The effect of incubator humidity on morbidity and mortality in preterm infants: A systematic review

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Background Since there is no well-accepted standard for delivery of incubator humidity for preterm infants. A meta-analysis is needed to summarize status of current research. Methods Searched 5 databases, including PubMed, the Cochrane Library, Embase, Ovid, and Web of Science, published between January 2000 and December 2023. Randomized control trials, prospective cohort studies and retrospective cohort studies were included if they assessed how different incubator humidity levels affected preterm infants with a gestational age < 34 weeks, published in English. Infection rates, the incidence of bronchopulmonary dysplasia and predischarge mortality were evaluated. Results Included in this review were 3 randomized control trials and 3 cohort studies including 801 preterm infants. Findings revealed that a high humidity level increased the incidence of infection in preterm infants ( RR = 1.26, 95% CI 1.02, 1.55, P = 0.03). No significant difference was found between a high humidity incubator humidity levels and the incidence of bronchopulmonary dysplasia or infant mortality. Conclusions This study found that high humidity levels had a significant impact on the incidence of infection. Implications for Practice and Research : Evidence from the two decades showed that high humidity levels significantly increased the incidence of infection in preterm infants. When considering a humidity delivery plan, the impact of high humidity levels on the incidence of infection should be carefully considered. High-quality, large-sample and multicenter trials are needed for further validation. preterm infants incubator humidity morbidity mortality meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Approximately 15 million preterm infants are born every year worldwide, and this number is increasing annually. 1 Due to the immature development of various organs, preterm infants are more vulnerable to serious diseases while hospitalized, including bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and other complications. Severe illness in preterm infants may even result in permanent disability or death. 2–5 Improving the clinical care of preterm infants and reducing the risk of serious complications are urgent issues in perinatal medicine that will enhance survival. There is consensus among health care professionals that humidification is advantageous in the treatment of many preterm infants. 6–8 Compared with term infants and late preterm, preterm infants have immature skin development and incomplete function. High transepidermal water loss (TEWL) through their thin skin layers results in large amounts of body fluid being lost through nondominant water loss, leading to dehydration, hypernatremia, and weight loss. 9,10 Previous studies have shown that TEWL is inversely correlated with ambient relative humidity. 11 By increasing incubator humidity in the early stages after birth, the daily fluid requirements of preterm infants can be reduced. 10 However, increased incubator humidity level also has side effects. Ambient humidity may slow the development of the skin barrier, 12 and persistently high humidity may accelerate microbial growth and reproduction, putting preterm infants at higher risk for developing infections. 13, 14 Current clinical practices involve varying levels of humidity. Neonatal intensive care units (NICUs) use a wide range of incubator humidity levels and durations. 15 In a survey of NICUs in France, Australia and New Zealand, the humidity levels ranged from 60–100%. 16 In a cross-sectional investigation involving Australia, Canada, the Czech Republic, India, and the United States, it was found that while all of the institutions surveyed had established guidelines for humidification in the NICU, the humidity settings varied considerably, both within institutions and between institutions and nations. 6 Through a systematic review Glass and Valdez indicated that a relative humidity of 60% − 70% is suggested in the first week after birth for preterm infants with a gestational age > 26 weeks. 8 Through a systematic review Kao, Chen and Lien indicated that for preterm infants with a gestational age ≤ 30 weeks or a weight ≤ 1000 grams, the relative humidity should be 70% − 80% in the first week after birth and 50% − 60% in the second week, and the duration should not exceed two weeks. 7 However, neither systematic review performed a meta-analysis. 7,8 A meta-analysis consolidates sample sizes to increase the potential of testing power by synthesizing the results of multiple small study samples where the data have similar characteristics.Thus, the meta-analysis method was applied to the current studies within our systematic review, in order to evaluate the impact of high incubator humidity levels on the incidence of morbidity and mortality in preterm infants. Methods Study Selection Criteria The inclusion criteria were as follows: ( 1 ) Pretem infants born at gestational age < 34 weeks. ( 2 ) Assess use of different levels of incubator humidity. ( 3 ) Study types included were Randomized control trials (RCTs), prospective cohort studies, and retrospective cohort studies. ( 4 ) Primary outcomes assessed were mortality and morbidity related to infection and BPD. Studies with missing data, studies for which data could not be extracted and studies published in languages other than English were not included. In our initial examination of the literature, we found that there were few high quality RCTs related to our research question and of those we found most had very small sample sizes. As such we decide to included cohort studies in our sample to increase the overall sample size. The range of high humidity levels is obscure. The Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN) suggested that infants with extremely low birth weight should be kept in an incubator with an ambient humidity level that ranges from 70–85%, depending on gestational age. 17 For the Glass and Valdez, it was suggested that the incubator humidity level should not exceed 70% when preterm infants developed a skin barrier in the first days of life and do not require the humidity protection to minimise evaporative heat loss 8 .NICU thermal environment standards specify 22–26°C (72–76°F) as an acceptable range for air temperature and 30–60% relative humidity 18 .Considering that the humidification level of most incubators starts at 70%, the initial humidity setting of the incubator was ≥ 70% in this study, which is regarded as a relative high humidity level for this research. Other interventions included an initial incubator humidity level of < 70% or no extra humidification. The primary outcome measures were infection rates, the incidence of BPD and infant mortality. For review, infection rates were defined as the presence of urine, blood or cerebrospinal fluid infections.According to the criteria of the National Institute of Child Health and Human Development (NICHD) in 2001, any premature infant with oxygen dependence (oxygen concentration > 21%) for more than 28 days was classified as having BPD. We used this same criteria for this review. Mortality was limited to include only predischarge mortality for this review. Literature searches and data extraction Several databases were searched, including PubMed, the Cochrane Library, Embase, Ovid, and Web of Science. Because the preliminary search showed that associated literature from the 20th century was limited, literature was searched published between January 2000 and December 2023 to ensure that the research findings precisely reflected current clinical practice. For the search strategy, a combination of subject terms, free words and Boolean logical operators were adopted. Manual search of relevant references were manually retrieved. The search terms were infant*/Preterm/Premature/Prematurity/Neonatal/“VLBW”/“ELBW” /incubator/Radiant Warmers/humidification/humid*/humidity. Two researchers reviewed the titles and abstracts and then selected which works should be included based on the inclusion and exclusion criteria. When the opinions of the two researchers differed, a third researcher with greater qualifications arbitrated the matter until consensus. The extracted data included basic data (author, year of publication, baseline situation), sample sizes, intervention measures, outcome indicators, etc. Risk of bias assessment and evidence evaluation RCTs were evaluated using the Cochrane Collaboration Network risk of bias assessment criteria. 19 Two researchers independently assessed literature quality in a double-blind manner. The following were assessed: random sequence generation, allocation concealment, the blinding of subjects and implementors, the blinding of outcome assessors, the integrity of outcome data, selective reporting of findings, and other sources of bias. On an article-by-article basis, each included study was assessed as having a "low risk of bias", a "high risk of bias" or an "unclear" risk of bias.The quality of the literature was divided into 3 levels: Grade A: Low bias and meeting all of the above criteria; Grade B: Moderate bias and meeting some of the above criteria; and Grade C: High risk of bias and not meeting any of the above criteria; submissions classified as Grade C were excluded. After the completion of independent assessments, the two researchers discussed and reached a consensus on the results of the assessment, and if there was a disagreement, a third researcher was consulted. The Newcastle‒Ottawa Scale (NOS) was used to evaluate the bias risk of cohort studies. 20 The NOS includes 4 items for subject selection (4 points), 1 item for comparability between groups (2 points) and 3 items for outcome measurement (3 points), for a total score of 9 points. Research quality was divided into high-quality research (final score ≥ 6), medium-quality research (final score = 5), and low-quality research (final score < 5). Only medium- and high-quality documents with a score of 5–9 were included in this study. The GRADE approach was used to assess evidence quality and recommendations. 