Original Investigation | Pediatrics

Association of Adherence to Surfactant Best Practice Uses With Clinical OutcomesAmong Neonates in SwedenPontus Challis, MD; Per Nydert, MScPharm, PhD; Stellan Håkansson, MD, PhD; Mikael Norman, MD, PhD

Abstract

IMPORTANCE While surfactant therapy for respiratory distress syndrome (RDS) in preterm infantshas been evaluated in clinical trials, less is known about how surfactant is used outside such aframework.

OBJECTIVE To evaluate registered use, off-label use, and omissions of surfactant treatment bygestational age (GA) and associations with outcomes, mainly among very preterm infants (GA<32 weeks).

DESIGN, SETTING, AND PARTICIPANTS This population-based cohort study used registry data for97 377 infants born in Sweden between 2009 and 2018. Infants did not have malformations andwere admitted for neonatal care. Data analysis was conducted from June 2019 to June 2020.

EXPOSURES Timing and number of surfactant administrations, off-label use, and omission of use.Registered use was defined by drug label (1-3 administrations for RDS). Omissions were defined assurfactant not administered despite mechanical ventilation for RDS.

MAIN OUTCOME AND MEASURES In-hospital survival, pneumothorax, intraventricularhemorrhage grade 3 to 4, duration of mechanical ventilation, use of postnatal systemiccorticosteroids for lung disease, treatment with supplemental oxygen at 28 days’ postnatal age andat 36 weeks’ postmenstrual age. Odds ratios (ORs) were calculated and adjusted for any prenatalcorticosteroid treatment, cesarean delivery, GA, infant sex, Apgar score at 10 minutes, and birthweight z score of less than −2.

RESULTS In total, 7980 surfactant administrations were given to 5209 infants (2233 [42.9%] girls;2976 [57.1%] boys): 629 (12.1%) born at full term, 691 (13.3%) at 32 to 36 weeks’ GA, 1544 (29.6%) at28 to 31 weeks’ GA, and 2345 (45.0%) at less than 28 weeks’ GA. Overall, 977 infants (18.8%)received off-label use. In 1364 of 3508 infants (38.9%) with GA of 22 to 31 weeks, the firstadministration of surfactant was given more than 2 hours after birth, and this was associated withhigher odds of pneumothorax (adjusted OR [aOR], 2.59; 95% CI, 1.76-3.83), intraventricularhemorrhage grades 3 to 4 (aOR, 1.71; 95% CI, 1.23-2.39), receipt of postnatal corticosteroids (aOR,1.57; 95% CI, 1.22-2.03), and longer duration of assisted ventilation (aOR, 1.34; 95% CI, 1.04-1.72) butalso higher survival (aOR, 1.45; 95% CI, 1.10-1.91) than among infants treated within 2 hours of birth.In 146 infants (2.8%), the recommended maximum of 3 surfactant administrations was exceeded butwithout associated improvements in outcome. Omission of surfactant treatment occurred in 203 of3551 infants (5.7%) who were receiving mechanical ventilation and was associated with lowersurvival (aOR, 0.49; 95% CI, 0.30-0.82). In full-term infants, 336 (53.4%) of those receivingsurfactant had a diagnosis of meconium aspiration syndrome. Surfactant for meconium aspirationwas not associated with improved neonatal outcomes.

(continued)

Key PointsQuestion What strategies for surfactant

treatment of newborn infants are used,

and how are these strategies associated

with outcomes?

Findings In this cohort study of 5209

infants who received 7980 surfactant

administrations, late surfactant

treatment (>2 hours after birth) was

provided for 39% of very preterm

infants and associated with higher

neonatal morbidity. Off-label use

occurred in 19% of infants without any

association to outcome, and treatment

omissions were associated with lower

survival.

Meaning In this study, adherence to

best practices for surfactant use in

newborn infants varied, with important

clinical implications for neonatal

outcomes.

+ Invited Commentary

+ Supplemental content

Author affiliations and article information arelisted at the end of this article.

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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Abstract (continued)

CONCLUSIONS AND RELEVANCE In this study, adherence to best practices and labels forsurfactant use in newborn infants varied, with important clinical implications for neonatal outcomes.

