Abstract
Introduction
The effect of the pandemic restrictions in the NICUs is not well studied. Necrotizing enterocolitis (NEC) is characterized by intestinal inflammation and bacterial invasion. This study aimed to investigate whether the incidence of NEC has changed during the COVID-19 pandemic in Sweden and whether it was associated with a change in the frequency of extremely preterm births.
Methods
Data were retrieved from the Swedish Neonatal Quality Register (SNQ) for infants registered between January 2017 and December 2021 born below a gestational age of 35 weeks. The registry completeness is 98–99%. The diagnosis of NEC was the primary outcome. Generalized linear model analysis was used to calculate the risk ratio for NEC.
Results
Totally 13,239 infants were included. 235 (1.8%) infants developed NEC, out of which 91 required surgical treatment. 8,967 infants were born before COVID-19 pandemic and 4,272 during. Median gestational age at birth was 32.8 weeks in both periods. The incidence of NEC was significantly lower during COVID-19 pandemic compared to the prior period (1.43 vs. 1.94%, p 0.037), but not the incidence of surgical NEC. The crude risk ratio of developing NEC during COVID-19 pandemic was 0.74 (95% CI: 0.55–0.98). The incidence of late-onset sepsis with positive culture was also declined during COVID-19 (3.21 vs. 4.15%, p value 0.008).
Conclusion
While we found significant reduction in the incidence of NEC and culture-positive late-onset sepsis during the COVID-19 pandemic, the number of extremely preterm births was unchanged.
Keywords: COVID-19 pandemic, Preterm infant, Necrotizing enterocolitis, Sepsis
Introduction
Necrotizing enterocolitis (NEC) is one of the dominating causes of morbidity and mortality in preterm infants [1]. NEC affects 5–7% of preterm neonates and 10–15% of preterm infants with a birth weight of <1,500 g [2]. The mortality rate for preterm infants with extremely low birth weight (<1,000 g) is still very high [3]. The pathogenesis of NEC is multifactorial, and still some factors remain unknown [1]. However, prematurity and low birth weight are the most reported risk factors for NEC [4, 5]. Other contributing risk factors include enteral feeding, intestinal ischemia and colonization with pathogenic bacteria [4]. Among maternal factors, chorioamnionitis, mode of delivery and preeclampsia have been suggested [4, 6–8]. Probiotic use in preterm infants has been associated with a decreased risk of NEC [9].
COVID-19 pandemic has changed routines in neonatal intensive care units (NICUs), mostly by stricter infection control measures and restricting visitor presence. During the COVID-19 pandemic in Sweden, anecdotal observations from pediatric surgical centers suggested less referrals of infants with NEC. Early during the pandemic, a Danish study reported that the rate of extremely preterm birth was reduced during the lockdown period of COVID-19 pandemic [10], and a single-center study from the UK reported an increased risk of stillbirths during the pandemic [11]. In contrast, a Swedish nationwide cohort study including 17,661 births found no increased risk of preterm or stillbirth in infants being born during April to May 2020, compared with April to May 2015–2019 [12]. These reports raised the questions whether the incidence of NEC decreased during the COVID-19 pandemic, and if so, was it associated with a decreased rate of extremely preterm births? This study aimed to investigate whether the incidence of NEC has changed during the COVID-19 pandemic in Sweden and whether it was associated with a change in the frequency of extremely preterm births.
Materials and Methods
Study Design
This was a retrospective cohort study. Data were reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist [13].
Population and Setting
The study was based on data retrieved from the Swedish Neonatal Quality Register (SNQ; www.snq.se) for infants registered from January 1, 2017 to December 31, 2021, born below a gestational age of 35 weeks. SNQ includes all infants born alive in Sweden who were admitted for neonatal care within 27 days after birth [14]. The registry completeness against other registers for preterm infants is 98–99% [14]. In 2020, probiotics were introduced for very preterm infants (born between 28 and 31 weeks of gestation).
