Necrotizing Enterocolitis in a Dutch Cohort of Very Preterm Infants: Prevalence, Mortality, and Long-Term Outcomes

Abstract

Introduction To improve counseling of parents and to guide care strategies, we studied the disease course and outcomes of necrotizing enterocolitis (NEC) up to 2 years of corrected age (CA) from a multidisciplinary perspective.

Materials and Methods This was a retrospective cohort study in preterm infants (birth weight < 1,500 g, gestational age < 32 weeks), diagnosed with NEC (Bell's stage ≥ II) from 2008 through 2020. Data on prevalence, mortality, surgery, intestinal failure (IF), growth, and neurodevelopment at 2-year follow-up were separately analyzed for medically and surgically treated children.

Results Of 3,456 preterm infants, 200 (6%) were diagnosed with NEC, of whom 135 developed an indication for surgery within 7 days after the diagnosis; 28/135 died before surgery, and 37/107 died after an open-and-close procedure. An enterostomy was constructed in 62 patients and an end-to-end anastomosis in 15. The postoperative course was described for 77 patients, of whom 23 developed surgical complications (12/23 incisional hernias, 9/23 anastomotic strictures), 13/77 a short bowel, and 25/77 IF. Sixty-day survival after birth for medical NEC patients was 88% (hazard ratio [HR]: 0.698; p = 0.318), and for surgically treated NEC patients was 40% (HR: 3.729; p < 0.001). At 2-year follow-up, one patient received parenteral nutrition. Severe delay in weight for age, motor, and cognitive development was seen in 3, 6, and 2%, respectively.

Conclusion In this cohort, the mortality rate was high, especially in surgically treated NEC patients. The surgical complication rate is comparable to previous studies, but in surviving patients, persisting IF and severe delay in growth and neurodevelopment at 2 years CA were relatively rare.

 

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Keywords

infant - surgery - medical treatment - intestinal failure - neurodevelopment

Introduction

Necrotizing enterocolitis (NEC) is one of the most common causes of death in preterm infants in neonatal intensive care units. The surviving infants face severe short- and long-term morbidities such as poor growth, short bowel syndrome, and neurodevelopmental impairment.[1] Despite improved treatment for prematurity, NEC-related mortality rates have increased over the years, likely because more preterm infants survive up to the age at which NEC occurs (with infants born earlier developing NEC at a later postnatal age).[2] Evidence is accumulating on modalities to prevent NEC, such as prenatal steroids, breast milk, donor milk, and probiotics, but as yet, little evidence is available for the treatment of NEC. Differences between both medical and surgical treatments, but also in end-of-life decision-making practices, may explain the reported wide variation in outcome after NEC.[3] [4] [5] [6]

More understanding of the prognosis of NEC is needed to reliably counsel parents and to guide treatment strategies aimed at improving survival without morbidity, as well as to guide moral decision-making on comfort care. Outcome data on NEC are scarce, especially regarding long-term outcomes.[4] [7] Moreover, most previous reports have focused on specific morbidities, from the perspective of either neonatology, pediatric gastroenterology, or pediatric surgery. From the perspective of patients or parents, the prognosis encompasses a full spectrum of domains, at least including survival, surgical complications, intestinal failure (IF), growth, and neurodevelopment.

This study aimed to describe the short- and long-term outcomes of NEC in a Dutch preterm population from a multidisciplinary perspective.

 

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Materials and Methods

Study Design and Population

This retrospective cohort study was part of the ongoing risk NEC study, designed to identify risk factors and describe outcomes related to NEC in very preterm infants since 2008 in the Erasmus University Medical Center Sophia Children's Hospital in Rotterdam, the Netherlands. The institutional medical ethics review board waived the need for specific approval of the risk NEC study according to the Dutch law (MEC-2013-409), based on the observational nature of the study; specific informed consent was not needed for the use of the retrospective data for this study.

Inclusion criteria were as follows: (1) gestational age less than 32 weeks and/or birth weight less than 1,500 g, (2) admission to the neonatal intensive care unit (NICU) of the Sophia Children's Hospital within the first 2 days of life, (3) born between January 1, 2008, and January 1, 2021, and (4) diagnosis of NEC stage II or III, defined according to modified Bell's criteria.[8] Infants were excluded (1) if they had NEC stage I, or spontaneous intestinal perforation, or (2) if they had been referred to our hospital for treatment of NEC or suspected NEC.

