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Maternal and neonatal risk factors for neonatal respiratory distress syndrome in term neonates in Cyprus: a prospective case–control study

Italian Journal of Pediatrics volume 47, Article number: 129 (2021) Cite this article

Abstract

Background

Neonatal respiratory distress syndrome (NRDS) is strongly associated with premature birth, but it can also affect term neonates. Unlike the extent of research in preterm neonates, risk factors associated with incidence and severity of NRDS in term neonates are not well studied. In this study, we examined the association of maternal and neonatal risk factors with the incidence and severity of NRDS in term neonates admitted to Neonatal Intensive Care Unit (NICU) in Cyprus.

Methods

In a prospective, case-control design we recruited term neonates with NRDS and non-NRDS admitted to the NICU of Archbishop Makarios III hospital, the only neonatal tertiary centre in Cyprus, between April 2017–October 2018. Clinical data were obtained from patients’ files. We used univariate and multivariate logistic and linear regression models to analyse binary and continuous outcomes respectively.

Results

During the 18-month study period, 134 term neonates admitted to NICU were recruited, 55 (41%) with NRDS diagnosis and 79 with non-NRDS as controls. In multivariate adjusted analysis, male gender (OR: 4.35, 95% CI: 1.03–18.39, p = 0.045) and elective caesarean section (OR: 11.92, 95% CI: 1.80–78.95, p = 0.01) were identified as independent predictors of NRDS. Among neonates with NRDS, early-onset infection tended to be associated with increased administration of surfactant (β:0.75, 95% CI: − 0.02-1.52, p = 0.055). Incidence of pulmonary hypertension or systemic hypotension were associated with longer duration of parenteral nutrition (pulmonary hypertension: 11Vs 5 days, p < 0.001, systemic hypotension: 7 Vs 4 days, p = 0.01) and higher rate of blood transfusion (pulmonary hypertension: 100% Vs 67%, p = 0.045, systemic hypotension: 85% Vs 55%, p = 0.013).

Conclusions

This study highlights the role of elective caesarean section and male gender as independent risk factors for NRDS in term neonates. Certain therapeutic interventions are associated with complications during the course of disease. These findings can inform the development of evidence-based recommendations for improved perinatal care.

Background

Neonatal Respiratory Distress Syndrome (NRDS) is the main cause of neonatal respiratory failure and death [1], as well as admission in Neonatal Intensive Care Unit (NICU) [2]. NRDS is more frequent in preterm neonates [3], but it can affect term neonates as well. Nevertheless, the underlying aetiologies of NRDS in term neonates are different to those of NRDS in preterm neonates [4], so that NRDS in term neonates is frequently perceived as a distinct pathology [5].

Even in term neonates the frequency of NRDS has been linked to gestational age [6] and caesarean section [7], especially when performed before 39 weeks of gestation [8,9,10,11]. Other risk factors that have been associated with NRDS in term neonates include neonatal asphyxia, maternal or fetal infection, premature rupture of membranes and male gender [12]. However, most publications on the association of risk factors with NRDS relied on retrospective or administrative data [13,14,15,16,17,18] or did not focus on NRDS severity, management and resolution [19,20,21,22]. The few studies that assessed the association of maternal or neonatal risk factors with incidence but also the outcomes and severity of NRDS in term neonates were limited by studying a mixed population of both preterm and term neonates [23,24,25] or by retrospective data collection [26].

In Cyprus, a country of 875,000 inhabitants, known for the very high frequency of caesarean section deliveries (52.2% of all deliveries in 2018) [27], the annual incidence of NRDS in term and pre-term neonates is currently unknown. Furthermore, the frequency of other risk factors for NRDS and their association with incidence and severity of NRDS has never been studied in this setting.

The aim of this study was to investigate prospectively the frequency of NRDS in term neonates in Cyprus and examine the association between prenatal, perinatal and postnatal factors with incidence and severity of NRDS among this population. We also aimed to examine the association of several therapeutic interventions with severity and complications of NRDS.

Methods

Study location

The study was performed at the grade III-IV NICU (48 infant beds capacity) of Archbishop Makarios III (NAM III) hospital which serves the whole of Cyprus as the single national tertiary referral centre for all high-risk pregnancies and neonates requiring intensive care support.

Study population and case-control selection

We obtained the total number of births in Cyprus for 2017 and 2018 from the Health Monitoring Unit of the Ministry of Health and the National Statistics Department, and the total number of neonates hospitalised in the NICU for the same period from the Unit’s records. Term neonates (gestational age ≥ 37 weeks) that were hospitalised in the NICU between April 2017 and October 2018 were prospectively recruited. Term neonates were defined as NRDS cases if they required mechanical ventilation and surfactant administration and fulfilled at least two of the following criteria: (a) tachypnea, (b) central cyanosis in room air, (c) expiratory grunting, (d) intercostals or jugular retractions and nasal flaring and (e) oxygen supplementation requirement during the first 2 days of life [5, 28]. Term neonates without NRDS that received standard neonatal nursing care were defined as controls. Neonates with known chromosomal abnormalities and congenital anatomical anomalies were excluded from the study.

Ethics approval

All guardians of participating neonates provided written informed consent and the study was approved by the Cyprus National Bioethics Committee (EEBK EΠ 2017.01.22) and the Research Committee of the Cyprus Ministry of Health (Protocol approval: 0416/2017).

