BackgroundPrematurity and infection with respiratory syncytial virus (RSV) are major risk factors for impaired lung function beyond the neonatal period.Research QuestionWhat are the long-term effects of palivizumab immunoprophylaxis in the first year of life on lung function and frequency of bronchitis episodes in 5- to 6-year-old preterm infants?Study Design and MethodsPreterm infants with a birth weight < 1,500 g (very low-birth weight infants [VLBWIs]) were enrolled in a German Neonatal Network cohort study between 2009 and 2016. Children were examined by a single follow-up team at 5 to 6 years of age. VLBWIs who received at least five doses of palivizumab were compared with children who never received palivizumab. Analyses were stratified by bronchopulmonary dysplasia (BPD) and gestational age. We analyzed FVC, FEV1, FEV1 to FVC ratio, and the risk of respiratory tract infections at 5 to 6 years of age via univariate analyses and linear and logistic regression models.ResultsOf 1,986 VLBWIs with follow-up at 5 to 6 years of age, 951 infants (48%) received immunoprophylaxis with palivizumab. Children with BPD (n = 1,019) showed a much lower FEV1 than children without BPD (median FEV1 z score, –1.51 vs –1.09; P < .001). However, FEV1 in children with BPD was not altered by palivizumab (median FEV1 z score in 698 children with BPD who received palivizumab, –1.57 [interquartile range (IQR), –0.75 to –2.43] vs in 320 children with BPD who did not receive palivizumab, –1.37 [IQR, –0.69 to –2.25]; P = .1). As for FEV1, we did not find any protective effects of palivizumab for other end points or in other risk groups.InterpretationPalivizumab immunoprophylaxis in VLBWIs is not associated with improved lung function or lower rates of respiratory tract infections in early school-age infants. Prematurity and infection with respiratory syncytial virus (RSV) are major risk factors for impaired lung function beyond the neonatal period. What are the long-term effects of palivizumab immunoprophylaxis in the first year of life on lung function and frequency of bronchitis episodes in 5- to 6-year-old preterm infants? Preterm infants with a birth weight < 1,500 g (very low-birth weight infants [VLBWIs]) were enrolled in a German Neonatal Network cohort study between 2009 and 2016. Children were examined by a single follow-up team at 5 to 6 years of age. VLBWIs who received at least five doses of palivizumab were compared with children who never received palivizumab. Analyses were stratified by bronchopulmonary dysplasia (BPD) and gestational age. We analyzed FVC, FEV1, FEV1 to FVC ratio, and the risk of respiratory tract infections at 5 to 6 years of age via univariate analyses and linear and logistic regression models. Of 1,986 VLBWIs with follow-up at 5 to 6 years of age, 951 infants (48%) received immunoprophylaxis with palivizumab. Children with BPD (n = 1,019) showed a much lower FEV1 than children without BPD (median FEV1 z score, –1.51 vs –1.09; P < .001). However, FEV1 in children with BPD was not altered by palivizumab (median FEV1 z score in 698 children with BPD who received palivizumab, –1.57 [interquartile range (IQR), –0.75 to –2.43] vs in 320 children with BPD who did not receive palivizumab, –1.37 [IQR, –0.69 to –2.25]; P = .1). As for FEV1, we did not find any protective effects of palivizumab for other end points or in other risk groups. Palivizumab immunoprophylaxis in VLBWIs is not associated with improved lung function or lower rates of respiratory tract infections in early school-age infants. Take-home PointStudy Question: Do preterm infants benefit from seasonal immunoprophylaxis with palivizumab in terms of long-term lung function and which risk groups have the greatest benefit?Results: In a cohort of 1,986 very low-birth weight infants with follow-up at 5 to 6 years of age, FEV1 was not altered by seasonal immunization with at least five doses of palivizumab in risk groups of preterm infants who were characterized by BPD and low gestational age.Interpretation: The risk-based approach of palivizumab subscriptions according to which high-risk preterm infants are passively immunized with five injections throughout