William Tarnow-Mordi

Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial

BACKGROUND Preterm, prelabour rupture of the fetal membranes (pPROM) is the commonest antecedent of preterm birth, and can lead to death, neonatal disease, and long-term disability. Previous small trials of antibiotics for pPROM suggested some health benefits for the neonate, but the results were inconclusive. We did a randomised multicentre trial to try to resolve this issue. METHODS 4826 women with pPROM were randomly assigned 250 mg erythromycin (n=1197), 325 mg co-amoxiclav (250 mg amoxicillin plus 125 mg clavulanic acid; n=1212), both (n=1192), or placebo (n=1225) four times daily for 10 days or until delivery. The primary outcome measure was a composite of neonatal death, chronic lung disease, or major cerebral abnormality on ultrasonography before discharge from hospital. Analysis was by intention to treat. FINDINGS Two women were lost to follow-up, and there were 15 protocol violations. Among all 2415 infants born to women allocated erythromycin only or placebo, fewer had the primary composite outcome in the erythromycin group (151 of 1190 [12.7%] vs 186 of 1225 [15.2%], p=0.08) than in the placebo group. Among the 2260 singletons in this comparison, significantly fewer had the composite primary outcome in the erythromycin group (125 of 1111 [11.2%] vs 166 of 1149 [14.4%], p=0.02). Co-amoxiclav only and co-amoxiclav plus erythromycin had no benefit over placebo with regard to this outcome in all infants or in singletons only. Use of erythromycin was also associated with prolongation of pregnancy, reductions in neonatal treatment with surfactant, decreases in oxygen dependence at 28 days of age and older, fewer major cerebral abnormalities on ultrasonography before discharge, and fewer positive blood cultures. Although co-amoxiclav only and co-amoxiclav plus erythromycin were associated with prolongation of pregnancy, they were also associated with a significantly higher rate of neonatal necrotising enterocolitis. INTERPRETATION Erythromycin for women with pPROM is associated with a range of health benefits for the neonate, and thus a probable reduction in childhood disability. However, co-amoxiclav cannot be routinely recommended for pPROM because of its association with neonatal necrotising enterocolitis. A follow-up study of childhood development and disability after pPROM is planned.

Broad-spectrum antibiotics for spontaneous preterm labour: The ORACLE II randomised trial

BACKGROUND Preterm birth after spontaneous preterm labour is associated with death, neonatal disease, and long-term disability. Previous small trials of antibiotics for spontaneous preterm labour have reported inconclusive results. We did a randomised multicentre trial to resolve this issue. METHODS 6295 women in spontaneous preterm labour with intact membranes and without evidence of clinical infection were randomly assigned 250 mg erythromycin (n=1611), 325 mg co-amoxiclav (250 mg amoxicillin and 125 mg clavulanic acid; n=1550), both (n=1565), or placebo (n=1569) four times daily for 10 days or until delivery, whichever occurred earlier. The primary outcome measure was a composite of neonatal death, chronic lung disease, or major cerebral abnormality on ultrasonography before discharge from hospital. Analysis was by intention to treat. FINDINGS None of the trial antibiotics was associated with a lower rate of the composite primary outcome than placebo (erythromycin 90 [5.6%], co-amoxiclav 76 [5.0%], both antibiotics 91 [5.9%], vs placebo 78 [5.0%]). However, antibiotic prescription was associated with a lower occurrence of maternal infection. INTERPRETATION This trial provides evidence that antibiotics should not be routinely prescribed for women in spontaneous preterm labour without evidence of clinical infection.