21 Evidence quality is divided into four categories by the GRADE approach: high, moderate, low, and very low. Observational studies receive a low grade, while randomized controlled trials receive a high rating. When the publication link has serious problems, the level of evidence decreases. The GRADE approach classifies downgrading reasons into five categories: risk of bias, inconsistency, indirectness, imprecision, and publication bias. Observational studies with large effect sizes, defined as an RR ≤ 0.5, are upgraded. Data analysis Review Manager 5.4 was used for completion of the metanalysis. Firstly, a quantitative synthesis analysis was conducted of all included studies, and then a second stratified analysis was conducted by study type (RCT or cohort study). For enumeration data, the relative risk (RR) and its 95% confidence interval (95% CI) were used to determine the effect size. Included studies were subjected to the heterogeneity test, and the fixed effect model was used with no statistical heterogeneity (P > 0.1, I² ≤ 50%); the random effect model was used for studies with statistical heterogeneity (P ≤ 0.1, I² > 50%). The combined effect size was used for hypothesis tests, and P < 0.05 indicated that the outcomes were statistically significant. STATA version 14 software (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP) was used to execute the sensitivity analysis and publication bias test (Egger test). Results The literature search and screening process is shown in Figure 1. A total of 801 subjects were included in 6 studies, including 3 randomized controlled trials (n = 246) and 3 cohort studies (n = 555). The demographics of population included studies are listed in table 1. The Cochrane Collaboration Risk of Bias Assessment Criteria were used to assess the risk of bias for the included RCTs. All three of the included randomized controlled trials received a grade of B for literature quality. Figure 2a and b displays the methodological quality assessment of the included studies. The three included cohort studies were evaluated for risk of bias using the NOS. According to the NOS, the three studies were relatively complete regarding the clarity of cohort study comparability and follow-up time, and they all received a NOS score ≥ 6, indicating high quality.Table 2 displays the information mentioned above. As shown in supplemental table 1, GRADE was used to evaluate the quality of the evidence. Figure.1 PRISMA Flow diagram of studies selection. Figure. 2 a Risk of bias in the included trials. b Risk of bias in the included trials. Table 1 Characteristics of included studies in systematic review Author year Country Study type Sample size (n) Sample Characteristics （GA,wk/BW,g） Humidity levels（%） Duration of humidity （day） Outcomes experimental control experimental control experimental control experimental control Helder 2008 Netherlands RCT 65 71 24-30w 80 70 14 14 Infection Mortality Meyer 2001 New Zealand RCT 30 30 <33w BW<1750g 70-80 None 3/5 0 Infection BPD Mortality Kong 2011 Australia RCT 25 25 ≤28 w BW500-1300g 80 70 12.7±0.6* 12.4± 1.3* Infection BPD Sung 2013 Korea Cohort 121 97 22-24w BW26w BW<1000g 95 60 7 7 Mortality Gaylord 2001 America Cohort 85 70 <30w BW<1000g 70 None No clear 0 Infection BPD Mortality Kim 2010 America Cohort 95 87 <30w BW<1000g 70-80 None 25.5± 1.1* 0 Infection BPD Mortality GA:gestational age,BW:birth weight,*Data presented as mean ± S Table 2 Cohort studies scored according to the the NOS scale Study Selection Comparability Outcome Score Gaylord 2001 4 1 2 7 Kim 2010 3 1 3 6 Sung 2013 3 1 3 7 Results of the meta-analysis The effect of a high humidity level on infection Overall, five studies 10, 2 2 -2 5 (n=583) compared the effect of a high humidity level on the incidence of infection in preterm infants. Utilizing the fixed effect model, the outcomes showed no heterogeneity among the studies when the effects of the included literature were combined. The meta-analysis results showed that a high humidity level increased the incidence of infection in preterm infants ( RR = 1.26, 95% CI 1.02, 1.55, P = 0.03). The incidence of infection was 1.26 times higher in the group with a high humidity level than in the group with a low humidity level (Figure 3a). Of the 5 studies considered above, three were RCTs (n=246) which compared the effect of a high humidity level on infection rates in premature infants. The findings of the meta-analysis revealed that using a high humidity level may increase the incidence of infection in preterm infants ( RR = 1.47, 95% CI 1.01, 2.14, P = 0.04), which was 1.47 times higher in the group with a high humidity level than in the group with a low humidity level. Also included above, two cohort studies (n=337) compared the effect of a high humidity level on infection rates in premature infants. According to the meta-analysis findings, there were no significant differences between the groups with high and low humidity levels ( RR = 1.16, 95% CI 0.91, 1.5, P = 0.23). The effect of a high humidity level on the incidence of BPD Four studies 10, 2 2 -2 5 (n=417) compared the effect of a high humidity level on the incidence of BPD in preterm infants. The combined effects of the included literature revealed no evidence of study heterogeneity (P = 0.29, I² = 19%), and thus we used the fixed effect model. The results revealed that there was no significant difference between the groups with high and low humidity levels ( RR = 1.07, 95% CI 0.86, 1.33, P = 0.53) (Figure 3b). Of the four studies included above, two RCTs 2 2 ,2 4 (n=110) compared the effect of a high humidity level on the incidence of BPD in preterm infants. According to the meta-analysis findings, using a high humidity level may put preterm infants at greater risk of BPD ( RR = 1.7, 95% CI 1.01, 2.86, P = 0.05). Within the two cohort trials, also included above, 10, 2 5 (n=307) each compared the effect of a high humidity level on the incidence of BPD in preterm infants. The results revealed that there was no significant difference between the groups with high and low humidity levels within the cohort studies ( RR = 0.97, 95% CI 0.76, 1.24, P = 0.82). The effect of a high humidity level on mortality Five studies 10, 2 3 -2 6 (n=751) compared the effect of a high humidity level on the incidence of mortality predischarge in preterm infants. The combined effects of the included literature revealed no evidence of study heterogeneity (P=0.14, I 2 =42%) and thus we used the fixed effect model. The results revealed that there was no significant difference between the groups with high and low humidity levels ( RR = 1.46, 95% CI 0.82, 2.6, P = 0.84) (Figure 3c). Of the above included studies, the two RCTs 2 3 , 2 4 (n=196) examined the effect of a high humidity level on mortality. The results revealed that there was no significant difference between the groups with high and low levels of humidity ( RR = 1.32, 95% CI 0.1, 17.66, P = 0.84). However, in the three cohort studies 10,2 5 , 2 6 comparing the effect of a high humidity level on mortality, the results revealed that a high humidity level significantly increased the mortality rate of preterm infants, which was 1.73 times higher in infants with a high humidity level than in infants with a low humidity level (RR = 1.73, 95% CI 1.17, 2.57, P = 0.006). Figure.3 Forest plot. a The effect of high humidity environments on the incidence of infection. b The effect of high humidity environments on the incidence of BPD.c The effect of high humidity environments on mortality. Sensitivity analysis After sensitivity analysis, as shown in Figure 4a,b and c, no significant effects on heterogeneity were demonstrated across studies. Figure.4 Sensitivity analysis. a The incidence of infection. b The incidence of BPD. c The incidence of mortality. Publication bias The results of the Egger test revealed that the infection rate (P = 0.286 > 0.05), BPD incidence rate (P = 0.208 > 0.05), and mortality rates (P = 0.993 > 0.05) were all unaffected by publication bias. Discussion This systematic review aimed to investigate the effect of incubator humidity levels on the morbidity and mortality in preterm infants. Quantitative synthesis analysis of all included studies were conducted, and stratified by study design, and then assessed the stability of the results. According to the meta-analysis of the studies that were included, there was a significant increase in the risk of infection in preterm infants when the incubator humidity level was high, and this result was particularly evident in RCTs (quality of evidence: moderate). This result was consistent with the research of Lynam 13 and Etienne 14 . Continuously high humidity can lead to faster growth and reproduction of microorganisms, which increases the risk of sepsis in preterm infants because humidity increases condensation inside the incubator. 13, 14 Due to the impact of high heat and humidity on the relatively colder inner wall of the incubator, more condensation may be produced. Prazad 27 found that volatile organic compound concentrations in the air increased when the humidity in the chamber was raised to 50%. When the average temperature and relative humidity of the incubator were set to high, the level of microbial contamination increased significantly. Pritik 28 noticed that the diversity of skin fungi was higher in environments with higher humidity when monitoring the skin flora of extremely preterm infants, indicating that humidity is closely related to the reproduction and growth of fungi. According to previous studies, mold grows in conditions with at least 70% humidity, while yeast and gram-positive and gram-negative bacteria grow in environments with 80–95% humidity. 29 However, the design of humidification systems in modern incubators have changed over time to decrease the risk of infection. 31 Double-walled incubators reduce condensation and incorporate hot-water equipment, which kills most organisms and keeps bacteria out of the air. 13 Significantly, there is still a risk of external microorganisms being introduced into this warm, moist environment by caregivers’ hands. To eliminate the impact of different incubators on the results for infection risk, a sensitivity analysis was conducted to determine whether the results were stable. Five studies 10, 22–24,26 used double-walled incubators, whereas Gaylord et al 25 used single-walled incubators. Figure 4 shows that excluding the study by Gaylord et al 25 did not affect the results. It is unclear whether the incubators used in the studies provided sterile humidity. Due to the studies being published between 2001 and 2013, further trials are needed to verify whether the conclusions of this article that high humidity levels may increase infection rates are applicable to modern incubators. Additional factors to examine, studies showed that the gestational age of the included subjects may affect the findings. 11, 29 Preterm infants with a lower gestational age need to be cared for in an incubator environment with a longer duration and higher initial humidity level, which may affect the incidence of infection. The maturity of skin barrier function in preterm infants depends on their gestational age. Regarding skin development, the epidermis matures gradually in the last quarter of pregnancy. 