JAMA Network Open. 2021;4(5):e217269. doi:10.1001/jamanetworkopen.2021.7269

Introduction

Surfactant therapy for respiratory distress syndrome (RDS) in preterm infants is an advancement inneonatology of the utmost importance.1,2 It leads to rapid improvement in oxygenation, decreasesthe need for ventilator support for RDS, and reduces mortality and air leaks by half.3-6 Early trials alsoreported a significantly diminished risk of chronic lung disease among survivors.7 However, theseresults have been challenged in more recent studies favoring noninvasive ventilatory support in thedelivery room instead of intubation and surfactant administration.6,8

As one of the most intensively studied interventions in neonatal care, surfactant therapy restson solid evidence.2 Numerous randomized clinical trials have been performed to determine theefficacy of different surfactant preparations, optimal timing of administration, and optimaldosage.2-4,7-9 Based on this bulk of evidence, recommendations and guidelines have beenpublished,5,10 forming the basis for licensed use of surfactant.

While surfactant use within the framework of clinical trials has been described, less is knownabout surfactant treatment and its outcomes outside such trials. Although observational data onpreterm infants receiving surfactant have been published,11-17 these studies provide little informationon the number of surfactant administrations and do not cover the full range of gestational ages (GA).In addition, there is often no information on indications for surfactant, the timing of administrations,and compliance to best practices. Off-label use and omission of use are also important areas thathave been poorly defined in terms of size of the problem and associations with outcome.18

The aim of this study was to assess adherence to surfactant best practices and to test forassociations with important clinical outcomes, particularly in very preterm infants (GA <32 weeks).For this purpose, prospectively collected registry data were used to form a national, population-based cohort of nearly 100 000 newborn infants admitted for neonatal care.

Methods

Ethical approval was obtained from the regional ethics review board in Stockholm, Sweden. A waiverof informed consent was granted because all parents received information regarding the processingof personal data to the Swedish Neonatal Quality Register (SNQ) with a right to opt out and have allpersonal information removed. This report follows the Strengthening the Reporting of ObservationalStudies in Epidemiology (STROBE) reporting guideline for cohort studies.19

Participants and SettingThe study was a national, population-based cohort study. The population consisted of all liveborninfants in Sweden between 2009 and 2018 (N = 1 144 432), of whom 67 810 (5.9%) were bornpreterm, ie, before 37 completed weeks’ GA. The study population consisted of all infants admittedfor neonatal care during the same period and reported in the SNQ (n = 107 901). To estimateassociations in a more homogeneous population and to reduce potential confounding, newborninfants admitted for inborn errors of metabolism, major malformations as defined by EUROCAT,20

chromosomal aberrations, or congenital infections (rubella, cytomegalovirus, toxoplasmosis) wereexcluded (n = 10 564). The final study population comprised 97 337 infants.

JAMA Network Open | Pediatrics Surfactant Best Practice Uses and Clinical Outcomes Among Neonates in Sweden

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In Sweden, there were 36 neonatal units during the study period. Delivery and initial neonatalcare of extremely preterm infants (GA <28 weeks) were centralized to 7 university hospitals in 6greater regions.

Data SourcesOpen-access statistics provided by Statistics Sweden was used to assess the total number of births.21

SNQ has prospectively collected data on neonatal procedures and outcomes for all infants in Swedenadmitted to neonatal care. The register has been described and validated, and completeness forpreterm infants has been found to be excellent.22 Information on extracorporeal membraneoxygenation (ECMO) treatment was validated against the Swedish Intensive Care Register.23

Exposures, Covariates, and OutcomesSurfactant use was considered the main exposure. In the study period, only 1 porcine surfactantpreparation (poractant alfa) was available in Sweden. Licensed use of surfactant included RDS as theindication and administration through an endotracheal tube.24 The licensed dose was 100 to 200mg/kg as a first bolus and 100 mg/kg for subsequent doses. The maximum number of recommendeddoses was 3.24 Use of surfactant outside these recommendations was categorized as off-label use.Omission of use was defined as no surfactant administered despite a diagnosis of RDS andmechanical ventilation starting within 3 days after birth.

SNQ contains information on 3 surfactant variables: surfactant administration (yes or no), thetiming of the first surfactant administration (postnatal age in minutes, hours, and days), and thenumber of administrations. The postnatal age at the first surfactant administration was verified in allcases against the time of birth. Data on timing of the first surfactant administration was missing in620 of 5209 infants (11.9%), and information on the number of administrations was missing in 257(4.9%). Rows with missing data were removed to perform analyses on full data sets. The typicalpractice was surfactant administration via endotracheal tube without immediate extubation. SNQ didnot collect information on the use of Less Invasive Surfactant Administration or Intubation-Surfactant-Extubation (INSURE) procedures.

