6.23 Neonatal Conditions - World Health Organization

6. Priority diseases and reasons for inclusion6.23 Neonatal conditionsSee Background Paper 6.23 (BP6 23Neonatal.pdf)BackgroundThe neonatal period is only the first 28 days of life and yet accounts for 40% of alldeaths in children under five.1 Even within the neonatal period there is wide variationin mortality rates, with 75% of all neonatal deaths occurring in the first week of life –including 25% to 45% in the first 24 hours after birth.2 In 2010, neonatal conditionsaccounted for 3 072 000 deaths worldwide.1 Among the many neonatal conditions, thethree major contributors to the global burden of disease are (in order of magnitude)premature birth, birth asphyxia, and neonatal infections.3,4Premature birth is defined as all births before 37 completed weeks of gestation or fewerthan 259 days since the first day of a woman’s last menstrual period. Complications ofpremature birth are the single largest contributor to neonatal mortality, due to the lackof necessary physical development. The survivors of premature birth may suffer lifelong effects. Neonatal sepsis is a blood infection that can be caused by a number ofdifferent bacteria. Neonatal sepsis can have an early-onset (within 24 hours of birth) orlate-onset (after eight days of life). Birth asphyxia is defined as the failure to establishbreathing or perfusion at birth.Neonatal conditions exert a heavy burden on families, society, and the health system.Because they occur in the first few weeks of life, neonatal conditions are majorcontributors to the global toll of DALYs (having the most potential Years Lived withDisability (YLD) and Years of Life Lost (YLL)).Developments since 2004Although a regional survival gaps exist, depending on where a baby is born, neonatalconditions are an issue of global concern. All regions have seen slower reductions inneonatal deaths compared to overall deaths for children under five. This has resultedin an increased share of neonatal deaths among the under-five deaths – up from 36% ofunder-five deaths in 1990 to 43% in 2011, a trend that is expected to continue.5 WithinEurope, Eastern Europe has consistently higher mortality rates and DALY burden forall three high-burden neonatal conditions (particularly neonatal sepsis and birthasphyxia-related neonatal encephalopathy) than Western and Central Europe.Remaining challengesAt present, preventive methods, diagnostic tools, and treatments for neonatalconditions remain limited, due to the complex causes of these conditions. Many of thecurrent preventive approaches focus on maternal health prior to the birth (for example,maternal immunization and efforts to ensure a healthy pregnancy). Furthermore,1

Priority Medicines for Europe and the World 2013 Updateencouraging results and promising safety profiles are emerging from preliminarystudies of maternal immunization with pneumococcal polysaccharide conjugatevaccines. 6 Alternative non-pharmaceutical prevention methods for pre-term birthinclude: birth spacing; optimizing pre-pregnancy weight; promoting healthy nutrition;promoting vaccination of children and adolescents; preventing sexually transmittedinfections (STIs), and promoting cessation of tobacco use.7 Several treatments exist forneonatal conditions that can lower the risk of maternal and neonatal mortality.However, these treatments are still not ideal, due to their formulation, packaging,and/or accessibility (Table 6.23.1).8,9,10Table 6.23.1: Pharmaceutical gaps of existing treatments for neonatal conditionsTreatmentCondition treatedGaps- Associated with adverseeffects to both mother andnewborn- Associated with increasedrisk of infection to bothmother and newborn- Non-ideal formulation andpackaging for neonatal use- Require a trained healthworker to administerTocolyticsInhibit pre-term labourCorticosteroidFoetal lung maturationAntibioticsTreat neonatal sepsisSurfactant preparationsTreat respiratory distress- Expensive to producesyndromeSeveral tocolytics (for example, oxytocin antagonists, betamimetics, calcium channelblockers, and magnesium sulphate) are available and are effective in suppressinglabour to allow enough time for antenatal corticosteroid treatment for foetal lungmaturation prior to delivery and/or to transfer mother and baby to a higher-levelfacility where appropriate care may be available.7,11 However, the effects on neonataloutcomes and foetal/maternal side-effects have not been shown to improve theperinatal outcome.Within the European Union, following the requirements of the Paediatric Regulation,the EMA produces a yearly updated "priority list" of medicines in need for children.12,13Neonates are included in these pan-European efforts. These Paediatric Regulationsrequire that any new drug, whatever its main target, should also be considered forpotential paediatric use which forces all pharmaceutical companies to thinkstrategically in terms of paediatric medicines.The 2012 Report of the UN Commission on Life-saving Commodities for Women andChildren recommended simple potential product innovations that need furtherresearch, particularly for the administration of gentamicin to treat neonatal infections2