11 Preterm infants born at a younger gestational age have less developed skin. The immaturity of skin barrier function in preterm infants is mainly related to the development of the stratum corneum. The stratum corneum, one of the skin structures, dissipates heat through evaporation, controls transepidermal water loss, and protects the body from pathogens and toxins. At approximately 24 weeks of gestation, stratum corneum development begins. Extremely-low-birth-weight infants with a gestational age of less than 24 weeks barely have stratum corneum, and premature infants born at less than 30 weeks gestation have only two to three stratum corneum layers. 12 There is evidence that by 30 to 32 weeks of gestational age, the stratum corneum has almost fully developed. 30 The AWHONN guideline mentioned that the length of time it takes for skin to mature, usually takes one weeks for preterm infants born at 25–29 weeks, 2–3 weeks for preterm born at 24 weeks and less. But small for gestational age infants' skin matures much faster than other babies. 17 Additionally, preterm infants need incubators with high initial humidity levels for extended periods, which may affect the incidence of infection. However, in the current research on the effect of incubator humidity on preterm infants, the gestational age of the included subjects was quite different, suggesting that future studies should be stratified based on gestational age. Notably, the following precautions might decrease the risk of neonatal infections and even late sepsis when the incubator is set to a high humidity level: reducing the duration of a high humidity level, thoroughly cleaning the incubator, and replacing the sterile water daily. 29, 32 This study did not find that a high incubator humidity level had significant effect on either the incidence of BPD or the mortality rate of preterm infants (quality of evidence: low). This is consistent with Kao’s research conclusion. 7 The principle of providing humidity is based on thermal regulation and reducing heat loss due to evaporation. In a dry and cold environment, the rate of evaporation heat exchange between the skin surface and the ambient air can be very high. 33 Increasing the incubator humidity level in the early stages after birth can continuously reduce insensible water loss, reduce the daily fluid requirements of extremely preterm infants, improve water and electrolyte balance and maintain thermal stability, reducing mortality rates. 10 There is not yet sufficient evidence to confirm the direct impact of a high incubator humidity levels on the incidence of BPD or the mortality rate of preterm infants. Further high-quality RCTs will be required to verify the outcome. However, the findings obtained for the two research types—RCTs and cohort studies—were distinct in this study after conducting stratified analysis. The subgroup analysis of RCTs showed higher risk of BPD and the cohort studies showed a higher mortality rate. There are two possible reasons for this difference: first, the sample size of the included RCTs was far smaller than that of the included cohort studies, which could explain the discrepancy. Three RCTs (n = 246) and three cohort studies (n = 555) were included in this study. Second, the baselines of two RCTs 22,24 and three cohort studies 10,25,26 were unbalanced. According to the assessment of included studies' quality of evidence, the combined effect size of the two RCTs was large (RR = 1.7) when analyzing how different humidity levels impacted the incidence of BPD in preterm infants. However, the sample size of this experimental group (n = 55) and control group (n = 55) was insufficient to meet the optimal information size standard, so the grade was downgraded by one level due to severe inaccuracy. When examining the effect of various humidity levels on the mortality of preterm infants, two RCTs were combined to achieve an I² of 66%, and the high heterogeneity produced severe inconsistency, so the grade was downgraded by one level. As some control groups were in a non-humidified environment and some were in a humidified environment, two RCTs and three cohorts were both downgraded by one level having serious indirectness. Even so, the heterogeneity between RCTs and cohort studies were not significant, less than 50%. This means that there may be some confounding factors in the different research designs that affect the results, and more research is needed to guide practice recommendations. Overall, merging all the studies yielded more reliable results. Therefore, the combined results from cohort studies and RCTs may represent the true situation rather than RCTs or cohort studies alone. Implications for Practice Evidence has demonstrated that when the initial incubator humidity level is high—at more than 70%— the incidence of infection in preterm infants is significantly increased. When creating a humidity delivery plan for preterm infants, the impact of high humidity levels on the infection rate of preterm infants should be carefully considered. To reduce the risk of infection in preterm infants, we can implement incubator disinfection and reduce the duration of a high humidity level when making a plan for humidity management. Implications for Research More large clinical trials and humidity-related research including preterm infants of differing gestational ages particularly those from younger gestational ages must be conducted in the future. Limitations of this study The search revealed that the number of pertinent experimental studies in the field, particularly RCTs, was small. The humidity levels in the control group of existing research designs varied significantly because there are no correlative standards regarding humidity for the care of preterm infants. Although still acceptable, the heterogeneity of the study designs may have led to smaller effect sizes. Due to the lack of data regarding the effects of factors such as humidity duration and humidity adjustment schemes on the outcomes, subgroup analysis on gestational age and birth weight was not conducted. Conclusions This review summarized the available evidence relating to the effect of humidity levels on complications and mortality in preterm infants. This study found that high humidity levels had a significant impact on the incidence of infection but had no impact on mortality or the incidence of bronchopulmonary dysplasia. Abbreviations NICUs – Neonatal Intensive Care Units BPD-bronchopulmonary dysplasia IVH-intraventricular hemorrhage PVL-periventricular leukomalacia TEWL-transepidermal water loss RCTs-randomized controlled trials Declarations Ethics approval and consent to participate ： Not Applicable Consent for publication ： Not Applicable Availability of data and materials ： All data generated or analyzed during this study are included in this published article and its supplementary information files. Competing interests: The authors declare that they have no competing interests. Funding: There is no support by a grant. Authors' contributions: Z.C. designed the study, collected, and analyzed data, drafted the initial manuscript, and reviewed and revised the manuscript; R.L. collected and analyzed data, reviewed, and revised the manuscript; H.W. reviewed and revised the manuscript; B.S. and Q.C. made supportive contributions and contributed to the critical revision of the manuscript.All authors have read and approved the manuscript. Acknowledgements: Not Applicable Other information The article was registered with PROSPERO. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Different from the protocol, the final outcome indicators that were not presented were the incidence of hypernatremia, intravascular hemolysis and patent ductus arteriosus. During the search process, it was found that few studies observed and described these indicators, resulting in the inability to conduct a meta-analysis [PROSPERO: CRD42023401195]. 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Pediatrics. 2001;108(2):395–401. 10.1542/peds.108.2.395 . Gaylord MS, Wright K, Lorch K, Lorch V, Walker E. Improved fluid management utilizing humidified incubators in extremely low birth weight infants. J Perinatol. 2001;21(7):438–43. 10.1038/sj.jp.7210561 . Sung SI, Ahn SY, Seo HJ, et al. Insensible water loss during the first week of life of extremely low birth weight infants less than 25 gestational weeks under high humidification. Neonatal Med. 2013;20(1):51–7. 10.5385/nm.2013.20.1.51 . Prazad P, Cortes D, Puppala B, Donovan R, Kumar S, Gulati A. Airborne concentrations of volatile organic compounds in neonatal incubators. J Perinatol. 2008;28(8):534–40. 10.1038/jp.2008.75 . Shah PA, Govindarajan V, Diggikar S, Rangaiah A, Devadas S, Kariyappa M. Exploring the Skin Mycobiome in Very Preterm babies during the early neonatal period in a Neonatal Intensive Care Unit of India. Trop Doct. 2022;52(2):362–4. 10.1177/00494755221077520 . Kurimoto T, Ibara S, Ishihara C, Naito Y, Hirakawa E, Yamamoto T. Incubator humidity and temperature control in infants born at 22–23 weeks' gestation. Early Hum Dev. 2022;166:105550. 10.1016/j.earlhumdev.2022.105550 . Kalia YN, Nonato LB, Lund CH, Guy RH. Development of skin barrier function in premature infants. J Invest Dermatol. 1998;111(2):320–6. 10.1046/j.1523-1747.1998.00289.x . Antonucci R, Porcella A, Fanos V. The infant incubator in the neonatal intensive care unit: unresolved issues and future developments. J Perinat Med. 2009;37(6):587–98. 10.1515/JPM.2009.109 . De Goffau MC, Bergman KA, De Vries HJ, et al. Cold spots in neonatal incubators are hot spots for microbial contamination. Appl Environ Microbiol. 2011;77(24):8568–72. 10.1128/AEM.06015-11 . Shukla VV, Ambalavanan N. Recent advances in bronchopulmonary dysplasia. Indian J Pediatr. 2021;88(7):690–5. 