Besides surfactant usage, information was also collected on the following covariates andpotential confounders: any prenatal corticosteroid treatment, mode of delivery, GA, postnatal age,sex, Apgar score, birth weight, and z score for birth weight (calculation based on the intrauterinegrowth curve).25 In infants with less than 28 weeks’ GA, birth in hospitals without level III neonatalintensive care was included as a covariate.

Diagnoses of lung diseases were categorized as RDS, transient tachypnea of the newborn(TTN), meconium aspiration syndrome (MAS), or other. Diagnostic criteria used were according tothe International Statistical Classification of Diseases and Related Health Problems, Tenth Revision(ICD-10) and a predefined manual for SNQ, available for all users (eTable 1 in the Supplement). If morethan 1 diagnosis was reported to the SNQ, all combinations of diagnoses including RDS were codedas RDS, and the combination MAS and TTN was coded as MAS.

Outcomes included in-hospital survival and, in survivors, pneumothorax; intraventricularhemorrhage (IVH) grades 3 to 4, defined according to Papile et al26; and indicators of the severity ofRDS, such as duration of mechanical ventilation (MV) or continuous positive airway pressure (CPAP)treatment, use of postnatal corticosteroids for lung disease, and supplemental oxygen at 28 days’postnatal age and at 36 weeks’ postmenstrual age (PMA). For MAS only, outcomes included use ofECMO treatment.

Statistical AnalysisData are presented as numbers and percentages or as medians and interquartile ranges (IQRs). Forcomparisons of surfactant use between regions and comparison between groups, the Pearson χ2 testand 2-sample t test were used. Changes over time were described with β regression.27

JAMA Network Open | Pediatrics Surfactant Best Practice Uses and Clinical Outcomes Among Neonates in Sweden

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To study any associations between surfactant usage (timing, number of administrations,off-label use, omission of use) and outcomes, adjusted odds ratios (aORs) and 95% CIs werecalculated using multiple logistic regression. In the logistic regression models, evidence-based (firstsurfactant administration within 2 hours after birth) and registered uses (number of administrations�3 and RDS as indication) were considered reference categories.

In the regression models for very preterm infants, the ORs were adjusted for any prenatalcorticosteroids, cesarean delivery, GA in days, sex, Apgar score at 10 minutes, and birth weight zscore less than −2. Mortality in extremely preterm infants, with less than 28 weeks’ GA, was alsoadjusted for being born in hospitals without level III neonatal intensive care. In all outcome analyses,infants born at 21 weeks’ GA were excluded (n = 13). The logistic regression model for full-terminfants with MAS was adjusted for GA in days, sex, birth weight z score less than −2, and Apgar scoreat 10 minutes.

To estimate goodness of fit in the logistic models, the Hosmer-Lemeshow test was used. P < .05or a 95% CI that does not include 1 for ORs were considered statistically significant differences, andall tests were 2-sided. Statistical analyses were conducted in R version 3.5.2 (R Project for StatisticalComputing), and figures were produced using the package ggplot2 version 3.3.3.

Results

In total, 7980 surfactant administrations were given to 5209 infants (2233 [42.9%] girls; 2976[57.1%] boys; 4.8% of all admissions for neonatal care): 629 (12.1%) were born at full term; 691(13.3%) at 32 to 36 weeks; 1544 (29.6%) at 28 to 31 weeks; and 2345 (45.0%) before 28 weeks. Thecorresponding proportions of admitted infants treated with surfactant were 629 of 58 238 (1.1%),691 of 30 403 (2.3%), 1544 of 5721 (27.0%), and 2345 of 2975 (78.8%), respectively.

The proportion of extremely preterm infants (GA <28 weeks) treated with surfactant variedfrom 419 of 580 (72.2%) to 512 of 597 (86.2%) in the 6 greater health care regions of Sweden(P = .001). In infants born at 28 to 31 weeks, the proportions treated with surfactant varied between114 of 552 (20.7%) and 360 of 1231 (29.1%) (P = .003). Overall treatment patterns did not changesignificantly over time (eFigure 1 in the Supplement).

Diagnoses in Infants Treated With SurfactantThe most common diagnosis in preterm infants treated with surfactant was RDS (4156 of 4580[90.7%]), followed by TTN (161 [3.5%]). In full-term infants, 336 of 629 receiving surfactant (53.4%)had MAS, 131 (20.8%) had RDS or TTN, and the remaining 162 (25.8%) had other diagnoses (Table 1).