Infection and preterm labour

10 Felkin RW. Notes of labour in Central Africa. Edinburgh Medical Journul1884; 29: 922-930. 1 I Tumer MJ. Delivery after one prcvious cesarean section. A m J Ohstet Gynecoll997; 176: 741-744. 12 Harrison KA. Pregnancy outcomc following previous caesarcan section, previous vesicovaginal fistula and previous surgical treatment of ectopic pregnancy. Br J Ohstet Gynaecol 1985; 92 Suppl5: 72-80. 13 White SM, Thorpe RG. Maine D. Emergency obstetric surgery pcrformed by nurses in Zaire. Lancet 1987; 2: 612-613. 14 Khan KS, Rizvi A. The partograph in the management of labor following ccsarcan section. Int JGynaecol Obstet 1995; 50: 151-1 57. 15 Begg CB, Berlin JA. Publication bias and dissemination of clinical research. JNat l Cancerlnst 1989; 81: 107-115. 16 Heyns 0s. The superiority of the South African Negro or Bantu as a parturient: Parts I and TI. J Obstet Gynaecol Br Einp 1946; 53: 405429. 17 Heyns OS, Shippel S. The superiority of the South African negro or Bantu as a parturient: Part 111. J Ohstet G-vnaecol Br Emp 1946; 53: 519-526. 18 Sibthorpe EM, Allbrook DB. A radiological survcy of the female pelvis in Uganda with addendum on the measurements of specimens of thc fcmale bony pclvis. J Obstet Gynaecol Br Emp 1958; 65: 600-605. 19 Walton SM. The antenatal and intrapartum management of patients with previous caesarean section scars. East Ajt Med J 1978; 55: 1-8. 20 Heyns OS, Hersch SS. The birthweight of urban Bantu including a consideration of the incidence of antenatal syphilis, stillbirth and premature labour. SAP JMedSci 1944; 9: 33-37. 21 Thubisi M, Ebrahim A, Moodley J, Shweni PM. Vaginal delivery aflcr previous caesarean section: is X-ray pelvinietry nccessary? Br J Ohstet G.ynaecoll993; 100: 421424. EPIP 1921; 28: 338-348. 22 Gebbie DAM. Cephalopelvic disproportion in Uganda-its aetiology and management [MD thesis]. Glasgow: University of Glasgow; 1969. 23 Cebbie DAM. The influence of maternal height on the outcomc of pregnancy. JTrop Ped 1966; 12: 22-23. 24 Thumau GR, Scates DH, Morgan MA. The fetal-pelvic index: a method of identifying fetal-pelvic disproportion in womcn attempting vaginal birth after previous ccsarcan section. Am J Obstet Gynecol

The UK neonatal staffing study: A prospective evaluation of neonatal intensive care in the UK

An evaluation of the organization of neonatal intensive care units (NICUs) ideally requires a controlled trial comparing outcomes for infants randomly allocated to different models of care between or within NICUs. As this is not currently feasible, the most reliable strategy is a risk-adjusted comparison of outcomes from nationally representative samples of NICUs with contrasting organizational characteristics. The UK Neonatal Staffing Study is a prospective observational study of 6400 infants from 48 randomly selected NICUs stratified by size, availability of consultant medical staff and nursing provision. Organizational characteristics will be related to mortality, morbidity such as major brain damage or nosocomial bacteraemia, as well as costs, staff well-being and satisfaction.

Artificial versus natural surfactant — Can we base clinical practice on a firm scientific footing?

Now that surfactant is in widespread use, clinical trials are beginning to address the critical question of whether the choice of surfactant really matters in terms of major morbidity and mortality. The trials reported so far focus on the effects of artificial and natural surfactant on acute gas exchange and duration of oxygen or ventilation therapy. Although the number of infants recruited to comparative trials of different surfactants is increasing, we are still a long way from being able reliably to answer the question ‘Which type of surfactant should we use and under what circumstances?’ In understanding the uncertainty in this field it is pertinent to consider the interrelationships between three levels of research for any new therapy in clinical science. At the first level animal studies or case reports suggest potential clinical benefits. At the second, more focused physiological studies and trials address questions of mechanism. At the third, definitive randomised trials compare major adverse clinical outcomes in human patients. Only studies conducted at this third level can finally establish clinical practice on a firm scientific footing. In this review, a preliminary meta-analysis of 801 patients recruited in three trials of artificial (Exosurf) versus natural (Survanta) surfactant shows no clear advantage for either surfactant but does not rule out moderate differences in major adverse outcomes. To establish reliably whether such differences exist will require large multicentre clinical trials. Since neonatal respiratory distress syndrome remains a common and life threatening disease, any moderate reductions in mortality and major morbidity which might be gained from using one type of surfactant rather than another would be important and well worth knowing about. Such clinical trials could answer more than one question by investigating the safety, efficacy and cost-effectiveness of each surfactant in pre-specified groups of patients stratified by initial clinical risk and illness severity and by simultaneously addressing other therapeutic issues using factorial designs. Despite their organisational problems, until such definitive “third level” comparative clinical trials of different surfactants are performed key questions for clinicians, patients and policy-makers will remain unanswered.

What do doctors record in the medical notes following discussion with the parents of sick premature infants

Abstract In a retrospective review of medical notes we determined: (1) how often doctors record discussions with the parents of very low birth weight (VLBW) infants during the neonatal period; (2) what details of any discussion they actually record and; (3) if they are more likely to record discussion with the parents of sicker infants. A random sample (30%) of all VLBW infants admitted between 1989 and 1993 to a regional NICU was reviewed, n = 87. No discussion was documented in 47 cases, one of whom died, 24 had a single episode of discussion recorded and 16 had two or more episodes recorded. Specific discussion about prognosis was only recorded in the notes of 27 babies. Discussion was more likely to be documented in sicker infants as measured by CRIB (clinical risk index for babies) score, t = −3.9, P<0.001. Conclusion A record of discussion between medical staff and parents is found in the medical notes of less than half of all VLBW infants. These findings may have practical, ethical and legal implications.