Research

The aim of this study of preterm infants 23-36 weeks' gestational age born in 1994-1996 in a hospital with neonatal intensive care facilities was to describe the variation with gestational age in the mortality rate and the causes of death, focusing on avoidable causes.

Data collected included gestational age, birthweight, and mortality during the primary hospitalisation, whether during the neonatal period (first 28 days after birth) or later. Data were included for infants transferred from our hospital to another. Gestational age in completed weeks was assigned according to the first antenatal ultrasound scan, or maternal dates if no ultrasound report was available. Birthweight ratio was calculated by dividing the infant's birthweight by the expected gender-specific median birthweight for that gestational age.⁵

Data were edited and analysed with SPSS for Windows.¹¹ Dichotomous variables were contrasted by ² analysis, and continuous variables were compared by Mann-Whitney U test,¹² as most data were skewed.

Sixty-eight infants died who were without lethal anomalies: 2.8% of the 2425 livebirths, but only 0.2% of infants of 32-36 weeks' gestational age (4/1759) (Box 4). Sixty-one died within 28 days of birth and seven (10.3%) died later during the primary hospitalisation. In the Australian and New Zealand Neonatal Network, 35 of 256 deaths (13.7%) of infants of less than 32 weeks' gestational age without lethal anomalies died during the primary hospitalisation but after 28 days of age.¹⁰ 

Respiratory problems: The mothers of 23 of the 30 infants who died from HMD or BPD had received antenatal corticosteroids. In the remaining seven cases, the gestational ages were 23 or 24 weeks. In six cases there was not enough time to give corticosteroids, five mothers presenting in advanced preterm labour and one with eclampsia. In the seventh case, the gestational age was 23 weeks and before birth the infant was considered incapable of surviving, yet was given full intensive care postnatally.

All 30 infants who died from HMD or BPD received exogenous surfactant after birth.

The one infant who died from pulmonary haemorrhage without HMD received antenatal corticosteroids and did not have respiratory distress after birth and therefore did not re- ceive exogenous surfactant; the fatal pulmonary haemorrhage occurred at three days of age.

The two infants who had HMD and pulmonary haemorrhage also received antenatal corticosteroids.

All three infants who died from pulmonary haemorrhage had received intramuscular vitamin K at birth. None had clinical signs of heart failure or a patent ductus arteriosus before the haemorrhage. None had clinical indications for an echocardiogram, hence subclinical cardiac dysfunction cannot be excluded.

Considering the 12 infants in the gestational age range 28-36 weeks who died without lethal anomalies, six died from sepsis, two from asphyxia, two from BPD, one from pulmonary haemorrhage, and one from SIDS. None died acutely from HMD.

Infections: In the 22 infants who died from sepsis without NEC, there were only two in whom the management might have been different.

In one infant of 30 weeks' gestational age the mother ignored the antenatal signs of sepsis for several days before presenting to hospital and delivering a moribund infant who died at 11 hours of age from E. coli pneumonia, despite full treatment, including appropriate antibiotics.

In the other infant, of 33 weeks' gestation, who died of herpes simplex, the clinical presentation was that of sepsis several days before death, but, in the absence of other features of herpes in the mother or infant, no antiviral therapy was given.

CVH and CPVL: Antenatal corticosteroids were given to the mothers of all nine infants in whom CVH or CPVL were major contributing causes of death. In addition to the five infants in whom CVH was a major cause of death, another 12 infants who died had a grade 3 or 4 CVH that was thought not to contribute substantially to their deaths.

The survival rate to hospital discharge in 1994 for infants free of lethal malformations cared for in neonatal nurseries at 23-31 weeks' gestational age was higher in our hospital than in reported data from the Australian and New Zealand Neonatal Network (Box 6).

The Australian and New Zealand Neonatal Network collects data from all the Australian and New Zealand Neonatal Intensive Care Units.¹⁰ In this data set, the denominator is limited to admissions to neonatal units, eliminating livebirths who die outside the neonatal unit, and hence augmenting the reported survival rates. Moreover, this data set is limited to infants up to 31 weeks' gestation and excludes those with lethal malformations. The numerator, however, includes deaths in the neonatal period and those beyond 28 days of age that occur during the primary hospitalisation.