Number of Surfactant AdministrationsIn total, 7980 surfactant administrations were given: 3082 infants (59.2%) received 1 administration,1345 (25.8%) received 2, 379 (7.3%) had 3, and 146 (2.8%) had 4 or more administrations. More thanhalf the infants (84 infants [57.5%]) who received 4 or more administrations were born extremelypreterm (Table 2; eFigure 2 in the Supplement).

Table 1. Respiratory Diagnoses in Infants Treated With Surfactant, Stratified by Gestational Age

Diagnosis

Infants, No. (%)

Gestational age, wkTotal(N = 5209)

<28(n = 2345)

28-31(n = 1544)

32-36(n = 691)

≥37(n = 629)

RDS 2219 (94.6) 1392 (90.2) 545 (78.9) 76 (12.1) 4232 (81.2)

TTN 27 (1.2) 72 (4.7) 62 (9.0) 55 (8.7) 216 (4.1)

MAS 0 (0.0) 0 (0.0) 2 (0.3) 336 (53.4) 338 (6.5)

None of the above or missing 99 (4.2) 80 (5.2) 82 (11.9) 162 (25.8) 423 (8.1)

Abbreviations: MAS, meconium aspiration syndrome;RDS, respiratory distress syndrome; TTN, transienttachypnea of the newborn.

JAMA Network Open | Pediatrics Surfactant Best Practice Uses and Clinical Outcomes Among Neonates in Sweden

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Timing of First Surfactant Administration and Association With OutcomesThe postnatal age at surfactant administration showed 3 distinctive peaks: the first and largest peakoccurred at 10 minutes after birth; the second, 8 to 10 hours’ postnatal age; and the third, at 24 to30 hours’ postnatal age (eFigure 3 in the Supplement). Timing of the first surfactant administrationshowed a clear association with GA, with 1513 extremely preterm infants (69.6%) treated withsurfactant within 1 hour after birth compared with 90 (15.8%) and 113 (22.6%) in moderately pretermand full-term infants (P = .001) (eTable 2 in the Supplement).

In 1364 of 3508 infants (38.9%) with 22 to 31 weeks’ GA, the first surfactant administration wasprovided after 2 hours’ postnatal age, ie, later than recommended in international guidelines.10 Thiswas associated with higher odds of pneumothorax (aOR, 2.59; 95% CI, 1.76-3.83), IVH grades 3 to 4(aOR, 1.71; 95% CI, 1.23-2.39), use of postnatal corticosteroids (aOR, 1.57; 95% CI, 1.22-2.03), andduration of CPAP (aOR, 1.34; 95% CI, 1.04-1.72) than in those who received the first surfactantadministration within 2 hours’ postnatal age. Duration of MV and need of supplemental oxygen at 28days of postnatal age or at 36 weeks PMA did not show any statistically significant association withtiming of first surfactant administration. However, in infants having their first surfactantadministration after 2 hours’ postnatal age, in-hospital survival was higher than among those withsurfactant administration within 2 hours’ postnatal age (1271 of 1364 [93.2%] vs 1690 of 2144[78.8%]; aOR, 1.45; 95% CI, 1.10-1.91) (Table 3). The higher survival among infants receiving their firstsurfactant administration after 2 hours’ postnatal age was confined to infants with 28 to 31 weeks’GA (aOR, 1.77; 95% CI, 1.03-3.06), whereas there was no statistically significant difference in survivalassociated with the timing of the first surfactant administration in infants born before 28 weeks’ GA.A sensitivity analysis excluding very preterm infants treated with surfactant for other diagnoses thanRDS (278 of 3889 infants [7.1%]) did not alter the results. The distributions of birth characteristicsamong very preterm infants by surfactant treatment and by timing of the first administration arepresented in eTable 3 in the Supplement.

