal birth outcomes has received considerable attention. Most of the previous assessment of antibiotic exposure during pregnancy relied on questionnaires and clinical prescriptions, and very few studies examined pregnancy exposure to antibiotics using human biomonitoring data.
To explore the association between the cumulative exposure of antibiotics during the whole pregnancy and neonatal birth measurements using biomonitoring data of antibiotics in meconium.
Three hundred and sixty nine pregnant women within the Maternal Psychological and Environmental Assessments of Kids Cohort Study were randomly selected into this study. Eighteen common antibiotics of six categories (six β‑lactams, three tetracyclines, four sulfonamides, one phenicols, one lincosamides and three fluoroquinolones) were selected as the target antibiotics in meconium. The measurement was conducted by ultraperformance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry platform. Neonatal birth measurements were obtained from the medical records. Multiple linear regression models were used to examine the associations of antibiotic exposure with neonatal birth outcome (birth weight, birth length) and placental growth indicators (placental surface area, placental weight). Logistic regressions were used to evaluate associations with small for gestational age (SGA) and large for gestational age (LGA).
Twelve of the eighteen antibiotics were found in 62.1% of the meconium, with detection rates ranging from 0.3% to 43.9%. The three antibiotics with the highest detection rates were chlortetracycline (43.9%), penicillin (16.5%) and chloramphenicol (10.8%), respectively. The highest antibiotic concentration among detected antibiotics was penicillin (24,243.15 μg/kg). The concentration of penicillin was positively associated with the birth weight (β: 0.025; 95% CIs: 0.003–0.047). A significant positive association was also observed between the concentration of chlortetracycline and the placental surface area (β: 2.559; 95% CIs: 0.296–4.822). These associations were sex related and mainly observed in female newborns. Exposure to penicillin was also found to be associated with increased risk of LGA, which was consistent with changes in birth weight.
Pregnancy exposure to certain antibiotics was associated with altered fetal growth and development, which may affect the normal growth trajectory of infants and children in later life.
Antibiotics in the Management of PROM and Preterm Labor
2012, Obstetrics and Gynecology Clinics of North America
Citation Excerpt :
Several early studies revealed promising results regarding the potential for a benefit from adjunctive antibiotic treatment for preterm labor. McGregor and colleagues,36 in 1986, randomized participants to oral erythromycin or a matching placebo and found significant pregnancy prolongation with antibiotic treatment (32.5 vs 22.4 days; P = .027); these women were more likely to deliver at term.38 However, these investigators were unable to replicate these findings in a subsequent study of intravenous clindamycin therapy,39 and neither study demonstrated reductions in newborn morbidities.
Effect of amoxicillin sulbactam in threatened preterm labour with intact membranes: A randomised controlled trial
2005, European Journal of Obstetrics and Gynecology and Reproductive Biology
Objective: To determine whether treatment with amoxicillin-sulbactam in women with threatened idiopathic preterm labour will prolong the gestation and reduce preterm birth rates in a Latin-American population.
Methods: A double-blind, placebo-controlled, randomized trial was conducted in 96 women who were hospitalized for preterm labour between 24 and 34 weeks of gestation at the Pereira Rossell Hospital, in Montevideo, Uruguay. The primary outcome measure was prematurity. The sample size was calculated a priori based on the hospital database. Statistical analyses were performed using the t-test, chi square, weighted mean difference (WMD) and relative risk (RR) with their confidence intervals (95% CI). Analysis by intention-to-treat.
Results: Out of 47 patients assigned for antibiotics, 43 completed the treatment. There were no significant statistical differences between antibiotics and placebo group in prematurity (RR:1.04, 95% CI: 0.59, 1.84), prolongation of pregnancy (WMD:0.23, 95% CI: −0.96, 1.42) and other perinatal outcomes.
Conclusion: Antibiotics did not prove to have benefits in improving perinatal outcomes in this Latin American population.
Erythromycin treatment in idiopathic preterm labor
2004, International Journal of Gynecology and Obstetrics
Infection as a cause of preterm birth
2003, Clinics in Perinatology

View all citing articles on Scopus

^☆: The Upjohn Company. Kalamazoo, Michigan funded the microbiologic studies.

View full text

Adjunctive erythromycin treatment for idiopathic preterm labor: Results of a randomized, double-blinded, placebo-controlled trial☆

Abstract

Am J Obstet Gynecol

Clin Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Incidence of low birth weight

MMWR

World Health Stat Q

Infectious processes and preterm birth

Prematurity: infection as an etiologic factor

Obstet Gynecol

Premature ruptured membranes and in utero fetal infection

Clin Obstet Gynecol

Premature labor. II. Bacterial sources of phospholipase

Obstet Gynecol

Hepatotoxicity of erythromycin estolate during pregnancy

Antimicrob Agents Chemother

Antibiotic inhibition of protease production by Pseudomonas aeruginosa

J Med Microbiol