Primary Outcome and Exposure
The diagnosis of NEC was our primary outcome. The diagnosis was taken from the register and made by clinicians. Bell stage < 2A was excluded from NEC diagnosis. For surgically treated infants with NEC, the diagnosis was manually verified from the surgical records and histopathology in all centers. Single intestinal perforation has not the same ICD code (P78.0) as NEC (P77) and was not included in the study.
Exposure was defined as time during COVID-19 restrictions/pandemic in Sweden (from March 1, 2020, until December 31, 2021), as testing for COVID-19 and restrictions started from the beginning of March. All clinical data was sourced from the SNQ register.
Statistical Analysis
Patient and clinical characteristics were reported using median and interquartile range or mean and standard deviation for continuous variables and frequencies and percentages for categorical variables. Mann-Whitney U test, Student t test, and χ2 or Fisher’s exact test were used, when appropriate, to compare clinical characteristics between patients before and during COVID. Generalized linear models were applied with log link to evaluate the association between COVID restriction time and the primary outcome. The results are presented as risk ratio (RR) and 95% confidence interval of NEC. Directed acyclic graph (DAG) was used to identify possible confounders that may induce noncausal association between COVID restrictions and NEC. The DAG was used for selection of covariates to include in the final model (online suppl. material; for all online suppl. material, see https://doi.org/10.1159/000536570). Multiple imputations were applied in case of missing data.
We used the statistical program STATA version 14.2 (StataCorp, TX, USA) to perform the analyses. A p value <0.05 was considered statistically significant.
Results
A total of 13,239 premature infants born before 35 weeks of gestation were included in the study. 8,967 infants were born before COVID-19 pandemic restrictions and 4,272 during the pandemic. 235 (1.8%) infants developed NEC, out of which 91 (38% of all NEC cases) required surgical treatment (Fig. 1).
Fig. 1.
Flowchart, patients.
Table 1 shows patient characteristics. Median gestational age was 32.9 weeks in both periods. The incidence of NEC was significantly lower during COVID-19 pandemic compared to the prior period (1.43 vs. 1.94%, p value 0.037), but not the incidence of surgical NEC (0.89 vs. 1.14%, p value 0.192). There were neither missing data for our exposure nor outcome variables. The crude RR of developing NEC was 0.74 (95% CI: 0.55–0.98), p value 0.038, but when adjusted for region, gestational age at birth, probiotics, intrauterine growth restriction, and chorioamnionitis, the RR was 0.80 (95% CI: 0.60–1.06), p value 0.112. Missing data were present for some variables such as chorioamnionitis, IUGR, region of birth. In all of these variables, the frequency of missing data was below 5%.
Table 1.
Cohort of preterm newborns (born <35 weeks of gestation) in Sweden
| Pre-COVID (n = 8,967) | COVID group (n = 4,272) | p value | |
|---|---|---|---|
| C-section, n (%) | 5,053 (56.35) | 2,530 (59.22) | 0.002 |
| Acute section among total section, n (%) | 4,686 (92.74) | 2,376 (93.91) | 0.056 |
| Ablation, n (%) | 801 (9.46) | 377 (8.94) | 0.344 |
| Preeclampsia/eclampsia, n (%) | 1,239 (14.64) | 650 (15.42) | 0.243 |
