==== Front PLoS One PLoS One plos PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0286997 PONE-D-23-01167 Research Article Physical Sciences Materials Science Materials Surfactants Biology and Life Sciences Developmental Biology Neonates People and Places Population Groupings Age Groups Children Infants People and Places Population Groupings Families Children Infants Biology and Life Sciences Population Biology Population Metrics Death Rates People and Places Geographical Locations Asia Iran Social Sciences Economics Health Economics Medicine and Health Sciences Health Care Health Economics Medicine and Health Sciences Health Care Health Care Policy Medicine and Health Sciences Pediatrics Comparing the clinical and economic efficiency of four natural surfactants in treating infants with respiratory distress syndrome Selecting the natural surfactants in treating infants with respiratory distress syndrome Izadi Reyhane Conceptualization Data curation Writing – original draft 1 https://orcid.org/0000-0001-6426-0256 Shojaei Payam Methodology Software Supervision 2 * https://orcid.org/0000-0002-3511-7925 Haqbin Arash Methodology 2 Habibolahi Abbas Investigation Supervision 3 Sadeghi-Moghaddam Parvaneh Investigation Supervision Writing – review & editing 4 1 Department of Health Care Management, School of Management and Information Sciences, Shiraz University of Medical Sciences, Shiraz, Iran 2 Department of Management, Shiraz University, Shiraz, Iran 3 Neonatal Health Department, Ministry of Health and Medical Education, Tehran, Iran 4 Neonatologist, Maternal Fetal and Neonatal Research Center, Tehran University of Medical Sciences, Tehran, Iran Grosek Stefan Editor University Medical Centre Ljubljana (UMCL) / Faculty of Medicine, University Ljubljana (FM,UL), SLOVENIA Competing Interests: The authors have declared that no competing interests exist. * E-mail: pshojaei@shirazu.ac.ir 30 6 2023 2023 18 6 e028699713 1 2023 27 5 2023 © 2023 Izadi et al 2023 Izadi et al https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Surfactant therapy has revolutionized the treatment of respiratory distress syndrome (RDS) over the past few decades. Relying on a new method, the current research seeks to compare four common surfactants in the health market of Iran to determine the best surfactant according to the selected criteria. The research was a cross-sectional, retrospective study that used the data of 13,169 infants as recorded on the information system of the Iranian Ministry of Health. To rank the surfactants used, the following indicators were measured: re-dosing rate, average direct treatment cost, average length of stay, disease burden, need for invasive mechanical ventilation, survival at discharge, and medical referrals. The CRITIC (criteria importance through intercriteria correlation) method was used to determine the weight of the indicators, and MABAC (multi-attributive border approximation area comparison) was used to prioritize the surfactants. Based on the seven selected indicators in this research (re-dosing rate, average length of stay, direct medical cost per one prescription, medical referral rate, survival at discharge, disability-adjusted life years, number of newborns in need of invasive mechanical ventilation) and using multi-criteria analysis method, Alveofact was identified as the worst surfactant in infants with either more or less than 32 weeks’ gestation. So that some criteria were worse in Alveofact group infants than other groups; for example, in the comparison of the Alveofact group with the average of the total population, it was found that the survival rate at discharge was 57.14% versus 66.43%, and the rate of re-dosing was 1.63 versus 1.39. BLES (bovine lipid extract surfactant) was the best alternative for infants more than 32 weeks’ gestation, whereas Survanta was identified as best option for infants with less than 32 weeks’ gestation. Curosurf showed an average level of functionality in the ranking. This study advises the policy makers in the field of neonatal health to increase the market share of more effective surfactants based on this study and other similar studies. On the other hand, neonatal health care providers are also advised to prioritize the use of more effective surfactants if possible, depending on the clinical conditions and desired improvements. The author(s) received no specific funding for this work. Data AvailabilityAll relevant data are within the paper and its Supporting information files. Data Availability All relevant data are within the paper and its Supporting information files. ==== Body pmc1. Introduction Respiratory distress is one of the most common causes of hospitalization in neonatal intensive care units (NICU). Reports suggest that 15% of full-term newborns and 29% of preterm newborns admitted to NICUs have acute respiratory complications [1]. The most prevalent types of respiratory distress are pneumonia, transient tachypnea of the newborn, meconium aspiration syndrome, and neonatal respiratory distress syndrome (RDS) [2]. Approximately 60% of infants with a gestational age of less than 30 weeks and 40% of infants weighing less than 1,500 g experience RDS [3]. RDS is a pulmonary disorder caused by alveolar surfactant deficiency, which can result in reduced alveolar surface tension, micro atelectasis, and decreased lung volume [4]. RDS often occurs due to defects in lung structure and an insufficient use of pulmonary surfactants [5, 6]. In addition, there are some RDS risk factors including diabetic mothers, preterm delivery, and the male gender [7]. Postnatal RDS involves symptoms such as blue skin and oral mucosa, rapid heartbeat, wheezing, chest indentation [8], pneumothorax, and intracranial hemorrhage [9]. In order to treat and prevent this disease, surfactant replacement therapy is used [10] Numerous studies have compared the types of surfactants [11–13]; some have reported that different types of surfactants were almost equally effective [14], while others suggested significant differences between them [15]. Zayek et al. stated that due to the existence of several alternative products of pulmonary surfactant, they compared calfactant and poractant alfa with the aim of determining the strong pharmacological advantage in terms of cost and clinical indicators, and the results indicated the superiority of calfactant [16]. Although the effectiveness of surfactants in the prevention and treatment of RDS in infants has been well established, it is still unknown which surfactant is more effective [17]. On the other hand, scoring systems can be used to measure the performance of single therapeutic intervention over a time period, or used to compare the performance of one therapeutic intervention to others [18]. Scoring systems are used in all areas of medicine. Several parameters are evaluated and rated with points according to their value in order to simplify a complex clinical situation with a score [19]. The establishment of scoring system in medical areas is of great significance to effectively determine the severity of the disease, the rate of treatment success, and guide the treatment of doctors [20]. In this study, using selected performance indicators extracted from similar studies [16, 21–24] and a scoring-ranking system of medical interventions [25–29], the most effective surfactant in the treatment of RDS in infants has been determined. To this end, CRITIC method was adopted to calculate the weight of each indicator, and MABAC method was used in order to prioritize the surfactants. These two methods were adopted in this study due to the fact that CRITIC and MABAC were successfully combined in previous studies and made reliable results [25]. However, separately, CRITIC was applied in drug prioritization [26] and MABAC was used in several areas including medicine logistics management [27], healthcare sectors evaluation [28], supplier selection [29]. According to the unpublished statistics of the Ministry of Health and interviews with policy makers in the field of neonatal health, the prescription of surfactant in neonates has been growing rapidly in Iran in recent years, and on the other hand, surfactant is one of the vital and expensive drugs in Iran’s pharmaceutical pharmacopoeia. Therefore, it is important to determine the type of superior surfactant that provides positive clinical results and is also economically viable, as it can help specialists and decision makers to make appropriate decisions. In addition, although many studies have been conducted on various aspects of respiratory distress in neonates and the effect of different surfactants on it, most of the studies in this regard have only described and compared the results by different types of surfactants. This study was conducted with the aim of determining the best and worst surfactants in the treatment of respiratory distress syndrome in infants in Iran’s health system. In this research, based on economic and clinical indicators, surfactants have been ranked for the first time with a new method. 2. Materials and methods 2.1 Research design and patient population This study was a cross-sectional, retrospective research that tried to evaluate the effectiveness of four types of surfactants and rank them. The population under study included all infants with RDS who underwent surfactant therapy in Iran in 2018. This study is registered under the ethic approval code “IR.TUMS.IKHC.REC.1400.380” on 26/12/2021 by Tehran University of Medical Sciences, and all the methods used in the present study are in accordance with relevant guidelines and regulations. The data of these infants were extracted using the census method, in fact, sampling was not done, and all eligible infants were included in the study using the census method. The entry and exit criteria were as follows: Inclusion criteria: All infants with RDS in Iran who had undergone surfactant therapy; Exclusion criteria: The following cases were excluded from the study: Infants with RDS who were discharged with the consent of their parents (or legal guardians) before full recovery, those who were not primarily diagnosed with RDS, and those with an unidentified gestational age. Also, infants who were referred to another center before surfactant administration were excluded from the study. The research data were extracted from the Iranian Maternal and Neonatal Network (IMAN net), as per the necessary permits and with the support of the Iranian Ministry of Health. It should be noted that the design of this national network is such that it is mandatory to record information for many variables, so the missing data in this study is minimal. Because the outcomes of surfactant injection could be different among different age groups [21], the data were analyzed separately for two groups of infants: those with a gestational age more than 32 weeks and those with a gestational age less than 32 weeks. To ensure that there is no significant difference in the baseline in the neonates of the four surfactant groups, four indicators of gestational age, birth weight, Apgar 1st minute and Apgar 5th minute were used, which indicate the general health status of the newborns at birth and before surfactant administration; And it was determined in advance that before the administration of surfactant, there was no statistically significant difference in the health status of infants in different surfactant groups (see some other variables in Table S3.1 in S3 File). 2.2 Study variables and measured outcomes The purpose of this study was to rank four natural surfactants used in Iran (Alveofact, Survanta, Curosurf and BLES) in the RDS treatment process. The indicators investigated in this research were extracted from the literature on this topic. The indicators that were included in the main analyzes of the article were previously determined to be statistically significantly different between the four groups of infants. Although there were some other relevant indicators, they were removed from the analysis due to the lack of statistically significant differences (see Table S3.1 in S3 File). The selected indicators are as follows: Redosing rate: A surfactant would be most efficacious when it required less redosing; Average length of stay (ALOS): This indicator referred to the length of hospital stay; Average direct cost of treatment: For each prescription, two types of cost were computed: fixed cost and variable cost. Fixed cost included consumables (chip tubes, NG tubes, etc.), which were the same for all prescriptions. Variable cost included the price of the surfactant vial in 2018, which varied according to the type of surfactant. By combining these two types of cost, the direct cost of treatment was determined in each case the surfactant was administered. Following that, given the number of doses for each infant, the average direct cost of treatment for each infant was determined. Finally, the average direct cost of treatment (as well as the total direct cost of treatment) was determined based on the type of surfactant used; Medical referral rate (severity of illness): In the Iranian health system, newborns receive surfactant only at specialized hospitals that have an NICU. According to interviews with the directors of the Neonatal Health Department (affiliated with the Ministry of Health) and the unpublished data from the Ministry, referrals after surfactant administration often occur due to clinical reasons and the severity of patients’ conditions. Therefore, the high rate of referrals in relation to a particular type of surfactant would indicate that the surfactant was not sufficiently effective. As a result of the lack of improvement or worsening of the health condition of the babies after receiving surfactant, these babies are referred to the specialized hospitals that have more advanced equipment, more facilities, more specialized manpower and more up-to-date technologies. In Iran’s health system, these hospitals are defined regionally and based on geographical proximity. Survival at discharge: A discharge order (issued by a doctor) represents the most ideal outcome for a newborn given his/her good health condition. A surfactant type that could lead to the ordered discharge of a greater percentage of newborns could be more effective in treating RDS. This criterion would help to determine the chances of the baby surviving after the administration of the surfactant in question. The term “survival” in this criterion was used to describe patients who were alive at the time of discharge from the hospital [30]. Disability-adjusted life years (DALY) (per 1,000 neonates with RDS): DALY measured the gap between the current state and the ideal state, or the state in which all people would live up to standard age in perfect health. According to life tables on the World Bank website, the standard life expectancy at birth in Iran is 75.40 years for men and 77.66 for women. This index, like other indicators, was calculated separately for all the four groups of surfactants under investigation. The DALY index, which is very important in prioritizing health interventions, was a combination of life time with disability and time lost due to premature death, calculated as follows: DALY=YLL+YLD where: YLL = years of life lost due to premature mortality. YLD = years lived with disability. In this study, this index was calculated by the method of the World Health Organization, taking into account the discounting rate of three percent and unequal age weighting [31]. The YLL formula is as follows: YLL=N/r*1–e−rL where: N = number of deaths. L = standard life expectancy at age of death (years). r = discount rate (discount rate of 0.03). In this formula N is considered as the number of neonatal deaths in four surfactant groups. The formula of YLD is as follows: YLD=IxDWxL1−e−rL/r where: I = number of incident cases (-). DW = disability weight (-). L = duration of disability (years). r = discount rate e = The number e, also known as Euler’s number, is a mathematical constant that is approximately equal to 2.71828. In this formula, I is the number of newborns in all four surfactant groups and L is ALOS. According to the WHO disability weight scale, the DW for lower respiratory tract infections is 0.28 [31]. Because RDS is a lower respiratory tract infection [32], in this study DW was considered to be 0.28. Number of newborns in need of invasive mechanical ventilation: A large number of newborns in need of invasive mechanical ventilation or a long period of invasive mechanical ventilation could reflect the low efficiency of an injected surfactant. 