respiratory syncytial virus season is not associated with improved spirometry scores at early school age. Study Question: Do preterm infants benefit from seasonal immunoprophylaxis with palivizumab in terms of long-term lung function and which risk groups have the greatest benefit? Results: In a cohort of 1,986 very low-birth weight infants with follow-up at 5 to 6 years of age, FEV1 was not altered by seasonal immunization with at least five doses of palivizumab in risk groups of preterm infants who were characterized by BPD and low gestational age. Interpretation: The risk-based approach of palivizumab subscriptions according to which high-risk preterm infants are passively immunized with five injections throughout respiratory syncytial virus season is not associated with improved spirometry scores at early school age. Very low-birth weight infants (VLBWIs) are particularly vulnerable to infectious diseases, and their vulnerability extends beyond the neonatal period into infancy, childhood, and adolescence.1Humberg A. Fortmann I. Siller B. et al.Preterm birth and sustained inflammation: consequences for the neonate.Semin Immunopathol. 2020; 42: 451-468Crossref PubMed Scopus (104) Google Scholar Premature birth, prematurity-related diseases such as bronchopulmonary dysplasia (BPD), and respiratory infections are independent risk factors for long-term respiratory impairment.2Narang I. Baraldi E. Silverman M. et al.Airway function measurements and the long-term follow-up of survivors of preterm birth with and without chronic lung disease.Pediatr Pulmonol. 2006; 41: 497-508Crossref PubMed Scopus (49) Google Scholar Respiratory syncytial virus (RSV) is the most frequently detected pathogen of lower airway infections in infancy.3Liese J. Forster J. Adams O. S2k-Leitlinie “Leitlinie zur Prophylaxe von schweren Erkrankungen durch Respiratory Syncytial Virus (RSV) bei Risikokindern.”.2018Google Scholar,4Gross M. Brune T. Jorch G. et al.Significance of respiratory syncytial virus (RSV) infection in the 1st year of life.Infection. 2000; 28: 34-37Crossref Scopus (8) Google Scholar In preterm infants (PIs), infections with RSV are associated with recurrent wheeze of early childhood (RWEC),5Prais D. Kaplan E. Klinger G. et al.Short- and long-term pulmonary outcome of palivizumab in children born extremely prematurely.Chest. 2016; 149: 801-808Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar although a causal relationship remains controversial.6Driscoll A.J. Arshad S.H. Bont L. et al.Does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma? Critical review of the evidence and guidance for future studies from a World Health Organization-sponsored meeting.Vaccine. 2020; 38 (4): 2435-2448Crossref PubMed Scopus (45) Google Scholar RWEC has been shown to lead to long-term respiratory impairment, including reduced FEV1.7Hadchouel A. Rousseau J. Rozé J.C. et al.Association between asthma and lung function in adolescents born very preterm: results of the EPIPAGE cohort study.Thorax. 2018; 73: 1174-1176Crossref PubMed Scopus (21) Google Scholar,8Lu S. Hartert T.V. Everard M.L. et al.Predictors of asthma following severe respiratory syncytial virus (RSV) bronchiolitis in early childhood.Pediatr Pulmonol. 2016; 51: 1382-1392Crossref PubMed Scopus (43) Google Scholar Approaches that attempt to explain underlying pathomechanisms include a shift from Th2-type to Th1-type immune responses in PIs driven by early microbial exposure leading to reduced IgE sensitization and atopy risk, but simultaneously promoting sustained inflammation processes.9Mitselou N. Andersson N. Bergström A. et al.Preterm birth reduces the risk of IgE sensitization up to early adulthood: a population-based birth cohort study.Allergy. 2022; 77: 1570-1582Crossref Scopus (4) Google Scholar Further hypotheses address different patterns of immunologic responses to viral infections such as eosinophilic inflammation in airway secretions, reduced interferon-γ production from mononuclear cells, and increased IL-10 secretion during convalescence, as well as disturbed airway physiologic features as a consequence of infection-related epithelial damage.10Gern J.E. Busse W.W. Relationship of viral infections to wheezing illnesses and asthma.Nat Rev Immunol. 