| PPROM (<v37), n (%) | 1,410 (16.66) | 715 (16.96) | 0.680 |
| Chorioamnionitis, n (%) | 213 (2.52) | 111 (2.63) | 0.700 |
| Diabetes, type 1, n (%) | 234 (2.69) | 119 (2.79) | 0.745 |
| Gestational diabetes, n (%) | 271 (3.20) | 158 (3.75) | 0.108 |
| Number of feti, n (%) | |||
| Singleton | 6,634 (73.98) | 3,188 (74.63) | 0.457 |
| Twins | 2,159 (24.08) | 1,013 (23.71) | |
| Triples | 170 (1.90) | 71 (1.66) | |
| Quadruples | 4 (0.04) | 0 (0.00) | |
| Antenatal steroids, n (%) | 4,951 (69.35) | 2,455 (69.35) | 0.847 |
| IUGR, n (%) | 999 (11.80) | 474 (11.25) | 0.357 |
| Female, n (%) | 4,114 (45.88) | 2,001 (46.84) | 0.300 |
| Gestational age, median (IQR) | 32.86 (30.14–34.14) | 32.86 (30.29–34.14) | 0.925 |
| Infants born <28 weeks, n (%) | 1,244 (13.87) | 571 (13.37) | 0.428 |
| Birthweight, median (IQR) | 1,865 (1,335–2,260) | 1,860 (1370–2263) | 0.547 |
| APGAR score, median (IQR) | 9 (7–10) | 9 (8–10) | 0.375 |
| Respiratory distress syndrome, n (%) | 2,503 (27.91) | 1,236 (28.93) | 0.223 |
| IVH grade 1, n (%) | 263 (3.17) | 148 (3.77) | |
| IVH grade 2, n (%) | 165 (1.99) | 61 (1.55) | |
| IVH grade 3, n (%) | 78 (0.94) | 40 (1.02) | |
| IVH grade 4, n (%) | 99 (1.19) | 60 (1.53) | 0.085 |
| hsPDA, medically treated, n (%) | 516 (5.75) | 228 (5.34) | 0.330 |
| hsPDA, surgically treated, n (%) | 100 (1.12) | 31 (0.73) | 0.034 |
| Parenteral nutrition, n (%) | 3,368 (37.56) | 1,643 (38.46) | 0.318 |
| Days of parenteral nutrition, median (IQR) | 7 (4–13) | 7 (4–12) | 0.123 |
| Early-onset sepsis (positive blood culture), n (%) | 61 (0.68) | 22 (0.52) | 0.256 |
| Early-onset infection (positive culture), n (%) | 86 (0.96) | 40 (0.94) | 0.889 |
| LOS (positive blood culture), n (%) | 371 (4.15) | 137 (3.21) | 0.008 |
| Late-onset infection (positive culture), n (%) | 640 (7.17) | 252 (5.91) | 0.007 |
| NEC, n (%) | 174 (1.94) | 61 (1.43) | 0.037 |
| Surgical NEC verified, n (%) | 66 (0.74) | 29 (0.68) | 0.715 |
| SIP, n (%) | 39 (0.43) | 14 (0.33) | 0.361 |
| Probiotics, n (%) | 232 (2.59) | 499 (11.68) | 0.000 |
| Oxygen need at 36 weeks, n (%) | 681 (7.59) | 282 (6.60) | 0.040 |
| Death, n (%) | 336 (3.75) | 165 (3.86) | 0.745 |
PPROM, premature rupture of membranes; IQR, interquartile range; IUGR, intrauterine growth restriction; IVH, intraventricular hemorrhage; hsPDA, hemodynamic significant patent ductus arteriosus; SIP, spontaneous intestinal perforation.
Multiple imputations with 5 imputations were used to test the impact of missing data in the final model. In the imputed dataset, the RR of developing NEC adjusted for Region, gestational age at birth, probiotics, IUGR, and chorioamnionitis was 0.78 (95% CI: 0.58–1.42), p value 0.086.
The incidence of late-onset sepsis (LOS) and infection (positive culture) was significantly reduced in the COVID-19 pandemic compared to the pre-COVID-19 period, and the rate of C-section increased significantly during the pandemic period. The frequency of patent ductus arteriosus treated surgically was also decreased during COVID-19 period. We found no significant differences between the groups for the other variables measured as shown in Table 1. We stratified the incidence of NEC for the target group of probiotic use (28–31 weeks of gestation). The reduction in NEC incidence was not specific for this gestational age group compared to NEC infants born <28 weeks or ≥32 weeks of gestation who did not receive probiotics.