2.3 Data analysis The data were primarily classified and analyzed in Excel and SPSS through items of descriptive statistics such as frequency, percentage, mean, and standard deviation. Following that, the CRITIC method was used to determine the weights of the indicators, while the MABAC method helped to rank the surfactants; Microsoft Excel was used to apply both analysis methods. 2.3.1 CRITIC method The CRITIC method was initially developed in 1995 by Diakoulaki et al. as a technique for calculating the weight of indicators in multi-criteria decision-making problems. In this method, the opinion of experts is not important and the relative weight of indicators is determined by correlation coefficients and standard deviation of data [33]. According to Diakoulaki et al. (1995), the steps of CRITIC method are as follows: Step 1: Similar to other multi-criteria decision-making methods, a decision matrix containing n indicators and m alternatives is developed in the first step. The decision matrix is then normalized using Eq (1) where xij is the value of each element of matrix, x min and x max are the minimum and maximum values of the matrix in each column, respectively. rij=xij−xminxmax−xmin (1) Step 2: In the next step, the value of c for each column of the decision matrix is calculated using Eq (2). rij represents elements of the normalized decision matrix, σ is the standard deviation of the data of each column and m is the number of indicators. c=σ∑i=1m(1−rij) (2) Step 3: In the final step, the value of c obtained for each column of the matrix is divided by the sum of the values of c, in order to obtain the final weight of each indicator, which is shown in Eq (3). w=c∑i=1mc (3) 2.3.2 MABAC method The MABAC method is a recently developed multi-criteria decision-making technique used to rank alternatives in multi-criteria decision-making models. The basis of the MABAC method originated from the definition of the distance of the indicator function of each alternative from the border approximation area. MABAC was developed by Pamučar & Ćirović (2015).[34]The steps of the MABAC method are presented as follows: Step 1: The initial decision matrix—including indicators and alternatives—is formed, where xij is the value of alternative i (i = 1, …, m) according to indicator j (j = 1, …, n). Step 2: The initial decision matrix is normalized according to Eqs (4) and (5) for the positive and negative indicators, respectively. nij=xij−minxijmaxxij−minxij,forbenefit (4) nij=maxxij−xijmaxxij−minxij,forcost (5) Step 3: Calculating the weighted normalized matrix (V). The elements of matrix V are determined based on Eq (6): Vij=wjnij+1 (6) where nij is the elements of normalized matrix and wj is the weight of indicator j. Step 4: Calculating the border approximation area (BAA) matrix. The BAA for all indicators (G) is determined based on Eq (7): gj=∏i=1mVij1m (7) Matrix G is formed as follows: G=g1⋯gn⋮⋱⋮g1⋯gn where n is the number of indicators. Step 5: Calculating the distance of alternative i from the BAA. This distance (qij) is determined as the difference between the elements of matrix V and matrix G (Eq (8)). Q=V−G=v11⋯v1n⋮⋱⋮vm1⋯vmn−g1⋯gn⋮⋱⋮g1⋯gn=q11⋯q1n⋮⋱⋮qm1⋯qmn (8) If qij > 0, alternative A is close to the ideal solution. If qij < 0, alternative A is close to the anti-ideal solution. Step 6: Prioritizing the alternatives. The sum of the distance of the alternatives from the BAA (the elements of matrix Q) is calculated based on Eq (9). The higher this value for each alternative i, the higher the ranking of that alternative. Si=∑j=1nqij,i=1,…,m (9) 3. Results 3.1 Patient demographics and clinical characteristics According to the inclusion and exclusion criteria of the study, the number of infants studied in this research decreased from 16551 to 13169 cases. The number of 1133 babies due to not having RDS problem, 1093 babies due to voluntary discharge, 1100 babies due to uncertain gestational age, and finally 56 cases due to referral to another hospital before surfactant administration, all these babies (3382 cases) were excluded from the study. The descriptive statistics of the study showed that 42.05% of the newborn infants were girls, the mean gestational age was 32.24 (±4.55) weeks, and the mean birth weight was 1876.94 (±813) grams. More than 74% of the infants were born by Cesarean section and the mean Apgar scores of the first and fifth minutes were 6.94 and 8.31, respectively. Table 1 shows the descriptive statistics of the surfactant groups. 10.1371/journal.pone.0286997.t001 Table 1 Patient characteristics of the overall study population and surfactant cohorts. Variables Overall Study Population (N = 13169) Alveofact BLES Curosurf Survanta (N = 308) (N = 2124) (N = 7788) (N = 2949) Gender  Female 5533(42.05) 131(42.53) 876(41.24) 3167(40.66) 1359(46.08) Gestational age  Mean, wk a 32.24 (±4.55) 32.19 (±4.41) 32.19 (±4.77) 32.27 (±4.58) 32.44 (±4.44)  ≤ 32 weeks 7227(54.87) 177(57.46) 1213(57.10) 4389(56.35) 1448(49.10) Birth weight  Mean, gr b 1876.94 (±813) 1856.42 (±715) 1836.06 (±852) 1906.37 (±839) 1908.91 (±849)  ≤ 1500gr 5376(40.82) 124(40.25) 976(45.95) 3275(42.05) 1465(49.67) Delivery method  Cesarean 9842(74.73) 233(75.64) 1567(73.77) 5752(73.85) 2290(77.65) Apgar Score  First minute Apgar c 6.94 6.94 6.94 6.93 6.95  Five-minute Apgar d 8.31 8.28 8.33 8.33 8.32 *Data are presented as number (%) 1 Vaginal birth after cesarean P-value: a = 0.07 / b = 0.09/ c = 0.18 / d = 0.13 3.2 Description of criteria The measurement of the outcomes after surfactant injection revealed that, except for ALOS, other outcomes were significantly different in relation to the types of surfactants. It was found that ALOS was 13.71 days. The average direct treatment cost was $398.49. Alveofact was the most expensive type and required the largest amount of re-dosing. The survival rate was 66.43%, as 26.10% of the infants died and 7.45% needed referrals due to the severity of their condition. The DALY index showed that 14820.53 days of healthy living were lost due to NRDS. The outcomes of administrating the surfactant types are shown in Table 2. 10.1371/journal.pone.0286997.t002 Table 2 Clinical and economic outcome for overall study population and surfactant cohorts. Variables Overall study population Alveofact BLES Curosurf Survanta Average length of stay, days 13.71 11.90 13.28 15.86 13.80 Average direct medical cost 398.49 627.94 258.35 385.61 322.05 Re-dosing rate 1.39 1.63 1.36 1.30 1.30 Needing invasive mechanical ventilation 5862(44.51) 163(52.92) 838(39.45) 3550(45.58) 1311(44.45) Medical referrals rate 1012 (7.68) 32(10.38) 275(12.94) 447(5.73) 228(7.73) Survival at discharge 8749(66.43) 176(57.14) 1272(59.88) 5258(67.51) 2043(69.27) Mortality rate, n 3438(26.10) 100(32.46) 577(27.16) 2083(26.74) 678(22.99) DALY, day (year) 14820.53(40.6041) 17909.77(49.0681) 14927.34(40.8968) 14983.65(41.0510) 13939.82(38.1912) YLL, day (year) 14799.98(40.5478) 17893.47(49.0232) 14909.05(40.8467) 14961.81(40.9912) 13920.79(38.1391) YLD, day (year) 20.57(0.0563) 16.41(0.0449) 18.32(0.0501) 21.86(0.0598) 19.03(0.0521) Amount (percentage) 3.3 The decision matrix The research decision matrix consisted of seven indicators for surfactant evaluation and four different types of surfactants as the alternatives. The seven relevant indicators were the re-dosing rate (I1), the average length of stay (I2), the average direct treatment cost (I3), medical referral rate (I4), survival at discharge (I5), and DALY per 1,000 infants (I6), and the number of infants in need of invasive mechanical ventilation (I7). In addition, the alternatives in the decision matrix were four different types of surfactant: Alveofact, BLES, Curosurf, and Survanta. Table 3 shows the decision matrix of the infants. 10.1371/journal.pone.0286997.t003 Table 3 Infant decision matrix. ≤32 >32 Type of surfactant I1 I2 I3 I4 I5 I6 I7 I1 I2 I3 I4 I5 I6 I7 Alveofact 1.75 13.91 675.7071 20 73 14238.2263 116 1.5 9.89 580.1830 12 103 3671.5466 47 BLES 1.40 17.27 266.2549 136 580 12289.5255 610 1.31 9.30 250.4575 139 692 2637.8212 228 Curosurf 1.35 21.28 402.1170 275 2404 11689.0680 2313 1.24 10.44 369.1220 172 2854 3294.5916 1237 Survanta 1.35 17.35 335.4233 117 794 11120.0987 754 1.24 10.24 308.6833 111 1249 2819.7182 557 As mentioned earlier, the weights of the indicators were measured through the CRITIC method by calculating the correlation coefficients and standard deviation of the data (see Table 4). 10.1371/journal.pone.0286997.t004 Table 4 Indicator weights. Gestational age I1 I2 I3 I4 I5 I6 I7 ≤32 0.1868 0.1143 0.1473 0.1200 0.1438 0.1429 0.1446 >32 0.1883 0.1060 0.1568 0.0999 0.1487 0.1445 0.1555 According to the results of the CRITIC method presented in Table 4, the most important indicator in evaluating the surfactants in both infants with a gestational age of more and less than 32 weeks was the “re-dosing rate” (I1). In addition, the least important indicator in the evaluation of the surfactant types for infants with a gestational age less than 32 weeks was the “average length of stay” (I2). The least important indicator for infants with a gestational age more than 32 weeks was the “medical referral rate” (I4). The resultant weights were used to rank the surfactants through the MABAC method. As mentioned above, following the steps of the MABAC method, the decision matrix was first normalized based on Eqs (4) and (5). It should be noted that all the indicators of the decision matrix, except for “survival at discharge” (I5), had a negative nature. After multiplying the weights obtained via the CRITIC method in the normalized decision matrix, the matrices of Vij and G were calculated according to Eqs (6) and (7). The Q matrix, then, was calculated through difference between the elements of matrix V and matrix G (Eq (8)). Ultimately, the final Si values were calculated based on the Eq (9). Table 5 shows these values; it should be noted that higher Si values would highlight the higher quality of an alternative. 10.1371/journal.pone.0286997.t005 Table 5 The values of Si. Type of surfactant Si (>32) Rank Si (= <32) Rank Alveofact -0.183981929 4 -0.152136722 4 BLES 0.238804661 1 0.140056915 2 Curosurf -0.000511128 3 0.01485928 3 Survanta 0.153497584 2 0.203576162 1 According to the results in Table 5, the best surfactant for infants with a gestational age less than 32 weeks was Survanta, followed by BLES and Curosurf. Alveofact was the last surfactant. In contrast, for infants with a gestational age more than 32 weeks, the best surfactant was BLES and the worst one was Alveofact. 3.4 Validation of results and sensitivity analysis In order to examine the obtained results using MABAC, the all type of surfactants will be ranked using two other methods: MAIRCA (multi-attributive ideal-real comparative analysis) method, [35]and VIKOR (VIseKriterijumska Optimizacija I Kompromisno Resenje) method [36]. The result of ranking the surfactants with these methods is shown in Table 6. As can be seen, there is very little difference between the rankings. 10.1371/journal.pone.0286997.t006 Table 6 Validation of results and sensitivity analysis. Type of surfactant VIKOR VIKOR MAIRCA MAIRCA Q (>32) Rank Q (< = 32) Rank Q (>32) Rank Q (< = 32) Rank Alveofact 1 4 1 4 0.1733 4 0.1552 4 BLES 0.1457 2 0.1647 2 0.0676 1 0.0822 2 Curosurf 0.6206 3 0.5239 3 0.1274 3 0.1135 3 Survanta 0.1008 1 0 1 0.0889 2 0.0663 1 The difference is only in rank 1 and 2. In this way, it has been proven that the results using the MABAC methods do not deviate from the results obtained using other methods. Although it was obvious that the deviations were not significant, the results were verified by applying Spearman’s correlation coefficient (SCC) [37]. The SCC values are given in Table 7. 10.1371/journal.pone.0286997.t007 Table 7 SCC values for alternative ranks obtained by different methods. VIKOR (<32) MABAC (<32) MAIRCA (<32) VIKOR (>32) MABAC (>32) MAIRCA (>32) VIKOR (<32) 1 VIKOR (>32) 1 MABAC (<32) 1 1 MABAC (>32) 0.8 1 MAIRCA (<32) 1 1 1 MAIRCA (>32) 0.8 1 1 As can be seen from Table 7, the SCC values range from 0.8 to 1. This presents a very high rank correlation value. Accordingly, it can be concluded that the results of the MABAC method are satisfactory, respectively, the robustness of the presented method has been proven. 4. Discussion The purpose of this study was to compare the performance of four surfactants based on seven selected indicators to determine the best surfactants, relying on the multi-criteria decision making method (MDCM) in Iran. Detailed discussions are provided below. 4.1 Comparative evaluation: Survanta and BLES as the best, Corsurf and Alveofact with weaker performance The findings of the study showed that in both groups of infants with a gestational age less and more than 32 weeks, Alveofact was the least preferable type, while Curosurf had an average level of functionality. It was also found that Survanta was the best choice for infants with a gestational age less than 32 weeks, while BLES was the best surfactant for infants with a gestational age more and more than 32 weeks. The two types were identified as the best surfactants. Survanta Reporting results consistent with those of the present study, Mussavi et al. revealed that in treating RDS through Survanta replacement therapy was more effective than administrating Alveofact [21]. In another similar study, Hammoud et al. compared the efficacy of Alveofact and Survanta in terms of illness severity and mortality. They also confirmed that neonates who received Survanta experienced fewer side-effects compared to those who received Alveofact. As such, Survanta was more effective [38]. BLES In a randomized controlled trial (RCT) by Lemyre et al., the efficacy and safety of BLES and Curosurf were compared. The results showed that although there was no significant difference in primary outcomes (extubation, bronchopulmonary dysplasia, etc.), in secondary outcomes Curosurf was associated with higher mortality and BLES with higher probability of survival. Therefore, BLES was recognized as the more effective surfactant [39]. Sarokolai et al. compared the adverse effects of BLES and Curosurf, observing that although the two surfactants had almost the same treatment efficacy, although BLES was a generally more reliable product for surfactant therapy [40]. Other studies, in line with the findings of the present research, confirmed that Survanta [21, 38] and BLES [39, 40] can perform better than other types of surfactants in some indicators. Curosurf The observations of Najafian et al. were in line with the results of this study. They found that the neonates with RDS who were of gestational age of 32 weeks, Curosurf showed less efficiency and less safety than Survanta and had more side-effects following its injection [3]. In a retrospective cohort study, Paul et al. stated that Curosurf had no superiority over Survanta in the treatment of RDS [41]. In another similar study by Baroutis et al., contrary to the findings of the present study, it was found that Alveofact and Curosurf had better functionality than Survanta [42]. Because more than half of the newborn infants in this study were less than 32 weeks of gestational age, the findings of Najafian et al. [3] were more relevant to those of this study. Alveofact Proquitté et al. measured clinical outcomes in neonates with RDS who were treated with Alveofact and Curosurf. It was found that there was no significant difference in clinical efficacy between the two groups [43]. In another study, Yalaz et al. compared the efficacy of two natural exogenous surfactants, namely Alveofact and Survanta, in the treatment of RDS. They showed no statistically significant differences in the final effects and adverse effects between the two groups [44]. Mussavi et al. compared the efficacy of Survanta and Alveofact in the surfactant treatment process of premature neonates with RDS. They found that some clinical variables were worse in certain age groups who received Alveofact [21]. 