2002; 2: 132-138Crossref PubMed Scopus (113) Google Scholar However, data on long-term outcomes of early RSV infection in VLBWIs are scarce.11Díez-Domingo J. Pérez-Yarza E.G. Melero J.A. et al.Social, economic, and health impact of the respiratory syncytial virus: a systematic search.BMC Infect Dis. 2014; 14 (31): 544Crossref PubMed Scopus (69) Google Scholar,12Fortmann M.I. Dirks J. Goedicke-Fritz S. et al.Immunization of preterm infants: current evidence and future strategies to individualized approaches.Semin Immunopathol. 2022; 3: 1-18Google Scholar Passive immunization of VLBWIs with the humanized monoclonal antibody palivizumab has been proven to reduce RSV-related hospitalization rates in PIs during the first year of life.13The IMpact-RSV Study GroupPalivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants.Pediatrics. 1998; 102: 531-537Crossref Scopus (1852) Google Scholar However, the IMPACT study—a randomized, double-masked, placebo-controlled trial—did not demonstrate effects on the total amount of days on the ICU after discharge from a primary hospital stay, duration of ventilation, or mortality,13The IMpact-RSV Study GroupPalivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants.Pediatrics. 1998; 102: 531-537Crossref Scopus (1852) Google Scholar whereas long-term outcomes have not been addressed in this study. To this day, a paucity of data is available regarding long-term effects of palivizumab beyond infancy. The ongoing discussion about the cost-effectiveness of RSV prophylaxis has led international committees to limit the indication for palivizumab immunization to high-risk infants, such as PIs and infants with chronic lung disease or congenital heart disease. Within the group of PIs, the indication for or against palivizumab prophylaxis according to international guidelines, such as the committees of Austria,14Resch B. Eber E. Ehringer-Schetitska D. et al.Respiratory-syncytial-virus-prophylaxe mit palivizumab.Pädiatr Pädologie. 2019; 54 (1): 270-276Google Scholar Sweden, Switzerland, Italy,15Bollani L. Baraldi E. Chirico G. et al.Revised recommendations concerning palivizumab prophylaxis for respiratory syncytial virus (RSV).Ital J Pediatr. 2015; 41 (15): 97Crossref PubMed Scopus (63) Google Scholar Canada,16Robinson J.L. Le Saux N. Preventing hospitalizations for respiratory syncytial virus infection.Paediatr Child Health. 2015; 20: 321-333Crossref Scopus (42) Google Scholar the United States,17American Academy of Pediatrics Committee on Infectious Diseases; American Academy of Pediatrics Bronchiolitis Guidelines CommitteeUpdated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection.Pediatrics. 2014; 134: 415-420Crossref PubMed Scopus (130) Google Scholar and the United Kingdom, mainly is based on gestational age (GA), postnatal age, and the presence or absence of BPD.3Liese J. Forster J. Adams O. S2k-Leitlinie “Leitlinie zur Prophylaxe von schweren Erkrankungen durch Respiratory Syncytial Virus (RSV) bei Risikokindern.”.2018Google Scholar These recommendations predominantly rest on the increased risk of a severe course of RSV infection in infants with BPD3Liese J. Forster J. Adams O. S2k-Leitlinie “Leitlinie zur Prophylaxe von schweren Erkrankungen durch Respiratory Syncytial Virus (RSV) bei Risikokindern.”.2018Google Scholar,18Jobe A.H. Bancalari E. Bronchopulmonary dysplasia.Am J Respir Crit Care Med. 2001; 163: 1723-1729Crossref PubMed Google Scholar and increased rehospitalization rates of extremely low-GA neonates with fewer than 28 weeks’ gestation without BPD.16Robinson J.L. Le Saux N. Preventing hospitalizations for respiratory syncytial virus infection.Paediatr Child Health. 2015; 20: 321-333Crossref Scopus (42) Google Scholar Data on long-term effects of palivizumab in PIs are limited and inconclusive, and none of the few studies that have been conducted were able—because of the low sample sizes—to stratify to risk groups targeted by immunization guidelines.5Prais D. Kaplan E. Klinger G. et al.Short- and long-term pulmonary outcome of palivizumab in children born extremely prematurely.Chest. 