Data collection

Maternal, anthropometric and medical data, were collected from the mothers’ medical notes. Maternal clinical data included pre-existing chronic conditions such as diabetes mellitus, thyroid gland disorders and heart disease as well as data on pregnancy complications, gestational diabetes, hypertensive disorders of pregnancy (eclampsia, preeclampsia), placental abnormalities, infections and mode of delivery. Mortality and neonatal clinical data were collected until discharge from the NICU. Neonatal clinical data included gestational age, respiratory distress diagnosis, requirement for neonatal resuscitation at the delivery room, meconium stained amniotic fluid, Apgar score, pH and base excess on admission, hypotension during the first 24 h of life, nutrition status, treatment received, NICU duration of hospitalization and respective complications. For neonates with NRDS, several other clinical parameters were also collected such as duration of mechanical ventilation, number of surfactant-replacement doses, NRDS complications (pneumothorax, pulmonary hypertension, hemodynamic instability), neonatal infection, antibiotic administration and nutrition management. Additionally, results of laboratory measurements (e.g. blood gases and blood glucose, lactic acid and creatinine levels) and brain and heart ultrasound findings were also collected.

Statistical analysis

Continuous variables are presented as means and 95% confidence intervals (95% CI) or medians and interquartile range (IQR), while categorical variables are presented as counts and percentages. Two-way comparisons between continuous variables were carried out using t-test and Mann-Whitney test for normally and non-normally distributed variables, respectively. Categorical variables were compared with chi-square test. Univariate and multivariate logistic regression analysis was carried out to assess the association of different variables with NRDS and crude and adjusted Odds Ratios (OR) were reported with 95% CI. Parameters that yielded significant associationsin the univariate analysis were included in the multivariate analysis. For the assessment of the effect of clinical parameters on NRDS severity, univariate and multivariate linear regression analyses were carried out. In addition, separate analyses were performed for three different measures of NRDS severity: (a) duration of NICU hospitalisation (b) duration of mechanical ventilation and (c) number of surfactant doses administered. All statistical analyses were performed using STATA 12 (StataCorp, TX). Pvalue < 0.05 was set as the cut-off for statistical significance.

Results

During years 2017 and 2018, there were 9229 and 9329 live births in Cyprus, respectively. In 2017, 662 neonates (245 term) were admitted to the tertiary referral NICU of Cyprus and in 2018, 661 (243 term). Among the term neonates admitted to the NICU, 22.0% were diagnosed with NRDS in 2017 and 23.5% in 2018. During the 18-month study period (April 2017–October 2018), a total of 134 term neonates were recruited, 55 with NRDS diagnosis and 79 non-NRDS neonates as controls (Table 1). The primary reasons for NICU admission for non-NRDS neonates were: jaundice requiring only phototherapy treatment (21,5%), low birth weight (5%), mild feeding difficulties (11.4%), transient tachypnea (39.3%), suspicion of early neonatal infection with negative subsequent blood culture (12.7%), mild perinatal stress (7.6%) and prolonged rupture of membranes (2.5%).

Table 1 Demographic, clinical and treatment characteristics of mothers and neonates
Full size table

NRDS and non-NRDS neonates had similar gestational age (38.3 weeks Vs 38.6 weeks, pvalue: 0.100), birthweight (3145.9 g Vs 3160 g, pvalue: 0.866) and maternal risk factors such as gestational diabetes (14.9% Vs 14.9%, pvalue: 0.997), preeclampsia (2% Vs 4%, pvalue: 0.542) and thrombophilia (2.1% Vs 4.0%, pvalue:0.559). However, in comparison to the non-NRDS controls, NRDS term neonates were more frequently males (74.5% Vs 53.6%, pvalue: 0.01), had a lower mean Apgar Score at 5 min (8.92 Vs 9.46, pvalue: 0.002) and were more frequently born by elective caesarean section (90.1% Vs 53.9%, pvalue:0.001). In addition, compared to non-NRDS controls, NRDS term neonates required neonatal resuscitation more frequently (46.2% Vs 22.2%, pvalue: 0.007), were characterised by lower pH (7.31 Vs 7.40, pvalue < 0.001) and lower base excess (− 6.72 Vs − 4.92 pvalue: 0.004), Lastly, duration of parenteral nutrition was higher among NRDS compared to non-NRDS neonates (8.24 days Vs 1.51, pvalue < 0.001), while there was a tendency for longer duration of intravenous antibiotics administration although the difference was not statistically significant (6.98 days Vs 5.86 days, pvalue: 0.115).

In univariate analysis, incidence of NRDS was significantly associated with male gender (OR: 2.64, 95% CI: 1.24–5.61, pvalue: 0.011), elective caesarean section (OR: 8.29, 95% CI: 2.16–31.81, pvalue: 0.002) and Apgar score at 5 min (OR: 0.64, 95% CI: 0.44–0.92, pvalue: 0.016). The significant association between male gender and elective caesarean section persisted after adjustment for other confounders in multivariate analysis. The adjusted OR for male gender was 4.35 (95% CI: 1.03–18.39, pvalue: 0.045) and the adjusted OR forelective caesarean section was 11.92 (95% CI: 1.80–78.95, pvalue: 0.010). The results of the univariate and multivariate analysis are presented in detail in Tables 2 and 3 respectively.