10.1007/s12098-021-03766-w . Additional Declarations No competing interests reported. Supplementary Files PRISMAchecklist.docx searchstrategy.docx supplementaltable1.docx Cite Share Download PDF Status: Published Journal Publication published 31 Mar, 2025 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 01 Jan, 2025 Reviews received at journal 31 Dec, 2024 Reviewers agreed at journal 22 Dec, 2024 Reviews received at journal 09 Dec, 2024 Reviewers agreed at journal 08 Dec, 2024 Reviewers agreed at journal 30 Nov, 2024 Reviewers invited by journal 25 Jun, 2024 Editor invited by journal 19 Jun, 2024 Editor assigned by journal 17 Jun, 2024 Submission checks completed at journal 17 Jun, 2024 First submitted to journal 10 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4558106","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":321401846,"identity":"031a6e45-ed45-460a-b575-ff9dd54df022","order_by":0,"name":"Zhiqin Chen","email":"","orcid":"","institution":"Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhiqin","middleName":"","lastName":"Chen","suffix":""},{"id":321401847,"identity":"70a23cc9-9e42-4cb7-b8af-2be157527f3c","order_by":1,"name":"Ruizi Lin","email":"","orcid":"","institution":"Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ruizi","middleName":"","lastName":"Lin","suffix":""},{"id":321401850,"identity":"c2ecc071-a011-4a58-a2f7-78b61ce7b5fc","order_by":2,"name":"Huixin Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYJACZgYGCQY2Bv7vHz4Y2NiRooXBjHFGQVoysVrAwIyZ58MhxgZCyg2Onz38urDNIrFPuiHtsY3BAWYG9sNHN+DVciYvzXpmm4Qxm8yB48Y5Bnf4GHjS0m7g02J2IMfMmLdNQo5NIrFBOsfgGTODBI8Zfi3n34C18LBJJDNIWxgcZmwgqOVGjvFjiC1pbNIMxGixv/EGGFDngH6RyGE27DFIS2Yj5BfJ/hzjzzxldYnzZ+QwPvjxx8aOn/3wMbxagIBNApVLQDkIMH8gQtEoGAWjYBSMZAAA74RCyGH8F24AAAAASUVORK5CYII=","orcid":"","institution":"Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":true,"prefix":"","firstName":"Huixin","middleName":"","lastName":"Wang","suffix":""},{"id":321401851,"identity":"5437e080-e2fe-40f8-8c59-7daaaf7658b7","order_by":3,"name":"Bijun Shi","email":"","orcid":"","institution":"Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Bijun","middleName":"","lastName":"Shi","suffix":""},{"id":321401853,"identity":"711cd1cc-74ca-44e8-98fa-fc68db528ae9","order_by":4,"name":"Qian Chen","email":"","orcid":"","institution":"Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-06-10 12:44:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4558106/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4558106/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12887-025-05538-3","type":"published","date":"2025-03-31T15:57:49+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60353944,"identity":"34bcf743-acca-4991-a57f-9b23caa81fae","added_by":"auto","created_at":"2024-07-15 23:49:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":807599,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA Flow diagram of studies selection.\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4558106/v1/45650c31530d57f7f13ba271.png"},{"id":60355028,"identity":"5694bab7-27e0-4fdb-aaea-6594460f6753","added_by":"auto","created_at":"2024-07-15 23:57:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":198233,"visible":true,"origin":"","legend":"\u003cp\u003ea Risk of bias in the included trials. b Risk of bias in the included trials.\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4558106/v1/39d84d45f21b83d2417d0734.png"},{"id":60353496,"identity":"91ea6112-add0-430f-b7f7-32b9736868e7","added_by":"auto","created_at":"2024-07-15 23:41:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2171110,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot. a The effect of high humidity environments on the incidence of infection. b The effect of high humidity environments on the incidence of BPD.c The effect of high humidity environments on mortality.\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4558106/v1/41c8783c5e57d864f504f7de.png"},{"id":60353497,"identity":"3c4e5937-569b-4cec-9307-9f5870535f59","added_by":"auto","created_at":"2024-07-15 23:41:23","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":633166,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity analysis. a The incidence of infection. b The incidence of BPD. c The incidence of mortality.\u003c/p\u003e","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4558106/v1/98e3745772c9bb23c5f5e65c.png"},{"id":80082068,"identity":"e71f4b0e-39d4-410a-94e9-568839bc1060","added_by":"auto","created_at":"2025-04-07 16:06:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1185113,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4558106/v1/735f3780-97d8-4bba-80c7-bcdb72f8602e.pdf"},{"id":60353492,"identity":"0466279e-c77e-452d-ab6e-4ee7d796c049","added_by":"auto","created_at":"2024-07-15 23:41:23","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29396,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMAchecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-4558106/v1/8806fe40106734b81de35e60.docx"},{"id":60353498,"identity":"57dd9ac3-7604-4fe8-88ba-cdb9ed466010","added_by":"auto","created_at":"2024-07-15 23:41:23","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":11587,"visible":true,"origin":"","legend":"","description":"","filename":"searchstrategy.docx","url":"https://assets-eu.researchsquare.com/files/rs-4558106/v1/249e18a57ca125c0fe2f8f8b.docx"},{"id":60353493,"identity":"2fe81946-8888-45da-a9fc-0513990362b3","added_by":"auto","created_at":"2024-07-15 23:41:23","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":19407,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaltable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4558106/v1/9c24833228f1969448a4ca54.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The effect of incubator humidity on morbidity and mortality in preterm infants: A systematic review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eApproximately 15\u0026nbsp;million preterm infants are born every year worldwide, and this number is increasing annually.\u003csup\u003e1\u003c/sup\u003e Due to the immature development of various organs, preterm infants are more vulnerable to serious diseases while hospitalized, including bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and other complications. Severe illness in preterm infants may even result in permanent disability or death.\u003csup\u003e2\u0026ndash;5\u003c/sup\u003e Improving the clinical care of preterm infants and reducing the risk of serious complications are urgent issues in perinatal medicine that will enhance survival.\u003c/p\u003e \u003cp\u003eThere is consensus among health care professionals that humidification is advantageous in the treatment of many preterm infants.\u003csup\u003e6\u0026ndash;8\u003c/sup\u003e Compared with term infants and late preterm, preterm infants have immature skin development and incomplete function. High transepidermal water loss (TEWL) through their thin skin layers results in large amounts of body fluid being lost through nondominant water loss, leading to dehydration, hypernatremia, and weight loss.\u003csup\u003e9,10\u003c/sup\u003e Previous studies have shown that TEWL is inversely correlated with ambient relative humidity.\u003csup\u003e11\u003c/sup\u003e By increasing incubator humidity in the early stages after birth, the daily fluid requirements of preterm infants can be reduced.\u003csup\u003e10\u003c/sup\u003e However, increased incubator humidity level also has side effects. Ambient humidity may slow the development of the skin barrier,\u003csup\u003e12\u003c/sup\u003e and persistently high humidity may accelerate microbial growth and reproduction, putting preterm infants at higher risk for developing infections.\u003csup\u003e13, 14\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCurrent clinical practices involve varying levels of humidity. Neonatal intensive care units (NICUs) use a wide range of incubator humidity levels and durations.\u003csup\u003e15\u003c/sup\u003e In a survey of NICUs in France, Australia and New Zealand, the humidity levels ranged from 60\u0026ndash;100%.\u003csup\u003e16\u003c/sup\u003e In a cross-sectional investigation involving Australia, Canada, the Czech Republic, India, and the United States, it was found that while all of the institutions surveyed had established guidelines for humidification in the NICU, the humidity settings varied considerably, both within institutions and between institutions and nations.\u003csup\u003e6\u003c/sup\u003e Through a systematic review Glass and Valdez indicated that a relative humidity of 60% \u0026minus;\u0026thinsp;70% is suggested in the first week after birth for preterm infants with a gestational age\u0026thinsp;\u0026gt;\u0026thinsp;26 weeks.\u003csup\u003e8\u003c/sup\u003e Through a systematic review Kao, Chen and Lien indicated that for preterm infants with a gestational age\u0026thinsp;\u0026le;\u0026thinsp;30 weeks or a weight\u0026thinsp;\u0026le;\u0026thinsp;1000 grams, the relative humidity should be 70% \u0026minus;\u0026thinsp;80% in the first week after birth and 50% \u0026minus;\u0026thinsp;60% in the second week, and the duration should not exceed two weeks.\u003csup\u003e7\u003c/sup\u003e However, neither systematic review performed a meta-analysis.\u003csup\u003e7,8\u003c/sup\u003e A meta-analysis consolidates sample sizes to increase the potential of testing power by synthesizing the results of multiple small study samples where the data have similar characteristics.Thus, the meta-analysis method was applied to the current studies within our systematic review, in order to evaluate the impact of high incubator humidity levels on the incidence of morbidity and mortality in preterm infants.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Selection Criteria\u003c/h2\u003e \u003cp\u003eThe inclusion criteria were as follows: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Pretem infants born at gestational age\u0026thinsp;\u0026lt;\u0026thinsp;34 weeks. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Assess use of different levels of incubator humidity. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Study types included were Randomized control trials (RCTs), prospective cohort studies, and retrospective cohort studies. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Primary outcomes assessed were mortality and morbidity related to infection and BPD. Studies with missing data, studies for which data could not be extracted and studies published in languages other than English were not included.\u003c/p\u003e \u003cp\u003eIn our initial examination of the literature, we found that there were few high quality RCTs related to our research question and of those we found most had very small sample sizes. As such we decide to included cohort studies in our sample to increase the overall sample size. The range of high humidity levels is obscure. The Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN) suggested that infants with extremely low birth weight should be kept in an incubator with an ambient humidity level that ranges from 70\u0026ndash;85%, depending on gestational age.\u003csup\u003e17\u003c/sup\u003e For the Glass and Valdez, it was suggested that the incubator humidity level should not exceed 70% when preterm infants developed a skin barrier in the first days of life and do not require the humidity protection to minimise evaporative heat loss\u003csup\u003e8\u003c/sup\u003e.NICU thermal environment standards specify 22\u0026ndash;26\u0026deg;C (72\u0026ndash;76\u0026deg;F) as an acceptable range for air temperature and 30\u0026ndash;60% relative humidity\u003csup\u003e18\u003c/sup\u003e.Considering that the humidification level of most incubators starts at 70%, the initial humidity setting of the incubator was \u0026ge;\u0026thinsp;70% in this study, which is regarded as a relative high humidity level for this research. Other interventions included an initial incubator humidity level of \u0026lt;\u0026thinsp;70% or no extra humidification.