All data were double-entered and then exported to tab-delimited text files. All analyses were performed with R (www.R-project.org) and EmpowerStats software (www.empowerstats.com, X&Y solutions, Inc, Boston, MA).
Among the 370 infants in the study, 245 (66.22%) were male and 125 (33.78%) were female infants. Of those, 276 (74.59%; 181 males and 95 females) received PS therapy, with a mean dose of (94.12 ± 36.35) mg/kg ([94.26 ± 37.53] mg/kg and [93.85 ± 34.08] mg/kg for male and female infants, respectively); 162 (63.04%; 108 males and 54 females) received INSURE treatment (tracheal intubation – use of PS – tracheal extubation using CPAP), the total mortality during hospitalization was 35 (9.46%; 26 males and 9 females). The demographic and clinical characteristics of maternal and infants were summarized in Table 1.
The univariate regression analysis showed that initial PS doses significantly correlated with mortality incidence (OR 0.98, 95% CI 0.97–0.99, P = .003), as a protective factor in the whole population. Interestingly, when the infants were separated by gender, the initial dose of PS only relevant to mortality incidence in male infants (OR 0.98, 95% CI 0.97–0.99, P = .006) rather than in female infants (OR 0.99, 95% CI 0.96–1.01, P = .242). The association between INSURE treatment and mortality incidence in male and female infants showed a similar trend ([OR 0.25, 95% CI 0.10–0.66, P = .005] and [OR 0.54, 95% CI 0.07–4.03, P = .547] for male and female infants, respectively). In addition, birth asphyxia ([OR 5.92, 95% CI 2.49–14.05, P < 0.001] in males [OR 8.80, 95% CI 1.74–44.59, P = .009] in females) and chest radiography grade ([OR 87.50, 95% CI 9.11–840.36, P < .001] in males [OR 12.07, 95% CI 1.03–379.8, P = .043] in females) were correlated with mortality incidence in both male and female infants; while gestational age ([OR 0.78, 95% CI 0.67–0.92, P = .003] in males [OR 0.91, 95% CI 0.71–1.17, P = .455] in females) and Apgar score ([OR 0.62, 95% CI 0.47–0.82, P = .001] in males [OR 0.66, 95% CI 0.37–1.15, P = .143] in females) correlated with mortality incidence only in male infants (Table 2).
In the multiple logistic regression of the whole study population, after adjusting for possible factors related to mortality incidence (eg, age at admission, gestational age, birth weight, birth asphyxia, Apgar score, and chest radiography grade), a linear relationship between the initial dose of PS and mortality risk was observed (Fig. 1A), when stratified by gender, a linear relationship between initial dose of PS and mortality incidence was observed in female patients; and a nonlinear relationship between initial dose of PS and mortality incidence was observed in male patients (Fig. 1B). We then performed a threshold effect analysis to determine the intersection point of the 2 curves, corresponding to the initial PS dose of 130 mg/kg.
The independent effect of initial dose of PS on mortality incidence was further analyzed. After adjusting for other variables, initial dose of PS remained negatively associated with mortality incidence (OR 0.98, 95% CI 0.96–0.99, P = .002); meanwhile, after dividing the initial dose of PS by 130 mg/kg, we found that higher PS dosages offered a protective factor in infants with RDS (OR 0.36, 95% CI 0.19–0.84, P = .011). Then we use gender as a stratification factor to further explore the effect of the initial PS dose on mortality incidence. As we expected, in male patients, after adjusting for potential confounding factors, the initial dose of PS remained negatively associated with mortality (OR 0.97, 95% CI 0.96–0.99, P = .005), when the initial dose of PS increased by 1 mg/kg, the risk of mortality decreased by 3%; the risk of mortality among infants who received PS doses ≥130 mg/kg fell by about 66%, compared to those who received lower doses <130 mg/kg (OR 0.34, 95% CI 0.17–0.88, P = .018); while in female patients, we failed to found a relationship between the initial dose of PS and mortality incidence either as a continuous variable (OR 0.99, 95% CI 0.96–1.02, P = .543), or as a categorical variable (OR 0.99, 95% CI 0.00–82.5, P = .998) (Table 3).