Table 2 Associations between risk factors and incidence of NRDS (univariate analysis)
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Table 3 Associations between risk factors and incidence of NRDS (multivariate analysis)
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The relationship between clinical parameters and severity of NRDS was evaluated using three different outcome measures (duration of NICU stay, duration of mechanical ventilation and number of surfactant doses administered). Duration ofNICU stay was found to be associated with late-onset infection (β: 5.91, 95% CI: 1.14–10.66, pvalue: 0.01) in the univariate analysis, but statistical significance was attenuated after adjustment for other factors, although the effect estimate and its direction were similar (β: 5.43, 95% CI: 1.40–12.27, pvalue: 0.114) (Table 4). In contrast, duration of mechanical ventilation was not affected by early-onset (β: 0.58, 95% CI: − 1.42-2.58, pvalue: 0.557) or late-onset (β: 0.06, 95% CI: − 2.54-2.67, pvalue: 0.960) infection (Table 5). When number of administered surfactant doses were examined as a measure of NRDS severity, a significant association with early-onset infection (β:0.98, 95% CI:0.50–1.46, pvalue < 0.001) and pulmonary hypertension (β:1.14, 95% CI:0.52–1.77, pvalue:0.001) were identified in the univariate analysis. In multivariate analysis, the association with early-onset infection demonstrated a similar magnitude of effect but was marginally non-significant (β:0.75, 95% CI: − 0.02-1.52, pvalue:0.055), while the effect of pulmonary hypertension was markedly attenuated (β:0.47, 95% CI: − 0.63-1.56, pvalue:0.388) (Table 6).

Table 4 Associations between clinical variables and duration of NICU stay
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Table 5 Associations between clinical variables and duration of mechanical ventilation
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Table 6 Associations between clinical variables and surfactant doses
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NRDS complicated with pulmonary hypertension was associated with significantly higher duration of parenteral nutrition (11 Vs 5 days, pvalue < 0.001) and more frequent need for blood transfusion (100% Vs 67%, pvalue: 0.045) when compared to NRDS without pulmonary hypertension. Similarly, in NRDS neonates, those with hypotension required parenteral nutrition for a significantly higher number of days (7 Vs 4 days, pvalue:0.010) and received blood transfusion more frequently (84.9% Vs 54.6%, pvalue:0.013) compared to those without hypotension. Between NRDS neonates with and without late-onset infection, no significant difference in the distribution of treatment modalities was observed (Supplementary Table 1).

Discussion

In this prospective, case-control study, we report the incidence and clinical characteristics of NRDS in term neonates in Cyprus and evaluate the association of prenatal, perinatal and postnatal risk factors with the appearance and severity of this condition. The annual incidence of NRDS, among term neonates admitted to the NICU in Cyprus, ranged from 22.0% in 2017 to 23.5% in 2018 and it was more frequent among males and neonates born with an elective caesarean section. Early-onset infection was marginally associated with increased administration of surfactant, while hypotension and pulmonary hypertension were associated with longer duration of parenteral nutrition and higher rate of blood transfusions.

A positive association between male gender and NRDS was reported by Zhao D et al. [29]. The protective effect of female gender can be explained by the augmenting effect of estrogens on alveolar development and surfactant production [30]. The important role of estradiol and progesterone for fetal lung development has been reported to be mediated by an increase in vascular endothelial growth factor (VEGF) [31], which stimulates the proliferation and maturation of alveolar type II cells [32]. In animal studies, chronic androgen exposure in utero was found to delay surfactant production in male embryos [33], possibly through the epidermal growth factor (EGF-R) and transforming growth factor-beta (TGFβ-R) signaling pathways [34].

Previous studies have demonstrated that elective caesarean section, in the absence of labor signs, is associated with increased risk for NRDS [4, 20, 35]. Onset of spontaneous labor has been shown to lead to rapid clearance of fetal lung fluids and lung maturation [10], while higher gestational age is predictive of a favorable respiratory prognosis even in term neonates undergoing elective caesarean section [36,37,38].

Very few studies have examined the association of clinical parameters with severity indices or outcomes in NRDS and most of them were limited by small sample size and inconsistencies in the examined risk factors [12, 39, 40]. In our study, we found late-onset and early-onset infection to be associated with duration of NICU stay and duration of mechanical ventilation respectively in univariate analysis. It is known that mechanical ventilation is an independent risk factor for development of neonatal infection [41, 42]. However, it is possible that development of septic shock as a result of early or late-onset infection may require or prolong the need for mechanical ventilation [43, 44]. Univariate analysis also demonstrated that pulmonary hypertension was associated with both longer duration of mechanical ventilation and increased number of surfactant doses. Although this finding was attenuated in multivariate analysis, it is in line with previous reports. More specifically, the mainstay for pulmonary hypertension management includes optimal lung expansion and adequate oxygenation [45,46,47], while exogenous surfactant administration has been shown to significantly improve outcomes of pulmonary hypertension secondary to NRDS [45, 48]. In our ventilated neonates, we implemented modern modes of mechanical ventilation with synchronized intermittent positive pressure ventilation (SIPPV), which has been shown to be associated with a shorter overall duration of ventilation in term neonates as compared to intermittent mandatory ventilation [49]. Nevertheless, more sophisticated methods of mechanical ventilation such as volume targeted ventilation are increasingly being used and have been shown to further improve clinical outcomes by allowing finer control of ventilated tidal volume [50, 51]. Well controlled ventilation avoids the risk of volutrauma due to high tidal volume, reduces hypocarbia and risk of brain injury in case of frequent tidal volume fluctuations and avoids very low expired tidal volume that has been associated with atelectotrauma and hypercarbia [52]. Future use of volume targeted ventilation in our NICU, is expected to further improve patient outcomes.

