Comprehensive assessment of the long-term effects of necrotizing enterocolitis and its treatment

Emerging evidence suggests that exposure to pain or opioids during the neonatal
period might have long-lasting effects. Rodent studies show that exposure to
pain during the neonatal period affects brain development and induces long-term
behavioural changes. Exposure to opioids in absence of pain also caused
neurotoxic effects in rodent studies, whereas exposure to opioids in presence
of pain mitigated these effects and may thus have a neuroprotective effect. In
humans, exposure to pain in the neonatal intensive care unit (NICU) has been
associated with changes in brain structure, impaired cognitive development and
altered pain sensitivity. Contradictory effects of neonatal opioid exposure
have been found in humans, which may reflect differences in the balance between
the exposure to pain and opioids. Since both exposure to pain and exposure to
opioids could harm brain development, it is essential to get this balance
right. A recent study in our NICU showed that despite analgesic therapy, the
majority of necrotizing enterocolitis (NEC) patients experienced pain during
the disease, which in some patients persisted for hours. Therefore, NEC
patients may suffer negative long-term consequences of neonatal pain. On top of
that, surgical treatment of NEC results in a scar and may thereby have
long-term effects on cosmetic outcome and quality of life.

To determine the long-term outcome after necrotizing enterocolitis during
neonatal life, regarding (pain) sensitivity, sensory processing, behaviour,
executive function, scar satisfaction (in surgically treated NEC patients), and
(health-related) quality of life in children aged 6-15 years.

A cross-sectional cohort study comparing outcomes of children with a history of
NEC with a gestational age- (GA), sex- and age-matched control group of preterm
born children without a history of NEC. Both conservatively and surgically
treated NEC patients will be included.

To our knowledge there are no medical risks associated with participation in
this study.
Participants will be visited at home (or a nearby location of their choice)
with the Sophia research bus, in order to minimize the logistical burden of
participation. The study session will take approximately 1 hour. It will
consist of Patient Reported Outcome Measurement to evaluate participants*
general wellbeing, assessment of mechanical detection sensitivity using Von
Frey filaments, assessment of mechanical pain sensitivity using a pressure
algometer, and assessment of thermal detection and pain sensitivity using the
Thermal Sensory Analyzer (TSA). These measurements are non-invasive and have
all been performed previously in children (Blankenburg et al., 2010; Valkenburg
et al., 2015; van den Bosch et al., 2017; Walker et al., 2009). The scar
assessment in surgically treated NEC patients consists of evaluation of the
cosmetic outcome by the researcher and evaluation of the patient*s satisfaction
with the scar using the SCAR-Q questionnaire.
To ensure participants are at ease during the study procedure, they will be
informed on forehand and will be asked to report their fear and pleasure during
the breaks using the Wong-Baker Faces Rating Scale (Wong & Baker, 1988). The
study is immediately terminated when the child gives a score of 5 (sad face on
the faces scale) or if the parents or the researcher rate the child with a
score of 5. Children participating in a previous TSA study reported low
Wong-Baker Faces Rating scores during the procedure, indicating that they
considered it fun rather than frightening (van den Bosch et al., 2013) .
While the child performs the measurements, the child*s parent/caregiver will be
requested to complete six questionnaires about their child: the Short Sensory
Profile (SSP), the Child Behavior Checklist (CBCL), the Behavior Rating
Inventory of Executive Function (BRIEF-2), the Chronic Pain Questionnaire
(CPQ), the Pediatric Quality of Life inventory (PedsQL), and the
Dutch-Child-AZL-TNO-Quality-of-Life (DUX-25). Completing these questionnaires
takes approximately an hour and can be done during the study visit via an
online portal, using an iPad which will be provided. Children aged 8 years or
older will also be asked to complete the CPQ, PedsQL and DUX-25 themselves.
They can do this before the study visit using the online portal. Completing
these three questionnaires takes approximately half an hour.
Overall, we consider the risk associated with participation in this study
negligible and the burden minimal. There are no benefits of participation to
the participant himself/herself or his or her family, except that participants
will receive a small gift. This research contributes important knowledge about
the long-term effects of NEC and neonatal pain and aims to improve pain
management for these vulnerable patients.