 

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Data Collection

Data retrieved from the risk NEC study database included sex, gestational age, birth weight, mode of delivery, type of milk feeding, postnatal age at onset of NEC, NEC stage, duration of NICU admission, and mortality. Additionally, all individual electronic patient records were screened for information on surgery, if any, and surgery-related complications, IF, and growth and neurodevelopmental outcomes at 2 years of corrected age (CA).

 

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Definitions

NEC was defined according to modified Bell's criteria stage II or III and categorized into medical or surgical NEC.[8] In case of uncertainty about the diagnosis or grading of NEC, three experts (a neonatologist [M.J.V.], a pediatric surgeon [C.M.G.K.D.], and a pediatric gastroenterologist [B.A.E.dK.]) were consulted independently. They each decided on these aspects, based on clinical symptoms, radiographic findings, surgical, and pathology reports. Any disagreements between the three experts were resolved in consensus meetings. The definitions used are presented in [Supplementary Table S1]. The incidence of NEC was calculated as the number of patients with NEC stage II or III divided by the total number of preterm infants with a gestational age less than 32 weeks and/or a birth weight less than 1,500 g, admitted to our NICU within the first 2 days of life.

 

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Long-Term Outcome Measures

Within the framework of the Dutch national neonatal follow-up program, infants were routinely invited at 2 years CA for the assessment of growth and neurodevelopment by a neonatologist or pediatric neurologist. For all age-related outcomes, age was corrected for prematurity.

Anthropometrics were analyzed using weight, height, and head circumference, sex, and age-corrected standard deviation scores (SDS), with normal population mean defined as SDS = 0. Fenton preterm growth charts[9] were used up to 50 weeks of postmenstrual age, and the World Health Organization growth references thereafter.[10]

For the evaluation of psychomotor and cognitive development, a trained pediatric physiotherapist and child psychologist applied the Dutch version of the Bayley Scales of Infant Development III (Bayley-III-NL).[11] Cognitive development was expressed as the mental developmental index (MDI); fine and gross motor development as the psychomotor developmental index (PDI). These indices are age standardized (normal population mean 100, standard deviation [SD] 15).[12] Major disability-free survival was calculated for all NEC patients with available outcomes at 2 years CA and was defined as being alive without moderate to severe neurodevelopmental impairment (no MDI or PDI < 70). Patients who had not reached 2-year follow-up, and those lost to follow-up, were not considered.

 

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Statistical Analysis

Data are summarized as means and SDs for medians and interquartile ranges (IQRs) depending on normality for continuous variables and as frequencies and percentages for categorical variables. Kaplan–Meier's survival analyses were conducted to calculate the median survival and duration of parenteral nutrition (PN) dependency. A Cox's regression analysis was conducted to predict survival in patients without NEC versus medical NEC patients and surgical NEC patients, adjusted for sex, gestational age, and birth weight SDS. To analyze a trend in mortality for NEC patients over time, the Cox's proportional hazard model was performed after additional adjustment for calendar year of birth. To test for trend over time in end-of-life decisions with initiation of comfort care, and in extreme prematurity among NEC patients, a chi-square test for trend was used based on the year of birth.

One-sample t-tests were used to compare age-corrected outcomes in our cohort with normal population means (for anthropometric and neurodevelopmental scores). Independent t-tests were used to compare mean outcomes of medical and surgical NEC patients. In a nonresponse analysis, we compared those lost to follow-up with those tested at 2 years CA, regarding gestational age and birth weight SDS using independent samples t-tests, and NEC grade using a chi-square test. A p-value of less than 0.05 was considered to indicate statistical significance. Data were analyzed using Statistical Package for the Social Sciences, Version 25.0 (IBM SPSS Statistics for Windows, Armonk, New York, United States).

