A small number of papers have been published describing the neurodevelopmental outcome of survivors of NEC. Some compare children who had NEC with those born ELBW who did not have NEC, others compare the outcomes of babies treated conservatively with those receiving surgery. Meta‐analyses can be usefully performed on non‐randomised studies,25
in which case caveats must be drawn in the interpretation of the results. Clearly, in comparing ELBW infants who had NEC with those that did not get NEC, we are comparing two populations rather than two groups of individuals randomly allocated from the same population.
Limitations of this type of study include the presence of confounding factors – it is impossible to quantify the effect of factors that are related to both NEC and neurodevelopmental impairment (eg prematurity); this is the most important threat to the validity of results from cohort studies.25
Epidemiological studies are prone to publication bias as only statistically significant findings may be published.26
Other problems which are likely to be greater in meta‐analyses of retrospective, non‐randomised studies include inadequate reporting of methods, variation in study design, variation in inclusion criteria and variation in presentation of results.26
Another potential problem with meta‐analysis of non‐randomised studies is combining data from different types of study design. In this meta‐analysis, we have combined data from cohort and case control studies, although where there were enough studies of each type to undertake two separate analyses, the results were consistent. We chose to combine studies by using odds ratios rather than relative risks as whereas it is appropriate to refer to odds ratios for both cohort and case‐control studies, relative risk cannot be calculated for case‐control studies. Interpretation of odds ratios in the same way as relative risks, however, can overestimate effect sizes where the event is frequent in the index group (as in our study) and the odds ratio is large27
(although most odds ratios we obtained were <2.5). Another potential problem with the approach that we have used is the fact that different papers have used different tools for measurement of neurodevelopmental outcome, although most studies that we included used one of two scores–Bayley scores or Griffiths Quotients.
Despite these limitations, we believe that our results show that neonates who have NEC can expect a significantly worse neurodevelopmental outcome that those VLBW neonates who do not have NEC. Although the risk seems small (OR 1.6), the risk of poor neurodevelopmental outcome is already great in VLBW infants, so any significantly increased risk is important. This results in 45% of NEC survivors having poor neurodevelopmental outcome. If a baby with NEC needs surgery, their neurological outcome becomes even worse (OR 2.34) compared to medically‐treated infants. This finding does not imply that one should not treat a neonate with perforated NEC surgically; it only implies that babies sick enough to require surgery have a worse outcome than those not sick enough to require surgery. In this study, we only included infants that had Bell's stage II or III NEC, as the signs and symptoms for stage I NEC are too non‐specific to make this a meaningful group for comparison. However, even the diagnosis of stage II and stage III NEC can be equivocal and we acknowledge that this is another potential shortcoming of this study.
Factors causing poor neurodevelopmental outcome in premature infants are complex. Neurogenesis, neuronal maturation and synaptogenesis contribute to brain development in the 2nd
trimester of pregnancy28
so extremely premature infants have a deficit in brain maturation. Postnatal continuation of these processes requires adequate nutrition, and may be adversely affected by many factors associated with prematurity and surgery. Indeed, a specific negative impact of NEC on cerebral growth is suggested by the finding that NEC is a significant predictor of smaller head circumference in ELBW infants.29
Damage to existing cerebral tissue is another likely contributor to poor neurological outcome. This can be caused by infection or inflammation, respiratory insufficiency, hypotension, acidosis, fluctuations in glycaemic control, disseminated intravascular coagulation, anaesthesia and transport. In particular, infection and sepsis, which may result from intestinal perforation and/or gangrene, have been highlighted as independent risk factors.9
They cause increased cytokines, which are implicated in the pathogenesis of periventricular leukomalacia, a major determinant of adverse neurological outcome.31
Surgery for NEC also causes a cytokine surge which could be responsible for white matter damage, and it would be interesting to determine if a surgical treatment with a lower degree of tissue trauma (peritoneal drainage) results in a better neurological outcome than laparotomy. Poor outcome may be independently associated with surgery, with or without NEC–28% of surviving ELBW infants who required surgery of any sort have a poor sensorieneural outcome.32
In favour of the severity of disease, rather than surgery per se
causing poor neurodevelopmental outcome, Adesanya et al.7
found that neurodevelopmental impairment was worse in infants who had perforated NEC than those with spontaneous bowel perforation.
Most of the studies had good rates of follow up suggesting that the results are representative, although a bias in overestimation of adverse outcomes has been found previously, as children with poor neurodevelopmental outcome are more likely to be retained for follow‐up.7
We analysed cohorts that were born over a wide period of time (1975–2002), which includes babies born before surfactant and high frequency oscillation were introduced. Although the mortality of ELBW neonates has improved, the effects on neurodevelopmental outcome are less well defined.2
What is already known on this topic
- Infants born prematurely have a risk of poor neurodevelopmental outcome.
- Previous studies reporting neurodevelopmental outcome of infants who have had necrotizing enterocolitis give conflicting results.
What this study adds
- Infants who survive necrotizing enterocolitis have a worse neurodevelopmental outcome than other extremely low birthweight survivors.
- Infants who require surgery for necrotizing enterocolitis have an even higher risk of poor outcome than those who receive only medical treatment.
Our findings on the overall rates of poor neurodevelopmental outcome in ELBW infants are comparable to recent population‐based prospective studies which demonstrated that 10% of extremely premature infants had severe motor disability, 2% were blind, 3% were deaf and 49% had some disability37
and that these disabilities persisted into childhood.38
The largest study in our review, that from the National Institute of Child Health,21
was the most complete in terms of available data, therefore in comparisons where only a few studies were included there is a risk that the results of smaller studies are subsumed. However, this paper reported on outcomes from sixteen different centres in the US and many of the other papers are from different countries, so pooling the results makes the results more applicable to patients outside the USA.
If neonates with NEC are at increased risk of adverse neurodevelopmental outcome, two questions arise: can we predict which babies will have an adverse outcome, and can we do anything to prevent it? Logistic regression and neural networks had low sensitivity and specificity for predicting major handicap in ELBW infants39
and although severely abnormal ultrasound has a high predictive value for adverse neurological outcome,23
up to 30% of ELBW survivors with normal neonatal ultrasound are found to have impairment at 18–22 months.40
MRI at school age has recently been suggested to be better predictor of IQ and motor performance than ultrasound,41
but whether neonatal MRI is a better predictor than ultrasound is not known.
Now that we know that infants with NEC are at increased risk of neurodevelopmental impairment we should ensure that neurodevelopmental assessment plays a part in the follow‐up of any new treatment. It is also important that parents and professionals are aware of the increased long term risks in these critically ill neonates.