In this long-term follow-up of children whose mothers were entered into the ORACLE I trial of antibiotics prescribed for women with PROM and no overt signs of infection, there is no evidence of any substantial long-term effect in children at age 7 years associated with the prescription of either erythromycin or co-amoxiclav. Although there were some apparent differences in a small number of secondary outcomes—eg, improvement in respiratory function with erythromycin and increased bowel disorders with co-amoxiclav—and despite the fact that these changes are biologically plausible and consistent with the short-term outcomes from the ORACLE I trial, they should be viewed with caution because of the large number of comparisons made.
The size of the ORACLE population made direct face-to-face assessment of outcome impracticable and thus we elected to obtain proxy information about the children from parents. This was possible using well validated and standardised parent report tools, namely the Health Utilities Index and the Strengths and Difficulties Questionnaire, to assess health-related quality-of-life and behaviour, respectively. Although these are validated ways of collecting outcome data, using a questionnaire may mean more subtle differences between the treatment groups were missed. Health conditions could only be assessed through parental report, which also leads to the potential for under reporting and some inaccuracy in ascertainment; in general, this might reduce the power to detect any associations present, since almost all the women in the study remained blind to their allocated treatment.
To achieve high follow-up rates using postal questionnaires is difficult. We used evidence-based strategies to optimise the response25 and developed our own randomised evidence during the conduct of the study to maximise response.11 We maintained regular contact with the women originally entered into the trial, allowing us to achieve a high follow-up rate of 75%. Nonetheless, disadvantaged groups are over-represented in the non-responders but there was no evidence of differential non-response between the randomised groups. Although this response rate is lower than that assumed in the initial power calculation, the increased prevalence of functional impairment resulted in power being increased overall.
Cognitive impairment is the most common disability associated with preterm birth.[26] and [27] School performance is affected by a range of disabilities, of which general cognitive function is the most important, although additional deficits of executive function28 and attention may be contributory in the preterm child.2 Although we were unable to achieve direct cognitive assessment, we were able to use anonymised results from national curriculum tests, which allowed us to examine the scholastic attainment for virtually the whole population of surviving children in England, which we have used as a proxy for cognitive outcome. While the results showed no treatment differences in the level of performance reached with either antibiotic, this group of children as a whole have educational attainment below national norms, in keeping with the excess of preterm children with poor academic attainment.2 Level scores are arguably rather weak measures of attainment; the power of these comparisons would have been increased by use of the raw scores for individual tests, but these are not available centrally.
In women with PROM, positive amniotic fluid cultures are found in 32% of cases at the time of presentation29 and in as many as 75% during subsequent labour.30 Antibiotics might therefore be expected to improve clinical outcomes in this situation. There is also increasing evidence that, in addition to preterm birth, intrauterine infection is an independent antecedent of other disability, particularly cerebral palsy31 and chronic lung disease.32 Prescription of antibiotics for PROM could prevent neurological and respiratory disability by prolonging pregnancy or by reducing inflammation. It is thus disappointing that the findings of decreased neonatal morbidity after receipt of erythromycin in ORACLE I have not translated into long-term benefit detectable within the measures we used. The reasons for this are not clear but might be linked to the length of antibiotic exposure, which in this group of women was fairly short, since about 60% gave birth within a week.8 There is also some evidence that antibiotic administration to women with PROM may neither eradicate nor prevent intra-amniotic infection. In a recent study of 18 women with intra-amniotic infection following PROM, only three showed no evidence of infection or inflammation after combination antibiotic treatment for 7–14 days and nine of 28 women with no evidence of intra-amniotic inflammation at admission developed inflammatory changes despite therapy; five of these nine women developed positive amniotic fluid cultures.33 This evidence suggests that other strategies are necessary to prevent the progress of infection and inflammatory changes in utero in the presence of ruptured membranes.
In the accompanying paper reporting the results of the ORACLE Children Study II34 in the presence of spontaneous preterm labour with intact membranes, we have observed an increase in the risk of any functional impairment with the use of erythromycin (with or without co-amoxiclav) and, particularly, increases in the numbers of children with cerebral palsy associated with the use of both erythromycin and co-amoxiclav. These results would suggest further caution should be used when considering the routine treatment of women with antibiotics where there is uncertainty about the diagnosis of PROM. It is clear that we need to better understand the role of infection in women with PROM and the role and wider effects of antibiotics in the perinatal period. However, it is important to clarify that the women in ORACLE I with PROM were entered into the trial when there was clinical uncertainty about the need to prescribe antibiotics—ie, they showed no overt clinical signs of maternal or fetal infection. It is critical that women with evidence of clinical infection are treated with antibiotics, since clinical chorioamnionitis remains an important cause of maternal, fetal, and neonatal death. The results of this study should not lead to fewer women with overt signs of maternal or fetal infection receiving treatment.
Contributors