Comparing data on cause of death is also difficult. Most government data collection sources, such as those in Victoria^7-9 and other States, rely on confidential reports. They may not obtain enough data to classify the cause of death, and rarely can they confirm the gestational age. The final report includes an individual infant under only one cause of death, even though there may be several equally contributing causes of death, such as the common combination of HMD and airleak, which caused 25% of deaths from non-lethal causes in our study.

Our system of clinicopathological conferences for each death, although not perfect, provided more detailed information about causes of death.

As regional data sources do not provide complete data on deaths during the primary hospitalisation at all gestational ages, we cannot compare survival rates for preterm infants (32-36 weeks) with those of term infants (37-42 weeks). However, we have calculated rates of neonatal survival in Victoria for livebirths free of lethal malformations with birthweight greater than 2499 g, assuming that the results would be similar for infants of 37-42 weeks' gestation. In our hospital, the neonatal survival rate for infants of 32-36 weeks' gestational age (99.77%) approached the neonatal survival rate expected of term infants in Victoria (99.95%).

The commonest causes of death were lethal anomalies, sepsis, and HMD. Deaths from lethal anomalies are over-represented in our hospital compared with Victoria as a whole as most have been diagnosed antenatally, and, in many cases, the mother has been transferred before birth from another hospital for management because of the fetal anomaly.

The death rate from infection is higher in our hospital than for Victoria, but this is probably because infants in our hospital live longer, and hence acquire infections, rather than dying soon after birth from other problems related to prematurity. E. coli and Group B streptococci remain the chief cause of septic deaths, particularly soon after birth, consistent with the observations of Isaacs et al.¹⁴ Staphylococcus species are an increasingly frequent cause of late infections,¹⁵ and of late deaths in our study.

HMD remains a leading cause of death for very preterm infants despite the fact that most mothers receive antenatal corticosteroid therapy and all infants receive exogenous surfactant. Improvements in exogenous surfactant offer hope of reducing mortality further, but other antenatal interventions, such as thyrotropin stimulating hormone,¹⁶ have been disappointing in large randomised controlled trials. HMD did not cause any deaths in our hospital in more mature preterm infants (28-36 weeks). Within the infants who died from HMD, the observation that those who also had an airleak were not as growth restricted as those who had no airleak might reflect some structural change within the lung or with use of pulmonary surfactant that is associated with growth restriction.

The problem of extreme intrauterine growth restriction is highlighted by the deaths from pulmonary haemorrhage in three infants, all with birthweight ratios below 0.55. The pulmonary haemorrhage was not caused by failure to give intramuscular vitamin K at birth.¹⁷ The mechanism for fatal pulmonary haemorrhage is unclear, but may represent acute left heart failure, contributed to by a patent ductus arteriosus. The association of pulmonary haemorrhage and fetal growth restriction is well known and may be related to histological changes in the ductus arteriosus in growth-restricted fetuses.¹⁸ Pulmonary haemorrhage is also seen more frequently with exogenous surfactant therapy,¹⁹ which was given to two of the three infants in our study who died of pulmonary haemorrhage.

Preventing prematurity, an obvious solution to the problem of higher death rates in preterm infants, remains an elusive goal. In all infants who died, few obvious preventable factors, apart from avoiding preterm birth, were evident. The Annual Report from the Victorian Consultative Council on Obstetric and Paediatric Mortality and Morbidity consistently identifies more avoidable factors in stillbirths than neonatal deaths.^7-9

In summary, mortality rates fell sharply between 23 and 28 weeks' gestational age, and few infants of more than 28 weeks' gestational age without lethal anomalies died. Survival rates for preterm infants of more than 31 weeks' gestational age approached the survival rates expected of term infants. There were few obvious avoidable factors in the deaths of any of the infants who died, either in the very preterm infants of 23-27 weeks' gestational age, or the more numerous preterm infants of 28-36 weeks' gestational age.

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Reprints will not be available from the authors.
Correspondence: Associate Professor Lex Doyle, Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052.
Email: l.doyle@obgyn-rwh.unimelb.edu.au

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