2016; 149: 801-808Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar,19Amitai N. Stafler P. Blau H. et al.Palivizumab following extremely premature birth does not affect pulmonary outcomes in adolescence.Chest. 2020; 158: 660-669Abstract Full Text Full Text PDF Scopus (8) Google Scholar,20Wenzel S.E. Gibbs R.L. Lehr M.V. et al.Respiratory outcomes in high-risk children 7 to 10 years after prophylaxis with respiratory syncytial virus immune globulin.Am J Med. 2002; 112 (1): 627-633Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Because these risk groups are characterized by a high risk of long-term impaired lung function that may be exacerbated by imbalanced immunologic responses to early infection with RSV, we hypothesized that certain GA-defined and BPD-defined VLBWI risk groups have long-term benefits resulting from seasonal RSV immunization. Accordingly, we performed an observational study in a large cohort of VLBWIs and evaluated the impact of palivizumab immunization on spirometry measurements and frequency of bronchitis episodes in risk-stratified groups of PIs at early school age. The German Neonatal Network (GNN; www.vlbw.de) is a population-based observational multicenter cohort study prospectively enrolling VLBWIs at 68 neonatal ICUs (NICU) in Germany. PIs with birth weight of < 1,500 g and a GA of 22 + 0 ≤ 36 + 6 weeks who were treated actively with intensive care were included. After informed written parental consent, a predefined dataset on general neonatal characteristics and antenatal and postnatal treatment and outcome was recorded for each patient at the participating centers. Clinical data until discharge from the hospital were collected by each participating NICU and were monitored yearly on site by GNN staff (study nurse or pediatrician trained in neonatology). After monitoring, the patient records were sent to the study center (Lübeck), where data were coded and evaluated. For this study, data were collected from infants born between January 1, 2009, and December 31, 2016. Details on patient selection are given in Figure 1. At 5 to 6 years of age, GNN-participating children were invited to a follow-up assessment by the study office. Within the invitation procedure, the study team contacted the clinic of birth for possible on-site follow-up examination dates. The contact database was searched randomly for possible candidates with focus set on VLBWIs born at fewer than 28 weeks’ gestation, but children born at more than 28 weeks’ gestation were not necessarily excluded. PIs who were born in the clinic of interest whose parents could be reached by telephone or post and were able to attend the follow-up appointment received an invitation letter. The procedure for invitation was identical for all participating centers. Children were assessed on site by a single GNN follow-up team blinded to any interventions or complications during primary NICU stay. Reproducibility of the results was ensured further by using identical instruments or equipment for all children, which were brought to the study sites by the GNN team. The follow-up included the performance of a hearing test, a visual screening, and spirometry. Parents were asked to answer questions concerning medical history and current medical needs, and detailed information on the children’s social background, illnesses, and general development and behavior. Data on the children’s vaccination history were generated by copying the children’s vaccination certificates in which all vaccinations that the child has received are documented (inpatient and outpatient vaccinations). Type of vaccination, date of vaccination, and number of immunizations were entered into the database. Apart from on-site follow-up, a questionnaire regarding the children’s health status was sent to the families on a yearly basis after discharge from the primary NICU stay. Spirometry was performed with an EasyOne spirometer (NDD Medizintechnik AG) by the study team’s physician at all sites. Although the maximum number of attempts was 10, the physician who supervised the performance of the spirometry assessed the quality of the spirometry evaluating the volume-time