 

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Results

Patient Characteristics

Between January 1, 2008, and January 1, 2021, a total of 3,456 infants with a gestational age less than 32 weeks and/or a birth weight less than 1,500 g were admitted to the NICU of the Erasmus MC Sophia Children's Hospital within the first 2 days of life. NEC stage II or III was diagnosed in 200 infants (incidence 6%). Baseline characteristics are presented in [Table 1]. NEC was diagnosed at a median postconceptional age of 28 weeks and 5 days (IQR: 27.43–31.15 weeks), at a median postnatal age of 11 days (IQR: 7–20 days). The flow chart in [Fig. 1] schematically shows the course of disease for both medical and surgical NEC patients, regarding surgical treatment and mortality.

Fig. 1 Flowchart of inclusion, disease course, and follow-up for patients with NEC II/III, up to 2 years of corrected age. ^†N, deceased; BW, birth weight; CA, corrected age (for prematurity); GA, gestational age; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit.

Table 1 Baseline characteristics of all NEC patients (n = 200)

Characteristic	n (%), mean ± SD, or median (IQR)
Sex, male	115 (58)
Gestational age, wk	26.43 (25.29–28.11)
Extreme preterm[a]	146 (73)
Birth weight, g	855 (700–1,058)
Birth weight[b], SDS	−0.05 ± 0.92
ELBW, < 1,000 g	145 (73)
Apgar score at 5 min (n = 199)	8 (6–9)
Multiple births	54 (27)
Cesarean section	110 (55)
Antenatal steroids	186 (93)
Type of feeding[c]
Only human milk	48 (24)
Only formula	21 (11)
Both	131 (66)
NEC stage II/NEC stage III	69 (34)/131 (66)

Abbreviations: ELBW, extremely low birth weight; IQR, interquartile range; NEC, necrotizing enterocolitis; SD, standard deviation; SDS, standard deviation score.

^a Gestational age less than 28 weeks.

^b Based on Fenton growth charts.[9]

^c During neonatal intensive care unit admission (before the diagnosis of NEC).

 

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Medical NEC

Medical NEC, defined as NEC without an indication for surgery within 7 days after NEC onset, was identified in 65 infants (33%), of whom 60 with NEC II and 5 with NEC III. NEC had developed at a median postconceptional age of 29.7 weeks (IQR: 28.1–32.1) in these infants. After conservative treatment, 14 infants (22%) showed clinical deterioration, for which they still underwent surgery after the first week of life. The short-term outcomes for medical NEC patients are presented in [Table 2].

Table 2 Short-term outcomes for surgical and medical NEC patients (n = 200)

	n (%) or median (IQR)	n (%) or median (IQR) or median (minimum–maximum)
	Surgical NEC (n = 135)	Medical NEC (n = 65)
Surgery	107 (79)	14[a] (22)
Fecal peritonitis	24 (22)	3 (21)
Resection	64 (60)	8 (57)
Small intestine	45 (70)	4 (50)
Large intestine	6 (9)	2 (25)
Both small and large intestine	13 (20)	2 (25)
Length of resection (small intestine), cm (n = 66[b])	12.8 (7.0–25.0)	7.0 (4.8–13.8)
Length of residual small intestine, cm (n = 29[c])	57.5 (35.0–80.0)	50.0 (40.0–160)
End-to-end anastomosis after resection	14 (22)	4 (50)
Clip and drop	4 (6)	0 (0)
Enterostomy formation after resection	46 (47)	5[d] (63)
Enterostomy formation without resection of intestines	5 (5)	6 (43)
Other surgery	1[e] (1)	2 (14)
Deceased < 30 d after diagnosis	83 (61)	8 (12)
Deceased < 30 d after surgery	53 (49)	3 (21)
Open-and-close procedure	37 (35)	1[f] (7)

Abbreviations: IQR, interquartile range; NEC, necrotizing enterocolitis.

^a Secondary surgery for complications of NEC greater than 7 days after diagnosis, due to strictures (n = 6), adhesions (n = 4), necrosis of intestines (n = 2), other: intestines showed signs of infection (layer of fibrin), but no visible necrosis or perforation; therefore, no resection or enterostomy formation took place (n = 1), perforation of intestines (n = 1).

^b Surgical NEC: n = 60, medical NEC: n = 6.

^c Surgical NEC: n = 26, medical NEC: n = 3.

^d One patient received both an enterostomy and an end-to-end anastomosis.

^e NEC of the stomach, perforation was closed.

^f Laparotomy for obstructive ileus 3 weeks after medical treatment for NEC, it was found that the majority of small intestine and colon was destructed, and no surgical options were possible.