4.2 Comparing the indicators based on surfactant types 4.2.1 Re-dosing rate (I1) The findings of this study showed that Alveofact required significantly higher amounts of re-dosing than the other three surfactants. Meanwhile, Survanta and Curosurf did not differ much in terms of this index. The findings of Mussavi et al., consistent with those of the present study, showed that the average number of surfactant injections among patients receiving Alveofact was significantly more than those who received Curosurf and Survanta, and that these two surfactants were not significantly different from each other [21]. Manizheh et al. also showed that surfactant re-dosing among neonates who received Alveofact was significantly more than those who were treated with Curosurf [22]. Contrary to the results of the present study, Fox et al. [45] and Mirzarahimi et al. [23] showed that Curosurf reduced the need for re-dosing compared to other surfactants. However, the findings observed by Mussavi et al. [21] were consistent with those of the present research, because their study was specifically similar with the present research in terms of its context (Iran), research sample, and the drugs investigated. 4.2.2 Average length of stay (I2) The highest ALOS index was found in the case of Curosurf, while the lowest value of this index was seen in the case of Alveofact. Corroborating the results of the present study, Manizheh et al. conducted a comparative study of preterm neonates with RDS and showed that ALOS was higher in the group using Curosurf than the one receiving Alveofact [22]. However, in another similar study, it was found that ALOS was higher in the group treated with Alveofact than in those receiving Survanta and Curosurf [21]. Because more than half of the newborns in this study were less than 32 weeks of gestational ag, the findings of Manizheh et al [22], who focused on preterm neonates, were more relevant to observations of this study. 4.2.3 Direct medical cost (I3) The results of this study showed that BLES and Survanta, as the superior surfactants, imposed significantly lower costs on the health system, compared to Alveofact and Curosurf. Sarokolai et al. examined the cost index in preterm neonates with RDS to determine the most efficacious type of surfactant, showing that this index was significantly lower in the group treated with BLES than the one receiving Curosurf. As such, in 91.50% of infants who received Curosurf, cost exceeded $200 (inflation-adjusted cost = $ 273.48), although that cost was only observed in case of 8.50% of infants who used BLES [40]. In a retrospective cohort study of infants at risk of RDS to compare the efficacy and safety of Calfactant and Curosurf, Zayek et al. found that the cost of Curosurf-based treatment per patient was $ 1,160.62 (inflation-adjusted cost: $1229.56), which was 38% higher than the cost imposed by using Calfactant ($838.34 (inflation-adjusted cost: $877.08)) [16]. Marsh et al conducted a study to compare the pharmacoeconomic profiles of Survanta and Curosurf via a cost-minimization analysis. These analyses would suggest Curosurf may offer a less costly, clinically-equivalent option. Different treatment models using Curosurf (compared to Survanta) resulted in cost savings ranging from 53% ($949.67 (inflation-adjusted cost: $1296.21)) to 20% ($180 (inflation-adjusted cost: $245.68)) [46]. In a study aimed at evaluating economic and therapeutic efficiency (based on drug therapy cost index, duration of respiratory support, duration of hospitalization, side effects, etc.), Brown et al. reported higher average medication costs ($1756.44 vs. $1329.78 (inflation-adjusted cost: $1860.77 vs. $1408.77)) for Poractant Alfa (Curosurf) compared with Beractant (Survanta). While many clinical indicators were not significantly different between the groups [47]. A cost-effectiveness analysis study of surfactant therapy in the treatment of NRDS showed that the use of Poractant Alfa (Curosurf) is a superior option compared to Beractant (Survanta). Cost-effectiveness ratio was €4585 ($5067.57) per saved life for Poractant Alfa and €5087 ($5590.35) per saved life for Beractant [48]. Another study aimed at comparing the efficacy and safety of bovine lung phospholipid and Poractant Alfa injection in the treatment of neonatal hyaline membrane disease showed that treatment costs in the for Poractant Alfa group were significantly lower than the bovine lung phospholipid group [49]. Note: all compared studies were adjusted for dollar currency and inflation (2018). 4.2.4 Medical referral rate/severity of illness (I4) The results of this study showed that, in general, infants who were forced to refer to other medical centers due to the deterioration of their clinical conditions had the highest and lowest number of referrals in the Alveofact and Curosurf groups, respectively. In a randomized controlled trial (RCT) study, pneumothorax in infants with a gestational age less than 32 weeks and PDA in infants with a gestational age more than 32 weeks were more likely in groups who received Alveofact, compared with those who received Curosurf and Survanta [21]. Najafian et al. observed similar rates of complication including sepsis, pneumonia, necrotizing enteric colitis (NEC), intraventricular hemorrhage (IVH), and retinopathy of prematurity (ROP) among groups who were treated with Curosurf and Survanta [3]. Given the framework of this study, the specific effects of surfactants cannot be stated with certainty. But in general, based on the results of this study and the available evidence [3, 21, 46], it can be stated that probably the severity of the illness in the case of Curosurf and Survanta was better than Alveofact and BLES. 4.2.5 Survival at discharge (I5) Investigating the neonatal outcome showed that those who were treated with Survanta, the best surfactant, showed the highest survival rate, which was the highest rate of discharge by a physician’s order and the lowest mortality rate. Evidence has shown that surfactant replacement therapy in neonates with RDS, regardless of the type of surfactant, increases the likelihood of survival [24]. The results of a clinical meta-analysis showed that natural surfactants significantly reduced mortality compared to artificial ones [50]. Among natural surfactants, however, Fujii et al. reported that survival was more likely in neonates receiving Curosurf [51]. Yet, in line with the results of this study, the findings of Bloom et al. confirmed that Survanta was more effective in increasing survival rates. They compared Survanta and BLES in a multicenter clinical trial, observing that in preventive surfactant prescriptions the probability of survival to discharge in neonates under 600 g was 74% among those who received Survanta and was 37% among those who received BLES. The groups, of course, were significantly different (P = 0.007) [24]. In general, it is clear that the use of surfactant increases the survival rate [24], and among the types of surfactants, animal-derived products are more effective than artificial ones [50]. Finally, among the types of animal surfactants, the results of this research, along with others [52], showed that Survanta was more efficient in increasing the survival rate or the survival at discharge. 4.2.6 Mortality rate/DALY(I6) It was found that mortality in infants using Survanta (the most effective surfactant) was significantly lower, and thus in this group, compared to the other three surfactants, a lower disease burden was imposed on the community. It was also found that a large part of DALY was related to YLL. Further evidence confirmed that in general about 93% of DALY was associated with YLL [53]. Evidence has shown that pharmaceutical innovation can leave different impacts on YLL, suggesting that some pharmaceutical classes are more successful [54]. As the results of this study clarified, Survanta was more effective and had the lowest YLL value. Frank et al. conducted an econometric study of the effect of pharmaceuticals on DALY and its two components, namely YLL and YLD. They showed that drugs launched between 1986 and 2001 reduced DALY by 2.31 million in 2016 [53]. In a study by Bloom et al., it was found that in prophylactic surfactant administration the group receiving Survanta had significantly less mortality than the one receiving BLES [52]. Comparing Survanta and Curosurf, Bozdag et al. found that in the case of pulmonary hemorrhage-related mortality, the two types were not significantly different [46]. Considering the results of this study, along with available evidence [52, 55], mortality was lower in groups that received Survanta, compared to other surfactants. Even studies that found results contrary to this observation [13, 46] did not usually report statistically significant differences. In general, it was found that Survanta, as the most effective surfactant, had the lowest mortality rate and the lowest YLL and DALY values. As further evidence suggests [54], drugs can affect the burden of disease in the community differently; among the four surfactants investigated in this study, Survanta mostly reduced the burden of RDS in Iran. 4.2.7 Invasive mechanical ventilation (I7) Analyzing this index showed that the infants who received the top two surfactants, Survanta and BLES, significantly needed less invasive ventilation. Another study that found similar results revealed that the need for invasive mechanical ventilation support in infants with a gestational age of more than 32 weeks who received Survanta was significantly lower than those who received Curosurf and Alveofact [21]. Mirzarahimi et al. found that the mean duration of ventilation was significantly shorter in infants treated with Survanta than those receiving Curosurf [23]. Najafian et al. reported a similar rate of need for continuous positive nasal air way pressure in groups treated with Curosurf and Survanta [3]. In general, studies that explored the need for invasive mechanical ventilation observed that Survanta was superior to other surfactant types in terms of the need for invasive mechanical ventilation [3, 21] or the length of the invasive mechanical ventilation period [23]. As with all retrospective studies, one of the inherent limitations of this study was the heterogeneity of the patients in the groups under investigation. Also, although the specialized research team tried to focus on the IMAN net data that reported “the severity of illness” as the main cause of referrals after surfactant administration, some referrals were caused by non-clinical and unexplained reasons that could not be perfectly categorized. These limitations, of course, were negligible in the entire research population. In addition, another limitation of this research is that although according to the evidence, the need for mechanical ventilation and its duration is one of the indications of the efficacy of surfactant therapy, it is possible that factors other than RDS caused it. In this research, we were limited to the data extracted from the Iranian Maternal and Neonatal Network (IMAN net), and it was not possible to comprehensively examine all the factors. Another main limitation of this research was the lack of proportion in the number of prescriptions in four types of surfactants. In fact, in Iran’s health system, the use of surfactant (and of course many other drugs) is not optional and depends on the political and economic conditions of the country. The specific political conditions of Iran, the presence of extensive sanctions and the sharp drop in currency value in different periods of time, lead to the non-existence of a certain type of surfactant or the presence of only a certain type of surfactant in the health market. It should be noted that according to the "National Guidelines for Surfactant Therapy in Neonates with Respiratory Distress", there is no recommendation to use or not use a specific type of surfactant in a specific group of infants. In general, according to the opinion of decision makers and policy makers in the field of newborn health in Iran, the most important issue affecting the choice of the type of surfactant is the country’s political-economic conditions, which affects the existence of various surfactants. 5. Conclusion The results showed that BLES was the best alternative for infants with a gestational age more than 32 weeks, whereas Survanta was the best option for infants with a gestational age of less than 32 weeks. Alveofact was the worst option for treating RDS. The results of this study were meant to help healthcare professionals and policymakers to make informed decisions and should not be used as a substitute for professional medical advice. Neonatal health policymakers are advised to focus on increasing the market share of highly effective surfactants. Future studies could rank a combination of artificial and natural surfactants and use more indicators to evaluate their functionality. Supporting information S1 File How to calculate MABAC and CRITIC methods in neonates < = 32. (DOCX) Click here for additional data file. S2 File How to calculate MABAC and CRITIC methods in neonates >32. (DOCX) Click here for additional data file. S3 File Baseline characteristics, abnormalities, and risk factors. (DOCX) Click here for additional data file. S4 File STROBE statement—Checklist of items that should be included in reports of cross-sectional studies. (DOC) Click here for additional data file. S5 File (XLSX) Click here for additional data file. The authors thank the neonatal department of the ministry of health, for providing statistical data from the Iranian Maternal and Neonatal Network (IMAN Net) to support the research. 10.1371/journal.pone.0286997.r001 Decision Letter 0 Grosek Stefan Academic Editor © 2023 Stefan Grosek 2023 Stefan Grosek https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version0 6 Mar 2023 PONE-D-23-01167Comparing the Clinical and Economic Efficiency of Four Natural Surfactants in Treating Infants with Respiratory Distress SyndromePLOS ONE Dear Dr. Shojaei, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== ACADEMIC EDITOR: Dear Authors, please find the comment of both reviewers and answered and amend your manuscript accordingly to their suggestions and remarks ​============================== Please submit your revised manuscript by Apr 20 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. 