curve and flow-volume curve of each test. In addition, the program includes an integrated technical validation of the volume loops. This way, only results of sufficient quality were used, whereas the test with the highest quality was selected for analysis. Interactive computer graphics were used to motivate the children for spirometry (ie, blowing up a balloon, blowing leaves from a tree). FEV1 and FVC were documented in liters and were analyzed as % predicted values based on a European reference population.21Zapletal A. Chalupová J. Forced expiratory parameters in healthy preschool children (3-6 years of age).Pediatr Pulmonol. 2003; 35: 200-207Crossref PubMed Scopus (98) Google Scholar In addition, the FEV1 and FVC z scores were calculated according to the Global Lung Function Initiative.22Quanjer P.H. Stanojevic S. Cole T.J. et al.Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.Eur Respir J. 2012; 40: 1324-1343Crossref PubMed Scopus (3735) Google Scholar An FEV1 of < 80% predicted was defined as an additional outcome parameter of our study because it was used frequently in observational reports.23Göpel W. Kribs A. Roll C. et al.Multi-centre randomised trial of invasive and less invasive surfactant delivery methods showed similar spirometry results at 5-9 years of age.Acta Paediatr. 2022; 111: 2108-2114Crossref PubMed Scopus (6) Google Scholar The Tiffeneau index, defined as the ratio of FEV1 to FVC, was calculated because sometimes disynaptic growth and mild lung obstruction are seen in infants with BPD and—if very mild—may not be diagnosed by a reduction in FEV1. The parental questionnaires as part of the GNN follow-up included information on the frequency of bronchitis within the last year, which served as secondary respiratory outcome of this study. The German guidelines on RSV prophylaxis (valid until August 2023 and currently being updated) recommend the application of five IM palivizumab doses during the RSV season at intervals of 4 weeks.3Liese J. Forster J. Adams O. S2k-Leitlinie “Leitlinie zur Prophylaxe von schweren Erkrankungen durch Respiratory Syncytial Virus (RSV) bei Risikokindern.”.2018Google Scholar The 4-week intervals should be observed strictly, especially at the beginning of the immunoprophylaxis. PIs younger than 24 months who were treated for severe BPD with supplemental oxygen, with a ventilator, or both within the 3 months before the start of the RSV season (November) are recommended to receive immunoprophylaxis with palivizumab.3Liese J. Forster J. Adams O. S2k-Leitlinie “Leitlinie zur Prophylaxe von schweren Erkrankungen durch Respiratory Syncytial Virus (RSV) bei Risikokindern.”.2018Google Scholar Infants younger than 6 months and of fewer than 28 + 6 weeks’ gestation optionally can be immunized. PIs between 29 + 0 and 34 + 6 weeks’ gestation can be indicated (no general recommendation) for immunoprophylaxis with palivizumab under strict consideration of additional risk factors (discharge into RSV season, severe underlying neurologic disease, nursery attendance or siblings in external childcare). Palivizumab is not indicated to prevent nosocomial RSV infection. International guidelines base their recommendations on palivizumab in PIs mainly on the presence or absence of BPD, GA, and postnatal age.14Resch B. Eber E. Ehringer-Schetitska D. et al.Respiratory-syncytial-virus-prophylaxe mit palivizumab.Pädiatr Pädologie. 2019; 54 (1): 270-276Google Scholar, 15Bollani L. Baraldi E. Chirico G. et al.Revised recommendations concerning palivizumab prophylaxis for respiratory syncytial virus (RSV).Ital J Pediatr. 2015; 41 (15): 97Crossref PubMed Scopus (63) Google Scholar, 16Robinson J.L. Le Saux N. Preventing hospitalizations for respiratory syncytial virus infection.Paediatr Child Health. 2015; 20: 321-333Crossref Scopus (42) Google Scholar GA was calculated from the best obstetric estimate based on early prenatal ultrasound and obstetric examination. Small for GA was defined as a birth weight less than the 10th percentile for GA according to sex-specific standards for birth weight by GA in Germany.24Voigt M. Rochow N. Straube S. et al.Birth weight percentile charts based on daily measurements for very preterm male and female infants at the age of 154-223 days.J Perinat Med. 2010; 38: 289-295Crossref Google Scholar According to the definition used in the German guideline on RSV prophylaxis,3Liese J. Forster J. Adams O. S2k-Leitlinie “Leitlinie zur Prophylaxe von schweren Erkrankungen durch Respiratory Syncytial Virus (RSV) bei Risikokindern.”