\u003c/p\u003e \u003cp\u003eThe primary outcome measures were infection rates, the incidence of BPD and infant mortality. For review, infection rates were defined as the presence of urine, blood or cerebrospinal fluid infections.According to the criteria of the National Institute of Child Health and Human Development (NICHD) in 2001, any premature infant with oxygen dependence (oxygen concentration\u0026thinsp;\u0026gt;\u0026thinsp;21%) for more than 28 days was classified as having BPD. We used this same criteria for this review. Mortality was limited to include only predischarge mortality for this review.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eLiterature searches and data extraction\u003c/h2\u003e \u003cp\u003eSeveral databases were searched, including PubMed, the Cochrane Library, Embase, Ovid, and Web of Science. Because the preliminary search showed that associated literature from the 20th century was limited, literature was searched published between January 2000 and December 2023 to ensure that the research findings precisely reflected current clinical practice. For the search strategy, a combination of subject terms, free words and Boolean logical operators were adopted. Manual search of relevant references were manually retrieved. The search terms were infant*/Preterm/Premature/Prematurity/Neonatal/\u0026ldquo;VLBW\u0026rdquo;/\u0026ldquo;ELBW\u0026rdquo;\u003c/p\u003e \u003cp\u003e/incubator/Radiant Warmers/humidification/humid*/humidity. Two researchers reviewed the titles and abstracts and then selected which works should be included based on the inclusion and exclusion criteria. When the opinions of the two researchers differed, a third researcher with greater qualifications arbitrated the matter until consensus. The extracted data included basic data (author, year of publication, baseline situation), sample sizes, intervention measures, outcome indicators, etc.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eRisk of bias assessment and evidence evaluation\u003c/h2\u003e \u003cp\u003eRCTs were evaluated using the Cochrane Collaboration Network risk of bias assessment criteria.\u003csup\u003e19\u003c/sup\u003e Two researchers independently assessed literature quality in a double-blind manner. The following were assessed: random sequence generation, allocation concealment, the blinding of subjects and implementors, the blinding of outcome assessors, the integrity of outcome data, selective reporting of findings, and other sources of bias. On an article-by-article basis, each included study was assessed as having a \"low risk of bias\", a \"high risk of bias\" or an \"unclear\" risk of bias.The quality of the literature was divided into 3 levels: Grade A: Low bias and meeting all of the above criteria; Grade B: Moderate bias and meeting some of the above criteria; and Grade C: High risk of bias and not meeting any of the above criteria; submissions classified as Grade C were excluded. After the completion of independent assessments, the two researchers discussed and reached a consensus on the results of the assessment, and if there was a disagreement, a third researcher was consulted.\u003c/p\u003e \u003cp\u003eThe Newcastle‒Ottawa Scale (NOS) was used to evaluate the bias risk of cohort studies.\u003csup\u003e20\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe NOS includes 4 items for subject selection (4 points), 1 item for comparability between groups (2 points) and 3 items for outcome measurement (3 points), for a total score of 9 points. Research quality was divided into high-quality research (final score\u0026thinsp;\u0026ge;\u0026thinsp;6), medium-quality research (final score\u0026thinsp;=\u0026thinsp;5), and low-quality research (final score\u0026thinsp;\u0026lt;\u0026thinsp;5). Only medium- and high-quality documents with a score of 5\u0026ndash;9 were included in this study.\u003c/p\u003e \u003cp\u003eThe GRADE approach was used to assess evidence quality and recommendations.\u003csup\u003e21\u003c/sup\u003e Evidence quality is divided into four categories by the GRADE approach: high, moderate, low, and very low. Observational studies receive a low grade, while randomized controlled trials receive a high rating. When the publication link has serious problems, the level of evidence decreases. The GRADE approach classifies downgrading reasons into five categories: risk of bias, inconsistency, indirectness, imprecision, and publication bias. Observational studies with large effect sizes, defined as an RR\u0026thinsp;\u0026le;\u0026thinsp;0.5, are upgraded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eReview Manager 5.4 was used for completion of the metanalysis. Firstly, a quantitative synthesis analysis was conducted of all included studies, and then a second stratified analysis was conducted by study type (RCT or cohort study). For enumeration data, the relative risk (RR) and its 95% confidence interval (95% CI) were used to determine the effect size. Included studies were subjected to the heterogeneity test, and the fixed effect model was used with no statistical heterogeneity (P\u0026thinsp;\u0026gt;\u0026thinsp;0.1, I\u0026sup2; \u0026le; 50%); the random effect model was used for studies with statistical heterogeneity (P\u0026thinsp;\u0026le;\u0026thinsp;0.1, I\u0026sup2; \u0026gt; 50%). The combined effect size was used for hypothesis tests, and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated that the outcomes were statistically significant. STATA version 14 software (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP) was used to execute the sensitivity analysis and publication bias test (Egger test).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe literature search and screening process is shown in Figure 1. A total of 801 subjects were included in 6 studies, including 3 randomized controlled trials (n\u0026nbsp;= 246) and 3 cohort studies (n\u0026nbsp;= 555).\u003c/p\u003e\n\u003cp\u003eThe demographics of population included studies are listed in table 1. The Cochrane Collaboration Risk of Bias Assessment Criteria were used to assess the risk of bias for the included RCTs. All three of the included randomized controlled trials received a grade of B for literature quality. Figure 2a and b displays the methodological quality assessment of the included studies. The three included cohort studies were evaluated for risk of bias using the NOS. According to the NOS, the three studies were relatively complete regarding the clarity of cohort study comparability and follow-up time, and they all received a NOS score \u0026ge; 6, indicating high quality.Table 2 displays the information mentioned above. As shown in supplemental table 1, \u0026nbsp;GRADE was used to evaluate the quality of the evidence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure.1\u0026nbsp;\u003c/strong\u003ePRISMA Flow diagram of studies selection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure. 2\u003c/strong\u003e\u0026nbsp; a Risk of bias in the included trials. b Risk of bias in the included trials.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003eCharacteristics of included studies in systematic review\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"791\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.962025316455696%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eAuthor year\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.481012658227849%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eCountry\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.582278481012659%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eStudy type\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.949367088607595%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eSample size\u003c/p\u003e\n \u003cp\u003e(n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.60759493670886%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eSample Characteristics\u003c/p\u003e\n \u003cp\u003e（GA,wk/BW,g）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.582278481012658%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eHumidity levels（%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.60759493670886%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eDuration of humidity\u0026nbsp;（day）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.227848101265822%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eOutcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.130434782608695%\" valign=\"top\"\u003e\n \u003cp\u003eexperimental\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\" valign=\"top\"\u003e\n \u003cp\u003econtrol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.673913043478262%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eexperimental\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.13768115942029%\" valign=\"top\"\u003e\n \u003cp\u003econtrol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.31159420289855%\" valign=\"top\"\u003e\n \u003cp\u003eexperimental\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.420289855072463%\" valign=\"top\"\u003e\n \u003cp\u003econtrol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.94927536231884%\" valign=\"top\"\u003e\n \u003cp\u003eexperimental\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.681159420289855%\" valign=\"top\"\u003e\n \u003cp\u003econtrol\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.962025316455696%\" valign=\"top\"\u003e\n \u003cp\u003eHelder 2008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.481012658227849%\" valign=\"top\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.582278481012659%\" valign=\"top\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.873417721518987%\" valign=\"top\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.075949367088608%\" valign=\"top\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.60759493670886%\" colspan=\"3\"\u003e\n \u003cp\u003e24-30w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10%\" valign=\"top\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.582278481012659%\" valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.746835443037975%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.860759493670885%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.227848101265822%\" valign=\"top\"\u003e\n \u003cp\u003eInfection\u003c/p\u003e\n \u003cp\u003eMortality\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.962025316455696%\" valign=\"top\"\u003e\n \u003cp\u003eMeyer 2001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.481012658227849%\" valign=\"top\"\u003e\n \u003cp\u003eNew Zealand\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.582278481012659%\" valign=\"top\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.873417721518987%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.075949367088608%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.60759493670886%\" colspan=\"3\"\u003e\n \u003cp\u003e\u0026lt;33w\u003c/p\u003e\n \u003cp\u003eBW\u0026lt;1750g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10%\" valign=\"top\"\u003e\n \u003cp\u003e70-80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.582278481012659%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.746835443037975%\" valign=\"top\"\u003e\n \u003cp\u003e3/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.860759493670885%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.227848101265822%\" valign=\"top\"\u003e\n \u003cp\u003eInfection\u003c/p\u003e\n \u003cp\u003eBPD\u003c/p\u003e\n \u003cp\u003eMortality\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.962025316455696%\" valign=\"top\"\u003e\n \u003cp\u003eKong 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.481012658227849%\" valign=\"top\"\u003e\n \u003cp\u003eAustralia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.582278481012659%\" valign=\"top\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.873417721518987%\" valign=\"top\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.075949367088608%\" valign=\"top\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.60759493670886%\" colspan=\"3\"\u003e\n \u003cp\u003e\u0026le;28 w\u003c/p\u003e\n \u003cp\u003eBW500-1300g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10%\" valign=\"top\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.582278481012659%\" valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.746835443037975%\" valign=\"top\"\u003e\n \u003cp\u003e12.7\u0026plusmn;0.6*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.860759493670885%\" valign=\"top\"\u003e\n \u003cp\u003e12.4\u0026plusmn; 1.3*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.227848101265822%\" valign=\"top\"\u003e\n \u003cp\u003eInfection\u003c/p\u003e\n \u003cp\u003eBPD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.962025316455696%\" valign=\"top\"\u003e\n \u003cp\u003eSung 2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.481012658227849%\" valign=\"top\"\u003e\n \u003cp\u003eKorea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.582278481012659%\" valign=\"top\"\u003e\n \u003cp\u003eCohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.873417721518987%\" valign=\"top\"\u003e\n \u003cp\u003e121\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.075949367088608%\" valign=\"top\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.49367088607595%\"\u003e\n \u003cp\u003e22-24w\u003c/p\u003e\n \u003cp\u003eBW\u0026lt;1000g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.113924050632912%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026gt;26w\u003c/p\u003e\n \u003cp\u003eBW\u0026lt;1000g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10%\" valign=\"top\"\u003e\n \u003cp\u003e95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.582278481012659%\" valign=\"top\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.746835443037975%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.860759493670885%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.227848101265822%\" valign=\"top\"\u003e\n \u003cp\u003eMortality\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.962025316455696%\" valign=\"top\"\u003e\n \u003cp\u003eGaylord 2001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.481012658227849%\" valign=\"top\"\u003e\n \u003cp\u003eAmerica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.582278481012659%\" valign=\"top\"\u003e\n \u003cp\u003eCohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.873417721518987%\" valign=\"top\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.075949367088608%\" valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.60759493670886%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;30w\u003c/p\u003e\n \u003cp\u003eBW\u0026lt;1000g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10%\" valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.582278481012659%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.746835443037975%\" valign=\"top\"\u003e\n \u003cp\u003eNo clear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.860759493670885%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.227848101265822%\" valign=\"top\"\u003e\n \u003cp\u003eInfection\u003c/p\u003e\n \u003cp\u003eBPD\u003c/p\u003e\n \u003cp\u003eMortality\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.962025316455696%\" valign=\"top\"\u003e\n \u003cp\u003eKim 2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.481012658227849%\" valign=\"top\"\u003e\n \u003cp\u003eAmerica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.582278481012659%\" valign=\"top\"\u003e\n \u003cp\u003eCohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.873417721518987%\" valign=\"top\"\u003e\n \u003cp\u003e95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.075949367088608%\" valign=\"top\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.60759493670886%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;30w\u003c/p\u003e\n \u003cp\u003eBW\u0026lt;1000g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10%\" valign=\"top\"\u003e\n \u003cp\u003e70-80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.582278481012659%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.746835443037975%\" valign=\"top\"\u003e\n \u003cp\u003e25.5\u0026plusmn; 1.1*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.860759493670885%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.227848101265822%\" valign=\"top\"\u003e\n \u003cp\u003eInfection\u003c/p\u003e\n \u003cp\u003eBPD\u003c/p\u003e\n \u003cp\u003eMortality\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eGA:gestational age,BW:birth weight,*Data presented as mean\u0026nbsp;\u0026plusmn;\u0026nbsp;S\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e Cohort studies scored according to the the NOS scale\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"589\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.93887945670628%\"\u003e\n \u003cp\u003eStudy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.882852292020374%\"\u003e\n \u003cp\u003eSelection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.466893039049236%\"\u003e\n \u003cp\u003eComparability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.129032258064516%\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.582342954159593%\"\u003e\n \u003cp\u003eScore\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.93887945670628%\"\u003e\n \u003cp\u003eGaylord 2001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.882852292020374%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.466893039049236%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.129032258064516%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.582342954159593%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.93887945670628%\"\u003e\n \u003cp\u003eKim 2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.882852292020374%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.466893039049236%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.129032258064516%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.582342954159593%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.93887945670628%\"\u003e\n \u003cp\u003eSung 2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.882852292020374%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.466893039049236%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.129032258064516%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.582342954159593%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eResults of the meta-analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe effect of a high humidity level on infection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall, five studies\u003csup\u003e10, 2\u003c/sup\u003e\u003csup\u003e2\u003c/sup\u003e\u003csup\u003e-2\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e(n=583)\u0026nbsp;compared\u0026nbsp;the effect\u0026nbsp;of a high humidity level on the incidence of infection in\u0026nbsp;preterm infants.\u0026nbsp;Utilizing the fixed effect model, the outcomes showed no heterogeneity among the studies when the effects of the included literature were combined. The meta-analysis results showed that a high humidity level increased the incidence of infection in\u0026nbsp;preterm infants\u0026nbsp;(\u003cem\u003eRR\u003c/em\u003e = 1.26, 95% \u003cem\u003eCI\u003c/em\u003e 1.02, 1.55, P = 0.03). The incidence of infection\u0026nbsp;was 1.26 times higher in the group with a high humidity level than in the group with a low humidity level\u0026nbsp;(Figure\u0026nbsp;3a).\u003c/p\u003e\n\u003cp\u003eOf the 5 studies considered above, three were\u0026nbsp;RCTs\u0026nbsp;(n=246) which\u0026nbsp;compared\u0026nbsp;the\u0026nbsp;effect\u0026nbsp;of a high humidity level on infection rates in premature\u0026nbsp;infants. The findings of the meta-analysis revealed that using a high humidity level may increase the incidence of infection in\u0026nbsp;preterm infants\u0026nbsp;(\u003cem\u003eRR\u0026nbsp;\u003c/em\u003e= 1.47, 95% \u003cem\u003eCI\u0026nbsp;\u003c/em\u003e1.01, 2.14, P = 0.04), which was 1.47 times higher in the group with a high humidity level than in the group with a low humidity level.\u003c/p\u003e\n\u003cp\u003eAlso included above, two cohort studies\u0026nbsp;(n=337)\u0026nbsp;compared\u0026nbsp;the\u0026nbsp;effect\u0026nbsp;of a high humidity level on infection rates in premature\u0026nbsp;infants.\u0026nbsp;According to the meta-analysis findings, there were no significant differences\u0026nbsp;between the groups with high and low humidity levels (\u003cem\u003eRR\u003c/em\u003e = 1.16, 95% \u003cem\u003eCI\u0026nbsp;\u003c/em\u003e0.91, 1.5, P = 0.23).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe effect of a high humidity level on the incidence of BPD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFour studies\u003csup\u003e10, 2\u003c/sup\u003e\u003csup\u003e2\u003c/sup\u003e\u003csup\u003e-2\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e(n=417)\u0026nbsp;compared the\u0026nbsp;effect\u0026nbsp;of\u0026nbsp;a high humidity level on the incidence of BPD in\u0026nbsp;preterm infants. The combined effects of the included literature revealed no evidence of study heterogeneity (P = 0.29, I\u0026sup2; = 19%), and thus we\u0026nbsp;used\u0026nbsp;the fixed effect model.\u0026nbsp;The results revealed\u0026nbsp;that\u0026nbsp;there\u0026nbsp;was no significant difference between the groups with high and low humidity levels (\u003cem\u003eRR\u003c/em\u003e = 1.07, 95% \u003cem\u003eCI\u003c/em\u003e 0.86, 1.33, P = 0.53)\u0026nbsp;(Figure\u0026nbsp;3b).\u003c/p\u003e\n\u003cp\u003eOf the four studies included above, two RCTs\u003csup\u003e2\u003c/sup\u003e\u003csup\u003e2\u003c/sup\u003e\u003csup\u003e,2\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e(n=110) compared\u0026nbsp;the\u0026nbsp;effect\u0026nbsp;of a high humidity level on the incidence of BPD in\u0026nbsp;preterm infants. According to the meta-analysis findings, using a high humidity level may put\u0026nbsp;preterm infants\u0026nbsp;at greater risk of BPD (\u003cem\u003eRR\u003c/em\u003e = 1.7, 95% \u003cem\u003eCI\u003c/em\u003e 1.01, 2.86, P = 0.05).