This study demonstrated that NRDS neonates with early-onset infection required increased surfactant administration as compared to NRDS neonates without early-onset infection. An increased requirement for surfactant therapy for early onset pneumonia has been previously reported in late preterm and term neonates [53], while a slower response to surfactant therapy was found in specific types of infection such as group B streptococcal pneumonia [54]. The most likely mechanism explaining the requirement of additional exogenous surfactant in early onset infection is the impairment of endogenous surfactant synthesis or secretion of proteinases and other microbial components that degrade or inhibit surfactant-associated proteins. These components have been found to be excreted by a number of different respiratory pathogens such as P. aeruginosa [55], adenovirus and respiratory syncytial virus [56, 57] and Aspergillus fumigatus [58]. Nevertheless, to date, the overall effect of surfactant therapy on mortality and pulmonary complications in infants with bacterial pneumonia is not clear and further research is required [59].

Pulmonary hypertension as well as systemic hypotension in NRDS term neonates were also strongly associated with duration of parenteral nutrition. Neonates in mechanical ventilation often have increased nutritional requirements and meeting these requirementsis a challenging task [60]. Parenteral nutrition is a necessary life sustaining practice [61] and according to the European Consensus Guidelines on the Management of Respiratory Distress Syndrome, administration of parenteral nutrition should be initiated as soon as possible to reduce growth delay in neonates [62]. Nevertheless, other authors suggest that parenteral nutrition should only be initiated after clinical stabilization of the neonate [63]. In our study, blood transfusion was more frequent in NRDS neonates compared to non-NRDS neonates, especially when NRDS was further complicated by pulmonary hypertension and systemic hypotension. Red blood cells transfusion is often required to prevent the effects of anemia among NRDS neonates [64] but administration should always adhere to standing guidelines due to the increased risk of complications [65].

The major strengths of this study include the prospective recruitment of participants as well as the prospective data collection which was characterised by high data completeness. Furthermore, the study benefits from a well-defined study population as twins and neonates with congenital abnormalities were excluded a priori. Lastly, given that NAM III hospital NICU serves as the only tertiary referral centre in Cyprus, the study population was not restricted by maternal socioeconomic status and thus results are not affected by selection bias and can be generalised across the socioeconomic spectrum. However, this work is also characterised by some limitations. For ethical reasons, neonates (with or without NRDS) that died during NICU hospitalisation, were not included in the study and thus the study is limited to only morbidity outcomes. Nevertheless, during the study period, mortality in the NICU among term neonates was very low (1/245 in 2017 and 0/243 in 2018). Furthermore, we assessed only short-term clinical severity outcomes and did not address the association of maternal and neonatal risk factors with long-term complications. Lastly, our dataset did not include information on neonatal morbidity scoring systems such as the Clinical Risk Index for Babies (CRIB) [66] that has been previously suggested to predict NRDS severity [67] in neonates.

Conclusions

Male gender and elective cesarean section are significant risk factors for NRDS among term neonates admitted to NICU. NRDS complicated with early-onset infection requires higher surfactant dose while hypotension and pulmonary hypertension are associated with higher duration of parenteral nutrition and higher rate of blood transfusion. To our knowledge, this is the first study to examine term NRDS population in Cyprus. In this respect, our results highlight the importance of specific risk factors in the development and severity of NRDS in term neonates and can be used to inform evidence-based NRDS management protocols in the NICU, develop strategic planning for obstetric management and hopefully set the basis for further epidemiological studies.

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available due to the requirements of Ethics approval but are available from the corresponding author on reasonable request.

Abbreviations

NRDS:

Neonatal Respiratory Distress Syndrome

NICU:

Neonatal Intensive Care Unit

OR:

Odds Ratio

CI:

Confidence interval

IQR:

Interquartile range

VEGF:

Vascular endothelial growth factor

EGF-R:

epidermal growth factor

TGFβ-R:

Transforming growth factor-beta

SIPPV:

Synchronized intermittent positive pressure ventilation

CRIB:

Clinical Risk Index for Babies

SNAP:

Score for Neonatal Acute Physiology

References

  1. Jing L, Yun S, Dong J, Zheng T, Li J, Lu L, et al. Clinical characteristics, diagnosis and management of respiratory distress syndrome in full-term neonates. Chin Med J. 2010;123(19):2640–4.

    Google Scholar 

  2. Rijal P, Shrestha M. Scenario of neonatal respiratory distress in tertiary hospital. Birth. 2018;14(10):6.

    Google Scholar 

  3. Welty SE, Rusin CG, Stanberry LI, Mandy GT, Gest AL, Ford JM, et al. Short term evaluation of respiratory effort by premature infants supported with bubble nasal continuous airway pressure using Seattle-PAP and a standard bubble device. PLoS One. 2018;13(3):e0193807. https://doi.org/10.1371/journal.pone.0193807.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Gouyon J, Ribakovsky C, Ferdynus C, Quantin C, Sagot P, Gouyon B. Burgundy perinatal network: severe respiratory disorders in term neonates. Paediatr Perinat Epidemiol. 2008;22(1):22–30. https://doi.org/10.1111/j.1365-3016.2007.00875.x.