The concomitant introduction of probiotics during 2020 in Sweden made our analysis difficult, so we performed a sensitivity analysis excluding infants who received probiotics to study the effect of probiotics in NEC incidence as demonstrated in Table 2. NEC incidence was 1.5% during COVID-19 compared to 2.0% pre-COVID-19, but this difference was not statistically significant (p value 0.09). The frequency of LOS, verified by blood culture, continued to show a significant reduction during COVID-19 pandemic, even after the exclusion of infants receiving probiotics.
Table 2.
Sensitivity analysis excluding probiotic infants
| Pre-COVID-19 group (n = 8,735) | COVID-19 group (n = 3,773) | p value | |
|---|---|---|---|
| NEC, n (%) | 170 (2.0) | 57 (1.5) | 0.09 |
| Surgical NEC, n (%) | 66 (0.8) | 29 (0.8) | 0.93 |
| LOS, n (%) | 361 (4.1) | 108 (2.9) | 0.001 |
Discussion
In this national cohort of 13,239 preterm infants born before 35 weeks of gestation, we found a statistically significant decrease of both NEC and LOS in preterm infants during the 22 months of COVID-19 pandemic in Sweden compared to the previous period. The number of extremely preterm births was unchanged.
While the direct impact of COVID-19 pandemic on public health and well-being has been devasting in many ways, its indirect effect in NICU has only now started to be studied [15]. As prematurity and low birth weight are the most important risk factor for NEC, one would expect that a decrease in NEC incidence could be explained by a decline in extremely preterm births. At the beginning of the COVID-19 pandemic, reports suggested a decrease in preterm births [16]. However, it was found that the frequency of extremely preterm birth remained consistent before and after the pandemic [16]. Subsequently, both a Scandinavian and a Swedish national study indicated that there was no evidence of a decline in preterm births following the introduction of COVID-19 mitigation measures [17]. In agreement with the mentioned studies, we observed no change in the frequency of extremely preterm deliveries during the two periods, which suggests that this factor cannot explain the reduced incidence of NEC. In contrast, a Danish study reported that the rate of extremely preterm birth was reduced during the lockdown period of COVID-19 pandemic [10]. A probable explanation of their opposed results could be a short observation period from 12 March to 14 April 2020 [10].
Another possible confounding factor in this analysis is the introduction of probiotics, which are suggested to reduce the incidence of NEC [18]. It is worth noting that in 2020, probiotics were introduced in Sweden for very preterm infants after the ESPGHAN recommendation [19]. To investigate if probiotics were the sole reason for the reduction in NEC incidence, we specifically examined the NEC incidence in the target group for probiotic use. However, our analysis did not support this hypothesis. We also conducted a sensitivity analysis by excluding infants who received probiotics to assess if the incidence of NEC remained significantly reduced. We found that the incidence of NEC remained lower, although the statistical significance was not reached. It is possible that there is an effect of probiotics in the reduction of NEC during COVID-19 period.
On the other hand, the frequency of LOS, verified by blood culture, continued to show a statistically significant decline during COVID-19 pandemic. This trend persisted even following the exclusion of infants receiving probiotics, rendering it a more relevant finding in this study. Reports of clusters of outbreaks of NEC suggest infectious agents as a casual factor [20]. A previous study from four Italian NICUs concluded that COVID-19-related implementation of NICU hygiene policies was likely to reduce the occurrence of LOS in high-risk settings [21].
Interestingly, the frequency of total C-section and acute C-section were increased during COVID-19 pandemic in our cohort. Reports indicate that pregnant women disrupted their regular antenatal care during this period and were more frequently admitted to the obstetric emergency department with emergencies requiring acute intervention [22]. The drop in frequency of surgical ligation for patent ductus arteriosus in Sweden reflects the international trend toward a less aggressive treatment for this disease in preterm infants [23].
The strength of our study is its population-based approach with clinical data sourced from the SNQ register with 98–99% completeness. Moreover, no data were missing for the exposure and the outcome.
