Ch6_23NeonatalJURNAL

8/11/2019 Ch6_23NeonatalJURNAL

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6. Priority diseases and reasons for inclusion

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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.1Even within the neonatal period there is wide variation

in 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 conditions

accounted for 3 072 000 deaths worldwide.1Among the many neonatal conditions, the

three major contributors to the global burden of disease are (in order of magnitude)

premature birth, birth asphyxia, and neonatal infections.3,4

Premature birth is defined as all births before 37 completed weeks of gestation or fewer

than 259 days since the first day of a womans last menstrual period. Complications of

premature birth are the single largest contributor to neonatal mortality, due to the lack

of necessary physical development. The survivors of premature birth may suffer life-

long effects. Neonatal sepsis is a blood infection that can be caused by a number of

different bacteria. Neonatal sepsis can have an early-onset (within 24 hours of birth) or

late-onset (after eight days of life). Birth asphyxia is defined as the failure to establish

breathing 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 major

contributors to the global toll of DALYs (having the most potential Years Lived with

Disability (YLD) and Years of Life Lost (YLL)).

Developments since 2004

Although a regional survival gaps exist, depending on where a baby is born, neonatal

conditions are an issue of global concern. All regions have seen slower reductions in

neonatal deaths compared to overall deaths for children under five. This has resulted

in 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. 5Within

Europe, Eastern Europe has consistently higher mortality rates and DALY burden for

all three high-burden neonatal conditions (particularly neonatal sepsis and birth

asphyxia-related neonatal encephalopathy) than Western and Central Europe.

Remaining challenges

At present, preventive methods, diagnostic tools, and treatments for neonatal

conditions remain limited, due to the complex causes of these conditions. Many of the

current preventive approaches focus on maternal health prior to the birth (for example,maternal immunization and efforts to ensure a healthy pregnancy). Furthermore,


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Priority Medicines for Europe and the World 2013 Update

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encouraging results and promising safety profiles are emerging from preliminary

studies of maternal immunization with pneumococcal polysaccharide conjugate

vaccines. 6 Alternative non-pharmaceutical prevention methods for pre-term birth

include: 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.7Several treatments exist for

neonatal 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).8,9,10

Table 6.23.1: Pharmaceutical gaps of existing treatments for neonatal conditions

Treatment Condition treated Gaps

Tocolytics Inhibit pre-term labour- Associated with adverse

effects to both mother and

newborn

Corticosteroid Foetal lung maturation

- Associated with increased

risk of infection to both

mother and newborn

Antibiotics Treat neonatal sepsis

- Non-ideal formulation and

packaging for neonatal use

- Require a trained health

worker to administer

Surfactant preparationsTreat respiratory distress

syndrome- Expensive to produce

Several tocolytics (for example, oxytocin antagonists, betamimetics, calcium channel

blockers, and magnesium sulphate) are available and are effective in suppressing

labour to allow enough time for antenatal corticosteroid treatment for foetal lung

maturation prior to delivery and/or to transfer mother and baby to a higher-level

facility where appropriate care may be available.7,11However, the effects on neonatal

outcomes and foetal/maternal side-effects have not been shown to improve the

perinatal 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.12,13

Neonates are included in these pan-European efforts. These Paediatric Regulations

require that any new drug, whatever its main target, should also be considered for

potential paediatric use which forces all pharmaceutical companies to think

strategically in terms of paediatric medicines.

The 2012 Report of the UN Commission on Life-saving Commodities for Women and

Children recommended simple potential product innovations that need further

research, particularly for the administration of gentamicin to treat neonatal infections


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(including fixed-dose presentations for needles and syringes, auto-disable syringes,

and micro-needle patch technology for administering gentamicin).10

A variety of surfactant preparations have been developed and tested, including

synthetic surfactants derived from animal sources, for treatment and prevention ininfants at risk of respiratory distress syndrome. Although both surfactant preparations

are effective, comparative reviews indicate that natural surfactants may have greater

efficacy. However, these are expensive to produce and supplies are limited.10

Meanwhile, the lack of rapid diagnostic tests often results in inappropriate use of

antibiotics, thereby increasing the risk of the development of antimicrobial resistance.