    Article  PubMed  Google Scholar 

  5. Reuter S, Moser C, Baack M. Respiratory distress in the newborn. Pediatr Rev. 2014;35(10):417–28; quiz 429. https://doi.org/10.1542/pir.35-10-417.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Van den Berg A, van Elburg RM, van Geijn HP, Fetter WP. Neonatal respiratory morbidity following elective caesarean section in term infants: a 5-year retrospective study and a review of the literature. Eur J Obstet Gynecol Reprod Biol. 2001;98(1):9–13. https://doi.org/10.1016/S0301-2115(01)00292-5.

    Article  PubMed  Google Scholar 

  7. Hansen AK, Wisborg K, Uldbjerg N, Henriksen TB. Risk of respiratory morbidity in term infants delivered by elective caesarean section: cohort study. BMJ. 2008;336(7635):85–7. https://doi.org/10.1136/bmj.39405.539282.BE.

    Article  PubMed  Google Scholar 

  8. Tita AT, Landon MB, Spong CY, Lai Y, Leveno KJ, Varner MW, et al. Timing of elective repeat cesarean delivery at term and neonatal outcomes. N Engl J Med. 2009;360(2):111–20. https://doi.org/10.1056/NEJMoa0803267.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Salemi JL, Pathak EB, Salihu HM. Infant outcomes after elective early-term delivery compared with expectant management. Obstet Gynecol. 2016;127(4):657–66. https://doi.org/10.1097/AOG.0000000000001331.

    Article  PubMed  Google Scholar 

  10. Ramachandrappa A, Jain L. Elective cesarean section: its impact on neonatal respiratory outcome. Clin Perinatol. 2008;35(2):373–93. https://doi.org/10.1016/j.clp.2008.03.006.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bennett CC, Johnson A, Field DJ. A comparison of clinical variables that predict adverse outcome in term infants with severe respiratory failure randomised to a policy of extracorporeal membrane oxygenation or to conventional neonatal intensive care. J Perinat Med. 2002;30(3):225–30. https://doi.org/10.1515/JPM.2002.031.

    Article  PubMed  Google Scholar 

  12. Liu J, Yang N, Liu Y. High-risk factors of respiratory distress syndrome in term neonates: a retrospective case-control study. Balkan Med J. 2014;31(1):64–8. https://doi.org/10.5152/balkanmedj.2014.8733.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Thygesen SK, Olsen M, Pedersen L, Henderson VW, Østergaard JR, Sørensen HT. Respiratory distress syndrome in preterm infants and risk of epilepsy in a Danish cohort. Eur J Epidemiol. 2018;33(3):313–21. https://doi.org/10.1007/s10654-017-0308-1.

    Article  PubMed  Google Scholar 

  14. Nobile S, Marchionni P, Carnielli VP. Neonatal outcome of small for gestational age preterm infants. Eur J Pediatr. 2017;176(8):1083–8. https://doi.org/10.1007/s00431-017-2957-1.

    Article  PubMed  Google Scholar 

  15. Lin C, Wang S, Hsu Y, Lin Y, Yeh T, Chang F. Risk for respiratory distress syndrome in preterm infants born to mothers complicated by placenta previa. Early Hum Dev. 2001;60(3):215–24. https://doi.org/10.1016/S0378-3782(00)00121-3.

    CAS  Article  PubMed  Google Scholar 

  16. Condò V, Cipriani S, Colnaghi M, Bellù R, Zanini R, Bulfoni C, et al. Neonatal respiratory distress syndrome: are risk factors the same in preterm and term infants? J Matern Fetal Neonatal Med. 2017;30(11):1267–72. https://doi.org/10.1080/14767058.2016.1210597.

    Article  PubMed  Google Scholar 

  17. Shen CL, Zhang Q, Hudson JM, Cole FS, Wambach JA. Genetic factors contribute to risk for neonatal respiratory distress syndrome among moderately preterm, late preterm, and term infants. J Pediatr. 2016;172:69–74. e2.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Niesłuchowska-Hoxha A, Cnota W, Czuba B, Ruci A, Ciaciura-Jarno M, Jagielska A, et al. A retrospective study on the risk of respiratory distress syndrome in singleton pregnancies with preterm premature rupture of membranes between 24. Biomed Res Int. 2018;2018:7162478.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Anadkat J, Kuzniewicz M, Chaudhari B, Cole F, Hamvas A. Increased risk for respiratory distress among white, male, late preterm and term infants. J Perinatol. 2012;32(10):780–5. https://doi.org/10.1038/jp.2011.191.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Alfarwati TW, Alamri AA, Alshahrani MA, Al-Wassia H. Incidence, risk factors and outcome of respiratory distress syndrome in term infants at academic Centre, Jeddah, Saudi Arabia. Med Arch. 2019;73(3):183–6. https://doi.org/10.5455/medarh.2019.73.183-186.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Baseer KAA, Mohamed M, Abd-Elmawgood EA. Risk factors of respiratory diseases among neonates in neonatal intensive care unit of Qena University hospital, Egypt. Ann Glob Health. 2020;86(1):22. https://doi.org/10.5334/aogh.2739.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Mortier I, Blanc J, Tosello B, Gire C, Bretelle F, Carcopino X. Is gestational diabetes an independent risk factor of neonatal severe respiratory distress syndrome after 34 weeks of gestation? A prospective study. Arch Gynecol Obstet. 2017;296(6):1071–7. https://doi.org/10.1007/s00404-017-4505-7.

