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.
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
including 25% to 45% in the first 24 hours after birth.
2
In 2010, neonatal conditions
accounted for 3 072 000 deaths worldwide.
1
Among 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% of
under-five deaths in 1990 to 43% in 2011, a trend that is expected to continue.
5
Within
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,
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 transmitted
infections (STIs), and promoting cessation of tobacco use.
7
Several 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 preparations
Treat 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.
7,11
However, 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 in
infants 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 may
be low because the mother is being treated with antibiotics and/or because only small
amounts of blood can be taken from newborns.
15
In 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 research
opportunities 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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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 respiratory
distress 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 diagnostics
for neonatal conditions require substantive investment and long-term support.


References

1
Liu 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.
3
The Global Burden of Disease: 2004 update. Geneva: WHO, 2008.
4
Lozano 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.
5
UNICEF, WHO, World Bank, UN Population Division. Level and trends in child mortality.
Geneva, UNICEF, 2012.
6
Quiambao BP et al. Maternal immunization with pneumococcal polysaccharide vaccine in the
Philippines. Vaccine, 2003, 21: 3451-3454.
7
March of Dimes, PMNCH, Save the Children, WHO. Born Too Soon: The Global Action Report on
Preterm Birth. Geneva, World Health Organization, 2012.
8
March of Dimes Preterm labor. Available at: http://www.marchofdimes.com/
pregnancy/pretermlabor_drugs.html . Last accessed 6 February 2013.
9
Every 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.
10
Curstedt T, Johansson J. New synthetic surfactanthow and when? Neonatology, 2006,
89(4):3369.
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11
Mackeen 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 at
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document
_listing_000068.jsp
13
European 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
14
English 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.
15
Neal PR et al. Volume of blood submitted for culture from neonates. J Clin Microbiol, 1986, 24:
353-356.