Adherence to Recommendations, Off-Label Use, and Association With OutcomesThe proportion of infants treated with surfactant for the only licensed indication in Sweden, ie, RDS,was 4232 of 5209 (81.2%), meaning that 977 infants (18.8%) received off-label use. The proportion

Table 2. Infants Treated With 1, 2, 3, or More Surfactant Administrations, by Gestational Age

Gestational age, wk

Infants, No. (%)

Surfactant administrations

No surfactant1 2 3 ≥4 Unknown21 (n = 13) 10 (76.9) 2 (15.4) 1 (7.7) 0 0 0

22 (n = 137) 46 (33.6) 49 (35.8) 14 (10.2) 10 (7.3) 1 (0.7) 17 (12.4)

23 (n = 327) 131 (40.1) 98 (30.0) 33 (10.1) 24 (7.3) 20 (6.1) 21 (6.4)

24 (n = 463) 213 (46.0) 142 (30.7) 47 (10.2) 13 (2.8) 14 (3.0) 34 (7.3)

25 (n = 563) 248 (44.0) 141 (25.0) 43 (7.6) 18 (3.2) 19 (3.4) 94 (16.7)

26 (n = 690) 275 (39.9) 133 (19.3) 55 (8.0) 11 (1.6) 15 (2.2) 201 (29.1)

27 (n = 782) 326 (41.7) 113 (14.5) 42 (5.4) 8 (1.0) 30 (3.8) 263 (33.6)

28 (n = 967) 307 (31.7) 103 (10.7) 27 (2.8) 10 (1.0) 17 (1.8) 503 (52.0)

29 (n = 1213) 283 (23.3) 119 (9.8) 22 (1.8) 10 (0.8) 23 (1.9) 756 (62.3)

30 (n = 1520) 241 (15.9) 62 (4.1) 18 (1.2) 4 (0.3) 18 (1.2) 1177 (77.4)

31 (n = 2021) 188 (9.3) 56 (2.8) 17 (0.8) 5 (0.2) 14 (0.7) 1741 (86.1)

32 (n = 3049) 143 (4.7) 51 (1.7) 9 (0.3) 3 (0.1) 12 (0.4) 2831 (92.9)

33 (n = 4634) 103 (2.2) 37 (0.8) 9 (0.2) 4 (0.1) 12 (0.3) 4469 (96.4)

34 (n = 7500) 104 (1.4) 36 (0.5) 6 (0.1) 5 (0.1) 7 (0.1) 7342 (97.9)

35 (n = 8540) 48 (0.6) 32 (0.4) 4 (0.05) 1 (0.01) 6 (0.1) 8449 (98.9)

36 (n = 6680) 35 (0.5) 19 (0.3) 1 (0.01) 1 (0.01) 3 (0.04) 6621 (99.1)

37-39 (n = 29 990) 133 (0.4) 35 (0.1) 5 (0.02) 9 (0.03) 23 (0.1) 29 785 (99.3)

≥40 (n = 28 248) 248 (0.9) 117 (0.4) 26 (0.1) 10 (0.04) 23 (0.1) 27 824 (98.5)

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treated with the recommended maximum of 3 surfactant administrations was 4806 of5209 (92.3%).

Omission of surfactant treatment occurred in 203 of 3551 infants (5.7%) who were receivingmechanical ventilation for RDS. In infants with less than 32 weeks’ GA, treatment omission wasassociated with lower survival compared with infants who received surfactant treatment (101 of 128[78.9%] vs 2414 of 2917 [82.8%]; aOR, 0.49; 95% CI, 0.30-0.82). However, proportions of infantstreated with postnatal corticosteroids and supplemental oxygen at 28 days’ postnatal age were lowerin infants surviving omissions of treatment than in infants treated with surfactant (Table 4).

There was no association between 4 or more administrations of surfactant and improvedoutcomes (eTable 4 in the Supplement). In addition, in full-term infants receiving mechanicalventilation for MAS (336 [55.4%]), there was no observational benefit of surfactant administration(eTable 5 in the Supplement).

Discussion

In this study, several clinically important observations were made regarding the use of surfactant inSweden: first, although very preterm infants were the main target group, we found that one-quarterof surfactant administrations were for full-term or moderately preterm infants. Second, significantregional variations in surfactant treatment were found, whereas administration patterns over time

Table 3. Surfactant Administration Within or After 2 Hours’ PNA and Associations With Survival, SelectedMorbidities, and Additional Respiratory Treatments in Infants With 22 to 31 Weeks’ Gestational Agea

Outcome

Infants receiving surfactant, No. (%) OR (95%CI)

≤2 h (n = 2144)b >2 h (n = 1364) Crude Adjustedc

In-hospital survival 1690 (78.8) 1271 (93.2) 3.67 (2.92-4.67) 1.45 (1.1-1.91)

