WHO recommendation on the type of surfactant for surfactant replacement therapy in newborns with respiratory distress syndrome

Father interacts with his 4 day old child on an incubator at a Neonatal Intensive Care Unit, India.

WHO recommendation on the type of surfactant for surfactant replacement therapy in newborns with respiratory distress syndrome



Either animal-derived or protein-containing synthetic surfactants can be used for surfactant replacement therapy in ventilated preterm newborns with respiratory distress syndrome.

(Conditional recommendation [only in health-care facilities where intubation, ventilator care, blood gas analysis, newborn nursing care and monitoring are available] based on moderate-quality evidence).


Publication history

First published: November 2015

Updated: No update planned

Assessed as up-to-date: November 2015



  • The GDG noted that protein-free synthetic surfactants increase the risk of pneumothorax when compared with animal-derived surfactant. This type of synthetic surfactant is no longer commercially available.



Preterm birth, defined as birth before 37 weeks of gestation, is the single most important determinant of adverse infant outcomes, in terms of survival and quality of life. (1)  Globally, it is the leading cause of perinatal and neonatal mortality and morbidity. (2) Preterm infants are particularly vulnerable to complications due to impaired respiration, difficulty in feeding, poor body temperature regulation and high risk of infection. (3-5) With the increasing contribution of neonatal deaths to overall child mortality, it is critical to address the determinants of poor outcomes related to preterm birth to achieve further reductions in child mortality. (6-8)

Infant mortality and morbidity from preterm birth can be reduced through interventions delivered to the mother before or during pregnancy, and to the preterm infant after birth. (9) Interventions can be directed at all women for primary prevention and reduction of the risk of preterm birth (e.g. smoking cessation programme) or aimed at minimizing the risk in women with known risk factors (e.g. progestational agents, cervical cerclage). (10) However, the most beneficial set of maternal interventions are those that are aimed at improving outcomes for preterm infants when preterm birth is inevitable (e.g. antenatal corticosteroids, magnesium sulfate and antibiotic prophylaxis). (9) Special care of the preterm newborn to prevent and treat complications of prematurity is also critical to newborn survival. In high-income countries, reductions in mortality rates in infants that were born preterm have been driven largely by improved care and, more importantly, by appropriate policy changes.



The recommendations were developed using standard operating procedures in accordance with the process described in the WHO handbook for guideline development (11). Briefly, these included (i) identification of priority questions and critical outcomes, (ii) retrieval of the evidence, (iii) assessment and synthesis of evidence, (iv) formulation of recommendations, and (v) planning for the dissemination, implementation, impact evaluation and updating of the guideline.

The scientific evidence underpinning the recommendations was synthesized using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (12). Up-to-date systematic reviews were used to prepare evidence profiles for the priority questions. WHO then convened a Technical Consultation in May 2014 where an international group of experts – the Guideline Development Group (GDG) – formulated and approved the recommendations based on the evidence profiles.

In November 2014, an online consultation of the GDG was conducted to review and revise the recommendations in the light of the findings of a large implementation trial of antenatal corticosteroids in low-resource countries.


Further information on procedures for developing this recommendation are available here.


Recommendation question

For this recommendation, we aimed to answer the following question:

  • In newly born preterm babies who have or are at risk of respiratory distress syndrome (P), is surfactant therapy (I), compared with routine care without surfactants (C), effective in reducing adverse newborn outcomes (O)? If so:
    •  How early should the surfactant therapy be started?
    • Should surfactants be given for prophylaxis in newborns where respiratory distress syndrome has not yet set in, or selectively when existing respiratory distress is worsening?
    • Which types of surfactant are effective – animal-derived or synthetic; protein-containing or protein-free?


Evidence summary

Synthetic surfactants versus natural (animal-derived) surfactants for preterm neonates with clinical and/or radiologically established respiratory distress syndrome (RDS)

The evidence for this recommendation was derived from two Cochrane reviews that directly compared the effects of a single dose or multiple doses of synthetic versus natural surfactants for SRT in preterm babies at risk of RDS or with radiological/clinical features of RDS. The surfactants were administered by the intra-tracheal route.

The first review by Soll et al. (13) evaluated the effects of SRT with protein-free synthetics whilst the second, by Pfister et al. (14), evaluated the use of protein-containing synthetic surfactants, both compared to natural surfactants. Protein-free synthetic versus natural surfactants

The review by Soll et al. (13) included 11 studies that used protein-free synthetic surfactant in the intervention group and compared its effects with the use of natural surfactants. These studies were conducted within intensive care units of hospitals in HICs. An updated search found two additional studies, which were included in the pooled analysis.