 

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Surgical NEC

Surgical NEC, defined as NEC with a surgical indication within 7 days after NEC onset, was identified in 135 infants (67%), of whom 9 with NEC II and 126 with NEC III. In these infants, NEC had developed at a median postconceptional age of 28.3 weeks (IQR: 27.0–30.9). For 90 infants (67%), the indication for surgical treatment was based on clinical deterioration despite intensive medical care, and for 45 infants (33%), on pneumoperitoneum visible on the abdominal radiograph. The short-term outcomes for surgical NEC patients are presented in [Table 2]. Twenty-two of the 135 surgical NEC patients (21%) had not been operated on after all, on account of hemodynamic instability and/or respiratory illness. They had died without any surgical intervention. Comfort care was given to 37 infants after an open-and-close procedure due to NEC with advanced necrosis throughout the (entire) intestinal tract, after which they had died. Analysis revealed not a significant change in the rate of open-and-close surgical procedures during the study period (p = 0.086). Seven of the 70 surgically treated patients underwent a second-look surgery shortly after a first clip-and-drop procedure.

 

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Postoperative Course

NEC surgery had been performed in 121 patients, of whom 44 (36%) had died within 48 hours after surgery. In these cases, the cause of death was generally ongoing sepsis due to NEC with respiratory and circulatory problems which became unresponsive to therapy. The postoperative course is described in more detail for the surviving 77 patients (of whom 13 initially had medical NEC) in [Table 3]. Twenty-nine patients (38%) required one or more relaparotomies, not including reversal of enterostomy. Surgical complications occurred after 23/77 (30%) of operations. An enterostomy was created in 62/77 (81%) patients, in which 6 cases was related with complications. A high-output enterostomy was seen in 27/62 (44%) enterostomy patients. The median time to enterostomy reversal (for n = 48) was 70.0 days (IQR: 53.3–100.0). Twelve patients died before reversal of the enterostomy, and 2 patients still had an enterostomy in situ at 2 years CA.

Table 3 Surgical and enterostomy-related complications (n = 77)

Complications	n (%)
Surgical complications[a]	23/77
Anastomotic strictures	9 (39)
Anastomotic leakage	2 (9)
Incisional hernia	12 (52)
Surgical site infection	5 (22)
Ileus due to adhesive bowel obstruction	1 (4)
Fascia dehiscence	1 (4)
Enterostomy-related complications	6/62
Severe prolapse	2 (33)
Fistula formation	2 (33)
Leakage	1 (17)
Infection	1 (17)
Complications related to enterostomy reversal[b]	10/48
Anastomotic stricture	4 (40)
Incisional hernia	2 (20)
Anastomotic leakage	2 (20)
Surgical site infection	2 (20)

^a Surgical complications in necrotizing enterocolitis (NEC) patients after the first laparotomy for NEC, with a maximum of two complications in one patient. All complications occurred in surgical NEC patients, except anastomotic strictures: surgical NEC patients: n = 8; medical NEC patient: n = 1.

^b Complications following enterostomy reversal. Reversal took place in 48/62 patients. All complications occurred in surgical NEC patients, except anastomotic strictures: surgical NEC patients: n = 2; medical NEC patients: n = 2; surgical site infection: surgical NEC patients: n = 1; medical NEC patients: n = 1.

 

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Survival

Sixty-day survival after birth was 91% for non-NEC patients; 88% for medical NEC patients (hazard ratio [HR]: 0.698; 95% confidence interval [CI]: 0.344–1.413; p = 0.318); and 40% for surgical NEC patients (HR: 3.729; 95% CI: 2.882–4.827; p < 0.001) ([Fig. 2]). In [Supplementary Table S2], the HRs for survival in these groups are presented, showing that surgical NEC (HR: 3.73; 95% CI: 2.88–4.83]; p < 0.001), but not medical NEC, increased the hazard for mortality, after correction for gestational age, birth weight SDS, and sex. The median time from NEC diagnosis to death was 1.0 day (IQR: 0–2.3). In NEC patients, there was no significant trend in mortality between 2008 and 2021 (p = 0.710; [Supplementary Table S3]).