Neonatal morbidity in survivors

Pneumothorax 60 (3.6) 114 (9.0) 2.68 (1.95-3.71) 2.59 (1.76-3.83)

IVH grade 3-4 148 (8.8) 88 (6.9) 0.78 (0.59-1.02) 1.71 (1.23-2.39)

MV duration >7 d 828 (49.0) 285 (22.4) 0.35 (0.30-0.42) 1.26 (0.98-1.63)

Postnatal corticosteroid use 415 (24.6) 164 (12.9) 0.46 (0.37-0.55) 1.57 (1.22-2.03)

CPAP duration >7 d 1370 (81.8) 820 (65.4) 0.42 (0.35-0.50) 1.34 (1.04-1.72)

Receipt of supplemental oxygen

28 d PNA 984 (58.2) 509 (40.0) 0.48 (0.41-0.56) 1.08 (0.89-1.32)

36 w PMA 713 (42.2) 333 (26.2) 0.49 (0.42-0.57) 1.07 (0.88-1.32)

Abbreviations: CPAP, continuous positive airwaypressure; IVH, intraventricular hemorrhage; MV,mechanical ventilation; OR, odds ratio; PMA,postmenstrual age; PNA, postnatal age.a Hosmer-Lemeshow test indicated goodness of fit for

survival (P = .44), pneumothorax (P = .40), IVHgrades 3 to 4 (P = .55), and supplemental oxygen at36 weeks’ PMA (P = .15), whereas goodness of fit waspoor (ie, P < .05) for the remaining outcomes.

b Reference category.c Adjusted for prenatal corticosteroid treatment,

cesarean delivery, gestational age in days, infant sex,Apgar score at 10 minutes, and birth weight z scoreof less than −2. Mortality was also adjusted for birthin hospitals without level III neonatal intensive care.

Table 4. Survival, Selected Morbidities, and Treatments in Infants With 22 to 31 Weeks’ Gestational AgeReceiving MV for Respiratory Distress Syndrome, Treated With Surfactant and Not Treated With Surfactanta

Outcome

Infants, No. (%) OR (95%CI)

Surfactant(n = 2917)b

No surfactant(n = 128) Crude Adjustedc

In-hospital survival 2414 (82.8) 101 (78.9) 0.78 (0.51-1.23) 0.49 (0.30-0.82)

Neonatal morbidity in survivors

Pneumothorax 170 (7.0) 15 (14.9) 2.30 (1.26-3.96) 1.84 (0.98-3.25)

IVH grades 3-4 242 (10.0) 7 (6.9) 0.67 (0.28-1.36) 0.85 (0.35-1.78)

MV duration >7 d 1098 (45.5) 24 (23.8) 0.37 (0.23-0.59) 0.70 (0.36-1.30)

Postnatal corticosteroid use 558 (23.1) 6 (5.9) 0.21 (0.08-0.44) 0.27 (0.09-0.64))

CPAP duration >7 d 1882 (78.7) 60 (60.6) 0.42 (0.28-0.65) 0.78 (0.46-1.33)

Supplemental oxygen

At 28 d PNA 1346 (55.8) 24 (23.8) 0.25 (0.15-0.39) 0.36 (0.21-0.60)

At 36 w PMA 973 (40.3) 28 (27.7) 0.57 (0.36-0.87) 0.97 (0.58-1.57)

Abbreviations: CPAP, continuous positive airwaypressure; IVH, intraventricular hemorrhage; MV,mechanical ventilation; OR, odds ratio; PMA,postmenstrual age; PNA, postnatal age.a Hosmer-Lemeshow test indicated goodness of fit for

survival (P = .86), IVH grades 3 to 4 (P = .49), andsupplemental oxygen at 36 weeks’ PMA (P = .18),whereas goodness of fit was poor (ie, P < .05) for theremaining outcomes.

b Reference category.c Adjusted for prenatal corticosteroid treatment,

cesarean delivery, gestational age in days, infant sex,Apgar score at 10 minutes, and birth weight z scoreless than −2. Mortality was also adjusted for birth inhospitals without level III neonatal intensive care.

JAMA Network Open | Pediatrics Surfactant Best Practice Uses and Clinical Outcomes Among Neonates in Sweden

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were stable. Third, 1 in 5 infants received surfactant off-label regarding indication or number ofadministrations, without any associations with improved outcome. Fourth, this study demonstratedthat adherence to best practice and administering surfactant within 2 hours after birth wasassociated with lower rates of pneumothorax, IVH grades 3 to 4, and receipt of postnatalcorticosteroids in very preterm survivors. However, very early surfactant administration, in this studypeaking approximately 10 minutes after birth, was also associated with increased mortality. Finally,omission of surfactant treatment was associated with lower survival in very preterm infants.