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Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. Additional Editor Comments: Dear Authors The theme of this manuscript is very interesting for neonatologists but the the whole manuscript has many ambiguities and inconsistencies addressed by the reviewers and myself too. I hope that after major revision this manuscript could be eligible for publication. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: No Reviewer #2: Yes ********** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: I Don't Know ********** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The submitted study is a study of high importance in neonatology However, it has methodological problems: - What are the clinical criteria chosen to redose surfactant adminsitration? Are they always the same between units? Do they vary according to gestational age? - Among the judgement criteria used is the length of hospital stay. However, this factor is very dependent on the gestational age of birth which does not seem to be taken into account in the calculation. -atuhros say that reffering to a NICU may depend on the severity of the patient. However, clinical severity can have some influence in the need of surfactant redosing. It seems that this factor is not considered Minor remarks the end of the first paragraph is confusing with RDS describing different lung distress the table 1 could be simplified (one line at a time) female are not male , <1500g is the opposite of >1500g ... 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Attachment Submitted filename: comments.docx Click here for additional data file. 10.1371/journal.pone.0286997.r002 Author response to Decision Letter 0 Submission Version1 24 May 2023 PONE-D-23-01167 Comparing the Clinical and Economic Efficiency of Four Natural Surfactants in Treating Infants with Respiratory Distress Syndrome PLOS ONE Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Authors’ response: Thank you for your positive feedback. Based on this email from you, we tried to fully implement the PLOS ONE's publication criteria. ============================== ACADEMIC EDITOR: • Dear Authors, please find the comment of both reviewers and answered and amend your manuscript accordingly to their suggestions and remarks Authors’ response: We carefully reviewed all the points raised by dear reviewers and responded to their suggestions and remarks. They gave us very valuable and useful comments. If they had a recommendation, we implemented it. If they wanted corrections, we did it. If there was any ambiguity for them, we answered it and attached additional information to clear the ambiguity. We tried to give full and comprehensive answers to all their comments. We spent a lot of time doing these revisions. However, if there are any other corrections or any new suggestions that the dear editors and respected reviewers consider necessary, please let us know about it, we will do it if possible. ============================== Please submit your revised manuscript by Apr 20 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Authors’ response: Thank you for giving us another deadline until May 30. A lot of revisions were needed, and we really needed this time. thanks again. ============================== Please include the following items when submitting your revised manuscript: • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. Authors’ response: Thank you for your guidance. We sent the following items when submitting our revised manuscript: 1. “Response to Reviewers” 2. “Revised Manuscript with Track Changes”: In this file, we have marked the changes made in the original manuscript with yellow highlighter. 3. “Manuscript” 4. S1_File 5. S2_File 6. S3_File 7. S4_File 8. S5_File 9. Research Ethics Committees Certificate 10. Iran's national guideline in surfactant therapy for neonates ============================== If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. Authors’ response: No thanks, we don't want to make any changes. As we said earlier, this research was not financially supported by any institution. ============================== If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. Authors’ response: This research is not a laboratory work and no laboratory protocol was used in it. We look forward to receiving your revised manuscript. Kind regards, Stefan Grosek, Ph.D., M.D., Academic Editor PLOS ONE ========================================================================================== Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Authors’ response: Thank you for this comment and for sending us these two links. We revised the manuscript point by point based on these two files. We tried to implement all the mentioned points, if there is a problem, please give us feedback. 2. Please amend your current ethics statement to address the following concerns: a) Did participants provide their written or verbal informed consent to participate in this study? b) If consent was verbal, please explain i) why written consent was not obtained, ii) how you documented participant consent, and iii) whether the ethics committees/IRB approved this consent procedure. Authors’ response: In this research, the data recorded in the national system have been used (Iranian Maternal and Neonatal Network (IMAN net)). In the data file used, the identity of the patients was hidden, no written or verbal consent was taken from anyone. This research is a retrospective study and the analyzed data was related to the whole country (about 16 thousand babies), and it was practically impossible to obtain consent. Access to the data was done with the official permission of the Ministry of Health of Iran. This research is approved by the ethics committee of Tehran University of Medical Sciences. In the method section, we stated this issue as follows: "This study is registered under the ethic approval code “IR.TUMS.IKHC.REC.1400.380” on 26/12/2021 by Tehran University of Medical Sciences, and all the methods used in the present study are in accordance with relevant guidelines and regulations." We also attached the relevant certificate under the title "Research Ethics Committees Certificate", please check it. 3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Authors’ response: The raw and preliminary data related to this research, which was extracted from the national system of Iran, is confidential and cannot be sent. However, the underlying data used to reach the conclusions presented in the manuscript can be submitted. We attached this data file in supporting information files with the title "S5_File". This data file is sufficient to support the correct implementation of research analytical techniques. If more data is needed, please let us know. Although this dataset (S5_File) and the information presented in S1_File and S2_File cover all the analyzes and data presented in the manuscript, we may be able to provide you with more data (if approved by the Neonatal Health Department of the Ministry of Health). Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. Additional Editor Comments: Dear Authors The theme of this manuscript is very interesting for neonatologists but the the whole manuscript has many ambiguities and inconsistencies addressed by the reviewers and myself too. I hope that after major revision this manuscript could be eligible for publication. Authors’ response: We appreciate the effort and time you have taken to provide feedback on our manuscript. We have carefully reviewed all concerns and have done our best to address each one, and we hope that our edits and responses satisfactorily address the issues and concerns raised. Your comments were very valuable and useful, on the other hand, we also spent a lot of time and effort to respond to your suggestions and corrections. In order to track recommended and performed corrections, please note the following color scheme: The green highlights show the reviewers' comments, the yellow highlights show revisions within the manuscript, and gray highlights indicate the authors' response to the reviewers' and editors' comments. And finally, although we have done our best to make corrections and recommendations according to the comments of the editor and reviewers, if you think more corrections are needed, we would like to know your opinions so that we can implement your suggestions if possible. ==========================================================================================   Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: No Reviewer #2: Yes Authors’ response: Thank you for your positive and negative feedback. In response to this comment, we attached two files S1_File and S2_File. In these two files, we have presented the main analysis (MABAC and CRITIC methods) and the process of extracting the results from the available data in full, to give you the assurance that the data technically supports the conclusion. You can check the technical analysis used in this research step by step, to ensure that the tests were done accurately. It should be noted that we did not have sampling and used the census. Although this issue was stated in the text of the manuscript, in response to this comment, we added the following text to the manuscript: "The data of these infants were extracted using the census method, in fact, sampling was not done, and all eligible infants were included in the study using the census method." If you have specific suggestions and recommendations regarding this question (Is the manuscript technically sound, and do the data support the conclusions?), please give us feedback. If it is possible for us, we will definitely do it. ________________________________________ 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: I Don't Know Authors’ response: Thank you for your honest response. The statistical analyzes used in this research are few and simple. The main analysis of this research is based on multi-criteria decision making methods. One of the strengths of this research is the use of this analysis method. We used the CRITIC method to determine the weight of the indicators and the MABAC method to prioritize the alternatives (four types of surfactants). To better understand these two methods, check the two files S1_File and S2_File. In these two, we have explained the analysis method completely and step by step. Also, to understand the nature of the CRITIC method, you can read the article by Diakoulaki et al. [1]. And for a better understanding of the MABAC method, if you wish, read the article by Pamučar & Ćirović [2]. Please ask us if you have any questions about these analysis methods. ________________________________________ 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes Authors’ response: Thank you for your comment. ________________________________________ 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes Authors’ response: Thank you for your positive comment. ________________________________________   5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The submitted study is a study of high importance in neonatology However, it has methodological problems: Authors’ response: We appreciate the effort and time you have taken to provide feedback on our manuscript. We have carefully reviewed all concerns and have done our best to address each one, and we hope that our edits and responses satisfactorily address the issues and concerns raised. Your comments were very valuable and useful, on the other hand, we also spent a lot of time and effort to respond to your suggestions and corrections. In order to track recommended and performed corrections, please note the following color scheme: The green highlights show the reviewers' comments, the yellow highlights show revisions within the manuscript, and gray highlights indicate the authors' response to the reviewers' and editors' comments. And finally, although we have done our best to make corrections and recommendations according to the comments of the editor and reviewers, if you think more corrections are needed, we would like to know your opinions so that we can implement your suggestions if possible. ****************************************************** - What are the clinical criteria chosen to redose surfactant adminsitration? Are they always the same between units? Do they vary according to gestational age? Authors’ response: Surfactant therapy for newborns in Iran is done according to the "National Guideline for Surfactant Prescription in Neonates". In this guideline, the re-dosing indicators are exactly the same for all four types of surfactants. In fact, in one section of this guideline, three indicators are written for re-dosing in all types of surfactants; and gestational age is not mentioned in any of these three indicators (Note: Because the gestational age in the four groups of infants examined was not statistically different, even if the re-dosing depended on the gestational age... it still did not affect the results of this research.). The document "National Guideline for Surfactant Prescription in Neonates" was published by the Iranian Ministry of Health in Persian language, and unfortunately, this document does not have an English version at all. Following your comment, we have attached the original version of this guideline, which is in Farsi. About this guideline, we must say that "European Consensus Guidelines on the Management of Respiratory Distress Syndrome" was one of its main references. It should be noted that although the main basis for compiling Iran's national guideline was the " European Consensus Guidelines...", other references (63 references) were also used in compiling this national guideline, and this guideline has been localized in all aspects to the conditions of Iran. In response to your opinion, we tried to briefly translate the three re-dosing indicators written in the Iranian National Guidelines into English, which are presented below: Indications for repeated use of the drug: - To repeat the prescription, make a decision based on the baby's need for oxygen and his/ her clinical condition. - Within 48 hours after the first administration of surfactant, if one of the following conditions exists, the indication is to repeat the administration of surfactant. o After 6 to 12 hours, the baby still has a tracheal tube and needs a mean airway pressure (MAP) of more than 7 cm H2O and oxygen of more than 40%. o With CPAP, with a minimum H2Opressure of 6-7 cm, there is a need for more than 40% oxygen. o Chest X-ray should be done before administering repeated doses. ****************************************************** - Among the judgement criteria used is the length of hospital stay. However, this factor is very dependent on the gestational age of birth which does not seem to be taken into account in the calculation. Authors’ response: Thank you for your review and comment. As we have written in Table 1 of the manuscript, the gestational age of the infants in the four investigated groups (according to the four types of surfactants examined) was not significantly different. Therefore, although the variable of gestational age can potentially affect the duration of hospitalization, in this study, since the variable of gestational age does not have a significant difference in the four groups, it cannot create a significant difference in the duration of hospitalization between the four groups under investigation. In other words, although the gestational age had an effect on the length of hospitalization, the extent of this effect was similar between the four investigated groups and did not create a significant difference between these four groups in terms of length of hospitalization). Therefore, the difference in the duration of hospitalization between the four investigated groups is probably for a reason other than the gestational age, because the gestational age of all four groups