A new publication from the NRN describes short term outcomes and care practices of babies from 22 to 28 weeks gestation born in recent years (2013 to 2018) and for those born in 2013-2016 results of evaluations of those followed to 2 years corrected age. Survival for the most immature infants, seems to continue to improve. Bell EF, et al. Mortality, In-Hospital Morbidity, Care Practices, and 2-Year Outcomes for Extremely Preterm Infants in the US, 2013-2018. JAMA. 2022;327(3):248-63.
Many of the results are compared with a previous cohort from the network, which had very similar enrolment criteria. In the previous cohort, survival to discharge of those born at 28 weeks was 94%, it was 90% at 27 weeks, 85% at 26 weeks gestation, and 77% at 25 weeks. The figures for the same GAs are now 98%, 98%, 90%, and 80%, therefore, even among these larger extremely preterm babies survival seems to still be trending upwards.
At 24 completed weeks GA 62% survived in the previous cohort compared to 70% in the new; almost all received active treatment in the recent cohort, that information isn’t given in the older study. At 23 weeks survival was 32% previously, and was 49% in the new article, with about 88% of the babies getting active treatment, among those 958 with active treatment survival to discharge (or one year of age if still hospitalised), was 56%. At 22 weeks there were 334 babies in the previous cohort with a 7% survival, which has improved now to 11% among all the babies delivered, but when restricting the analysis to only those 201 (of 550, 37%) who received active intervention, survival was 30%. A lot of the deaths of the 22 and 23 week infants were within the first 12 hours, (21% and 11% mortality at <12h of age). Many of the other complications and interventions are reported for those surviving >12h.
The network reports how many babies had limitations of life-sustaining interventions, and the percentage that this applied to was 36% of the babies born at 22 weeks (who survived >12h), progressively decreasing to about 2% at 28 weeks. Of the babies at 22 and 23 weeks gestation who survived >12h (n=159 and 856), 133 and 779 survived more than 3 days, 77 and 609 survived to 28 days, for a final numerical survival to discharge of 60 and 535. I recount these numbers just to point out that late death occurs among these infants, often after multiple complications, but the majority of deaths occur relatively early.
Complications of prematurity are also reported, including NEC, showing a small reduction from 10.3 to 8.9% between the 2 cohorts, and a relatively modest trend to increasing incidence with lower GA (5% at 28 weeks, 11% at 22, 24 and 25 weeks, 15% at 23 weeks). Severe intracranial hemorrhage does not seem to have changed overall at about 14%, despite the much higher survival at 22 and 23 weeks, who had an incidence of 38 and 36% respectively.
As many other cohorts have shown, there seems to be an increase in chronic lung disease, from 45 to 49% overall, with about 80% still on oxygen at 36 weeks for babies at the lowest 3 weeks of GA. As an exercise I calculated “death or BPD”, at 22 weeks 97% had this outcome, and at 23 weeks it was 95%.
Cystic PVL was unchanged from the previous publication and did not differ across GAs,at around 4%.
During the recruitment of this cohort, there were a few things changing in neonatology, some of which should lead to further improvements in these figures:
Delayed cord clamping was being introduced during this period, and in this cohort only about 40% had delayed clamping. This intervention has been shown to improve survival, so future cohorts should benefit from this. In this cohort some received cord milking, which I think the data shows should not be used as a replacement for delayed clamping.
Antenatal steroids were only given to 30% of the babies who delivered at 22 weeks, and 81% of the 23 weekers, compared to about 90% to the more mature babies. Proactive care co-ordinated with the obstetric team can have major impacts on survival of the most profoundly immature. Although such babies were not included in the majority of RCTs of antenatal steroids, all the observational data show a survival benefit of steroids at 22 and 23 weeks. They can be given as soon as a mother presents with threatened extremely preterm delivery, in order to give time for them to have an effect, even if a decision regarding active intensive care has not yet been taken.
Probiotics were given to a minority of the babies, only 10%, if you read this blog you will know my opinion on this, the network meta-analysis showed a substantial benefit of a mixture containing Bifidobacterium longum susbsp. infantis on the frequency of NEC.
There were many babies who did not receive human milk; I think that donor milk is now universally available, which may not have been the case at the beginning of this cohort, but should also have an impact on NEC. Of all the interventions that we must ensure are applied universally to very preterm infants, human breast milk feeding should be top of the list.
Late onset sepsis is depressingly very common in the most immature babies, most centres have on-going quality control initiatives to reduce nosocomial sepsis, and although important, they have been of limited impact in the most extremely preterm infant. In the Canadian Neonatal Network, quality improvement initiatives using the EPIQ framework have led to a progressive decrease in late-onset sepsis for babies of >25 weeks. If you compare the following 2 graphs from 2013 and 2020, there is a substantial reduction in late-onset culture-positive sepsis between the 2 years, until you reach the <25 weeks stratum, where the incidence seems to have gone up. These data are among infants who survived more than 2 days, and are the proportion who experienced at least one culture-positive sepsis, about 25% of whom had more than one sepsis episode. Part of this worsening may be due to the increased survival of infants at 22, 23 and 24 weeks gestation, as there are many more patient days at risk in 2020 than there were in 2013.
These results point out the extreme importance of further research in ways to reduce sepsis, by improving skin and intestinal barrier function (some studies showing a reduction in LOS with probiotics, and meta-analysis usually confirming a benefit), and supporting and improving immune function. An interesting discussion from a Japanese neonatologist (Isayama T. The clinical management and outcomes of extremely preterm infants in Japan: past, present, and future. Transl Pediatr. 2019;8(3):199-211) points out that gloving, masking and gowning are often universally applied during routine care in Japan, where the incidence of late-onset sepsis is very much lower than in North America and Europe. It makes me wonder whether that approach would be worth instituting, especially for the highest risk babies, an whether the recent extra restrictions imposed by the pandemic might have had an effect on sepsis. One advantage of universal extra precautions would be to inhibit people from touching and disturbing the babies. Previous data have suggested that universal gloving, applied in an NICU because of a hospital-wide policy during RSV season, reduced late-onset sepsis. Randomized controlled trials have confirmed this benefit.
And of course, decreasing lung injury: although cause of death is not reported in this cohort, being very difficult to ascertain in a large database, many infants who die late have severe respiratory failure. If we can improve lung injury we may well improve survival, and certainly will decrease adverse long-term pulmonary outcomes which have a serious impact on health-related quality of life. What are the potential hopeful interventions for reductions in lung injury? Prophylactic budesonide, given with surfactant, is one potential that is being studied in several multicentre trials. Finally figuring out when postnatal steroids should be given, which molecule, in what dose, for how long, would be great. Late surfactant therapy in babies still intubated who are starting to develop chronic lung disease has not been adequately studied, but seemed to improve long term lung health in the French study.
Unfortunately, for many interventions, the most immature babies, who may not have the same response to more mature preterm infants, have been excluded from trials. Hopefully, in the future there will be no minimum GA or birth weight for eligibility; surely any baby for whom intensive care is instituted should be eligible for research to try and improve outcomes for future similar babies.
In the next post I will discuss the longer term outcomes from this publication.