Study characteristics
The total number of publications identified for screening was 1694. The process of selection of eligible studies are depicted in the Fig 2. A total of 27 studies were found to fulfill the eligibility criteria and included in the review. The number of neonate included in these studies was 574,692. Of these, 39,965 neonates developed confirmed NEC. The studies covered a broader geographical areas globally (table 3). Some regions had multiple studies other areas had none. A total of eight studies were reported from the United States covering a number of states including: California, Texas, Atlanta, Connecticut, and New York (3,6,9,27–31). Multiple studies were also reported from the Europe including Poland, Romania, Finland, Belgium, Sweden and Switzerland(12,13,28,32–34). Also, four studies were done in China, Korea, Singapore and Malaysia (14,16,35,36). Three studies from Australia (4,37,38), one from the Middle East (7) and one from India (42).
The publication year of the studies ranged from 1988 to 2019, but the majority were carried out after 2000. Some of the studies focused on evaluating a certain exposure (7,9,33,37), however, the data presented in these papers were not limited to the exposure groups and data from the general population was extracted to compute the incidence.
Qualitative Review
Andersone et al. reviewed a cohort data from the California Office Statewide Health Planning And Development [OS HPD] (28). Upon retrograde calculation of the number of NEC cases and dividing them by a total number of NICU preterm babies the incidence of NEC was 9.1%. Whilst, Patole et al conducted a retrospective cohort study reviewing 1,755 neonates who were less than 34 weeks of gestation (37). The aim was to study the effect on the incidence of NEC. In the control group (prior to the initiation of probiotic), there were 835 babies. Among those 250 were preterm with gestational age less than 28 weeks. Stage II or above NEC was found in 16 cases (6% of preterm controls).
Stoll et al. (26) analyzed data on 9575 newborns with very low birthweight and extremely low gestational age. The incidence in this population was 11%. Llanos et al. (3) reported the incidence among VLBW infants therefore was 3.29%. They used a retrospectively conducted a population-based survey from six counties in New York State. Holeman et al. analyzed the hospital discharge data from the Kid’s Inpatient Database from the year 2000 (39). Among those born with weight less than 1500 g, the number of cases was 2554 and the rate was 4342.8 per 100,000 live births annually with an incidence of 4.3%. Fanaroff et al. evaluated VLBW infants and compared three periods of time: 1987-1988, 1993-1994, and 1999-2000 (40). The analysis aimed to compare the outcome across the time periods. They showed that the incidence of NEC did not change over time.
Bajwa et al. reviewed the data from the Swiss neonatal network that conatins comprehensive population-based data of all infants in Switzerland (34). The analysis included 368,055 infants born between 2000 and 2004, Ahle et al. collected data from the Swedish National Board of Health and Welfare, the National Patient Register, the Swedish Medical Birth Register and The National Cause of Death Register between 1987 and 2009 (12). The incidence of NEC in less than 750g, 750-999 g, 1000-1499 g and 1500-2499 g were 5.31%, 4.16%, 1.52%, and 0.007%, respectively.
Verstrate et al. based on a retrospective cohort of 5134 neonatal intensive care unit admissions from a single hospital Belgium found 973 cases were born with a very low birthweight of less than 1500 g (32). The incidence of NEC with stage II or above, in this subgroup was 16.23% . Härkin et al. reviewed the data from the national Registry of preterm infants born between 2005 and 2013 in Finland (33). The incidence of NEC among preterm babies was therefore 16.58%. Wójkowska-Mach et al. reviewed the Polish Neonatal Surveillance Network for all VLBW infants recorded in the national registry. They used clinical criteria for the definition of NEC and 79 of 910 babies developed NEC (13).
Suciu et al. reviewed data from three tertiary centers in Romania. The study included 480 preterm babies born before 28 weeks of gestation (41). The incidence was estimated to be 16.6%. The Bell’s criteria were used to define cauterizing enterocolitis as stage II and above in this study. Agarwal et al. collected data from the single largest neonatal center in Singapore with a vitality threshold defined at 25 weeks of gestation (36). The database included all neonates who are with VLBW and gestational age less than 29 weeks. Bell’s classification was used to define NEC. 50 babies among 835 developed NEC.
Qian et al. reported data extracted retrospectively from 95 major referral centers and hospitals in china covering a large area of 29 provinces (35). VLBW infants were specified and the incidence of NEC according to Bell’s criteria was presented in 2011. The data included 46,686 infants of whom, 8727 were born with VLBW. The incidence of confirmed NEC in VLBW infants was 6.5 among a cohort of 8727 infants.