\u0026nbsp;Within the two cohort\u0026nbsp;trials, also included above,\u003csup\u003e10, 2\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e(n=307) each compared the\u0026nbsp;effect\u0026nbsp;of\u0026nbsp;a\u0026nbsp;high humidity level on the incidence of\u0026nbsp;BPD\u0026nbsp;in\u0026nbsp;preterm infants.\u0026nbsp;The results revealed that there\u0026nbsp;was no significant difference between the groups with high and low humidity levels within the cohort studies (\u003cem\u003eRR\u003c/em\u003e = 0.97, 95%\u003cem\u003e\u0026nbsp;CI\u003c/em\u003e 0.76, 1.24, P = 0.82).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe effect of a high humidity level on mortality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFive studies\u003csup\u003e10, 2\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e\u003csup\u003e-2\u003c/sup\u003e\u003csup\u003e6\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e(n=751)\u0026nbsp;compared the\u0026nbsp;effect\u0026nbsp;of\u0026nbsp;a high humidity level on the incidence of\u0026nbsp;mortality predischarge\u0026nbsp;in\u0026nbsp;preterm infants. The combined effects of the included literature revealed no evidence of study heterogeneity (P=0.14,\u0026nbsp;I\u003csup\u003e2\u003c/sup\u003e=42%) and thus we used the fixed effect model.\u0026nbsp;The results revealed\u0026nbsp;that\u0026nbsp;there was no significant difference between the groups with high and low humidity levels (\u003cem\u003eRR\u003c/em\u003e = 1.46, 95% \u003cem\u003eCI\u003c/em\u003e 0.82, 2.6, P = 0.84) (Figure 3c).\u003c/p\u003e\n\u003cp\u003eOf the above included studies, the two RCTs\u003csup\u003e2\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e\u003csup\u003e, 2\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e(n=196)\u0026nbsp;examined the effect of a high humidity level on mortality. The results revealed that there was no significant difference between the groups with high and low levels of humidity (\u003cem\u003eRR\u0026nbsp;\u003c/em\u003e= 1.32, 95% \u003cem\u003eCI\u003c/em\u003e 0.1, 17.66, P = 0.84). However, in the three cohort studies\u003csup\u003e10,2\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e2\u003c/sup\u003e\u003csup\u003e6\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003ecomparing the effect of a high humidity level on mortality, the results revealed that a high humidity level significantly increased the mortality rate of preterm infants, which was 1.73 times higher in infants with a high humidity level than in infants with a low humidity level (RR = 1.73, 95% CI 1.17, 2.57, P = 0.006). \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure.3\u003c/strong\u003e Forest plot. a The effect of high humidity environments on the incidence of infection. b The effect of high humidity environments on the incidence of BPD.c The effect of high humidity environments on mortality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSensitivity analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter sensitivity analysis, as shown in Figure 4a,b and c, no significant effects on heterogeneity were demonstrated across studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure.4\u003c/strong\u003e Sensitivity analysis. a The incidence of infection. b The incidence of BPD. c \u0026nbsp;The incidence of mortality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication bias\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of the Egger test revealed that the infection rate (P = 0.286 \u0026gt; 0.05), BPD incidence rate (P = 0.208 \u0026gt; 0.05), and mortality rates (P = 0.993 \u0026gt; 0.05) were all unaffected by publication bias.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis systematic review aimed to investigate the effect of incubator humidity levels on the morbidity and mortality in preterm infants. Quantitative synthesis analysis of all included studies were conducted, and stratified by study design, and then assessed the stability of the results.\u003c/p\u003e \u003cp\u003eAccording to the meta-analysis of the studies that were included, there was a significant increase in the risk of infection in preterm infants when the incubator humidity level was high, and this result was particularly evident in RCTs (quality of evidence: moderate). This result was consistent with the research of Lynam\u003csup\u003e13\u003c/sup\u003e and Etienne\u003csup\u003e14\u003c/sup\u003e. Continuously high humidity can lead to faster growth and reproduction of microorganisms, which increases the risk of sepsis in preterm infants because humidity increases condensation inside the incubator.\u003csup\u003e13, 14\u003c/sup\u003e Due to the impact of high heat and humidity on the relatively colder inner wall of the incubator, more condensation may be produced. Prazad\u003csup\u003e27\u003c/sup\u003e found that volatile organic compound concentrations in the air increased when the humidity in the chamber was raised to 50%. When the average temperature and relative humidity of the incubator were set to high, the level of microbial contamination increased significantly. Pritik\u003csup\u003e28\u003c/sup\u003e noticed that the diversity of skin fungi was higher in environments with higher humidity when monitoring the skin flora of extremely preterm infants, indicating that humidity is closely related to the reproduction and growth of fungi. According to previous studies, mold grows in conditions with at least 70% humidity, while yeast and gram-positive and gram-negative bacteria grow in environments with 80\u0026ndash;95% humidity.\u003csup\u003e29\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHowever, the design of humidification systems in modern incubators have changed over time to decrease the risk of infection.\u003csup\u003e31\u003c/sup\u003e Double-walled incubators reduce condensation and incorporate hot-water equipment, which kills most organisms and keeps bacteria out of the air.\u003csup\u003e13\u003c/sup\u003e Significantly, there is still a risk of external microorganisms being introduced into this warm, moist environment by caregivers\u0026rsquo; hands. To eliminate the impact of different incubators on the results for infection risk, a sensitivity analysis was conducted to determine whether the results were stable. Five studies\u003csup\u003e10, 22\u0026ndash;24,26\u003c/sup\u003e used double-walled incubators, whereas Gaylord et al\u003csup\u003e25\u003c/sup\u003e used single-walled incubators. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows that excluding the study by Gaylord et al\u003csup\u003e25\u003c/sup\u003e did not affect the results. It is unclear whether the incubators used in the studies provided sterile humidity. Due to the studies being published between 2001 and 2013, further trials are needed to verify whether the conclusions of this article that high humidity levels may increase infection rates are applicable to modern incubators.\u003c/p\u003e \u003cp\u003eAdditional factors to examine, studies showed that the gestational age of the included subjects may affect the findings.\u003csup\u003e11, 29\u003c/sup\u003e Preterm infants with a lower gestational age need to be cared for in an incubator environment with a longer duration and higher initial humidity level, which may affect the incidence of infection. The maturity of skin barrier function in preterm infants depends on their gestational age. Regarding skin development, the epidermis matures gradually in the last quarter of pregnancy.\u003csup\u003e11\u003c/sup\u003e Preterm infants born at a younger gestational age have less developed skin. The immaturity of skin barrier function in preterm infants is mainly related to the development of the stratum corneum. The stratum corneum, one of the skin structures, dissipates heat through evaporation, controls transepidermal water loss, and protects the body from pathogens and toxins. At approximately 24 weeks of gestation, stratum corneum development begins. Extremely-low-birth-weight infants with a gestational age of less than 24 weeks barely have stratum corneum, and premature infants born at less than 30 weeks gestation have only two to three stratum corneum layers.\u003csup\u003e12\u003c/sup\u003eThere is evidence that by 30 to 32 weeks of gestational age, the stratum corneum has almost fully developed.\u003csup\u003e30\u003c/sup\u003eThe AWHONN guideline mentioned that the length of time it takes for skin to mature, usually takes one weeks for preterm infants born at 25\u0026ndash;29 weeks, 2\u0026ndash;3 weeks for preterm born at 24 weeks and less. But small for gestational age infants' skin matures much faster than other babies.\u003csup\u003e17\u003c/sup\u003e Additionally, preterm infants need incubators with high initial humidity levels for extended periods, which may affect the incidence of infection. However, in the current research on the effect of incubator humidity on preterm infants, the gestational age of the included subjects was quite different, suggesting that future studies should be stratified based on gestational age. Notably, the following precautions might decrease the risk of neonatal infections and even late sepsis when the incubator is set to a high humidity level: reducing the duration of a high humidity level, thoroughly cleaning the incubator, and replacing the sterile water daily.\u003csup\u003e29, 32\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis study did not find that a high incubator humidity level had significant effect on either the incidence of BPD or the mortality rate of preterm infants (quality of evidence: low). This is consistent with Kao\u0026rsquo;s research conclusion.\u003csup\u003e7\u003c/sup\u003e The principle of providing humidity is based on thermal regulation and reducing heat loss due to evaporation. In a dry and cold environment, the rate of evaporation heat exchange between the skin surface and the ambient air can be very high.\u003csup\u003e33\u003c/sup\u003e Increasing the incubator humidity level in the early stages after birth can continuously reduce insensible water loss, reduce the daily fluid requirements of extremely preterm infants, improve water and electrolyte balance and maintain thermal stability, reducing mortality rates.\u003csup\u003e10\u003c/sup\u003e There is not yet sufficient evidence to confirm the direct impact of a high incubator humidity levels on the incidence of BPD or the mortality rate of preterm infants. Further high-quality RCTs will be required to verify the outcome.