    Article  PubMed  Google Scholar 

  23. Natile M, Ventura ML, Colombo M, Bernasconi D, Locatelli A, Plevani C, et al. Short-term respiratory outcomes in late preterm infants. Ital J Pediatr. 2014;40(1):52. https://doi.org/10.1186/1824-7288-40-52.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Tochie JN, Choukem S, Langmia RN, Barla E, Koki-Ndombo P. Neonatal respiratory distress in a reference neonatal unit in Cameroon: an analysis of prevalence, predictors, etiologies and outcomes. Pan Afr Med J. 2016;24(1):152.

    PubMed  PubMed Central  Google Scholar 

  25. Xu X, Chao C, Yan C, Liu Y, Ling L, Xiong H, et al. Epidemiology of respiratory distress and the illness severity in late preterm or term infants: a prospective multi-center study. Chin Med J. 2010;123(20):2776–80.

    PubMed  Google Scholar 

  26. Wu XJ, Zhang XD, Shi LP. Retrospective analysis of elective caesarean section and respiratory distress syndrome in the term neonates. Zhonghua Er Ke Za Zhi. 2009;47(9):658–61.

    PubMed  Google Scholar 

  27. Ministry of Health. Perinatal health indicators, Cyprus public and private maternity units 2014-2016. 2018. Available at: https://www.moh.gov.cy/moh/moh.nsf/All/4C6E956BEF3F6B3AC22579C600279631/$file/Perinatal%20Health%20Report%202018_Cyprus%20Maternity%20Units%202014-2016.pdf.

    Google Scholar 

  28. Qian L, Liu C, Guo Y, Jiang Y, Ni L, Xia S, et al. Current status of neonatal acute respiratory disorders: a one-year prospective survey from a Chinese neonatal network. Chin Med J. 2010;123(20):2769–75.

    PubMed  Google Scholar 

  29. Zhao D, Zou L, Lei X, Zhang Y. Gender differences in infant mortality and neonatal morbidity in mixed-gender twins. Sci Rep. 2017;7(1):1–6.

    Article  Google Scholar 

  30. Seaborn T, Simard M, Provost PR, Piedboeuf B, Tremblay Y. Sex hormone metabolism in lung development and maturation. Trends Endocrinol Metab. 2010;21(12):729–38. https://doi.org/10.1016/j.tem.2010.09.001.

    CAS  Article  PubMed  Google Scholar 

  31. Trotter A, Hilgendorff A, Kipp M, Beyer C, Kueppers E, Kiossis E, et al. Gender-related effects of prenatal administration of estrogen and progesterone receptor antagonists on VEGF and surfactant-proteins and on alveolarisation in the developing piglet lung. Early Hum Dev. 2009;85(6):353–9. https://doi.org/10.1016/j.earlhumdev.2008.12.013.

    CAS  Article  PubMed  Google Scholar 

  32. Raoul W, Chailley-Heu B, Barlier-Mur A, Delacourt C, Maître B, Bourbon JR. Effects of vascular endothelial growth factor on isolated fetal alveolar type II cells. Am J Phys Lung Cell Mol Phys. 2004;286(6):L1293–301. https://doi.org/10.1152/ajplung.00157.2003.

    CAS  Article  Google Scholar 

  33. Dammann CE, Ramadurai SM, McCants DD, Pham LD, Nielsen HC. Androgen regulation of signaling pathways in late fetal mouse lung development. Endocrinology. 2000;141(8):2923–9. https://doi.org/10.1210/endo.141.8.7615.

    CAS  Article  PubMed  Google Scholar 

  34. Whitsett JA, Weaver TE, Lieberman MA, Clark JC, Daugherty C. Differential effects of epidermal growth factor and transforming growth factor-beta on synthesis of Mr = 35,000 surfactant-associated protein in fetal lung. J Biol Chem. 1987;262(16):7908–13. https://doi.org/10.1016/S0021-9258(18)47654-5.

    CAS  Article  PubMed  Google Scholar 

  35. Benzouina S, Boubkraoui ME, Mrabet M, Chahid N, Kharbach A, Elhassani A, et al. Fetal outcome in emergency versus elective cesarean sections at Souissi Maternity Hospital, Rabat, Morocco. Pan Afr Med J. 2016;23(1):197.

    PubMed  PubMed Central  Google Scholar 

  36. Phaloprakarn C, Tangjitgamol S, Manusirivithaya S. Timing of elective cesarean delivery at term and its impact on maternal and neonatal outcomes among Thai and other southeast Asian pregnant women. J Obstet Gynaecol Res. 2016;42(8):936–43. https://doi.org/10.1111/jog.13016.

    Article  PubMed  Google Scholar 

  37. Pirjani R, Afrakhteh M, Sepidarkish M, Nariman S, Shirazi M, Moini A, et al. Elective caesarean section at 38–39 weeks gestation compared to> 39 weeks on neonatal outcomes: a prospective cohort study. BMC Pregnancy Childbirth. 2018;18(1):140. https://doi.org/10.1186/s12884-018-1785-2.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Doan E, Gibbons K, Tudehope D. The timing of elective caesarean deliveries and early neonatal outcomes in singleton infants born 37–41 weeks’ gestation. Aust N Z J Obstet Gynaecol. 2014;54(4):340–7. https://doi.org/10.1111/ajo.12220.