is similar. In addition, the main goal of the research is to investigate the clinical-economic effects of various surfactants. For this purpose, variables that were statistically significantly different were included in MABAC and CRITIC analyses. The variable of gestational age was not significantly different between the infants in the four investigated groups. We looked for indicators that were significantly different between the four groups of infants and then included them in MABAC and CRITIC analysis. In fact, the variables that were included in the multi-criteria decision analysis (MABAC and CRITIC method) were definitely statistically significantly different between the four groups of infants. And about other variables that were not significantly different between groups of infants, these variables were never included in the main analyzes of the manuscript at all. Thank you again for your feedback. If you have any special suggestion about this comment, please share it with us. ****************************************************** -atuhros say that reffering to a NICU may depend on the severity of the patient. However, clinical severity can have some influence in the need of surfactant redosing. It seems that this factor is not considered. Authors’ response: Thank you very much for taking the time to review this manuscript. I'm sorry, I think that maybe I didn't understand your meaning from this comment correctly and accurately. I will answer you based on my current understanding of this comment. If there is any ambiguity or we have not answered your question correctly, please tell us more clearly what you mean. What we meant by "referring to a NICU may depend on the severity of the patient" was actually the severity of the disease after surfactant administration. Based on your comment, we corrected this sentence as follows: "Also, although the specialized research team tried to focus on the IMAN net data that reported “the severity of illness” as the main cause of referrals after surfactant administration, some referrals were caused by non-clinical and unexplained reasons that could not be perfectly categorized." As shown in Table 1 of the manuscript, infants in the four surfactant groups do not differ significantly based on baseline characteristics. In Table 1 of the manuscript, we only stated five very common characteristics that were reported by other similar studies, to avoid data overload in the manuscript. While the research team, from the beginning of this research, based on the comprehensive data set that was extracted from the Iranian Maternal and Neonatal Network (IMAN net), examined the groups of infants in terms of many characteristics that their data is available in the system, and it was found that there is no significant difference in these characteristics. But due to the large number of these variables, it is challenging to present them in the text of the manuscript, express the results and discuss them; and the research team prefers to report only common variables used in other similar studies (the variables in Table 1 of the manuscript are taken from similar studies; with the aim of showing the baseline parameters indicating the general state of health between the four investigated groups, in which there was no significant difference in infants). In fact, with the aim of ensuring that the babies of the four groups were similar before the administration of surfactant, we examined a large number of variables that directly and indirectly affected the subject of the research, and finally it was found that most of these variables had no significant difference between the four groups (variables related to the clinical conditions of the newborn, risk factors related to the mother, and diseases and abnormalities of newborns, etc.). Consider the severity of the disease in two situations, before and after the administration of surfactant. Before the administration of surfactant, some key indicators that influence the severity of the disease (gestational age, birth weight), or can potentially indicate the severity of the disease (Apgar score (min 1 and 5), were not significantly different between the four groups of infants (a large number of other variables affecting the severity of the disease are written in Table 1 of the manuscript and Table S3.1 in S3_File, please check them.). So, in short.... . . All infants were similar in terms of baseline parameters affecting disease severity . . On the other hand, all these babies had RDS. . . All of them received surfactant. . . And only some of them were referred after receiving surfactant... . . Therefore, it can be concluded that because the infants of the four groups did not differ significantly in many factors affecting the severity of the disease or the indicators showing the severity of the disease before the administration of surfactant, but the amount of their referral due to the severity of the disease after the administration of surfactant was significantly different... So, depending on the type of surfactant, probably the prescribed surfactant was not as effective as it should be, and as a result, the severity of the respiratory disease increased (or recovery did not occur); In other words, it is likely that the lack of effect of the first dose depending on the type of surfactant (and not the severity of the disease) has led to the repetition of subsequent doses. In addition, it should be noted that some of these referrals are for reasons other than the severity of the disease, which we have already mentioned in the limitations of the research. We stated that some of these referrals may be due to reasons other than the severity of the disease, which is not possible for us to investigate further. This is as follows: "….., some referrals were caused by non-clinical and unexplained reasons that could not be perfectly categorized. These limitations, of course, were negligible in the entire research population." Thank you again for carefully reviewing this manuscript. If you have any suggestion in this regard, please share it with us. ****************************************************** Minor remarks the end of the first paragraph is confusing with RDS describing different lung distress Authors’ response: Thank you for your valuable comment. There was a typo at the end of the first paragraph, thank you for giving us feedback. We have edited this sentence as follows: “The most prevalent types of respiratory distress are pneumonia, transient tachypnea of the newborn, meconium aspiration syndrome, and neonatal respiratory distress syndrome (RDS) [2].” ****************************************************** Minor remarks the table 1 could be simplified (one line at a time) female are not male , <1500g is the opposite of >1500g ... Authors’ response: Thank you for this comment. According to your comment, we corrected and simplified Table 1. Please check it in the manuscript. It should be noted that some authors did not agree with this edit in Table 1, but in the end, because the information in this table is completely written in In Table S3 of S3_File in Appendices, we made this edit according to your comment. Please check it in the manuscript.________________________________________ Reviewer #2: I appreciate authors who have brought into the light about unattended facet of newborn care. There should be a STROBE checklist attached with (manuscript) to address all the aspects of observational studies. Please find comments in word file. needs major revision. Authors’ response: We appreciate the effort and time you have taken to provide feedback on our manuscript. We have carefully reviewed all concerns and have done our best to address each one, and we hope that our edits and responses satisfactorily address the issues and concerns raised. Your comments were very valuable and useful, on the other hand, we also spent a lot of time and effort to respond to your suggestions and corrections. In order to track recommended and performed corrections, please note the following color scheme: The green highlights show the reviewers' comments, the yellow highlights show revisions within the manuscript, and gray highlights indicate the authors' response to the reviewers' and editors' comments. And finally, although we have done our best to make corrections and recommendations according to the comments of the editor and reviewers, if you think more corrections are needed, we would like to know your opinions so that we can implement your suggestions if possible. Please check our responses and revisions to the comments raised in the Word file on the following pages. Also, thank you for suggesting that we complete the STROBE checklist. Based on this comment, we completed the STROBE checklist. If corrections were needed based on this checklist, we made them and marked these revisions in the manuscript with yellow highlights. We have attached this checklist under the title "S4_File", please check it. ________________________________________ 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes: anurag fursule Authors’ response: Dear Dr. Anurag Fursule and dear reviewer#1, we sincerely appreciate you. You gave us very valuable and useful comments. If you have a recommendation, we implemented it; If you wanted corrections, we did it; If there was any ambiguity, we answered it and attached additional data to clear the ambiguity. We tried to give a complete and comprehensive answer to all your comments, however, tell us any other corrections you think are necessary. Also, if you have any suggestions, let us know and we will do it if possible. ________________________________________ [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.   The comments raised in the Word file by Reviewer 2: I appreciate authors who have brought into the light about unattended facet of newborn care. We appreciate the effort and time you have taken to provide feedback on our manuscript. We have carefully reviewed all concerns and have done our best to address each one, and we hope that our edits and responses satisfactorily address the issues and concerns raised. Your comments were very valuable and useful, on the other hand, we also spent a lot of time and effort to respond to your suggestions and corrections. In order to track recommended and performed corrections, please note the following color scheme: The green highlights show the reviewers' comments, the yellow highlights show revisions within the manuscript, and gray highlights indicate the authors' response to the reviewers' and editors' comments. And finally, although we have done our best to make corrections and recommendations according to the comments of the editor and reviewers, if you think more corrections are needed, we would like to know your opinions so that we can implement your suggestions if possible. ************************************************************************************* There should be a STROBE checklist attached with (manuscript) to address all the aspects of observational studies. Authors' response: Thank you for suggesting that we complete the STROBE checklist. Based on this comment, we completed the STROBE checklist. If corrections were needed based on this checklist, we made them and marked these revisions in the manuscript with yellow highlights. We have attached this checklist under the title "S4_File", please check it. ************************************************************************************* Abstract 1. CRITIC/MABAC/BLES acronym should be expanded Authors' response: Thanks for reminding us of this. According to your comment, these abbreviations were explained in the abstract. Please check these in the manuscript. These revisions are as follows: MABAC (multi-attributive border approximation area comparison) CRITIC (criteria importance through intercriteria correlation) BLES (bovine lipid extract surfactant) 2. The standard terminology for Live discharge rate should be survival at discharge. Authors' response: You suggested a very suitable term, thank you very much. We reviewed the entire text of the manuscript and replaced the term "survival at discharge" with "live discharge rate" and "survival to hospital discharge rate". You can check these changes in the text of the manuscript, we corrected it in 8 places of the article. The places in the manuscript where this editing was done are as follows: In the method and results of the abstract, in part "2.2 Study Variables and Measured Outcomes" in the method section of the manuscript, in Table 2, twice in the section "3.3 The Decision Matrix", twice in the section "4.2.5 Survival at discharge (I5)". 3. Some scores denoting the inferiority of Alveofactant should be mentioned in the abstract. The display of numbers will amplify the effect on reader about overall results of study. Authors’ response: Thank you for your suggestion. According to your comment, we added some of these scores, which indicated that Alveofact surfactant was inferior, in the results section of the abstract. This revision is as follows: ...", Alveofact was identified as the worst surfactant in infants with either more or less than 32 weeks’ gestation. So that some criteria were worse in Alveofact group infants than other groups; for example, in the comparison of the Alveofact group with the average of the total population, it was found that the survival rate at discharge was 57.14% versus 66.43%, and the rate of re-dosing was 1.63 versus 1.39." ************************************************************************************* Introduction 1. It is very long. RDS is well studied entity so the history and type of surfactants can be ignored. Authors’ response: Thank you very much for your suggestion. According to your comment, the history and type of surfactants were removed from the introduction section, and it was only stated in one sentence that surfactants are used to treat RDS. The red sentences were removed, and the yellow highlighted sentence was added. These revisions are as follows: o “In order to treat and prevent this disease, surfactant replacement therapy is used [11]." o Fujiwara, a Japanese scientist, conducted a LANDMARK study in 1980, and for the first time in the history of the disease treated ten premature babies with RDS using artificial surfactants [10]. Surfactant replacement therapy has revolutionized the treatment of neonatal respiratory failure in recent decades. Surfactants are used to treat and prevent RDS, although there are debates about the symptoms that would justify surfactant administration. There are currently various artificial and natural surfactants available in commercial health markets worldwide [11]. o Evidence suggests natural surfactants are more effective [12]. o In the Iranian health market, there are four natural surfactants available: Beractant (Survanta), Bovactant (Alveofact), Poractant Alpha (Curosurf), BLES. o Curosurf is derived from minced porcine lungs, whereas the other three types are bovine extracts [13]. 