This is the first study to apply Sartwell’s modeling for incubation periods to NEC. We demonstrate that the age of NEC onset fits Sartwell’s log normal model of incubation periods. Incubation periods fitting Sartwell’s model imply a single identifiable factor or point exposure that initiates a chain of events leading to illness (7, 19)
. For NEC, the incubation period is age of NEC onset, with birth as the point of exposure.
Such a good fit suggests that an event at or soon after birth could be necessary, though perhaps not sufficient, for the development of this devastating disorder. Birth as an important event in NEC development is not a new concept, given its absence in utero, but the log normal occurrence of age of NEC diagnosis does suggest that the day of diagnosis of NEC is less affected by exposure to environmental factors within the NICU than the process of parturition and introduction to extra-uterine life. These distributions, while not negating the roles of other precipitating co-factors, do compel us to scrutinize biologic processes that begin in the immediate neonatal period as the controlling driver of NEC.
What could be such an early postnatal precipitant of NEC? Recent hypotheses implicate bacterial colonization (18, 20–22)
in the development of NEC. The fetal intestine is sterile in utero
with colonization beginning only after birth. If bacterial colonization at or soon after following birth is analogous to exposure to infectious agents that cause various illnesses in Sartwell’s model, then a log normal model regardless of gestational age would result, as we demonstrate. However, we also must account for what appears to be non-random deviation from the model prediction. Whether lower than predicted rates of occurrence in early days of life are related to temporary protection from initial antibiotic exposures, or other yet-to-be discerned variables, is not now clear. It is plausible that varying degrees of intestinal tract development, related to in utero development, could account for some of the differences for time to NEC development between gestational age categories. This again highlights the likely interaction between events that begin in parturition, and that continue post-natally.
This also is the first study of NEC to model the effect of gestation on age of onset. While an inverse relationship between gestational age and day of NEC diagnosis has been previously reported (25–28)
, ours is the first description and quantification of its non-linear nature. ( and ). By including the disproportionately longer age to onset for infants at very early gestational ages (1/gestational age) we were able to account for 50% of the variability in age of NEC onset. This degree of contribution from a single factor is somewhat unusual within complicated biologic systems, particularly the complex preterm infant. Gestational age has typically accounted for 30% or less of variation evident in other common preterm morbidities, including neurodevelopmental outcomes (29, 30)
. The importance of gestation age to timing of onset again points to an interaction between events related to birth, and stage of intestinal development.
The NEC rate reported in this study (5.1%) resembles recent studies (2, 3, 31)
. Also, the mortality rates of 23.8% for all children with NEC, and ≥ 40% for patients ≤28 weeks of gestational age, are similar to previous series (6, 27, 32–34)
, and confirm the described inverse relationship between NEC mortality and gestational age (3, 31, 35)
. These high mortality rates highlight the lack of progress made over this time interval in treating this devastating disease.
We wish to note several limitations of this study. First, we used day of NEC diagnosis as the end of the incubation period, but it is possible that the radiographic manifestations required for inclusion in the study represent a pathologic process that began earlier, so our estimates of age of onset are therefore inaccurate. However, in the absence of an identifiable herald sign of NEC that more precisely represents its onset, we and others are necessarily obligated to use the date of the radiographic abnormality as the most defensible and definable point of NEC onset. Second its retrospective nature limits our ability to account for potential variables that could have impacted age of onset, beyond gestational age.
In conclusion, Sartwell’s model, when applied to NEC, demonstrates log normality across all gestational age groups. The adherence of age of NEC onset to this model of incubation periods further supports a theory of NEC causation that is strongly influenced by a point exposure, in this case birth. The incubation period appears to start at or soon after birth, quite likely from a point source acquisition of sensitizing microbes. Gestational age differences in response to birth are evident as indicated by the continued correlation between GA and age of diagnosis of NEC. But birth, regardless of gestational age, and not subsequently occurring events, appear to be most critical event in terms of starting the clock that leads to NEC.