\u003c/p\u003e \u003cp\u003eHowever, the findings obtained for the two research types\u0026mdash;RCTs and cohort studies\u0026mdash;were distinct in this study after conducting stratified analysis. The subgroup analysis of RCTs showed higher risk of BPD and the cohort studies showed a higher mortality rate. There are two possible reasons for this difference: first, the sample size of the included RCTs was far smaller than that of the included cohort studies, which could explain the discrepancy. Three RCTs (n\u0026thinsp;=\u0026thinsp;246) and three cohort studies (n\u0026thinsp;=\u0026thinsp;555) were included in this study. Second, the baselines of two RCTs\u003csup\u003e22,24\u003c/sup\u003e and three cohort studies\u003csup\u003e10,25,26\u003c/sup\u003ewere unbalanced. According to the assessment of included studies' quality of evidence, the combined effect size of the two RCTs was large (RR\u0026thinsp;=\u0026thinsp;1.7) when analyzing how different humidity levels impacted the incidence of BPD in preterm infants. However, the sample size of this experimental group (n\u0026thinsp;=\u0026thinsp;55) and control group (n\u0026thinsp;=\u0026thinsp;55) was insufficient to meet the optimal information size standard, so the grade was downgraded by one level due to severe inaccuracy. When examining the effect of various humidity levels on the mortality of preterm infants, two RCTs were combined to achieve an I\u0026sup2; of 66%, and the high heterogeneity produced severe inconsistency, so the grade was downgraded by one level. As some control groups were in a non-humidified environment and some were in a humidified environment, two RCTs and three cohorts were both downgraded by one level having serious indirectness. Even so, the heterogeneity between RCTs and cohort studies were not significant, less than 50%. This means that there may be some confounding factors in the different research designs that affect the results, and more research is needed to guide practice recommendations. Overall, merging all the studies yielded more reliable results. Therefore, the combined results from cohort studies and RCTs may represent the true situation rather than RCTs or cohort studies alone.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eImplications for Practice\u003c/h2\u003e \u003cp\u003eEvidence has demonstrated that when the initial incubator humidity level is high\u0026mdash;at more than 70%\u0026mdash; the incidence of infection in preterm infants is significantly increased. When creating a humidity delivery plan for preterm infants, the impact of high humidity levels on the infection rate of preterm infants should be carefully considered. To reduce the risk of infection in preterm infants, we can implement incubator disinfection and reduce the duration of a high humidity level when making a plan for humidity management.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eImplications for Research\u003c/h2\u003e \u003cp\u003eMore large clinical trials and humidity-related research including preterm infants of differing gestational ages particularly those from younger gestational ages must be conducted in the future.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eLimitations of this study\u003c/h2\u003e \u003cp\u003eThe search revealed that the number of pertinent experimental studies in the field, particularly RCTs, was small. The humidity levels in the control group of existing research designs varied significantly because there are no correlative standards regarding humidity for the care of preterm infants. Although still acceptable, the heterogeneity of the study designs may have led to smaller effect sizes. Due to the lack of data regarding the effects of factors such as humidity duration and humidity adjustment schemes on the outcomes, subgroup analysis on gestational age and birth weight was not conducted.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis review summarized the available evidence relating to the effect of humidity levels on complications and mortality in preterm infants. This study found that high humidity levels had a significant impact on the incidence of infection but had no impact on mortality or the incidence of bronchopulmonary dysplasia.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n \u003cli\u003eNICUs\u0026nbsp;\u0026ndash; Neonatal Intensive Care Units\u003c/li\u003e\n \u003cli\u003eBPD-bronchopulmonary dysplasia\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eIVH-intraventricular hemorrhage\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePVL-periventricular leukomalacia\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTEWL-transepidermal water loss\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRCTs-randomized controlled trials\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eAll data generated or analyzed during this study are included in this published article and its supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003eThere \u0026nbsp;is no \u0026nbsp;support by a grant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003eZ.C. designed the study, collected, and analyzed data, drafted the initial manuscript, and reviewed and revised the manuscript; R.L. collected and analyzed\u0026nbsp;\u003c/p\u003e\n\u003cp\u003edata, reviewed, and revised the manuscript; H.W. reviewed and revised the manuscript; B.S. and Q.C. made supportive contributions and contributed to the critical revision of the manuscript.All authors have read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003eNot Applicable\u003c/p\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eOther information\u003c/h2\u003e \u003cp\u003eThe article was registered with PROSPERO. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Different from the protocol, the final outcome indicators that were not presented were the incidence of hypernatremia, intravascular hemolysis and patent ductus arteriosus. During the search process, it was found that few studies observed and described these indicators, resulting in the inability to conduct a meta-analysis [PROSPERO: CRD42023401195].\u003c/p\u003e \u003cp\u003eThere were no sources of financial or nonfinancial support for the review. The review authors have no competing interests.\u003c/p\u003e "},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHowson CP, Kinney MV, Mcdougall L, Lawn JE, Born Too Soon Preterm Birth Action Group. Born too soon: preterm birth matters. 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Indian J Pediatr. 2021;88(7):690\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12098-021-03766-w\u003c/span\u003e\u003cspan address=\"10.1007/s12098-021-03766-w\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"preterm infants, incubator humidity, morbidity, mortality, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-4558106/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4558106/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo assess the association between different incubator humidity levels and clinical outcomes in preterm infants.\u003c/p\u003e\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSince there is no well-accepted standard for delivery of incubator humidity for preterm infants. A meta-analysis is needed to summarize status of current research.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eSearched 5 databases, including PubMed, the Cochrane Library, Embase, Ovid, and Web of Science, published between January 2000 and December 2023. Randomized control trials, prospective cohort studies and retrospective cohort studies were included if they assessed how different incubator humidity levels affected preterm infants with a gestational age\u0026thinsp;\u0026lt;\u0026thinsp;34 weeks, published in English. Infection rates, the incidence of bronchopulmonary dysplasia and predischarge mortality were evaluated.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIncluded in this review were 3 randomized control trials and 3 cohort studies including 801 preterm infants. Findings revealed that a high humidity level increased the incidence of infection in preterm infants (\u003cem\u003eRR\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.26, 95% \u003cem\u003eCI\u003c/em\u003e 1.02, 1.55, P\u0026thinsp;=\u0026thinsp;0.03). No significant difference was found between a high humidity incubator humidity levels and the incidence of bronchopulmonary dysplasia or infant mortality.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis study found that high humidity levels had a significant impact on the incidence of infection.\u003c/p\u003e\u003ch2\u003eImplications for Practice and Research\u003c/h2\u003e \u003cp\u003e: Evidence from the two decades showed that high humidity levels significantly increased the incidence of infection in preterm infants. When considering a humidity delivery plan, the impact of high humidity levels on the incidence of infection should be carefully considered. High-quality, large-sample and multicenter trials are needed for further validation.\u003c/p\u003e","manuscriptTitle":"The effect of incubator humidity on morbidity and mortality in preterm infants: A systematic review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-15 23:41:18","doi":"10.21203/rs.3.rs-4558106/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-01T18:53:53+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-31T10:17:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"178837902952517733756429264511152740013","date":"2024-12-22T05:17:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-09T16:54:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"320889649745902646126761212255255906512","date":"2024-12-08T11:04:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"88056565193296551047898465025504195065","date":"2024-11-30T08:08:28+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-25T18:40:24+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-19T16:23:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-17T15:13:39+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-17T15:13:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2024-06-10T12:42:37+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bd7ff8fa-7023-4518-af2f-b5cf217a991f","owner":[],"postedDate":"July 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-07T16:02:21+00:00","versionOfRecord":{"articleIdentity":"rs-4558106","link":"https://doi.org/10.1186/s12887-025-05538-3","journal":{"identity":"bmc-pediatrics","isVorOnly":false,"title":"BMC Pediatrics"},"publishedOn":"2025-03-31 15:57:49","publishedOnDateReadable":"March 31st, 2025"},"versionCreatedAt":"2024-07-15 23:41:18","video":"","vorDoi":"10.1186/s12887-025-05538-3","vorDoiUrl":"https://doi.org/10.1186/s12887-025-05538-3","workflowStages":[]},"version":"v1","identity":"rs-4558106","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4558106","identity":"rs-4558106","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}