The symptoms of neonatal sepsis are often very similar to other life-threatening

diseases (such as necrotizing enterocolitis and perinatal asphyxia), making it difficult

to 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 small

amounts of blood can be taken from newborns. 15In addition, the results of these

diagnostic tests take up to 48 hours, which is often too long to wait as the condition of a

neonate with neonatal sepsis can deteriorate rapidly.7

Research needs

In order to reduce neonatal mortality rates, there is a need to boost the number of

innovative products in the R&D pipeline especially new rapid diagnostic tools and

appropriate treatments. More specifically, pharmaceutical gaps that offer researchopportunities include:

Pre-term birth:

Development of a more simplified dosing regimen and single dose packaging of

tocolytics 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 to

prevent respiratory distress syndrome.

Clearly labelled, pre-packaged or pre-filled delivery systems for antenatal

corticosteroid products.

Sepsis:

Rapid diagnostics for neonatal sepsis to prevent late or inadequate administration

of 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 with

fewer side-effects for newborns.

Development of diagnostic tools for neonatal conditions, which can help reduce

the inappropriate use of antibiotics.


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Priority Medicines for Europe and the World 2013 Update

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Development of new and effective antibiotics to treat bacterial infections that are

or 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 achieve

the Millennium Development Goal 4 of reducing under-five mortality by two-thirds by

2015. This could have a major impact in reducing the global burden of disease as these

conditions have the most potential YLL and YLD. Although the burden of neonatal

disease is largest in developing countries, the proportion of neonatal deaths in under-

five 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.

References

1Liu L et al. Global, regional, and national causes of child mortality: an updated systematic

analysis for 2010 with time trends since 2000. The Lancet,2012, 379(9832): 2151 2161.

2

Lawn JE, Zupan J. 4 million neonatal deaths: When? Where? Why? 2005. Available at:http://www.unasus-ufpel.net/dspace/handle/123456789/209. 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 in

1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. The Lancet,

2012, 380(9859):2095128.

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 the

Philippines. Vaccine,2003, 21: 3451-3454.

7March of Dimes, PMNCH, Save the Children, WHO. Born Too Soon: The Global Action Report on

Preterm 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 at:

http://www.everywomaneverychild.org/component/content/article/1-about/316-injectable-

antibiotics-for-newborn-sepsis--product-profile-. Last accessed 6 February 2013.

10Curstedt T, Johansson J. New synthetic surfactanthow and when? Neonatology,2006,89(4):3369.
http://www.unasus-ufpel.net/dspace/handle/123456789/209http://www.unasus-ufpel.net/dspace/handle/123456789/209http://www.marchofdimes.com/pregnancy/pretermlabor_drugs.htmlhttp://www.marchofdimes.com/pregnancy/pretermlabor_drugs.htmlhttp://www.marchofdimes.com/pregnancy/pretermlabor_drugs.htmlhttp://www.marchofdimes.com/pregnancy/pretermlabor_drugs.htmlhttp://www.everywomaneverychild.org/component/content/article/1-about/316-injectable-antibiotics-for-newborn-sepsis--product-profile-http://www.everywomaneverychild.org/component/content/article/1-about/316-injectable-antibiotics-for-newborn-sepsis--product-profile-http://www.everywomaneverychild.org/component/content/article/1-about/316-injectable-antibiotics-for-newborn-sepsis--product-profile-http://www.everywomaneverychild.org/component/content/article/1-about/316-injectable-antibiotics-for-newborn-sepsis--product-profile-http://www.everywomaneverychild.org/component/content/article/1-about/316-injectable-antibiotics-for-newborn-sepsis--product-profile-http://www.marchofdimes.com/pregnancy/pretermlabor_drugs.htmlhttp://www.marchofdimes.com/pregnancy/pretermlabor_drugs.htmlhttp://www.unasus-ufpel.net/dspace/handle/123456789/209


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11Mackeen AD et al. Tocolytics for preterm premature rupture of membranes. Cochrane Database

Syst Rev,2011, Issue 10. Art.No. CD007062.

12

European Medicines Agency Pediatric regulation 26 January 2007 available athttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document

_listing_000068.jsp

13European Medicines Agency Revised priority list for studies into off-patent paediatric

medicinal products for the 7th Call of the Seventh Framework Programme (FP7) of the

European Commission (Work Programme 2013, to be published in July 2012)13 January 2012

EMA/98717/2012 Rev. 2012 Human Medicines Development and Evaluation

14English M, Ngama M, Mwalekwa L, Peshu N. Signs of illness in Kenyan infants aged less

than 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.
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000068.jsphttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000068.jsphttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000068.jsphttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000068.jsphttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000068.jsp

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