.2018Google Scholar BPD was divided into two grades: moderate or severe BPD was defined as supplemental oxygen or ventilatory support at 36 weeks’ postmenstrual age and mild BPD was defined as supplemental oxygen or ventilatory support at 28 days of age but not at 36 weeks’ postmenstrual age.25Jobe A.H. Bancalari E. Bronchopulmonary dysplasia.Am J Respir Crit Care Med. 2001; 163: 1723-1729Crossref PubMed Scopus (3840) Google Scholar,26Steinhorn R. When does BPD begin?.J Pediatr. 2017; 187: 3Abstract Full Text Full Text PDF Scopus (2) Google Scholar The bronchitis risk at 5 to 6 years of age was defined by the number of bronchitis episodes within the last year, measured by a parental questionnaire that was filled out at the follow-up visit. RSV season was defined as between November 1 and March 31, based on surveillance data of the Centers for Disease Control and Prevention.3Liese J. Forster J. Adams O. S2k-Leitlinie “Leitlinie zur Prophylaxe von schweren Erkrankungen durch Respiratory Syncytial Virus (RSV) bei Risikokindern.”.2018Google Scholar All study parts were approved by the University of Lübeck Ethical Committee and the committees of the participating centers (Identifier: 08-022; date of approval: June 27, 2008). Informed consent was obtained from all parents. Data were analyzed with SPSS Statistics version 28.0 software (IBM). The global type I error level was set to 0.05. All P values given are two-sided. Incomplete datasets were not included (Fig 1). To address the effects of RSV prophylaxis, we compared infants with seasonal RSV prophylaxis (at least five doses of palivizumab) with unimmunized infants. Subsequent analyses were performed by stratifying to the main criteria considered for indication of palivizumab, which are BPD and GA. We used multivariate logistic and linear regression models and known outcome confounders as independent variables: GA per week, multiple birth, blood culture-positive sepsis,1Humberg A. Fortmann I. Siller B. et al.Preterm birth and sustained inflammation: consequences for the neonate.Semin Immunopathol. 2020; 42: 451-468Crossref PubMed Scopus (104) Google Scholar BPD,27Spiegler J. Preuß M. Gebauer C. et al.Does breastmilk influence the development of bronchopulmonary dysplasia?.J Pediatr. 2016; 169: 76-80.e4Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar nicotine exposure, elder siblings, discharge into RSV season, immunization against influenza, and feeding with human milk at NICU discharge.28Härtel C. Pagel J. Rupp J. et al.Prophylactic use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics and outcome in very low birth weight infants.J Pediatr. 2014; 165: 285-289.e1Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Notably, FEV1 z scores already are adjusted for important confounders such as sex and postnatal age.21Zapletal A. Chalupová J. Forced expiratory parameters in healthy preschool children (3-6 years of age).Pediatr Pulmonol. 2003; 35: 200-207Crossref PubMed Scopus (98) Google Scholar,22Quanjer P.H. Stanojevic S. Cole T.J. et al.Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.Eur Respir J. 2012; 40: 1324-1343Crossref PubMed Scopus (3735) Google Scholar ORs and 95% CIs were calculated to identify the effect of RSV prophylaxis on outcomes. To address the problem of multiple comparisons, we performed Bonferroni corrections for multivariate analyses to protect from statistical type I errors. Additional information derived from Bonferroni correction is indicated in Table 2.Table 1Clinical Characteristics of Study Cohort Stratified by Passive RSV Immunization StatusCharacteristicNot Passively Immunized (n = 1,035; 52.1%)Passively Immunized (n = 951; 47.9%)P ValueaP values for univariate analyses were derived from the χ2 test, if not otherwise indicated.Total (N = 1,986)Gestational age, wk, median (IQR)29.6 (28.3-30.9)27.1 (25.6-28.6)< .001bMann-Whitney U test.28.4 (26.7-30.0)Birth weight, g, median (IQR)1,200 (980-1,370)900 (706-1,120)< .001bMann-Whitney U test.1,050 (820-1,290)Sex, male, % (95% CI)49.1 (46.0-52.1)51.3 (48.1-54.5).3250.1 (48.0-52.3)Multiple births, % (95% CI)39.3 (36.4-42.3)37.2 (34.2-40.3).3338.3 (36.2-40.5)Vaginal birth, % (95% CI)8.2 (6.7-10.0)10.2 (8.4-12.3).039.2 (8.0-10.5)Discharge into (pre-)RSV season (September-March), % (95% CI)49.8 (46.7-52.8)52.2 (50.0-56.4).151.4 (49.2-53.6)Immunization against influenza (any exposure), % (95% CI)14.0 (12.8-17.2)30.6 (28.0-33.2)< .00123.3 (21.6-25.1)Hexavalent and pneumococcal immunizations99.3 (98.7-99.7)99.8 (99.3-100).1399.5 (99.2-99.8)Outcomes, % (95% CI). . .. . .. . .. . . Mild BPD25.1 (22.6-27.9)48.7 (45.5-51.9)< .00136.4 (34.2-28.6) Moderate to severe BPD5.8 (4.5-7.4)24.7 (22.0-27.5)< .00114.9 (13.3-16.5)BPD = bronchopulmonary dysplasia; IQR = interquartile range; RSV = respiratory syncytial virus.a P values for univariate analyses were derived from the χ2 test, if not otherwise indicated.b Mann-Whitney U test. Open table in a new tab Table 2Clinical Characteristics of Subcohort of Infants of Fewer Than 29 Weeks’ Gestation Stratified by Passive RSV Immunization StatusCharacteristicNot Passively Immunized (n = 360; 32.1%)Passively Immunized (n = 761; 67.9%)P ValueaP values for univariate analyses were derived from the χ2 test, if not otherwise indicated.Total (N = 1,121)Gestational age, wk, median (IQR)27.6 (26.3-28.9)26.6 (25.1-27.9)< .001bMann-Whitney U test.27.0 (25.4-28.0)Birth weight, g, median (IQR)980 (745-1,130)840 (666-990)< .001bMann-Whitney U test.870 (690-1,050)Sex, male, % (95% CI)50.6 (45.4-55.7)50.6 (47.0-54.1).9950.6 (47.7-53.3)Multiple births, % (95% CI)35.0 (30.2-40.0)35.7 (32.4-39.2).8135.5 (32.7-38.3)Vaginal birth, % (95% CI)12.8 (9.6-16.5)11.1 (9.0-13.5).5711.6 (9.9-13.6)Discharge into (pre-)RSV season (September-March), % (95% CI)43.9 (38.8-49.0)53.7 (50.2-57.3).00250.6 (47.7-53.5)Outcomes, % (95% CI). . .. . .. . .. . . Mild BPD53.6 (48.4-58.7)57.3 (53.8-60.8)< .00156.1 (53.2-59.0) Moderate to severe BPD11.9 (8.9-15.6)28.1 (25.0-31.4)< .00122.9 (20.5-25.5)BPD = bronchopulmonary dysplasia; IQR = interquartile range; RSV = respiratory syncytial virus.a P values for univariate analyses were derived from the χ2 test, if not otherwise indicated.b Mann-Whitney U test. Open table in a new tab BPD = bronchopulmonary dysplasia; IQR = interquartile range; RSV = respiratory syncytial virus. BPD = bronchopulmonary dysplasia; IQR = interquartile range; RSV = respiratory syncytial virus. Within the study period from January 1, 2009, through December 31, 2016, 12,973 VLBWIs were discharged in 63 participating GNN sites. Detailed information on included and excluded VLBWIs are given in the study flow chart (Fig 1). For 3,572 VLBWIs, follow-up investigations were performed. When compared with VLBWIs who were not followed up, infants with follow-up were characterized by a lower median GA (28.2 weeks [interquartile range (IQR), 26.3-29.7 weeks] vs 29.1 weeks [IQR, 26.9-31.0 weeks]; P < .001) and lower birth weight (990 g [IQR, 775-1,240 g] vs 1,130 g [IQR, 850-1,360 g]; P < .001), and multiple birth was overrepresented in the follow-up cohort. Two hundred fifteen children at follow-up did not provide vaccination cards or data on RSV immunization was incomplete. Of 3,357 VLBWIs with detailed information on the history of immunizations, 2,100 children had received at least one dose of palivizumab, whereas 1,257 children never received immunoprophylaxis against RSV. For the analysis of respiratory outcomes at early school age, we included only children with a complete dataset, so that 115 children with missing information on the number of bronchitis episodes and 642 children without spirometry data were excluded. Detailed information on children with missing spirometry data can be found in the flowchart caption of Figure 1. When compared with the group of children with spirometry data, those without such data were characterized by a lower median GA (27.4 weeks [IQR, 25.6-29.6 weeks] vs 28.3 weeks [IQR, 26.6-29.7 weeks]; P < .001) and low