It is important to acknowledge the limitations of this study, including the retrospective design, the extended duration of the study period, and inherent complexity of our exposure variable. This study involves a substantial cohort of infants, necessitating acknowledgment of the potential risk for statistical overpowering. The central question revolves around explaining the clinical effect of the observed reduction in the incidence of NEC. While the reduction attains statistically significance for the entire cohort, such significance is not evident in the stratification or in the sensitivity analysis. In our assessment, the concurrent reduction in LOS serves to enhance the clinical significance of the findings in this study. We recognize the challenges in assessing the indirect consequences of the COVID-19 pandemic on neonatal health indicator such as the incidence of NEC. Future studies are warranted to elucidate this issue.
Conclusion
While we found a statistically significant reduction in the incidence of NEC and culture-positive LOS during the COVID-19 pandemic, the number of extremely preterm births was unchanged in this study. One potential contributor is the concurrent introduction of probiotics. However, it is difficult to ascertain whether the observed reduction is attributable to probiotics, to the infection control measures during the COVID-19 pandemic, or influenced by the ongoing improvements in neonatal care over time.
Acknowledgments
We would like to thank our statisticians, Johan Zetterqvist at Karolinska Institutet for his precious statistical advice and Fabian Söderdahl, Statisticon AB, for his assistance with the statistical analyses.
Statement of Ethics
The study was approved by the Swedish Ethical Authority, registration number 2021-03249. Since all data were anonymized, the need for informed consent was waived by the Swedish Ethical Authority.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding Sources
No funding was received.
Author Contributions
Elena Palleri’s contribution to the study: design study, methodology, data curation, investigation, formal analysis, and writing the initial manuscript. Anna Svenningsson’s contribution to the study: data collection, investigation, and editing of the manuscript. Laszlo Markasz’s contribution to the study: investigation, reviewing, and editing of the manuscript. Helene Engstrand Lilja1’s contribution to the study: design, writing ethical approval, methodology, supervision of the formal analysis, reviewing, and editing of the manuscript.
Funding Statement
No funding was received.
Data Availability Statement
Data privacy regulations prohibit deposition of individual-level data to public repositories, and the ethical approval does not cover public sharing of data for unknown purposes. These restrictions were imposed by the Swedish Ethical Review Authority. Upon contact with the corresponding author, data can be shared if the aims of data use are covered by an ethical approval.
Supplementary Material
References
- 1. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. 2011;364(3):255–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Luig M, Lui K. Epidemiology of necrotizing enterocolitis--part ii: risks and susceptibility of premature infants during the surfactant era: a regional study. J Paediatr Child Health. 2005;41:174–9. [DOI] [PubMed] [Google Scholar]
- 3. Fitzgibbons SC, Ching Y, Yu D, Carpenter J, Kenny M, Weldon C, et al. Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg. 2009;44(6):1072–6; discussion 1075-1076. [DOI] [PubMed] [Google Scholar]
- 4. Samuels N, van de Graaf RA, de Jonge RCJ, Reiss IKM, Vermeulen MJ. Risk factors for necrotizing enterocolitis in neonates: a systematic review of prognostic studies. BMC Pediatr. 2017;17(1):105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Lu Q, Cheng S, Zhou M, Yu J. Risk factors for necrotizing enterocolitis in neonates: a retrospective case-control study. Pediatr Neonatol. 2017;58(2):165–70. [DOI] [PubMed] [Google Scholar]
- 6. Been JV, Lievense S, Zimmermann LJ, Kramer BW, Wolfs TG. Chorioamnionitis as a risk factor for necrotizing enterocolitis: a systematic review and meta-analysis. J Pediatr. 2013;162(2):236–42.e2. [DOI] [PubMed] [Google Scholar]