RDS is a leading cause of high mortality rates in newborns. Previous studies have shown that RDS accounts for 10% to 20% of infant mortality around the world.[17–19] In the current study, 35 (9.46%) infants died due to RDS in the 6 months following consultation, which is consistent with previous studies. Since 1990s, the introduction of multiple PS therapies has substantially improved outcomes among newborns with RDS. The physiological functions of surfactants include the ability to lower surface tension and the ability to rapidly adsorb and spread, which is associated with the respiratory cycle. A series of studies have shown that a sufficient amount of PS given during the initial stages of treatment may shorten the duration of respiratory support and improve the outcomes. One recent study has suggested that male preterm infants are more likely to experience RDS than females. Another research using an ovine model of preterm birth showed that poorer respiratory adaptation in male preterm lambs (born at 0.9 of term) was likely due to lower lung compliance than in females, and that this difference may result from sex differences in surfactant phospholipid composition and function. Whether the surfactant replacement therapy has similar gender-based efficacy in infants, and whether male and female infants have similar sensitivities to PS treatment have not yet been studied. The present study was thus designed to determine whether the efficacy of surfactant replacement therapy among infants could be influenced by gender. To the best of our knowledge, the present study is the first clinical study to demonstrate that male infants and female infants respond differently to PS treatment. We found that males exhibited a lower sensitivity than females to PS replacement therapy and that, for male infants, an increased initial dose of PS at least 130 mg/kg should be used to treat RDS.
A certain number of clinical and pharmacokinetic studies have shown that a higher dose of surfactant is more efficient in the clinical treatment of RDS. The initial surfactant dose of 100 mg/kg is based on the fact that serum-derived protein inhibitors and inflammatory mediators that inactivate the surfactant system in RDS accumulate progressively; thus, treatment in the initial phase is effective with the 100 mg/kg dose. In the current study, the initial dose of PS was 50 to 240 mg/kg. In the multiple logistic regression of the whole study population, we found that a linear relationship between the initial dose of PS and risk of mortality was observed after adjusting for age at admission, gestational age, birth weight, birth asphyxia, Apgar score, and chest radiography grade, and that the risk of mortality reduced 2% for every 1 mg/kg increase of the initial dose of PS application. This is consistent with the evidence that the use of exogenous PS may be associated with a decreased mortality risk. Then we use gender as a stratification factor to further explore whether gender influenced the efficacy of PS on mortality incidence. In the smooth plot, a nonlinear relationship between the initial dose of PS and mortality risk was observed in male infants; whereas a linear relationship between the initial dose of PS and mortality risk was observed in female infants. The intersection point of the 2 curves corresponds to the initial 130 mg/kg dose of PS. In male patients, the risk of mortality reduced 3% for every 1 mg/kg increase of the initial dose of PS. Mortality rates among infants who received PS doses ≥130 mg/kg fell about 66% compared to those who received PS doses <130 mg/kg. However, in female patients, the smooth plot between the initial dose of PS and the risk of mortality showed that although the initial dose of PS <130 mg/kg, the treatment remained effective in improving the outcomes.
Birth asphyxia and chest X-ray findings are also important outcome predictors of RDS. In the current study, infants with birth asphyxia had an about 6.50 folds increase in mortality, compared to those without birth asphyxia. Infants with higher chest radiography grades suffered from higher risk of mortality, which is consistent with previous studies. Some studies also have shown that neonatal factors, such as low gestational age, low birth weight, and male sex, are predictors of poor outcomes of RDS.[27–30] In this study, we found that male infants with low gestational ages and low Apgar scores had higher mortality than females.
The most important limitation of our study was that it was a retrospective cohort study based on the medical records from northwest China. Therefore, some indicators were missing and could not be analyzed. Many cases also ceased treatment for economic reasons. Although we excluded these latter cases to reduce the interference of subjective factors, it inevitably reduced our study population. Thus, nationwide well-designed prospective cohort trials are needed for future studies.
In conclusion, our study showed that among newborn infants who were diagnosed with RDS, female babies had a better response to surfactant treatment than male babies. For the male infants, the effect of surfactant replacement therapy was not as good as expected if the initial dose of PS <130 mg/kg.
The authors thank Northwest China Neonatal Collaboration for assistance with the data support. The authors also thank Ms Liu from the Institute of Integrated Medical Information for assistance with the data analysis.
Conceptualization: Li Liu.
Data curation: Juan Zhang, Huiling Fu.
Formal analysis: Chen Chen.
Investigation: Chen Chen, Tian Tian, Juan Zhang, Huiling Fu.
Methodology: Li Liu.
Project administration: Li Liu.
Supervision: Li Liu.
Writing – original draft: Chen Chen, Juan Zhang, Huiling Fu.
Writing – review & editing: Chen Chen, Tian Tian.
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Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
gender; infants; pulmonary surfactant; respiratory distress syndrome