Fig. 2 Kaplan–Meier's curve showing survival up to 60 days after birth, for all patients (follow-up was complete) with a gestational age less than 32 weeks and/or birth weight less than 1,500 g, admitted to the neonatal intensive care unit within 2 days after birth. The colored lines represent proportional survival for infants with no NEC II/III (blue), medical NEC (no surgical indication within 7 days after NEC onset, red), and surgical NEC (surgical indication for surgery within 7 days after NEC onset, green). The colored numbers at the bottom of the figure represent the numbers of patients still “at risk” for death. Sixty-day survival for no NEC: 91%, for medical NEC: 88% (p = 0.318), and for surgical NEC: 40% (p < 0.001*). NEC, necrotizing enterocolitis. *Statistically significantly different at p < 0.05.

 

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Short Bowel Syndrome and Intestinal Failure

After NEC surgery, a short bowel was present in 13 of 77 operated patients (17%). The median length of the remaining small intestine in these patients was 35.0 cm (IQR: 30.0–40.0). One patient with short bowel died 2 weeks after surgery. Twenty-five of 77 operated patients (32%) developed IF after surgery, of whom 11 had a short bowel. One patient with IF died from the consequences of sepsis at the age of 8 months. Within 6 months after surgery, 20/25 (80%) infants with IF had been weaned off from PN. At 2 years CA, only one patient still required PN, which was given at home. For IF patients, the median PN-dependency duration was 147.0 days (IQR: 104.5–194.3). For all surviving NEC patients together, this was 36.5 days (IQR: 16.3–84.5).

 

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Growth and Neurodevelopment

At 2-year follow-up, one or more long-term outcomes were measured for 72 of 106 surviving NEC patients. Seventeen patients were lost to follow-up, and 17 patients had not reached 2 years CA yet. Patients lost to follow-up generally had a higher gestational age (p = 0.012) compared with follow-up patients, but neither NEC stage (p = 0.054) nor birth weight SDS (p = 0.183) differed between these groups ([Supplementary Table S4]). The data at follow-up are presented in [Table 4]. Mean weight for age was significantly lower than the population mean (−0.33 SDS, p = 0.003). Mean height and head circumference for age did not differ from the normal population mean (p = 0.429 and p = 0.463, respectively). No significant differences between surgical and medical NEC patients were found in anthropometric parameters.

Table 4 Long-term outcomes for NEC patients at 2 years corrected age (n = 72)

	All NEC (n = 72)	Surgical NEC (n = 35)	Medical NEC (n = 37)	p-Value[a]
	n (%), mean ± SD, or median (IQR)
Growth outcome at 2 y CA
Height for age, SDS (n = 67)	−0.10 ± 1.08	−0.23 ± 1.08	0.02 ± 1.08	0.356
Height for age, SDS < − 2	2/67	1/33	1/34
Weight for age, SDS (n = 68)	−0.33 ± 0.89	−0.36 ± 0.86	−0.30 ± 0.93	0.775
Weight for age, SDS < − 2	2/68	1/34	1/34
Head circumference for age, SDS (n = 56)	0.12 ± 1.22	0.01 ± 1.02	0.21 ± 1.38	0.549
Head circumference for age, SDS < − 2	3/56	0/26	3/30
Neurodevelopmental outcome at 2 y CA
Motor development, PDI (n = 54)[b]	94.0 ± 14.6	91.0 ± 12.6	97.0 ± 16.0	0.132
Mild delay, PDI 70–84	11/54	5/27	6/27
Moderate to severe delay, PDI < 70	3/54	1/27	2/27
Cognitive development, MDI (n = 63)[b]	93.3 ± 12.0	92.4 ± 10.1	94.2 ± 13.5	0.552
Mild delay, MDI 70–84	15/63	6/33	9/33
Moderate to severe delay, MDI < 70	1/63	0/33	1/33
Cerebral palsy	3 (4%)	0/34	3/39
Nonspecified neurodevelopmental delay	1 (1%)	0/34	1/39

Abbreviations: CA, corrected age (for prematurity); IQR, interquartile range; MDI, mental developmental index; NEC, necrotizing enterocolitis; PDI, psychomotor developmental index; SDS, standard deviation score.

^a Independent samples t-tests were performed to compare surgical and medical NEC patients. Statistically significantly different at p < 0.05.