2. The utility of functionality scores should be discussed in modern medicine Authors’ response: Thank you very much for your valuable suggestion. According to your comment, an explanation about scoring in medicine was added to the introduction section. You can check it in the third paragraph of the introduction. These revisions are as follows: “Although the effectiveness of surfactants in the prevention and treatment of RDS in infants has been well established, it is still unknown which surfactant is more effective [17]. On the other hand, scoring systems can be used to measure the performance of single therapeutic intervention over a time period, or used to compare the performance of one therapeutic intervention to others [18]. Scoring systems are used in all areas of medicine. Several parameters are evaluated and rated with points according to their value in order to simplify a complex clinical situation with a score [19]. The establishment of scoring system in medical areas is of great significance to effectively determine the severity of the disease, the rate of treatment success, and guide the treatment of doctors [20]. In this study, using selected performance indicators extracted from similar studies [16, 21-24] and a scoring-ranking system of medical interventions [25-29], the most effective surfactant in the treatment of RDS in infants has been determined. To this end, CRITIC method was adopted to calculate the weight of each indicator, and MABAC method was used in order to prioritize the surfactants. These two methods were adopted in this study due to the fact that CRITIC and MABAC were successfully combined in previous studies and made reliable results [25].” ************************************************************************************* Methods 1. “A surfactant would be most functional when it required less redosing;”- I would rather use word efficacious than functional in this sentence. Authors’ response: Thank you for your suggestion. According to your comment, this sentence was edited as follows: “A surfactant would be most efficacious when it required less redosing;” 2. Medical referral rate: where are babies referred after surfactant administration.? Authors’ response: The process of surfactant therapy for newborns is only and necessarily performed in the NICU. The equipment and the level of expertise of human resources in the NICU of different hospitals in Iran can be very different depending on the region. In all NICUs, surfactant injection is possible. If the clinical condition of the patient (neonate) worsens after the injection of surfactant (or does not improve) and the patient needs a neonatal subspecialty and more specialized care and more advanced equipment, it will inevitably be referred to another hospital. In fact, the decision to refer a patient to a center with a better NICU happens in two situations: (1) Or the patient is referred before surfactant administration; (2) Or the patient is referred after surfactant administration. Babies of group (1) were not included in the study at all, because the reason for the referral of these babies could be anything other than the effect of surfactant. We explained this issue in the manuscript exit criteria section. This is as follows: "Also, infants who were referred to another center before surfactant administration were excluded from the study." And the neonates of group (2), they have been referred to centers with more equipped NICUs, with more specialized manpower and more advanced facilities (sub-specialized hospitals at a higher referral level) than the hospital where they were born. In response to your comment, we have added additional explanations in this regard to the manuscript, which are as follows: "As a result of the lack of improvement or worsening of the health condition of the babies after receiving surfactant, these babies are referred to the super specialty hospitals that have more advanced equipment, more facilities, more specialized manpower and more up-to-date technologies. In Iran's health system, these hospitals are defined regionally and based on geographical proximity." Based on the interview we had with the directors of the Department of Neonatal Health of the Ministry of Health of Iran: They stated that most of the babies in this group (group (2)) had to be referred due to the lack of improvement in their health condition and even worsening of their condition. On the other hand, considering that the babies in the four surfactant groups did not differ significantly in many demographic characteristics, baseline parameters, clinical conditions, diseases and abnormalities, etc. (Please see Table 1 in the manuscript and Table S3.1 in S3_File), all of them had RDS, received surfactant, and were referred after that.... therefore, it can be concluded that probably the prescribed surfactant was not as effective as it should be, and as a result, the severity of the respiratory disease increased. Other similar studies with similar target population and research objectives used this index like ours. However, there are other potential reasons for referral (considering the above explanations and the homogeneity of the babies in the four groups, this type of referral is few). Based on the interview we had about this comment with experts in this field in the Ministry of Health, it was stated that the percentage of this type of referrals in the entire target population of this research is very small and can be ignored. We have previously mentioned this as one of the limitations of the research. It is as follows: "Also, although the specialized research team tried to focus on the IMAN net data that reported “the severity of illness” as the main cause of referrals, some referrals were caused by non-clinical and unexplained reasons that could not be perfectly categorized. These limitations, of course, were negligible in the entire research population." Based on the data set that the research team has and has done the analysis, it is possible but very difficult to separate referrals by reason. If the dear reviewer insists on separating the types of referrals, we will do so, although our prediction is that the results will not change because referral for non-clinical reasons are very few. Please let us know your decision on this matter. I think that maybe I did not understand your meaning from this question exactly. If I didn't answer your question correctly, please give us feedback more clearly what is your purpose of this question. Thank you again for the time you spent on this manuscript and the feedback you gave us. If you think we need to make corrections or revisions, we will gladly accept them if possible. 3. Sample size calculation for study? Authors’ response: Dear reviewer, the entire research population (i.e. All infants with RDS in Iran who had undergone surfactant therapy) were included in the study by census method, which included 16,551 cases; And only those who met the exclusion criteria were excluded from the study, as a result of which the research population decreased from 16,551 to 13,169. In fact, all eligible babies were included in the research with the census method. These explanations about the size of the studied population are presented in the section "2.1 Research Design and Patient Population". And the number of research population is stated in the first paragraph of the results section. However, in response to your comment, we emphatically stated that sampling was not done and all eligible infants were included in the study. Thank you again for your valuable comments. The mentioned revisions were added to the "2.1 Research Design and Patient Population " section, which are as follows: “The data of these infants were extracted using the census method, in fact, sampling was not done, and all eligible infants were included in the study using the census method." 4. How were MABAC and CRITIC computed? Any software? Authors’ response: Excel software was used to perform MABAC and CRITIC calculations. In line with your comment, a sentence was added to the relevant paragraph as follows: “The data were primarily classified and analyzed in Excel and SPSS through items of descriptive statistics such as frequency, percentage, mean, and standard deviation. Following that, the CRITIC method was used to determine the weights of the indicators, while the MABAC method helped to rank the surfactants; Microsoft Excel was used to apply both analysis methods. " Authors’ response: Regarding how to calculate MABAC and CRITIC, we have tried to provide brief and comprehensive explanations in the manuscript, which you can see in the "2.3.1 CRITIC" and "2.3.2 MABAC" sections. Also, in order to avoid additional writing in the manuscript, we mentioned Diakoulaki (1995) reference about CRITIC method and Pamučar & Ćirović (2015) reference about MABAC method, which readers can refer to if they want to know more specialized information. However, in response to your comment about how to calculate these two methods, we have attached a Word file under the title "S1_ File and S2_File". In this file, the calculation steps of both methods are written in detail separately for babies less than and more than 32 weeks of gestational age. We thank you again for this comment, surely this attached file will provide a better understanding for the readers. 5. MABAC and CRITIC background calculation and description are not need? Authors’ response: In response to your comments, a file titled " S1_File & S2_File" has been attached, which includes calculations related to MABAC and CRITIC methods. please check it. In addition, we have written the background of these specialized techniques (MABAC and CRITIC) in the manuscript, which you can check. These are as follows: 2.3.1 CRITIC method The CRITIC method was initially developed in 1995 by Diakoulaki et al. as a technique for calculating the weight of indicators in multi-criteria decision-making problems. In this method, the opinion of experts is not important and the relative weight of indicators is determined by correlation coefficients and standard deviation of data [33]. According to Diakoulaki et al. (1995), the steps of CRITIC method are as follows: 2.3.2 MABAC method The MABAC method is a recently developed multi-criteria decision-making technique used to rank alternatives in multi-criteria decision-making models. The basis of the MABAC method originated from the definition of the distance of the indicator function of each alternative from the border approximation area. MABAC was developed by Pamučar & Ćirović (2015) [34]. The steps of the MABAC method are presented as follows: ************************************************************************************* Results 1. Gestational age and Birth weight should be mentioned as mean (standard deviation) Authors’ response: Thank you very much for your valuable comment. According to your suggestion, we wrote the mean (standard deviation) for birth weight and gestational age. We made these corrections in part "3.1 Patient Demographics and Clinical Characteristics" of the Results section in Table 1 and the paragraph above it. You can check these corrections in the manuscript. These corrections are as follows: Gestational age: Mean, wk a 32.24 (±4.55) 32.19 (±4.41) 32.19 (±4.77) 32.27 (±4.58) 32.44 (±4.44) Birth weight: Mean, gr b 1876.94 (±813) 1856.42 (±715) 1836.06 (±852) 1906.37 (±839) 1908.91 (±849) 2. The proportion of babies receiving surfactants (all types) were more in babies > 1500 g. Authors’ response: It should be noted that the data used in this research was extracted from a national system (Iranian Maternal and Neonatal Network (IMaN)). Therefore, the numerical values of the indicators used in this research are beyond the authority and control of the research team (the research team can only send data upon reasonable request). The data of this system is confidential and access to it is limited, and it can only be accessed with official permits for managerial-executive and research purposes, so there is no possibility of distorting this data. Based on the unpublished information of this department and interviews with the experts of this department, the verification of the data of this system has already been done with other executive purposes; Therefore, you can be sure of the correctness and accuracy of the data. Regarding the variable of birth weight of babies, we have only reported it descriptively. In addition, according to Iran's national guideline for the administration of surfactant in neonates (under the title "National Guideline for Surfactant Prescription in Neonates"), the weight of neonates at birth is not a direct indicator for the administration or non-administration of surfactant. In this national guideline, there are four indicators for the prescription of surfactant, each indicator includes two variables, and when both variables are in specific and predetermined conditions, the neonatologist should prescribe surfactant, and the so-called surfactant prescription is considered reasonable (rational) in those conditions. These indicators for the administration of surfactant in neonates based on the national guidelines of Iran are as follows: o Indicator 1: Premature neonates who need endotracheal intubation during postpartum resuscitation in the delivery /operating room. o Indicator 2: Premature neonates reaching the stabilized health status in the delivery/operating room with nasal continuous positive airway pressure (NCPAP) and also need to increase continuous positive airway pressure (CPAP) to a maximum of 8 cm/H2O and FIO2 to more than 30% to 40% in order to maintain arterial oxygen saturation within an acceptable range. o Indicator 3: Premature neonates showing typical respiratory distress syndrome (RDS)radiographic symptoms in the first 48 hours of life with a chest radiograph. o Indicator 4: Premature or mature neonates with respiratory diseases who require endotracheal intubation. Table 1. Summary of four indicators for surfactant prescription in infants, based on Iran's national guidelines Prescription indicators Indicator variables Surfactant prescription should be done under the following conditions: Indicator 1: Variables a and b Variable a: Gestational age ≤ 259 days (37weeks( Variable b: Advancement in resuscitation operations in the operating /delivery room In need of resuscitation by intubation in the operating/delivery room Indicator 2: Variables a and b Variable a: gestational age ≤ 259 days) 37weeks ( Variable b: Type of Respiratory support before surfactant prescription and Status of the need for increasing CPAP and FIO2 NCPAP and need to increase CPAP > 8 cm/H2O or FIO2 > 30% Indicator3: Variables a and b Variable a: gestational age Variable b: chest radiograph during the first 48 hours after birth ≤ 259 days )37 weeks( Indicator4: Variables a and b Variable a: Type of the respiratory distress disease Abnormal (with typical RDS radiographic signs) Variable b: Advancement in resuscitation operations RDS or MAS or PNA As you can see, although gestational age is one of the important variables in the three indicators for surfactant administration, birth weight is not directly mentioned in any of the indicators for surfactant prescription. It is true that the birth weight is affected by the gestational age, but according to the national guidelines of Iran, it is not directly used as an indicator for deciding on surfactant administration (we have attached the original version of the national guideline for the administration of surfactant in neonates, which was published by the Ministry of Health of Iran, in the additional files). On the other hand, based on this guideline, babies less than 37 weeks of gestational age (provided they have the conditions mentioned in the guideline (Table 1)) are eligible to receive surfactant. And by examining the average weight of live babies born in the age group below 37 weeks, we determined that this average is over 1500 grams (average birth weight for neonates≤37 weeks=1686.75 grams). Therefore, although the mean weight of the babies receiving surfactant (all types) was over 1500 grams, their gestational age was less than 37 weeks; And according to Iran's national guidelines, gestational age is the criterion for prescribing surfactant, not birth weight. Below is the average weight for babies ≤37 weeks, separated by surfactant types (the research team can send the data file upon reasonable request). Table 2. The average weight of newborns ≤ 37 weeks by surfactant type Average birth weight for infants≤37 weeks Type of surfactant (Number of neonates≤37) 1670.728571 Alveofact (N =281) 1636.731771 BLES (N =1921) 1710.077087 Curosurf (N =7057) 1729.477675 Survanta (N =2598) 1686.753776 Total (N =11857) In addition to all the explanations we provided above (that the criterion for prescribing surfactant is gestational age and not birth weight, and it was found that the group of infants who were eligible to receive surfactant in terms of age, their average weight was more than 1500 grams); In addition to these explanations, based on interviews with the directors of the Neonatal Health Department of the Iranian Ministry of Health and evidence, it was stated that... In Iran's health system, the capabilities and facilities to provide care and keep premature babies alive in different regions are very different. In some areas of Iran (especially border provinces like Zahedan, etc.), the condition of NICUs is not suitable in terms of equipment and manpower, and premature babies and babies under 1500 grams (especially under 1200 grams) have very little chance of survival. For this reason and due to the limited number of beds and facilities in the NICU, in these areas, as an unwritten routine, more manpower and facilities are spent on babies with higher weight and older age because their chances of survival are higher. On the other hand, in many of these areas, although they have a high reproduction rate, prenatal care is often very poor and the injection of antenatal corticosteroids is not done well. As a result, although it is expected that babies above 1500 do not have severe respiratory distress, in these areas even babies with higher weight and higher gestational age do not have good health conditions and may need surfactant injection. In general, in the border and deprived areas of Iran, which often have a high birth rate, babies under 1500 grams have very little chance of survival, and babies over 1500 grams have a high rate of respiratory distress, contrary to expectations. Therefore, this issue is one of the possible reasons for the higher amount of surfactant prescribed for babies above 1500 grams. 