Neonatal death: Neonates who received proteinfree synthetic surfactant had similar risk of overall neonatal mortality compared to natural surfactants (RR 1.07, 95% CI 0.99–1.17; 12 studies, 5447 babies).

Severe neonatal morbidity: The risk of pneumothorax (including pneumo-mediastinum and pneumo-pericardium) was 49% higher with the use of the protein-free synthetic surfactants compared with the use of natural ones (RR 1.49, 95% CI 1.26–1.77; 5381 neonates). There were no significant differences in the risks of BPD (RR 1.00, 95% CI 0.92–1.10; 7 studies, 4006 preterm neonates), IVH (RR 0.95, 95% CI 0.83–1.09; 9 studies, 4969 neonates) or sepsis (RR 0.99, 95% CI 0.90–1.08; 10 studies, 5244 neonates) between the groups receiving the two types of surfactants.


Protein-containing synthetic versus natural surfactants

The systematic review by Pfister et al. (14) included two studies that compared the effects of the newer generation of protein-containing surfactants with those of natural surfactants on mortality and morbidity outcomes when used in newborns with clinical or radiological features of RDS or at risk of RDS. An updated search identified no additional studies eligible for inclusion.

Neonatal death: There was no significant difference in the risk of mortality between the use of protein-containing synthetic surfactant compared to natural surfactants (RR 0.79, 95% CI 0.61–1.02; 2 studies, 1028 neonates).

Severe neonatal morbidity: Among preterm babies with RDS, use of protein-containing synthetic surfactants was associated with a lower risk of NEC compared with natural surfactants (RR 0.60, 95% CI 0.42–0.86). There was inconclusive evidence of differences in the risks of pulmonary haemorrhage (RR 0.73, 95% CI 0.51–1.06; 1028 neonates), BPD (RR 0.99, 95% CI 0.84–1.18; 1028 neonates), air leaks (RR 1.00, 95% CI 0.73–1.37; 1028 neonates), sepsis (RR 1.01, 95% CI 0.85–1.19; 785 neonates) and IVH (RR 1.52, 95% CI 0.73–3.13; 243 neonates).


Further information and considerations related to this recommendation can be found in the WHO guidelines, available at:




Implementation considerations

  • The successful introduction of this recommendation into national programmes and health-care services depends on well-planned and participatory consensus-driven processes of adaptation and implementation. The adaptation and implementation processes may include the development or revision of existing national guidelines or protocols based on this recommendation.
  • The recommendation should be adapted into a locally appropriate document that can meet the specific needs of each country and health service. Any changes should be made in an explicit and transparent manner.
  • A set of interventions should be established to ensure that an enabling environment is created for the use of the recommendations, and that the behaviour of the healthcare practitioner changes towards the use of this evidence-based practice.
  • In this process, the role of local professional societies is important and an all-inclusive and participatory process should be encouraged.


Research implications

The GDG identified that further research on the following high-priority questions is needed:

  • What is the efficacy of surfactants in a context where antenatal corticosteroids and early CPAP is provided (without immediate obligatory mechanical ventilation) for babies who are at risk of respiratory distress syndrome (e.g. InSURE – intubation, surfactant replacement therapy and extubation)?


Related links

WHO recommendations on interventions to improve preterm birth outcomes (2015) –full document and evidence tables


Supporting systematic reviews:

Soll R, Blanco F. Natural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2001

Pfister RH, Soll RF, Wiswell T. Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndrome. Cochrane Database Syst Rev. 2007


Other links of interest

Managing Complications in Pregnancy and Childbirth: A guide for midwives and doctors

Pregnancy, Childbirth, Postpartum and Newborn Care: A guide for essential practice

WHO Programmes: Sexual and Reproductive health

Maternal Health

Infant, Newborn Health



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  14. †Pfister RH, Soll RF, Wiswell T. Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndrome. Cochrane Database Syst Rev. 2007;3:CD006069.


Citation: WHO Reproductive Health Library. WHO recommendation on the type of surfactant for surfactant replacement therapy in newborns with respiratory distress syndrome (November 2015). The WHO Reproductive Health Library; Geneva: World Health Organization.