^b Bayley Scales of Infant Development (Bayley-III-NL) was used; normal population mean = 100 (SD = 15).

Neurodevelopmental assessment showed that mean motor and cognitive development scores of the follow-up patients were significantly lower than those in the general population (mean PDI 94.0, p = 0.004 and mean MDI 93.3, p < 0.001, respectively). Moderate to severe motor impairment was seen in 3/54 (6%) and moderate to severe cognitive impairment in 1/63 (2%) of the NEC patients (none was impaired in both domains). Three patients were described with cerebral palsy and one patient with nonspecified neurodevelopmental delay, for which reason they could complete the BSID-III-NL. Significant differences in motor or cognitive outcomes between surgical and medical NEC patients were not found (p = 0.132 and p = 0.552, respectively).

Major disability-free survival at 2 years CA was calculated for all 166 patients with mortality data (n = 94) or follow-up data (n = 72, of whom 4 with major disability) available as 68/166 (41%).

 

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Discussion

This study described the course of NEC in a Dutch preterm population, with the ultimate aims to gain a better understanding of the burden of disease from a multidisciplinary perspective, to evaluate care, and better inform and counsel parents of affected infants.

We found NEC in 6% of very preterm infants and survival after NEC was 53%. Surgical complications developed in 30%, 32% developed IF, and 3 to 6% had severe growth or neurodevelopmental impairment.

Globally, the incidence of NEC among very premature infants is reported to be around 7%, and NEC-related death rates vary between 20 and 50%,[13] [14] [15] [16] which figures correspond well to our findings. Despite advancement of neonatal care over the years and decreased overall neonatal mortality in the Netherlands,[17] the mortality rate for NEC remained unchanged between 2008 and 2020 in our center. A likely explanation is that more and more infants are delivered at a gestational age of 24 to 25 weeks, who are at greater risk for death due to gestational age itself.[18] Especially, the 60-day survival rate of surgical NEC patients in the cohort of the present study of 40% is lower than the one both Dutch and international studies report,[3] [13] which might indicate more severe illness in our population. Berkhout et al estimated the NEC-associated mortality in a Dutch population of 56 extremely preterm infants with extremely low birth weight (ELBW) at 21%. This population included 63% NEC II and 37% NEC III patients.[13] The NEC II/III distribution in our study population was rather the opposite, with more NEC III (67%) than NEC II (33%) patients; thus, more patients with more advanced, severe NEC. Other indicators of high disease severity in the present study population are the high rates of extremely premature infants (73%), infants with ELBW (73%), and (near) pan-intestinal necrosis with open-and-close procedures (35%). In addition, the surgical NEC group included NEC patients who were preterminal, and too unstable to undergo surgery, or with an otherwise unfavorable prognosis, and who deceased without surgery. In the literature, surgical NEC is often defined as “NEC patients who underwent surgery,” without any description of those who after all were not operated. NEC severity is generally underestimated when these most severe cases are ignored. In the current study, exclusion of those not operated on would increase the 60-day survival rate in surgical NEC patients from 40 to 50%. We cannot tell whether the high numbers of nonoperated deceased infants and open-and-close procedures might suggest that the process to decide when to operate remains challenging due to a sometimes very quick and fulminant disease course. In addition, we must also consider the local tendency to critically appraise an infant's current clinical situation and future prognosis (including quality of life) to make an end-of-life decision in the infant's best interest. A recent study of 80 infants with medical or surgical NEC reported an overall mortality of 36%; however, the mortality in 23 infants with pan-intestinal necrosis was 96%.[19] This extremely high mortality rate confirms the severity of the disease and underscores the need for more research into primary prevention and early recognition of NEC to reduce the risk of fulminant disease.