6. Priority diseases and reasons for inclusion(including fixed-dose presentations for needles and syringes, auto-disable syringes,and micro-needle patch technology for administering gentamicin).10A variety of surfactant preparations have been developed and tested, includingsynthetic surfactants derived from animal sources, for treatment and prevention ininfants at risk of respiratory distress syndrome. Although both surfactant preparationsare effective, comparative reviews indicate that natural surfactants may have greaterefficacy. However, these are expensive to produce and supplies are limited.10Meanwhile, the lack of rapid diagnostic tests often results in inappropriate use ofantibiotics, thereby increasing the risk of the development of antimicrobial resistance.The symptoms of neonatal sepsis are often very similar to other life-threateningdiseases (such as necrotizing enterocolitis and perinatal asphyxia), making it difficultto accurately diagnose and treat. 14 Even with the few diagnostic tools that exist,pathogenic organisms remain difficult to identify. The bacterial load in neonates maybe low because the mother is being treated with antibiotics and/or because only smallamounts of blood can be taken from newborns. 15 In addition, the results of thesediagnostic tests take up to 48 hours, which is often too long to wait as the condition of aneonate with neonatal sepsis can deteriorate rapidly.7Research needsIn order to reduce neonatal mortality rates, there is a need to boost the number ofinnovative products in the R&D pipeline – especially new rapid diagnostic tools andappropriate treatments. More specifically, pharmaceutical gaps that offer researchopportunities include:Pre-term birth: Development of a more simplified dosing regimen and single dose packaging oftocolytics to prevent or delay premature labour. Development of tocolytics with fewer side-effects in mothers and newborns. Evidence-based protocols for the use of injectable antenatal corticosteroids toprevent respiratory distress syndrome. Clearly labelled, pre-packaged or pre-filled delivery systems for antenatalcorticosteroid products.Sepsis: Rapid diagnostics for neonatal sepsis to prevent late or inadequate administrationof necessary antibiotics. Appropriate product formulation and packaging for treating neonatal sepsis,especially low-dose injectable gentamicin. Development of shorter course antibiotics, oral antibiotics, and antibiotics withfewer side-effects for newborns. Development of diagnostic tools for neonatal conditions, which can help reducethe inappropriate use of antibiotics.3

Priority Medicines for Europe and the World 2013 Update Development of new and effective antibiotics to treat bacterial infections that areor will soon become resistant to current antibiotics (see Chapter 6.1).Birth asphyxia: Development of effective and lower-cost synthetic surfactants to treat respiratorydistress syndrome in newborns. Development of a more stable oral surfactant.Efforts to address neonatal conditions need to be prioritized in order to help achievethe Millennium Development Goal 4 of reducing under-five mortality by two-thirds by2015. This could have a major impact in reducing the global burden of disease as theseconditions have the most potential YLL and YLD. Although the burden of neonataldisease is largest in developing countries, the proportion of neonatal deaths in underfive deaths is highest in developed countries, making this an issue of global concern.The development of innovative and more affordable pharmaceuticals and diagnosticsfor neonatal conditions require substantive investment and long-term support.References1Liu L et al. Global, regional, and national causes of child mortality: an updated systematicanalysis for 2010 with time trends since 2000. The Lancet, 2012, 379(9832): 2151 – 2161.2Lawn JE, Zupan J. 4 million neonatal deaths: When? Where? Why? 2005. Available 6789/209 . Last accessed 20 January 2013.3The Global Burden of Disease: 2004 update. Geneva: WHO, 2008.4Lozano R et al. Global and regional mortality from 235 causes of death for 20 age groups in1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. The Lancet,2012, 380(9859):2095–128.5UNICEF, WHO, World Bank, UN Population Division. Level and trends in child mortality.Geneva, UNICEF, 2012.6Quiambao BP et al. Maternal immunization with pneumococcal polysaccharide vaccine in thePhilippines. Vaccine, 2003, 21: 3451-3454.7March of Dimes, PMNCH, Save the Children, WHO. Born Too Soon: The Global Action Report onPreterm Birth. Geneva, World Health Organization, 2012.8March of Dimes – Preterm labor. Available at: http://www.marchofdimes.com/pregnancy/pretermlabor drugs.html . Last accessed 6 February 2013.9Every Woman Every Child – Injectable Antibiotics for Newborn Sepsis. Available or-newborn-sepsis--product-profile- . Last accessed 6 February 2013.10Curstedt T, Johansson J. New synthetic surfactant–how and when? Neonatology, 2006,89(4):336–9.4

6. Priority diseases and reasons for inclusion11Mackeen AD et al. Tocolytics for preterm premature rupture of membranes. Cochrane DatabaseSyst Rev, 2011, Issue 10. Art.No. CD007062.12European Medicines Agency Pediatric regulation 26 January 2007 available athttp://www.ema.europa.eu/ema/index.jsp?curl pages/regulation/document listing/documentlisting 000068.jsp13European Medicines Agency Revised priority list for studies into off-patent paediatricmedicinal products for the 7th Call of the Seventh Framework Programme (FP7) of theEuropean Commission (Work Programme 2013, to be published in July 2012)13 January 2012EMA/98717/2012 Rev. 2012 Human Medicines Development and Evaluation14English M, Ngama M, Mwalekwa L, Peshu N. Signs of illness in Kenyan infants aged lessthan 60 days. Bull World Health Organ, 2004, 82: 323-329.15Neal PR et al. Volume of blood submitted for culture from neonates. J Clin Microbiol, 1986, 24:353-356.5

6.23 Neonatal conditions See Background Paper 6.23 (BP6_23Neonatal.pdf) Background The neonatal period is only the first 28 days of life and yet accounts for 40% of all deaths in children under five.1 Even within the neonatal period there is wide variation in mortality rates, with 75% of all neonatal deaths occurring in the first week of life –