Antibiotic Therapy and Preterm Labor
Abstract & Commentary
Thorp and associates reviewed 107 articles dealing with the use of antibiotics to lengthen pregnancy in patients with preterm labor (PTL). After applying stringent inclusion criteria, Thorp et al eventually extracted data from 14 randomized clinical trials (RCTs), which evaluated antibiotics vs. placebo or no treatment. They evaluated 3 end points: length of prolongation of pregnancy; gestational age at birth; and birth weight.
One study showed improvement in all 3 outcomes. Five studies indicated no improvement in any of the variables. Four found significant prolongation of pregnancy and 2 found a decrease in the proportion of preterm deliveries.
The RCT meta-analysis revealed modest benefits from antibiotics: significant pregnancy lengthening by 6 days, a significant increase in gestational age at delivery by only 4 days, and a non-significant increase in birth weight by 70 g. (Thorp JM Jr, et al. Am J Obstet Gynecol. 2002;186:587-592.)
Comment by John C. Hobbins, MD
The obvious rationale for the use of antibiotics in PTL is that infection is the culprit behind many preterm deliveries. However, since PTL can result from a myriad of causes, it is difficult from the available literature to tell what percentage of patients in PTL would truly benefit from antibacterial therapy. There is no uniformity of opinion among researchers with regard to antibiotics in PTL. However, 2 vocal factions have emerged: the totally committed and the naysayers. Fortunately, many investigators still seem to be on the fence while waiting for more data to surface before deciding whether antibiotics for all PTLs make sense.
Based on the available data, one cannot dismiss an infectious etiology for at least some PTLs. The prevailing current theory is that bacteria take an extra membranous pathway upward from the cervix, alighting in a location where they set up an active area of infection. Here, phospholipase A is liberated from interaction with the decidua. This, in turn, results in the release of arachidonic acid from the membranes, which is the precursor of the prostaglandins causing contractions.
Theoretically, all this can happen without the bacteria seeding the amniotic cavity, an event that occurs later in this scenario. In a series of publications spanning 10 years, Roberto Romero and his various team members demonstrated that between 9.2% and 12.8% of patients admitted with PTL and intact membranes had a positive amniotic fluid culture, and that 32% of patients who delivered within 48 hours had a positive culture. The group then went on to show that a cytokine, interleukin-6, was the most sensitive amniotic fluid indicator of intra-amniotic infection, followed by WBC count, glucose, and Gram stain. Later, in the same clinical setting, the group showed that elevations of various cytokines were more indicative of histologic evidence of chorioamnionitis than a positive amniotic fluid culture, suggesting that an infectious process, not yet of intra-amniotic proportions, can be responsible for PTL and delivery.
If we were to theorize that only 20-30% of PTLs are related to infection, then one would have to treat 3-4 patients with antibiotics for the one that could possibly benefit from the treatment. This could have some bearing on the modest benefit demonstrated in the above meta-analysis. Also, it is clear that most patients randomized into the above studies are not in true PTL, and therefore, the effect of any treatment would be diluted appreciably. Last, in 11 of the 14 studies in the meta-analysis, ampicillin was used, which may not be the right antibiotic to do the job.
For these reasons, certainly the concept of antibacterial therapy may not have been given a fair chance to succeed, especially if there had been a better noninvasive way to identify those patients who had an early infection.
That said—now a word of caution. There is now a strong suspicion that cerebral palsy (CP) may be more related to intrauterine infection than fetal hypoxia. The Romero team has shown in the rabbit that white matter lesions similar to periventricular leukomalacia (PVL), a precursor of CP, can be produced by introducing Escherichia coli into the intrauterine cavity. In a separate study, they found various inflammatory cytokine activity in the brains with 15 of 17 neonates with PVL, compared with only 3 of 17 matched control specimens without PVL. Last, in another study, cord blood cytokines were demonstrated to be significantly elevated in infants born preterm with evidence of PVL, compared with preterms without the finding by the third day of life. In fact, IL-6 elevations were noted in 74% of infants with PVL, and this finding stood alone when multivariate analysis weeded out other variables such as chorioamnionitis. This latter result implies that the cytokines might be the cause of PVL, rather than simply being the innocent harbinger of intra-uterine infection.
This investigation suggests that some fetuses would benefit more from being in a nursery than from being continuously exposed in utero to bacteria/cytokines, and that attempts to prolong pregnancy through tocolytics and possibly ineffective antibiotics may not be a good idea.
Frankly, it is difficult to be dogmatic about whether patients with preterm contractions empirically should be given antibiotics. Certainly, it is more important to determine through cervical length and/or fetal fibronectin whether a patient is really in PTL before undertaking any type of antilabor therapy.
Dr. Hobbins is Professor and Chairman, Department of OB/GYN Tufts University School of Medicine, Boston, Massachusetts.
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