3. The average length of stay was quite short considering the GA and weight. Explanation? Authors’ response: The findings of this study show that the average length of stay for the group of babies under 32 weeks who are naturally underweight (probably under 1500 gr) is 17.45 days. According to Table 3 in the manuscript, these values are: Alveofact=9.89, BLES=9.30, Curosurf 10.44, Survanta=10.24. On the other hand, the findings showed that the average length of stay for the group of babies over 32 weeks who are naturally heavier (probably over 1500 gr) is 9.96 days. According to Table 3 in the manuscript, these values are: Alveofact= 13.91, BLES= 17.27, Curosurf= 21.28, Survanta= 17.3. Therefore, with the decrease in the gestational age of babies (and most likely their weight loss), their average length of stay has obviously increased, which seems reasonable. There are other evidences from Iran similar to the results of our study (in terms of average length of stay considering birth weight and gestational age). For example: o Example 1, Mousavi et al.'s study [3]: Comparison of the Efficacy of Three Natural Surfactants (Curosurf, Survanta, and Alveofact) in the Treatment of Respiratory Distress Syndrome Among Neonates. In this study, the average length of stay of neonates is 15.06 days (in our study, 13.71 days), while the average birth weight is 1839 grams (in our study, 1876.94 grams) and the average gestational age is 31.57 weeks (in our study, 32.24 weeks). Comparing the results of our study with this study shows that although the average length of stay in Mousavi's study was 1.38 days longer than in our study, the babies in this study had lower weight (37 gr) and lower gestational age (0.67 weeks) compared to our study. Table 2. From the study of Mousavi et al. Variable Type of Surfactant Survanta Alveofact Curosurf Duration of hospital stay (mean ± SD) (days) 15.37 ± 14.2 15.47 ± 12.5 14.35 ± 12.6 Birth weight (mean ± SD) (gr) 1829 ± 782 1815 ± 729 1873 ± 859 Gestational age (mean ± SD) (weeks) 31.56 ± 3.8 31.46 ± 3.6 31.70 ± 3.8 o Example 2, Gharehbaghi et al.'s study [4]: Comparing the Efficacy of two Natural Surfactants, Curosurf and Alveofact, in Treatment of Respiratory Distress Syndrome in Preterm Infants. In this study, the average gestational age of the examined babies is 28.36 weeks (in our study, 32.24 weeks) and their average weight is 1316.50 grams (in our study, 1876.94 grams), while their average length of stay is 24.84 days (in our study, 13.71 days). It is clear that although in Gharehbaghi et al.'s study, the average length of stay of the infants was about 11 days longer than the infants in our study, but their age was about one month (3.88 weeks) less and their weight was 560 grams less than the infants in our study. Table 1. From the study of Gharehbaghi et al. Variable Type of Surfactant Curosurf group Alveofact group Gestational age, wk 28.53±1.96 28.20±2.27 Birth weight, g 1350±555 1283±430 Mean duration of hospitalization 25.25±20.61 24.50±23.85 o Example 3, Najafian et al.'s study [5]: Comparison of efficacy and safety of two available natural surfactants in Iran, Curosurf and Survanta in treatment of neonatal respiratory distress syndrome. In this study, the average length of stay in the Survanta group infants is 15.36 days (in our study for infants in the Sorvanta group: 13.80 days), while their gestational age is 31.96 weeks (in our study for infants in the Sorvanta group: 32.44 weeks). From this comparison, it is clear that although the age of the babies in our study is only 0.48 weeks (equivalent to 3.36 days) more than the babies in Najafian et al.'s study, the average length of stay of the babies in our study is 1.56 days less than the babies in Najafian et al.'s study; these figures seem reasonable (more weight and less length of stay). It should be noted that the data used in this research was extracted from a national system (Iranian Maternal and Neonatal Network (IMaN)). Therefore, the numerical values of the indicators used in this research are beyond the authority and control of the research team (the research team can only send data upon reasonable request). About the index of average length of stay, we selected this index based on similar studies, and we extracted the numerical values recorded for this index from the mentioned system and then analyzed it, without any change or manipulation. This national system is under the direct supervision of the Neonatal Health Department of the Ministry of Health of Iran. The data of this system is confidential and access to it is limited, and it can only be accessed with official permits for managerial-executive and research purposes, so there is no possibility of distorting this data. Based on the unpublished information of this department and interviews with the experts of this department, the verification of the data of this system has already been done with other executive purposes; Therefore, you can be sure of the correctness and accuracy of the data. In a 40-minute online session, questions were asked by the first author and experts answered and provided guidance (some of the questions mentioned by the reviewers and editors in the manuscript review process). The interviewees were: Abbas Habibelahi and Parisa Mohagheghi as experts of neonatal department in ministry of health; Mohammad Heydarzadeh as the director of neonatal department in ministry of health. In addition to the fact that studies from Iran in terms of the average length of stay based on gestational age and birth weight were in line with the results of our study, policy makers in the field of newborn health also confirmed these figures. Based on the interview with them, they stated that due to the lack of hospital beds, especially for babies in Iran, the overall effort is to reduce the length of stay as much as possible so that people in need can be hospitalized faster. It seems that such figures about the average length of stay according to weight and gestational age are common in Iran. 4. DALY/YLL/YLD should be expressed in years. Authors’ response: Thank you very much for your valuable comment. According to your suggestion, we also expressed the values of DALY/YLL/YLD in the form of years. Please check this revision in Table 2. Although DALY/YLL/YLD values have been reported and calculated based on the day in order to increase the accuracy of calculations in the decision matrix, these values are also written in the form of years in Table 2) according to your comment). These are as follows: DALY, day (year) 14820.53(40.6041) 17909.77(49.0681) 14927.34(40.8968) 14983.65(41.0510) 13939.82(38.1912) YLL, day (year) 14799.98(40.5478) 17893.47(49.0232) 14909.05(40.8467) 14961.81(40.9912) 13920.79(38.1391) YLD, day (year) 20.57(0.0563) 16.41(0.0449) 18.32(0.0501) 21.86(0.0598) 19.03(0.0521) 5. Can the course of babies included in studies be compared? Number of babies needing invasive/non invasive ventilation, shock, IVH, PVL, etc. These all factors can also have bearing on the indicators. Authors’ response: Yes, this comparison is possible, we examined a large number of variables before conducting the main research analyzes. The research team, from the beginning of this research, based on the comprehensive data set that was extracted from the Iranian Maternal and Neonatal Network (IMAN net), examined the groups of infants in terms of many characteristics that their data is available in the system, and it was found that there is no significant difference in these characteristics. But due to the large number of these variables, it is challenging to present them in the text of the manuscript, express the results and discuss them; and the research team prefers to report only common variables used in other similar studies. However, based on this comment we made extensive corrections, and provided a lot of information. Please pay attention to the following explanations: In Table 1 of the manuscript, we only stated five very common characteristics that were reported by other similar studies, to avoid data overload in the manuscript; the information in this table briefly shows the similarity of four groups of infants based on baseline parameters. And in Table 2, to perform the main analysis of the manuscript (MABAC and CRITIC), we selected the variables that were firstly commonly used by other researchers and secondly those variables had a statistically significant difference between the four groups. In fact, the variables that were included in the multi-criteria decision analysis (MABAC and CRITIC method) were definitely statistically significantly different between the four groups of infants. And about other variables that were not significantly different between groups of infants, these variables were never included in the main analyzes (MABAC and CRITIC method) of the manuscript at all. Therefore, if a variable was related but was not included in multi-criteria decision analysis, either its data was not available or it was not statistically different between infants. For example, regarding the number of infants who need invasive/non-invasive ventilation, the index of non-invasive ventilation was not significantly different between the four groups of infants, but the index of invasive ventilation was significantly different. Therefore, the invasive ventilation index was considered in the main analyzes of the research (MABAC and CRITIC method); While non-invasive ventilation was not considered. In the text of the manuscript, mechanical ventilation means invasive mechanical ventilation. In response to your comment, we have corrected this term throughout the manuscript (Invasive mechanical ventilation replaced mechanical ventilation). Based on your feedback, we added IVH, PVL and a large number of other variables that had the potential to directly and indirectly affect the research results to the appendices (but based on the available data, these variables were not significantly different between the babies of the four groups). We provided a descriptive report of these variables and added Table S3.1 in S3_File. And we mentioned them briefly in the text of the manuscript. As follows: “And it was determined in advance that before the administration of surfactant, there was no statistically significant difference in the health status of infants in different surfactant groups (see some other variables in Table S3.1 in S3_File).” "The indicators investigated in this research were extracted from the literature on this topic. The indicators that were included in the main analyzes of the article were previously determined to be statistically significantly different between the four groups of infants. Although there were some other relevant indicators, they were removed from the analysis due to the lack of statistically significant differences (see Table S3.1 in S3_File). The selected indicators are as follows:” By expressing this comment, you have provided us with this opportunity to publish our extensive collection of data and analysis. Thank you again. It should be noted that in expressing the results and discussion in the text of the manuscript, we strongly emphasized everywhere that the ranking done in the types of surfactants is based on a number of selected indicators. And finally, although based on the comprehensive data set we had and by referring to similar studies, the most important variables (indicators) related to the subject of this research were considered, nevertheless, it may be a variable whose data was not accessible to the research team. For example, about the shock variable that you mentioned, there was no data recorded in the national network of Iran. According to your comment, we stated this issue as one of the limitations of the research and we hope it will be acceptable. We stated this limitation as follows: “In this research, we were limited to the data extracted from the Iranian Maternal and Neonatal Network (IMAN net), and it was not possible to comprehensively examine all the factors.” If you have a specific suggestion or recommendation about this comment, please share it with us; If we can, we will implement your suggestion. ********************************************************************************************* Discussion 1. The evidence on efficacy of surfactants is already there so the studies which have looked at surfactant in a similar perspective (economic efficacy). Authors’ response: According to the research team's search, in all the studies conducted to compare the types of surfactants, economic efficiency has been investigated along with clinical efficiency, and we did not find a study that only investigated economic efficiency. The studies presented in the section "4.2.3 Direct medical cost (I3)" have also often been conducted with the aim of evaluating the economic-clinical efficiency. According to your comment, we wrote the purpose of the mentioned studies in the section "4.2.3 Direct medical cost (I3)". Please check these changes in the main text of the manuscript (Sarokolai et al: to determine the most efficacious type of surfactant,; Zayek et al: to compare the efficacy and safety of Calfactant and Curosurf; Marsh et al: to compare the pharmacoeconomic profiles of Survanta and Curosurf via a cost-minimization analysis; Brown et al: a study aimed at evaluating economic and therapeutic efficiency; Another study aimed at comparing the efficacy and safety of bovine lung phospholipid and Poractant Alfa; A cost-effectiveness analysis