An experimental model for intraamniotic infection and preterm labor in rhesus monkeys

Objective: Our purpose was to describe the temporal and quantitative relationship between intraamniotic infection and preterm labor in a nonhuman primate model. Study Design: On day 130 of gestation (term 167 days) four chronically instrumented rhesus monkeys (Macaca mulatta) were infected with an intraamniotic inoculation of 106 colony-forming units of group B streptococci. Four additional noninfected monkeys were followed up to spontaneous parturition as controls. Amniotic fluid was serially sampled in all monkeys both before and after inoculation for bacterial growth, tumor necrosis factor-α, interleukin-1 β, interleukin-6, prostaglandin E2, and prostaglandin F2α, and uterine activity was continuously recorded. Results: Increases in uterine contractility occurred 28 hours (range 14 to 40 hours) after inoculation and were preceded by increases in amniotic fluid cytokines and prostaglandins. Intraamniotic concentrations of tumor necrosis factor-2α, interleukin-6, and interleukin-1α all rose dramatically 9, 15, and 18 hours after infection and 10 to 20 hours before increases in uterine contractility. In spontaneous parturition only interleukin-6 concentrations rose moderately (from 0.1 to 1.2 ng/ml). Increases in prostaglandin E2 and prostaglandin F2α paralleled those of the cytokines. Peak prostaglandin concentrations in intraamniotic infection exceeded by severalfold concentrations seen in spontaneous parturition (16,046 pg/ml vs 2765 pg/ml for prostaglandin E2, p < 0.05; and 5547 pg/ml vs 708 pg/ml for prostaglandin F2α, p < 0.05). In spite of intraamniotic infection none of the monkeys were febrile or had peripheral leukocytosis at the onset of labor. Conclusion: In the rhesus monkey, after intraamniotic infection, there is a predictable and sequential increase in amniotic fluid tumor necrosis factor-α, interleukin-1 β, and interleukin-6, followed by increases in prostaglandin E2 and prostaglandin F2α. These increases all occur before an increase in uterine contractility and before clinical signs of infection. Our data provide evidence for a cause-and-effect relationship between intraamniotic infection and preterm labor and support the utility of measuring interleukin-6 or other cytokines in the diagnosis of intraamniotic infection.