Youn et al. reported a large cohort from South Korea. Among a total of 2,326 infant with VLBW, 145 (6.8%) were diagnosed with confirmed NEC stage II of above (16). Boo et al. collected data retrospectively from 31 neonatal intensive care units around Malaysia on NEC defined by Bell’s criteria among VLBW infants. Among the 3601 babies included, 222 developed NEC. Of these 197 had NEC II and 25 were NEC III or above according to Bell’s staging criteria. The incidence was 6.2% (14). Luig et al. reported data on all infants born between 24 to 28 weeks of gestation in New South Wales and England, over three different time periods: 1986-1987, 1992-1993, and 1998-1999 (4). The population included 1,655 cases from the three groups divided to 360, 622, and 673 cases in time periods 1986-1987, 1992-1993, and 1998-1999 respectively. Over the entire population the incidence was 7.67%.
Wong et al. conducted a retrospective cohort study reviewing 2,549 neonates from 10 neonatal intensive care units serving New South Wales in Australia (38). This study population accounted for all preterm infants in the region of Australia between 1998 and 2004. The conducted the analysis complaining those exposed to steroids and those who were not. The incidence of NEC was 7.8% as 199 cases developed necrotizing enterocolitis among 2,549 preterm babies born before 29 weeks of gestation.
Narang et al. 1993, collected 2200 admissions to the NICU during the period January 1986to September 1990 (42). Among them 33 developed NEC (Bell’s stage ≥2). The incidence was 1.5%. Chedid et al. reviewed 173 newborns from 1 Tertiary Referral Center in UAE, Al Ain. All the cohort were born with weight less than 1500 g [very low birthweight infants] (7). NEC was diagnosed clinically. Among the study population, 10 babies developed confirmed NEC. The incidence of NEC was 5.8%.
Lodha et al. 2019, compared neonatal outcomes after deferred cord clamping and immediate cord clamping in extremely low-gestational-age neonates from tertiary neonatal intensive care units participating in theestimated incidence based on Canadian Neonatal Network in 2019 was 9% (43)9%.
Boghossaan et al. 2018, examined infants of gestational ages 22 to 29 weeks born between January 2006 and December 2016 at a Vermont Oxford Network center in the United States were. NEC developed in 18,129 among the 194,736 infants. The incidence of NEC was 9% (44). Persson et al. 2018, conducted a retrospective cohort study at 7 national networks in high-income countries that are part of the International Neonatal Network for Evaluating Outcomes in Neonates and used prospectively collected data on 76,360 very preterm, singleton infants. 2,077 infants developed NEC and the incidence was 3%(45).
Suzuki et al. 2018, retrospectively examined 8,245 extremely preterm infants born between 2008 and 2012 using Neonatal Research Network database in Japan. They estimated incidence to be 4% (46). Boghossian et al. 2018, collected 138,869 large for gestational age infant’s data from 852 US centers participating in the Vermont Oxford Network. The incidence of NEC was 7% (10,376 new cases)(47). Beltempo et al. 2018, collected data about extremely preterm infants born from 22 to 28 weeks’ gestational age Canadian Neonatal Network. Study population was 9,230 among them 778 developed NEC. The incidence of NEC was 8% (48).
Assessment of Risk of Bias
The quality assessment of 23 individual studies carried out as per Hoy et al (18) (figure 1) criteria are tabulated in table 2.
Quantitative Analysis of Incidence
The FEM using the double arcsine transformation resulted in a pooled incidence of NEC in VLBW infants to be 7.0 % (95% CI: 7.0%-7.0%) (Fig. 3). However, due to significant heterogeneity as indicated by I2 value of 100% and the Cochrane Q- statistics (value =7473; P <0.0001), a QEM was used to pool the data using the arcsine transformation and resulted in a pooled estimate of 6.0% (95% CI: 4.0% - 9.0%) (Fig. 4). Furthermore, a sensitivity analysis using REM was also as a form of sensitivity analysis and the pooled estimate of REM was 7.0% (95% CI: 6.0% - 8.0 %) (Fig. 5).
Publication bias
Hunter’s modified funnel Plot (24) as appropriate for the incidence data used to evaluate the publication bias appear to not to show a serious concern (Fig 6). Further, the Eggers regression confirmed that publication bias was not statistically significant (two tailed p-value= 0.80). The Kendall’s Tau test statistics was also not statistically indicating less likely that these studies encountered publication bias (two tailed p-value = 0.936).
Subgroup Analysis
There was no significant regional variation between North America, Western Europe and Australia as well as Asia as shown in the table 4. They were both similar to the global estimate as well as indicated by the 95% confidence intervals. There appear to some variation between HIC and LMIC countries, although these differences were not statistically significant. No significant variation between VLBW infants and extremely premature was found.
Meta-Regression
There was a statistically significant increase in the log event rate over time, quantified by the publication year. (Fig 7).