study of surfactant therapy in the treatment of NRDS ). In addition, in response to your comment, we added other studies that were conducted with the aim of examining the economic-clinical efficiency (including studies: Brown et al.'s study: A cost-effectiveness analysis study; Another study aimed at comparing the efficacy and safety of bovine lung phospholipid and Poractant Alfa). Please check the revisions related to this comment in the "4.2.3 Direct medical cost (I3)" section. These are as follows: “4.2.3 Direct medical cost (I3) The results of this study showed that BLES and Survanta, as the superior surfactants, imposed significantly lower costs on the health system, compared to Alveofact and Curosurf. Sarokolai et al. examined the cost index in preterm neonates with RDS to determine the most efficacious type of surfactant, showing that this index was significantly lower in the group treated with BLES than the one receiving Curosurf. As such, in 91.50% of infants who received Curosurf, cost exceeded $200 (inflation-adjusted cost = $ 273.48), although that cost was only observed in case of 8.50% of infants who used BLES [40]. In a retrospective cohort study of infants at risk of RDS to compare the efficacy and safety of Calfactant and Curosurf, Zayek et al. found that the cost of Curosurf-based treatment per patient was $ 1,160.62 (inflation-adjusted cost: $1229.56), which was 38% higher than the cost imposed by using Calfactant ($838.34 (inflation-adjusted cost: $877.08)) [16]. Marsh et al conducted a study to compare the pharmacoeconomic profiles of Survanta and Curosurf via a cost-minimization analysis. These analyses would suggest Curosurf may offer a less costly, clinically-equivalent option. Different treatment models using Curosurf (compared to Survanta) resulted in cost savings ranging from 53% ($949.67 (inflation-adjusted cost: $1296.21)) to 20% ($180 (inflation-adjusted cost: $245.68)) [46]. In a study aimed at evaluating economic and therapeutic efficiency (based on drug therapy cost index, duration of respiratory support, duration of hospitalization, side effects, etc.), Brown et al. reported higher average medication costs ($1756.44 vs. $1329.78 (inflation-adjusted cost: $1860.77 vs. $1408.77)) for Poractant Alfa (Curosurf) compared with Beractant (Survanta). While many clinical indicators were not significantly different between the groups [47]. A cost-effectiveness analysis study of surfactant therapy in the treatment of NRDS showed that the use of Poractant Alfa (Curosurf) is a superior option compared to Beractant (Survanta). Cost-effectiveness ratio was €4585 ($5067.57) per saved life for Poractant Alfa and €5087 ($5590.35) per saved life for Beractant [48]. Another study aimed at comparing the efficacy and safety of bovine lung phospholipid and Poractant Alfa injection in the treatment of neonatal hyaline membrane disease showed that treatment costs in the for Poractant Alfa group were significantly lower than the bovine lung phospholipid group [49].” 2. I am not sure how the cost can be compared from different countries at different time points. Cost is variable and dependent on plethora of factors. Authors’ response: Other evidence including Sarokolai et al [6], Marsh et al [7], Zayek et al [8], Yuan et al [9], Yagudina et al [10], and Brown et al [11] have also used the cost index to compare the efficacy and pharmacoeconomics of different surfactants. In all the studies reported in the "4.2.3 Direct medical cost (I3)" section, the price of surfactant (according to the type of surfactant) and the number of prescription doses are considered as one of the most important cost components. Therefore, comparing these studies based on the type of cost is correct and possible. (For example, Sarokolai et al.'s study: surfactant vial cost (BLES recipient paid less because BLES was cheaper than Curosurf); Marsh et al.'s study: surfactant vial cost and number of doses (the only cost to be compared between drugs for CMA considered, the cost of the initial and subsequent doses); Zayek et al.'s study: surfactant vial cost and its different doses (costs per patient are determined by the price difference between the 2 products and the average number of doses per patient); etc.) On the other hand, as you mentioned, since the mentioned costs are related to different countries and different periods of time, therefore, their direct comparison is not correct. As a result, based on your comment, we converted the costs mentioned in different studies into a single currency unit (dollars), and then adjusted them according to the inflation rate of the country under study (Since the data of 2018 was used for the analysis of this study and the data of the most recent study compared with this research was also for 2018, therefore the adjustment was made according to the inflation rate until 2018). We made this edit in the form of "(inflation-adjusted cost: $)", and we used the World Data site (https://www.worlddata.info/inflation.php ) to determine the inflation rate of the countries. Thank you very much for this valuable comment, these corrections will definitely improve the quality of the manuscript. Please check the revisions related to this comment in the "4.2.3 Direct medical cost (I3)" section. These are as follows: “4.2.3 Direct medical cost (I3) The results of this study showed that BLES and Survanta, as the superior surfactants, imposed significantly lower costs on the health system, compared to Alveofact and Curosurf. Sarokolai et al. examined the cost index in preterm neonates with RDS to determine the most efficacious type of surfactant, showing that this index was significantly lower in the group treated with BLES than the one receiving Curosurf. As such, in 91.50% of infants who received Curosurf, cost exceeded $200 (inflation-adjusted cost = $ 273.48), although that cost was only observed in case of 8.50% of infants who used BLES [40]. In a retrospective cohort study of infants at risk of RDS to compare the efficacy and safety of Calfactant and Curosurf, Zayek et al. found that the cost of Curosurf-based treatment per patient was $ 1,160.62 (inflation-adjusted cost: $1229.56), which was 38% higher than the cost imposed by using Calfactant ($838.34 (inflation-adjusted cost: $877.08)) [16]. Marsh et al conducted a study to compare the pharmacoeconomic profiles of Survanta and Curosurf via a cost-minimization analysis. These analyses would suggest Curosurf may offer a less costly, clinically-equivalent option. Different treatment models using Curosurf (compared to Survanta) resulted in cost savings ranging from 53% ($949.67 (inflation-adjusted cost: $1296.21)) to 20% ($180 (inflation-adjusted cost: $245.68)) [46]. In a study aimed at evaluating economic and therapeutic efficiency (based on drug therapy cost index, duration of respiratory support, duration of hospitalization, side effects, etc.), Brown et al. reported higher average medication costs ($1756.44 vs. $1329.78 (inflation-adjusted cost: $1860.77 vs. $1408.77)) for Poractant Alfa (Curosurf) compared with Beractant (Survanta). While many clinical indicators were not significantly different between the groups [47]. A cost-effectiveness analysis study of surfactant therapy in the treatment of NRDS showed that the use of Poractant Alfa (Curosurf) is a superior option compared to Beractant (Survanta). Cost-effectiveness ratio was €4585 ($5067.57) per saved life for Poractant Alfa and €5087 ($5590.35) per saved life for Beractant [48]. Another study aimed at comparing the efficacy and safety of bovine lung phospholipid and Poractant Alfa injection in the treatment of neonatal hyaline membrane disease showed that treatment costs in the for Poractant Alfa group were significantly lower than the bovine lung phospholipid group [49].” 3. The need for mechanical ventilation can be due to multiple reasons or other single etiologic factors than RDS. Authors’ response: Thank you very much for this comment. Yes, you are right, the need for mechanical ventilation may be due to reasons other than RDS. But it should be noted that the target population of this research is infants who were firstly diagnosed with RDS, and secondly, surfactant was prescribed to them. And, as evidence shows, one of the short-term effects of surfactant injection is reducing the need for mechanical ventilation [12]. And in the population studied in this research, like other similar studies, the need for mechanical ventilation after surfactant injection can indicate the effectiveness of the surfactant. Mousavi et al.'s study [3], and Mirzarahimi et al.'s study [12], which had the same target population and research objectives as our research, have used this index (need for mechanical ventilation) as an index to measure the effectiveness of various surfactants (a summary of these studies is provided below). Some of the evidence reviewed to respond to this comment: � Mousavi et al.'s study [3]: o Title: Comparison of the Efficacy of Three Natural Surfactants (Curosurf, Survanta, and Alveofact) in the Treatment of Respiratory Distress Syndrome Among Neonates o Clinical parameters for comparing three surfactants: hospital-stay length, mechanical ventilation requirement, and... o Result: InSurE failure and mechanical ventilation support requirement in neonates over 32 weeks was significantly lower in the Survanta group (P = 0.019). And .... � Mirzarahimi et al.'s study [12]: o Title: Comparison efficacy of Curosurf and Survanta in preterm infants with respiratory distress syndrome o Clinical parameters for comparing two surfactants: hospital-stay length, need for ventilation, repeated doses, mortality rate, and... o Result: …but the need for repeated doses in Curosurf group and need for ventilation in Survanta group is less than others/ … and in mean duration of ventilation Survanta group with 8 days was lower than Curosurf group with 10.5 days [P=0.001]. � Dani et al.'s study [13]: o Title: Analysis of the cost-effectiveness of surfactant treatment (Curosurf) in respiratory distress syndrome therapy in preterm infants: early treatment compared to late treatment o Parameters for comparing three surfactants: The duration of the need for mechanical ventilation, and Variation in Mechanical Ventilation cost o Result: The cost of treatment with surfactant was greater in the early group, but this was compensated by the greater cost of treatment with Mechanical Ventilation (MV) in the late group. In addition, as shown in Table 1 of the manuscript, infants in the four surfactant groups do not differ significantly based on baseline characteristics. In Table 1 of the manuscript, we only stated five very common characteristics that were reported by other similar studies, to avoid data overload in the manuscript. While the research team, from the beginning of this research, based on the comprehensive data set that was extracted from the Iranian Maternal and Neonatal Network (IMAN net), examined the groups of infants in terms of many characteristics that their data is available in the system, and it was found that there is no significant difference in these characteristics. But due to the large number of these variables, it is challenging to present them in the text of the manuscript, express the results and discuss them; and the research team prefers to report only common variables used in other similar studies. In fact, with the aim of ensuring that the babies of the four groups were similar before the administration of surfactant, we examined a large number of variables that directly and indirectly affected the subject of the research, and finally it was found that most of these variables had no significant difference between the four groups (variables related to the clinical conditions of the newborn, risk factors related to the mother, and diseases and abnormalities of newborns, etc.). Many of these variables directly and indirectly affect the "need for mechanical ventilation" index. Considering the large number of investigated variables, therefore, it can probably be concluded that many reasons or factors other than RDS, which may affect the "need for mechanical ventilation" index, are probably not significantly different between the four investigated groups. However, we also mention this issue as one of the limitations of the research. Additionally, based on your comments, we provided a descriptive report of these variables and added Table S3.1 in S3_File. And we mentioned them briefly in the text of the manuscript. By expressing this comment, you have provided us with this opportunity to publish our extensive collection of data and analysis. Thank you again. It should be noted that although some variables that affect the need for mechanical ventilation have been reported, it is still not possible to comprehensively examine all factors and we are limited to the data recorded in the national system. Based on your comment, we stated this issue as one of the limitations of the research in the manuscript. We thank you again for this valuable comment. If you have specific advice in this regard, please share it with us and we will do it if we can. Please check these revisions in the last paragraph of the discussion section. These revisions are as follows: “In addition, another limitation of this research is that although according to the evidence, the need for mechanical ventilation and its duration is one of the indications of the efficacy of surfactant therapy, it is possible that factors other than RDS caused it. In this research, we were limited to the data extracted from the Iranian Maternal and Neonatal Network (IMAN net), and it was not possible to comprehensively examine all the factors. Another main limitation…”   References: 1. Diakoulaki, D., G. Mavrotas, and L. Papayannakis, Determining objective weights in multiple criteria problems: The critic method. Computers & Operations Research, 1995. 22(7): p. 763-770. 2. Pamučar, D. and G. Ćirović, The selection of transport and handling resources in logistics centers using Multi-Attributive Border Approximation area Comparison (MABAC). Expert systems with applications, 2015. 42(6): p. 3016-3028. 3. Mussavi, M., K. Mirnia, and K. 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Attachment Submitted filename: Response to Reviewers.docx Click here for additional data file. 10.1371/journal.pone.0286997.r003 Decision Letter 1 Grosek Stefan Academic Editor © 2023 Stefan Grosek 2023 Stefan Grosek https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version1 29 May 2023 Comparing the Clinical and Economic Efficiency of Four Natural Surfactants in Treating Infants with Respiratory Distress Syndrome PONE-D-23-01167R1 Dear Dr. Shojaei, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. 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Reviewers' comments: 10.1371/journal.pone.0286997.r004 Acceptance letter Grosek Stefan Academic Editor © 2023 Stefan Grosek 2023 Stefan Grosek https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 22 Jun 2023 PONE-D-23-01167R1 Comparing the clinical and economic efficiency of four natural surfactants in treating infants with respiratory distress syndrome Dear Dr. Shojaei: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Professor Stefan Grosek Academic Editor PLOS ONE ==== Refs References 1 Aynalem Y.A. , et al ., Incidence of respiratory distress and its predictors among neonates admitted to the neonatal intensive care unit, Black Lion Specialized Hospital, Addis Ababa, Ethiopia. PloS one, 2020. 15 (7 ): p. e0235544. doi: 10.1371/journal.pone.0235544 32609748 2 Edwards M.O. , Kotecha S.J. , and Kotecha S. , Respiratory distress of the term newborn infant. 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