    Article  PubMed  Google Scholar 

  39. Bhutta ZA, Yusuf K. Profile and outcome of the respiratory distress syndrome among newborns in Karachi: risk factors for mortality. J Trop Pediatr. 1997;43(3):143–8. https://doi.org/10.1093/tropej/43.3.143.

    CAS  Article  PubMed  Google Scholar 

  40. Wong JJ, Loh TF, Testoni D, Yeo JG, Mok YH, Lee JH. Epidemiology of pediatric acute respiratory distress syndrome in Singapore: risk factors and predictive respiratory indices for mortality. Front Pediatr. 2014;2:78.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Padula MA, Dewan ML, Shah SS, Padula AM, Srinivasan L, McGowan KL, et al. Risk factors associated with laboratory-confirmed bloodstream infections in a tertiary neonatal intensive care unit. Pediatr Infect Dis J. 2014;33(10):1027–32. https://doi.org/10.1097/INF.0000000000000386.

    Article  PubMed  Google Scholar 

  42. Hornik CP, Fort P, Clark RH, Watt K, Benjamin DK Jr, Smith PB, et al. Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units. Early Hum Dev. 2012;88:S69–74. https://doi.org/10.1016/S0378-3782(12)70019-1.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wynn JL, Wong HR. Pathophysiology and treatment of septic shock in neonates. Clin Perinatol. 2010;37(2):439–79. https://doi.org/10.1016/j.clp.2010.04.002.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Rocha G, Soares P, Goncalves A, Silva AI, Almeida D, Figueiredo S, et al. Respiratory care for the ventilated neonate. Can Respir J. 2018;2018:1–12. https://doi.org/10.1155/2018/7472964.

    Article  Google Scholar 

  45. Nair J, Lakshminrusimha S. Update on PPHN: mechanisms and treatment. Proc Semin Perinatol. 2014;38(2):78–91. https://doi.org/10.1053/j.semperi.2013.11.004.

    Article  Google Scholar 

  46. Lai M, Chu S, Lakshminrusimha S, Lin H. Beyond the inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Pediatr Neonatol. 2018;59(1):15–23. https://doi.org/10.1016/j.pedneo.2016.09.011.

    Article  PubMed  Google Scholar 

  47. Lakshminrusimha S, Swartz DD, Gugino SF, Ma C, Wynn KA, Ryan RM, et al. Oxygen concentration and pulmonary hemodynamics in newborn lambs with pulmonary hypertension. Pediatr Res. 2009;66(5):539–44. https://doi.org/10.1203/PDR.0b013e3181bab0c7.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH, et al. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. J Pediatr. 1998;132(1):40–7. https://doi.org/10.1016/S0022-3476(98)70482-2.

    CAS  Article  PubMed  Google Scholar 

  49. Chowdhury O, Greenough A. Neonatal ventilatory techniques - which are best for infants born at term? Arch Med Sci. 2011;7(3):381–7. https://doi.org/10.5114/aoms.2011.23400.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Chakkarapani AA, Adappa R, Ali SKM, Gupta S, Soni NB, Chicoine L, et al. “Current concepts of mechanical ventilation in neonates”–part 1: basics. Int J Pediatr Adolesc Med. 2020;7(1):15–20. https://doi.org/10.1016/j.ijpam.2020.03.003.

    Article  Google Scholar 

  51. Klingenberg C, Wheeler KI, McCallion N, Morley CJ, Davis PG. Volume-targeted versus pressure-limited ventilation in neonates. Cochrane Database Syst Rev. 2017;10:CD003666.

    PubMed  Google Scholar 

  52. Klingenberg C, Wheeler KI, Davis PG, Morley CJ. A practical guide to neonatal volume guarantee ventilation. J Perinatol. 2011;31(9):575–85. https://doi.org/10.1038/jp.2011.98.

    CAS  Article  PubMed  Google Scholar 

  53. Deshpande S, Suryawanshi P, Ahya K, Maheshwari R, Gupta S. Surfactant therapy for early onset pneumonia in late preterm and term neonates needing mechanical ventilation. J Clin Diagn Res. 2017;11(8):SC09–12. https://doi.org/10.7860/JCDR/2017/28523.10520.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Herting E, Gefeller O, Land M, van Sonderen L, Harms K, Robertson B, et al. Surfactant treatment of neonates with respiratory failure and group B streptococcal infection. Pediatrics. 2000;106(5):957–64. https://doi.org/10.1542/peds.106.5.957.

    CAS  Article  PubMed  Google Scholar 

  55. Henderson FC, Miakotina OL, Mallampalli RK. Proapoptotic effects of P. aeruginosa involve inhibition of surfactant phosphatidylcholine synthesis. J Lipid Res. 2006;47(10):2314–24. https://doi.org/10.1194/jlr.M600284-JLR200.

    CAS  Article  PubMed  Google Scholar 

  56. Miakotina OL, McCoy DM, Shi L, Look DC, Mallampalli RK. Human adenovirus modulates surfactant phospholipid trafficking. Traffic. 2007;8(12):1765–77. https://doi.org/10.1111/j.1600-0854.2007.00641.x.