We evaluated surfactant use on a population level according to the manufacturer’s label and tothe European Consensus Guidelines on the Management of RDS.10,24 A European survey study28

from 2011 collected data on timing, dose, and preparation from 173 European neonatal intensive careunits (NICUs) and concluded that surfactant therapy was implemented according to guidelines.29

Our findings of significant off-label use and omissions of treatment challenge this conclusion. Two USnetwork studies from more than 340 NICUs18,30 evaluated surfactant use according to the US Foodand Drug Administration label, which states that the infant should require ventilatory support forRDS to receive surfactant.18 These studies defined INSURE administration and treatment after 30weeks’ gestation as the 2 most common reasons for off-label use.18,30 In addition, they found nosignificant association between surfactant treatment and lowered mortality or morbidity in preterminfants with GA longer than 30 weeks.30

The evidence for treating RDS with surfactant is strong.10 For best effect, especially amongextremely preterm infants,3,4 a policy of early rescue surfactant is advocated.10,24 Our findings ofsignificantly lower neonatal morbidity in infants treated with surfactant within 2 hours after birth andof increased mortality in infants in which surfactant therapy was omitted underline the importanceof this recommendation. However, and of particular concern, there was lower survival in the groupreceiving early surfactant administration, also after adjusting for some of the most important factorsfor infant survival, ie, use of prenatal corticosteroids, GA, Apgar score, and centralization ofcare.11,31-33 A possible explanation for an increased mortality is unmeasured confounding byindication, ie, infants with the most severe RDS were treated early but also suffered highermortality.34,35 In addition, we did not control for obstetric complications, such as chorioamnionitis,infections, and bleeding. However, it cannot be excluded that the higher mortality among infantsgiven surfactant very early could be a warning signal. In line with our findings, advanced resuscitationin the delivery room, including endotracheal intubation, particularly of infants in good condition atbirth and among less immature infants, has recently been associated with increased mortality.36

Lung recruitment, preferably during spontaneous breathing, may also improve the efficacy ofsurfactant treatment.37

The term off-label use refers to a use that is not approved by a national drug agency.38,39

Off-label use does not imply that drug use is improper, ineffective, or experimental.39,40 In contrastto most drugs used in the NICU,41,42 surfactant is extensively studied, with more than 400publications, providing strong evidence for its use.2,5,43 However, TTN was reported as an indicationfor surfactant therapy in 4% of the infants in this study, most of them born moderately preterm orat full term. The use of surfactant for this self-limiting disorder that requires minimal intervention44,45

can be questioned, especially when considering the risk of intubation.46-49 The same concerns arevalid for other indications, such as early-onset pneumonia and lung hemorrhage.50,51 Surfactant hasbeen shown to decrease oxygen need in congenital pneumonia,52 but this recommendation isconsidered weak and of low evidence.10

The natural pool of surfactant has been reported to be as low as 2 to 10 mg/kg in extremelypreterm infants compared with approximately 100 mg/kg in the full-term infant.53,54 This mayexplain why some infants, particularly those with very low GA, received 4 or more surfactantadministrations. However, it is reasonable to assume that the recommended regimen of 3administrations resulted in a total dose of 300 to 400 mg/kg, which would be sufficient to substitutesurfactant deficiency until the endogenous production begins at 48 to 78 hours’ postnatal age.10,24

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Our findings of no additional benefit after 3 surfactant administrations are in line with such aninterpretation.

Treating MAS with surfactant has been described as potentially being useful.10,55 We found noassociation between surfactant treatment of MAS and a reduction in pneumothorax. This finding is inline with 2 previous systematic reviews55,56 but in contrast to a recent multicenter randomizedclinical trial showing a reduction of death, ECMO treatment, and pneumothorax in 100 full-terminfants treated with surfactant and inhaled nitric oxide for various diagnoses, most commonly MASand pneumonia.57

Strengths and LimitationsThe major strengths of this study are the population-based design of surfactant use in Swedenmonitored over a decade, a higher granularity of included variables than in previous studies, and alarge number of participants, enabling us to perform adjusted outcome analysis with sufficientpower. Although used and analyzed in retrospect, all data were prospectively collected bystandardized definitions and procedures.