Surgical complication rates as high as 50 to 70% have been reported in previous studies on NEC surgery, including recurrence of NEC, short bowel syndrome, sepsis, and enterostomy-related complications.[5] [20] [21] The lower surgical complication rate in our cohort (of 30%) may partly reflect underestimation, as short bowel syndrome was reported as a separate outcome and data on sepsis were not available for the total cohort. A possible explanation for fewer enterostomy-related complications in the present study is the relatively short median time to reversal of 70 days as compared with 124 to 128 days in previous studies.[5] [22]

In the present study, a short bowel was present in a minority of patients and nearly all had been weaned from PN at 2 years CA. In a cohort of 63 infants with a short bowel (either due to NEC or other gastrointestinal emergencies), Fallon et al estimated a 38% chance of weaning from PN at 2 years CA.[23] This discrepancy in findings of persisting IF may be attributed to our multidisciplinary management of pediatric short bowel syndrome, which is an important factor in improving outcomes for children with IF.[24]

In a large recent systematic review, Jones and Hall reported severe neurodevelopmental delay in 25 to 59% of surviving NEC patients, with the highest risks among surgically treated ELBW infants.[3] In an American cohort of 28 infants with a history of severe surgical NEC (defined as residual bowel length < 30 cm), severe neurodevelopmental disability was found in 8 infants (29%).[4] Neurodevelopmental outcomes in NEC survivors appear to be better in the present cohort (with only 2 and 6% with severe cognitive and motor delay, respectively), but these absolute figures need to be interpreted with caution because of the possible influence of bias. The patients lost to follow-up had higher gestational age compared with follow-up patients, which may have led to an underestimation of neurodevelopment since lower gestational age is associated with worse neurodevelopmental outcomes and vice versa.[25] However, in the follow-up patients who had a neurodevelopmental assessment, motor and cognitive scores were not always complete, possibly related to children not being able to perform or finish the test due to neurodevelopmental delay. It cannot be ruled out that the low rate of neurodevelopmental delay is related to selection of survivors with relatively good postoperative and long-term outcomes.

The main strength of this study lies in the detailed description—from a multidisciplinary perspective—of the short-term course of disease for surgical NEC patients in a relatively large NICU population. Considering the high proportion of infants with a 2-year follow-up, this description offers insight into the prognosis of NEC. Important long-term outcomes are reported, such as IF, growth, and neurodevelopment, on which data are limited in existing literature. Furthermore, clear definitions were applied for all assessed outcomes, including multidisciplinary definition and grading of NEC. By not excluding cases with a surgical indication who were too ill to be operated, and classifying them as surgical NEC, we provide a realistic picture of the severity of this condition.

Inevitably, this study has limitations, of which one is the retrospective design, resulting in missing data on (ethical) decision-making and details on surgical procedures. Other relevant outcomes, such as behavioral problems, poor general health, deafness, and blindness, were not considered, which otherwise would have been of great value. Another clear limitation is the relatively short follow-up period up to 2 years CA, which is too short to gain true insight into long-term prognosis as specific deficits in neurodevelopment might not emerge until later.[26] To better serve patients and their families, but also to gain prospective data on more value-based outcomes, we have recently started a dedicated follow-up program for NEC patients at least into school age. We hope to extend this multidisciplinary program into adolescence, as a means to obtain more crucial information on the late effects of NEC on health, neurodevelopment, and psychological outcomes.

This study provides new insights, but also new questions, for health care professionals, families, and patients. Possible long-term cardiometabolic effects of altered growth and body composition require further study.[27] Even more importantly, data on patient-reported outcomes, such as the physical and psychological well-being of affected patients and their families, are urgently needed for NEC patients. Our data support further research into primary prevention, early detection, supportive therapy (such as immunomodulation), and further improvement of surgical treatment (timing, techniques), which seem all needed to improve the prognosis of NEC.

 

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Conclusion

In conclusion, the mortality rate in the studied cohort was high, especially in surgically treated NEC patients. Surviving patients seem to have a low risk of persisting IF or severe impairment in growth or neurodevelopment. How to improve the prognosis, in especially surgical NEC, needs further investigation.

 

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Conflict of Interest

None declared.

Acknowledgments

We would like to express gratitude to the infants and their parents for participating in the follow-up program. Also, we would like to acknowledge the medical staff of the departments of Neonatology (including Annelies Ham for assistance in data management) and Pediatric Surgery of the Sophia Children's Hospital in Rotterdam for creating the opportunity to carry out this study and providing data. We thank Ko Hagoort for reviewing this manuscript.

^* These authors share the last authorship as they contributed equally to the article.

• References

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Publication History

Received: 18 July 2021

Accepted: 13 December 2021

Article published online:
10 January 2022