    CAS  Article  PubMed  Google Scholar 

  57. Bruce SR, Atkins CL, Colasurdo GN, Alcorn JL. Respiratory syncytial virus infection alters surfactant protein a expression in human pulmonary epithelial cells by reducing translation efficiency. Am J Phys Lung Cell Mol Phys. 2009;297(4):L559–67. https://doi.org/10.1152/ajplung.90507.2008.

    CAS  Article  Google Scholar 

  58. Haczku A, Atochina EN, Tomer Y, Chen H, Scanlon ST, Russo S, et al. Aspergillus fumigatus-induced allergic airway inflammation alters surfactant homeostasis and lung function in BALB/c mice. Am J Respir Cell Mol Biol. 2001;25(1):45–50. https://doi.org/10.1165/ajrcmb.25.1.4391.

    CAS  Article  PubMed  Google Scholar 

  59. Tan K, Lai NM, Sharma A. Surfactant for bacterial pneumonia in late preterm and term infants. Cochrane Database Syst Rev. 2012;(2).

  60. Dassios T, Hayes K. Nutrition in neonates with respiratory disorders. Curr Nutr Food Sci. 2013;9(1):3–9.

    CAS  Google Scholar 

  61. Calkins KL, Venick RS, Devaskar SU. Complications associated with parenteral nutrition in the neonate. Clin Perinatol. 2014;41(2):331–45. https://doi.org/10.1016/j.clp.2014.02.006.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Te Pas A, et al. European consensus guidelines on the management of respiratory distress syndrome–2019 update. Neonatology. 2019;115(4):432–50. https://doi.org/10.1159/000499361.

    Article  PubMed  Google Scholar 

  63. Moon K, Athalye-Jape GK, Rao U, Rao SC. Early versus late parenteral nutrition for critically ill term and late preterm infants. Cochrane Database Syst Rev. 2018;2018(9).

  64. Whyte RK, Jefferies AL, Canadian Paediatric Society, Fetus and Newborn Committee. Red blood cell transfusion in newborn infants. Paediatr Child Health. 2014;19(4):213–7. https://doi.org/10.1093/pch/19.4.213.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Goel R, Josephson CD. Recent advances in transfusions in neonates/infants. F1000Res. 2018;7. https://doi.org/10.12688/f1000research.13979.1 eCollection 2018.

  66. Garg B, Sharma D, Farahbakhsh N. Assessment of sickness severity of illness in neonates: review of various neonatal illness scoring systems. J Matern Fetal Neonatal Med. 2018;31(10):1373–80. https://doi.org/10.1080/14767058.2017.1315665.

    Article  PubMed  Google Scholar 

  67. Hiles M, Culpan A, Watts C, Munyombwe T, Wolstenhulme S. Neonatal respiratory distress syndrome: chest X-ray or lung ultrasound? A systematic review. Ultrasound. 2017;25(2):80–91. https://doi.org/10.1177/1742271X16689374.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors are grateful to the study participants for their participation and to the nursing staff of “Archbishop Makarios III” hospital for their cooperation.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Author notes

  1. Paraskevi Stylianou-Riga and Theodora Boutsikou are contributed equally as co-first authors.

Authors and Affiliations

  1. Neonatal Intensive Care Unit, “Archbishop Makarios III” Hospital, Nicosia, Cyprus

    Paraskevi Stylianou-Riga & Thalia Papadouri

  2. Respiratory Physiology Laboratory, Medical School, University of Cyprus, 2029 Aglantzia, Nicosia, Cyprus

    Paraskevi Stylianou-Riga, Panayiotis Kouis, Paraskevi Kinni, Marina Krokou, Andriani Ioannou & Panayiotis K. Yiallouros

  3. Neonatal Department, Aretaieio Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Paraskevi Stylianou-Riga, Theodora Boutsikou, Zoi Iliodromiti & Nicoletta Iacovidou

  4. Neonatal Unit, First Department of Pediatrics, ‘Aghia Sophia’ Children’s Hospital, Athens, Greece

    Tania Siahanidou

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Contributions

PSR, NI, PKY and TB contributed substantially to the study hypothesis and study design. PSR, PK, MK, AI and TP participated in data collection and prepared the study dataset. TS and ZI participated in data cleaning and data quality control. PSR and PK performed the statistical analysis and PSR, PK, TB prepared the first draft of the manuscript. NI, PKY contributed towards interpretation of findings and all authors have read, revised and approved the final version of the manuscript.

Corresponding author

Correspondence to Paraskevi Stylianou-Riga.

Ethics declarations

Ethics approval and consent to participate

All guardians of participating neonates provided written informed consent and the study was approved by the Cyprus National Bioethics Committee (EEBK EΠ 2017.01.22) and the Research Committee of the Cyprus Ministry of Health (Protocol approval: 0416/2017).

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Not applicable

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The authors declare that they have no competing interests.

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Supplementary Information

Additional file 1: Table S1.

Association of treatment modalities and NRDS complications.

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Stylianou-Riga, P., Boutsikou, T., Kouis, P. et al. Maternal and neonatal risk factors for neonatal respiratory distress syndrome in term neonates in Cyprus: a prospective case–control study. Ital J Pediatr 47, 129 (2021). https://doi.org/10.1186/s13052-021-01086-5

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Keywords

  • Neonatal respiratory distress syndrome
  • Maternal risk factors
  • Neonatal risk factors
  • Caesarean section

Italian Journal of Pediatrics

ISSN: 1824-7288

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