This study also has limitations. The observational study design limits the conclusions that can bedrawn, and no causality of the described associations can be confirmed. The outcome characteristicsanalysis must be interpreted with caution, as unmeasured or unknown confounding may haveoccurred. Although the final models for survival were adjusted for several important factors knownto affect outcomes, confounding because of the severity of illness may have occurred.34,35

Unfortunately, the dosage of surfactant was not available in the register and therefore could not beassessed or analyzed herein.58 Two European studies59,60 from 2016 and 2019 evaluated the dosageof surfactant and found that both undertreatment and overtreatment were common.

Conclusions

In this study, there was a high proportion of off-label surfactant use. Early administration ofsurfactant in RDS as a best practice is supported by our findings of lower incidences of several majorneonatal morbidities and of increased mortality if surfactant treatment is omitted. However, theincreased mortality associated with immediate surfactant administration in the delivery room,especially in more mature infants, may favor a less invasive approach than that presently practiced inSweden. Finally, while surfactant treatment might have a role in treating MAS, randomized clinicaltrials are needed before routine use can be recommended.

ARTICLE INFORMATIONAccepted for Publication: March 3, 2021.

Published: May 5, 2021. doi:10.1001/jamanetworkopen.2021.7269

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Challis Pet al. JAMA Network Open.

Corresponding Author: Pontus Challis, MD, Department of Clinical Sciences, Paediatrics, Umeå University,901 85 Umeå, Sweden (pontus.challis@umu.se).

Author Affiliations: Department of Clinical Sciences, Paediatrics, Umeå University, Umeå, Sweden (Challis,Håkansson); Division of Pediatrics, Department of Clinical Science, Intervention and Technology, KarolinskaInstitutet, Stockholm, Sweden (Nydert, Norman); Department of Neonatology, Karolinska University Hospital,Stockholm, Sweden (Nydert, Norman).

Author Contributions: Drs Challis and Håkansson had full access to all of the data in the study and takeresponsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Challis, Håkansson, Norman.

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Drafting of the manuscript: Challis, Håkansson, Norman.

Critical revision of the manuscript for important intellectual content: Challis, Nydert, Håkansson.

Statistical analysis: Challis, Nydert.

Obtained funding: Challis, Norman.

Administrative, technical, or material support: All authors.

Supervision: Håkansson, Norman.

Conflict of Interest Disclosures: Dr Norman reported receiving speaker fees from Chiesi Pharma AB during theconduct of the study. No other disclosures were reported.

Funding/Support: The Swedish Neonatal Quality Register and the Swedish Pregnancy Register are funded by theSwedish Government (Ministry of Health and Social Affairs) and the body of Regional Health Care Providers. Thisstudy was supported by an unrestricted research grant from Chiesi Pharma, by grants from a regional agreementon clinical research between Region Stockholm and Karolinska Institutet, and by the Childhood Foundation of theSwedish Order of Freemasons.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection,management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; anddecision to submit the manuscript for publication.

Additional Contributions: We thank all neonatal departments in Sweden for contributing and sharing data to thequality registers. We are grateful for the support from the Swedish Public Health Agency.

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SUPPLEMENT.eTable 1. Predefined Diagnostic Criteria Used in Swedish Neonatal Quality RegistereTable 2. Postnatal Age at First Surfactant Administration Stratified by Gestational AgeeTable 3. Selected Characteristics in Very Preterm Infants (22-31 weeks’ GA) Treated With Surfactant or NotTreated with Surfactant and Surfactant Administration Within of After 2 Hours’ Postnatal AgeeTable 4. Outcome Characteristics of Very Preterm Infants (22-31 weeks’ GA) Treated With 3 Administrations ofSurfactant vs Those With 4 or More Administrations of SurfactanteTable 5. Survival, Selected Morbidities, and Treatments in Full-Term Infants Receiving Mechanical Ventilation forMeconium Aspiration Syndrome and Treated Off-Label With Surfactant or NoteFigure 1. Proportions of Very (28-31 weeks’ GA) and Extremely Preterm (<28 weeks’ GA) Infants Treated WithSurfactant in Sweden by Study Year and Greater RegioneFigure 2. Proportions of Infants Treated With 1, 2, 3, or More Surfactant Administrations, by GAeFigure 3. Density Plot for Postnatal Age at First Administration of Surfactant

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