- 7. Travers CP, Clark RH, Spitzer AR, Das A, Garite TJ, Carlo WA. Exposure to any antenatal corticosteroids and outcomes in preterm infants by gestational age: prospective cohort study. Bmj. 2017;356:j1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Downard CD, Grant SN, Maki AC, Krupski MC, Matheson PJ, Bendon RW, et al. Maternal cigarette smoking and the development of necrotizing enterocolitis. Pediatrics. 2012;130(1):78–82. [DOI] [PubMed] [Google Scholar]
- 9. Sharif S, Meader N, Oddie SJ, Rojas-Reyes MX, McGuire W. Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants. Cochrane Database Syst Rev. 2023;7:CD005496. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Hedermann G, Hedley PL, Baekvad-Hansen M, Hjalgrim H, Rostgaard K, Poorisrisak P, et al. Danish premature birth rates during the covid-19 lockdown. Arch Dis Child Fetal Neonatal Ed. 2021;106(1):93–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Khalil A, von Dadelszen P, Draycott T, Ugwumadu A, O’Brien P, Magee L. Change in the incidence of stillbirth and preterm delivery during the covid-19 pandemic. Jama. 2020;324(7):705–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Pasternak B, Neovius M, Soderling J, Ahlberg M, Norman M, Ludvigsson JF, et al. Preterm birth and stillbirth during the covid-19 pandemic in Sweden: a nationwide cohort study. Ann Intern Med. 2021;174(6):873–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative . The strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies. Plos Med. 2007;4(10):e296. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Norman M, Kallen K, Wahlstrom E, Hakansson S; SNQ Collaboration . The Swedish neonatal quality register - contents, completeness and validity. Acta Paediatr. 2019;108(8):1411–8. [DOI] [PubMed] [Google Scholar]
- 15. Ryan L, Plotz FB, van den Hoogen A, Latour JM, Degtyareva M, Keuning M, et al. Neonates and covid-19: state of the art: neonatal sepsis series. Pediatr Res. 2022;91(2):432–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Jasper B, Stillerova T, Anstey C, Weaver E. Reduction in preterm birth rates during and after the covid-19 lockdown in queensland Australia. Aust N Z J Obstet Gynaecol. 2022;62(6):851–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Oakley LL, Ortqvist AK, Kinge J, Hansen AV, Petersen TG, Soderling J, et al. Preterm birth after the introduction of covid-19 mitigation measures in Norway, Sweden, and Denmark: a registry-based difference-in-differences study. Am J Obstet Gynecol. 2022;226(4):550.e1–550.e22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Underwood MA. Probiotics and the prevention of necrotizing enterocolitis. J Pediatr Surg. 2019;54(3):405–12. [DOI] [PubMed] [Google Scholar]
- 19. van den Akker CHP, van Goudoever JB, Shamir R, Domellöf M, Embleton ND, Hojsak I, et al. Probiotics and preterm infants: a position paper by the european society for paediatric gastroenterology hepatology and nutrition committee on nutrition and the european society for paediatric gastroenterology hepatology and nutrition working group for probiotics and prebiotics. J Pediatr Gastroenterol Nutr. 2020;70(5):664–80. [DOI] [PubMed] [Google Scholar]
- 20. Magnusson A, Ahle M, Swolin-Eide D, Elfvin A, Andersson RE. Population-based study showed that necrotising enterocolitis occurred in space-time clusters with a decreasing secular trend in Sweden. Acta Paediatr. 2017;106(7):1097–102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Indrio F, Salatto A, Amato O, Bartoli F, Capasso L, Corvaglia L, et al. Covid-19 pandemic in the neonatal intensive care unit: any effect on late-onset sepsis and necrotizing enterocolitis? Eur J Pediatr. 2022;181(2):853–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Hekimoglu B, Akturk Acar F. Effects of covid-19 pandemic period on neonatal mortality and morbidity. Pediatr Neonatol. 2022;63(1):78–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Ngo S, Profit J, Gould JB, Lee HC. Trends in patent ductus arteriosus diagnosis and management for very low birth weight infants. Pediatrics. 2017;139(4):e20162390. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data privacy regulations prohibit deposition of individual-level data to public repositories, and the ethical approval does not cover public sharing of data for unknown purposes. These restrictions were imposed by the Swedish Ethical Review Authority. Upon contact with the corresponding author, data can be shared if the aims of data use are covered by an ethical approval.